FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bousfiha, A Jeddane, L Al-Herz, W Ailal, F Casanova, JL Chatila, T Conley, ME Cunningham-Rundles, C Etzioni, A Franco, JL Gaspar, HB Holland, SM Klein, C Nonoyama, S Ochs, HD Oksenhendler, E Picard, C Puck, JM Sullivan, KE Tang, MLK AF Bousfiha, Aziz Jeddane, Leila Al-Herz, Waleed Ailal, Fatima Casanova, Jean-Laurent Chatila, Talal Conley, Mary Ellen Cunningham-Rundles, Charlotte Etzioni, Amos Franco, Jose Luis Gaspar, H. Bobby Holland, Steven M. Klein, Christoph Nonoyama, Shigeaki Ochs, Hans D. Oksenhendler, Eric Picard, Capucine Puck, Jennifer M. Sullivan, Kathleen E. Tang, Mimi L. K. TI The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Primary immunodeficiencies; classification; IUIS PID expert committee ID DIAGNOSIS; DEFICIENCY; WORLDWIDE; DISEASES AB There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification. C1 [Bousfiha, Aziz; Jeddane, Leila; Ailal, Fatima] King Hassan II Univ, Clin Immunol Unit, A Harouchi Hosp, Ibn Roshd Med Sch, Casablanca, Morocco. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Jabriya, Kuwait. [Al-Herz, Waleed] Al Sabah Hosp, Allergy & Clin Immunol Unit, Dept Pediat, Kuwait, Kuwait. [Casanova, Jean-Laurent; Conley, Mary Ellen] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, New York, NY 10021 USA. [Casanova, Jean-Laurent; Picard, Capucine] Howard Hughes Med Inst, New York, NY USA. [Casanova, Jean-Laurent] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, INSERM UMR1163, Paris, France. [Casanova, Jean-Laurent] Univ Paris 05, Imagine Inst, Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, Pediat Hematol & Immunol Unit, Paris, France. [Chatila, Talal] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Cunningham-Rundles, Charlotte] Mt Sinai Sch Med, Dept Med & Pediat, New York, NY USA. [Etzioni, Amos] Technion Israel Inst Technol, Meyer Childrens Hospital, Haifa, Israel. [Franco, Jose Luis] Univ Antioquia, Grp Primary Immunodeficiencies, Medellin, Colombia. [Gaspar, H. Bobby] UCL Inst Child Hlth, London, England. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Munich, Germany. [Nonoyama, Shigeaki] Natl Def Med Coll, Dept Pediat, Saitama, Japan. [Ochs, Hans D.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Ochs, Hans D.] Seattle Childrens Res Inst, Seattle, WA USA. [Oksenhendler, Eric] Hop St Louis, AP HP, Dept Clin Immunol, Paris, France. [Oksenhendler, Eric] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Picard, Capucine] Hop Necker Enfants Malad, AP HP, Ctr Etude Deficits Immunitaires, Paris, France. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Puck, Jennifer M.] UCSF Benioff Childrens Hosp, San Francisco, CA USA. [Sullivan, Kathleen E.] Childrens Hosp Philadelphia, Dept Pediat, Div Allergy Immunol, Philadelphia, PA 19104 USA. [Tang, Mimi L. K.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Tang, Mimi L. K.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia. [Tang, Mimi L. K.] Royal Childrens Hosp, Dept Allergy & Immunol, Melbourne, Vic, Australia. RP Bousfiha, A (reprint author), King Hassan II Univ, Clin Immunol Unit, A Harouchi Hosp, Ibn Roshd Med Sch, Casablanca, Morocco. EM profbousfiha@gmail.com FU NIAID NIH HHS [R18 AI048693] NR 9 TC 33 Z9 34 U1 3 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 IS 8 BP 727 EP 738 DI 10.1007/s10875-015-0198-5 PG 12 WC Immunology SC Immunology GA CX7HN UT WOS:000365872900004 PM 26445875 ER PT J AU Shallom, SJ Moura, NS Olivier, KN Sampaio, EP Holland, SM Zelazny, AM AF Shallom, Shamira J. Moura, Natalia S. Olivier, Kenneth N. Sampaio, Elizabeth P. Holland, Steven M. Zelazny, Adrian M. TI New Real-Time PCR Assays for Detection of Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Group SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID MACROLIDE RESISTANCE; CYSTIC-FIBROSIS; MASSILIENSE; SUSCEPTIBILITY; CHELONAE; COHORT; GENE; IDENTIFICATION; INFECTIONS; DIAGNOSIS AB Members of the Mycobacterium abscessus group (MAG) cause lung, soft tissue, and disseminated infections. The oral macrolides clarithromycin and azithromycin are commonly used for treatment. MAG can display clarithromycin resistance through the inducible erm (41) gene or via acquired mutations in the rrl (23S rRNA) gene. Strains harboring a truncation or a T28C substitution in erm (41) lose the inducible resistance trait. Phenotypic detection of clarithromycin resistance requires extended incubation (14 days), highlighting the need for faster methods to detect resistance. Two real-time PCR-based assays were developed to assess inducible and acquired clarithromycin resistance and tested on a total of 90 clinical and reference strains. A SYBR green assay was designed to distinguish between a full-length and truncated erm (41) gene by temperature shift in melting curve analysis. Single nucleotide polymorphism (SNP) allele discrimination assays were developed to distinguish T or C at position 28 of erm (41) and 23S rRNA rrl gene mutations at position 2058 and/or 2059. Truncated and full-size erm (41) genes were detected in 21/90 and 69/90 strains, respectively, with 64/69 displaying T at nucleotide position 28 and 5/69 containing C at that position. Fifteen isolates showed rrl mutations conferring clarithromycin resistance, including A2058G (11 isolates), A2058C (3 isolates), and A2059G (1 isolate). Targeted sequencing and phenotypic assessment of resistance concurred with molecular assay results. Interestingly, we also noted cooccurring strains harboring an active erm (41), inactive erm (41), and/or acquired mutational resistance, as well as slowly growing MAG strains and also strains displaying an inducible resistance phenotype within 5 days, long before the recommended 14-day extended incubation. C1 [Shallom, Shamira J.; Moura, Natalia S.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov FU Intramural Research Programs of the Clinical Center, NIAID; NHLBI; NIH FX This research was supported in part by the Intramural Research Programs of the Clinical Center, NIAID, and NHLBI, NIH. NR 29 TC 4 Z9 4 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2015 VL 53 IS 11 BP 3430 EP 3437 DI 10.1128/JCM.01714-15 PG 8 WC Microbiology SC Microbiology GA CX3UY UT WOS:000365626200009 PM 26269619 ER PT J AU Park, IK Hsu, AP Tettelin, H Shallom, SJ Drake, SK Ding, L Wu, UI Adamo, N Prevots, DR Olivier, KN Holland, SM Sampaio, EP Zelazny, AM AF Park, In Kwon Hsu, Amy P. Tettelin, Herve Shallom, Shamira J. Drake, Steven K. Ding, Li Wu, Un-In Adamo, Nick Prevots, D. Rebecca Olivier, Kenneth N. Holland, Steven M. Sampaio, Elizabeth P. Zelazny, Adrian M. TI Clonal Diversification and Changes in Lipid Traits and Colony Morphology in Mycobacterium abscessus Clinical Isolates SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID NONTUBERCULOUS MYCOBACTERIA; CYSTIC-FIBROSIS; SP-NOV; BIOSYNTHESIS; TUBERCULOSIS; MASSILIENSE; ROUGH; EPIDEMIOLOGY; PHAGOCYTOSIS; MEMBRANE AB The smooth-to-rough colony morphology shift in Mycobacterium abscessus has been implicated in loss of glycopeptidolipid (GPL), increased pathogenicity, and clinical decline in cystic fibrosis (CF) patients. However, the evolutionary phenotypic and genetic changes remain obscure. Serial isolates from nine non-CF patients with persistent M. abscessus infection were characterized by colony morphology, lipid profile via thin-layer chromatography and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), sequencing of eight genes in the GPL locus, and expression level of fadD23, a key gene involved in the biosynthesis of complex lipids. All 50 isolates were typed as M. abscessus subspecies abscessus and were clonally related within each patient. Rough isolates, all lacking GPL, predominated at later disease stages, some showing variation within rough morphology. While most (77%) rough isolates harbored detrimental mutations in mps1 and mps2, 13% displayed previously unreported mutations in mmpL4a and mmpS4, the latter yielding a putative GPL precursor. Two isolates showed no deleterious mutations in any of the eight genes sequenced. Mixed populations harboring different GPL locus mutations were detected in 5 patients, demonstrating clonal diversification, which was likely overlooked by conventional acid-fast bacillus (AFB) culture methods. Our work highlights applications of MALDI-TOF MS beyond identification, focusing on mycobacterial lipids relevant in virulence and adaptation. Later isolates displayed accumulation of triacylglycerol and reduced expression of fadD23, sometimes preceding rough colony onset. Our results indicate that clonal diversification and a shift in lipid metabolism, including the loss of GPL, occur during chronic lung infection with M. abscessus. GPL loss alone may not account for all traits associated with rough morphology. C1 [Park, In Kwon; Hsu, Amy P.; Ding, Li; Wu, Un-In; Adamo, Nick; Prevots, D. Rebecca; Holland, Steven M.; Sampaio, Elizabeth P.; Zelazny, Adrian M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Tettelin, Herve] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Shallom, Shamira J.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov OI WU, UN-IN/0000-0001-8182-6071 FU Divisions of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute; Clinical Center, National Institutes of Health FX This work was supported by the Divisions of Intramural Research of the National Institute of Allergy and Infectious Diseases, the National Heart, Lung and Blood Institute, and the Clinical Center, National Institutes of Health. NR 35 TC 7 Z9 7 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2015 VL 53 IS 11 BP 3438 EP 3447 DI 10.1128/JCM.02015-15 PG 10 WC Microbiology SC Microbiology GA CX3UY UT WOS:000365626200010 PM 26292297 ER PT J AU Liu, X Schiffman, M Hulbert, A He, ZH Shen, ZP Koutsky, LA Xi, LF AF Liu, Xia Schiffman, Mark Hulbert, Ayaka He, Zhonghu Shen, Zhenping Koutsky, Laura A. Xi, Long Fu TI Association of Human Papillomavirus 31 DNA Load with Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3 SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VIRAL LOAD; NATURAL-HISTORY; IN-SITU; CANCER; INFECTION; LESIONS; WOMEN; CLEARANCE; DISEASE; INTEGRATION AB The association between human papillomavirus 31 (HPV31) DNA loads and the risk of cervical intraepithelial neoplasia grades 2 and 3 (CIN2-3) was evaluated among women enrolled in the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS), who were monitored semiannually over 2 years and who had HPV31 infections detected at >= 1 visit. HPV31 DNA loads in the first HPV31-positive samples and in a random set of the last positive samples from women with >= 2 HPV31-positive visits were measured by a real-time PCR assay. CIN2-3 was histologically confirmed at the same time as the first detection of HPV31 for 88 (16.6%) of 530 women. After adjustment for HPV31 lineages, coinfection with other oncogenic types, and the timing of the first positive detection, the odds ratio (OR) per 1-log-unit increase in viral loads for the risk of a concurrent diagnosis of CIN2-3 was 1.5 (95% confidence interval [CI], 1.2 to 1.9). Of 373 women without CIN2-3 at the first positive visit who had >= 1 later visit, 44 had subsequent diagnoses of CIN2-3. The initial viral loads were associated with CIN2-3 diagnosed within 6 months after the first positive visit (adjusted OR, 1.5 [95% CI, 1.0 to 2.4]) but were unrelated to CIN2-3 diagnosed later. For a random set of 49 women who were tested for viral loads at the first and last positive visits, changes in viral loads were upward and downward among women with and without follow-up CIN2-3 diagnoses, respectively, although the difference was not statistically significant. Results suggest that HPV31 DNA load levels at the first positive visit signal a short-term but not long-term risk of CIN2-3. C1 [Liu, Xia; Hulbert, Ayaka; Shen, Zhenping; Xi, Long Fu] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Koutsky, Laura A.; Xi, Long Fu] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liu, Xia] China Med Univ, Shengjing Hosp, Dept Obstet & Gynecol, Liaoning, Peoples R China. [He, Zhonghu] Peking Univ, Sch Oncol, Key Lab Carcinogenesis & Translat Res, Beijing 100871, Peoples R China. RP Xi, LF (reprint author), Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. EM longfu@u.washington.edu FU National Cancer Institute, National Institutes of Health [CA133569]; Plan of Cultivating Future Talents award from Shengjing Hospital, China Medical University FX The research reported in this publication was supported by the National Cancer Institute, National Institutes of Health (grant CA133569). X.L. was financially supported by a Plan of Cultivating Future Talents award from Shengjing Hospital, China Medical University. NR 32 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2015 VL 53 IS 11 BP 3451 EP 3457 DI 10.1128/JCM.01279-15 PG 7 WC Microbiology SC Microbiology GA CX3UY UT WOS:000365626200012 PM 26292291 ER PT J AU Sarkar, S Rivera, EM Engle, RE Nguyen, HT Schechterly, CA Alter, HJ Liang, TJ Purcell, RH Hoofnagle, JH Ghany, MG AF Sarkar, Souvik Rivera, Elenita M. Engle, Ronald E. Nguyen, Hanh T. Schechterly, Cathy A. Alter, Harvey J. Liang, T. Jake Purcell, Robert H. Hoofnagle, Jay H. Ghany, Marc G. TI An Epidemiologic Investigation of a Case of Acute Hepatitis E SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID E VIRUS-INFECTION; ORGAN-TRANSPLANT RECIPIENTS; UNITED-STATES; ENZYME-IMMUNOASSAY; NATIONAL-HEALTH; BLOOD-DONORS; ANTIBODIES; FRANCE; SWINE; HEV AB Hepatitis E virus (HEV) is considered a zoonotic infection in developed nations. A case of acute hepatitis E in a researcher following a scalpel injury while working on a pig prompted a seroepidemiologic study to identify potential modes of transmission and determine the seroprevalence of HEV among animal handlers at the institute. Sera from personnel (n = 64) in two animal facilities and age/sex-matched blood donors (n = 63) as controls were tested for IgG anti-HEV and, if positive, for IgM anti-HEV and HEV RNA. Sera and stool from pigs aged 6 to 12 weeks from the breeding farm and older pigs from animal facilities were tested similarly. The median age of personnel was 36 years, 74% were white, 56% were male, and 74% had direct exposure to pigs. The prevalence of anti-HEV was 3.1% among personnel compared to 3.2% among blood donors; none were positive for IgM anti-HEV or HEV RNA. IgG anti-HEV was detected in sera from 10% of pigs aged 6 to 8 weeks, 80% aged 10 weeks, 100% aged 12 weeks, and 76% aged >12 weeks. HEV RNA was detected in stool but not sera from three 12-week-old pigs. Sequencing revealed HEV genotype 3 with similar to 10% difference between the patient and pig sequences. Parenteral transmission is a potential mode of acute HEV infection. The low and similar seroprevalence of anti-HEV between the at-risk group and age-matched blood donors suggests low transmission risk with universal precautions among animal handlers. C1 [Sarkar, Souvik; Rivera, Elenita M.; Liang, T. Jake; Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Engle, Ronald E.; Nguyen, Hanh T.; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Schechterly, Cathy A.; Alter, Harvey J.] NIH, Transfus Transmitted Viruses Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Sarkar, Souvik/0000-0002-9358-4257 FU Intramural Research Program of NIAID; Intramural Research Program of NIDDK FX This research was supported by the Intramural Research Programs of NIAID and NIDDK. NR 37 TC 0 Z9 1 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD NOV PY 2015 VL 53 IS 11 BP 3547 EP 3552 DI 10.1128/JCM.01189-15 PG 6 WC Microbiology SC Microbiology GA CX3UY UT WOS:000365626200026 PM 26338861 ER PT J AU Mikhail, AS Partanen, A Yarmolenko, P Venkatesan, AM Wood, BJ AF Mikhail, Andrew S. Partanen, Ari Yarmolenko, Pavel Venkatesan, Aradhana M. Wood, Bradford J. TI Magnetic Resonance-Guided Drug Delivery SO MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA LA English DT Article DE MR imaging; Drug delivery; Tumor targeting; Nanomedicine; Cancer; Thermosensitive liposome; High-intensity focused ultrasound; Imaging guidance ID INTENSITY FOCUSED ULTRASOUND; TEMPERATURE-SENSITIVE LIPOSOMES; HUMAN TUMOR XENOGRAFT; NONINVASIVE FUNCTIONAL NEUROSURGERY; SOLID TUMORS; THERMOSENSITIVE LIPOSOMES; CANCER-THERAPY; HIFU ABLATION; ANIMAL-MODELS; VX2 TUMORS AB The use of clinical imaging modalities for the guidance of targeted drug delivery systems, known as image-guided drug delivery (IGDD), has emerged as a promising strategy for enhancing antitumor efficacy. Magnetic resonance (MR) imaging is particularly well suited for IGDD applications because of its ability to acquire images and quantitative measurements with high spatiotemporal resolution. The goal of IGDD strategies is to improve treatment outcomes by facilitating planning, real-time guidance, and personalization of pharmacologic interventions. This article reviews basic principles of targeted drug delivery and highlights the current status, emerging applications, and future paradigms of MR-guided drug delivery. C1 [Mikhail, Andrew S.; Partanen, Ari; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Partanen, Ari] Philips Healthcare, Andover, MA 01810 USA. [Yarmolenko, Pavel] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Venkatesan, Aradhana M.] MD Anderson Canc Ctr, Dept Diagnost Radiol, Sect Abdominal Imaging, Houston, TX 77030 USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM bwood@nih.gov OI Partanen, Ari/0000-0003-1985-149X; Mikhail, Andrew/0000-0001-9206-5765 FU Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH); NIH [Z1A CL040015-06] FX This work was supported by the Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH). NIH and Celsion Corp. have a Cooperative Research and Development Agreement (CRADA). NIH and Philips Healthcare have a CRADA supported by NIH Grant # Z1A CL040015-06. Dr A. Partanen is a paid employee of Philips Healthcare. The content of this article 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 81 TC 2 Z9 2 U1 4 U2 19 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1064-9689 EI 1557-9786 J9 MAGN RESON IMAGING C JI Magn. Reson. Imaging Clin. N. Am. PD NOV PY 2015 VL 23 IS 4 BP 643 EP + DI 10.1016/j.mric.2015.05.012 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CX0HN UT WOS:000365377600014 PM 26499281 ER PT J AU Campbell-Washburn, AE Faranesh, AZ Lederman, RJ Hansen, MS AF Campbell-Washburn, Adrienne E. Faranesh, Anthony Z. Lederman, Robert J. Hansen, Michael S. TI Magnetic Resonance Sequences and Rapid Acquisition for MR-Guided Interventions SO MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA LA English DT Article DE Real-time MR imaging; MR image reconstruction; Parallel imaging; Non-Cartesian imaging ID STATE FREE PRECESSION; COMMODITY GRAPHICS HARDWARE; PASSIVE CATHETER TRACKING; PLANAR IMAGING EPI; REAL-TIME MRI; PROJECTION RECONSTRUCTION; TEMPORAL RESOLUTION; SPIRAL TRAJECTORIES; COIL SELECTION; GRAPPA AB Interventional Magnetic resonance (MR) uses rapid imaging to guide diagnostic and therapeutic procedures. One of the attractions of MR-guidance is the abundance of inherent contrast mechanisms available. Dynamic procedural guidance with real-time imaging has pushed the limits of MR technology, demanding rapid acquisition and reconstruction paired with interactive control and device visualization. This article reviews the technical aspects of real-time MR sequences that enable MR-guided interventions. C1 [Campbell-Washburn, Adrienne E.; Faranesh, Anthony Z.; Lederman, Robert J.; Hansen, Michael S.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Campbell-Washburn, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, 9000 Rockville Pike,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM adrienne.campbell@nih.gov RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; lederman, robert/0000-0003-1202-6673 FU National Heart, Lung, and Blood Institute Division of Intramural Research [Z01-HL006039, Z01-HL005062] FX The authors disclose that this work was supported by the National Heart, Lung, and Blood Institute Division of Intramural Research (Z01-HL006039, Z01-HL005062). The National Heart, Lung, and Blood Institute and Siemens Medical Systems have a Cooperative Research and Development Agreement (CRADA). NR 85 TC 0 Z9 0 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1064-9689 EI 1557-9786 J9 MAGN RESON IMAGING C JI Magn. Reson. Imaging Clin. N. Am. PD NOV PY 2015 VL 23 IS 4 BP 669 EP + DI 10.1016/j.mric.2015.05.006 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CX0HN UT WOS:000365377600016 PM 26499283 ER PT J AU Desler, C Frederiksen, JH Angleys, M Maynard, S Keijzers, G Fagerlund, B Mortensen, EL Osler, M Lauritzen, M Bohr, VA Rasmussen, LJ AF Desler, Claus Frederiksen, Jane H. Angleys, Maria Maynard, Scott Keijzers, Guido Fagerlund, Birgitte Mortensen, Erik Lykke Osler, Merete Lauritzen, Martin Bohr, Vilhelm A. Rasmussen, Lene Juel TI Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline SO MITOCHONDRION LA English DT Article DE Alzheimer's disease; Cognitive decline; Mitochondrial bioenergetics; Mitochondrial ROS; Deoxyribonucleotide levels ID ALZHEIMERS-DISEASE; MITOCHONDRIAL DYSFUNCTION; DEMENTIA; POOLS; DNA AB Mitochondrial bioenergetics, mitochondrial reactive oxygen species (ROS) and cellular levels of nucleotides have been hypothesized as early indicators of Alzheimer's disease (AD). Utilizing relative decline of cognitive ability as a predictor of AD risk, we evaluated the correlation between change of cognitive ability and mitochondrial bioenergetics, ROS and cellular levels of deoxyribonucleotides. Change of cognitive abilities, scored at ages of approximately 20 and 57 was determined for a cohort of 1985 male participants. Mitochondrial bioenergetics, mitochondrial ROS and whole-cell levels of deoxyribonucleotide triphosphates were measured in peripheral blood mononuclear cells (PBMCs) from a total of 103 selected participants displaying the most pronounced relative cognitive decline and relative cognitive improvement. We show that relative cognitive decline is associated with higher PBMC content of deoxythymidine-triphosphate (MP) (20%), but not mitochondrial bioenergetics parameters measured in this study or mitochondrial ROS. Levels of dTTP in PBMCs are indicators of relative cognitive change suggesting a role of deoxyribonucleotides in the etiology of AD. (C) 2015 The Authors. Elsevier B.V. and Mitochondria Research Society. C1 [Desler, Claus; Frederiksen, Jane H.; Angleys, Maria; Maynard, Scott; Keijzers, Guido; Fagerlund, Birgitte; Mortensen, Erik Lykke; Lauritzen, Martin; Bohr, Vilhelm A.; Rasmussen, Lene Juel] Ctr Hlth Aging, Copenhagen, Denmark. [Desler, Claus; Frederiksen, Jane H.; Angleys, Maria; Maynard, Scott; Keijzers, Guido; Rasmussen, Lene Juel] Univ Copenhagen, Dept Cellular & Mol Med, DK-1168 Copenhagen, Denmark. [Fagerlund, Birgitte] Mental Hlth Ctr Glostrup, CNSR, Ctr Clin Intervent & Neuropsychiat Schizophrenia, Lundbeck Fdn, Glostrup, Denmark. [Mortensen, Erik Lykke; Osler, Merete] Univ Copenhagen, Dept Publ Hlth, DK-1168 Copenhagen, Denmark. [Osler, Merete] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Lauritzen, Martin] Univ Copenhagen, Dept Neurosci & Pharmacol, Copenhagen N, Denmark. [Lauritzen, Martin] Glostrup Cty Hosp, Dept Clin Neurophysiol, Glostrup, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Bethesda, MD 20892 USA. RP Rasmussen, LJ (reprint author), Ctr Hlth Aging, Copenhagen, Denmark. EM lenera@sund.ku.dk OI desler, claus/0000-0002-0125-004X; Osler, Merete/0000-0002-6921-220X FU Nordea-fonden; Danish Council for Independent Research-Natural Sciences FX This work was supported by a grant from Nordea-fonden (LJR, VB, ELM, ML) and the The Danish Council for Independent Research-Natural Sciences (LJR, CD). NR 16 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2015 VL 25 BP 34 EP 37 DI 10.1016/j.mito.2015.09.002 PG 4 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA CX8DW UT WOS:000365933800005 PM 26408413 ER PT J AU Jagoda, EM Bhattacharyya, S Kalen, J Riffle, L Leeder, A Histed, S Williams, M Wong, KJ Xu, BY Szajek, LP Elbuluk, O Cecchi, F Raffensperger, K Golla, M Bottaro, DP Choyke, P AF Jagoda, Elaine M. Bhattacharyya, Sibaprasad Kalen, Joseph Riffle, Lisa Leeder, Avrum Histed, Stephanie Williams, Mark Wong, Karen J. Xu, Biying Szajek, Lawrence P. Elbuluk, Osama Cecchi, Fabiola Raffensperger, Kristen Golla, Meghana Bottaro, Donald P. Choyke, Peter TI Imaging the Met Receptor Tyrosine Kinase (Met) and Assessing Tumor Responses to a Met Tyrosine Kinase Inhibitor in Human Xenograft Mouse Models with a [Tc-99m] (AH-113018) or Cy 5(**) (AH-112543) Labeled Peptide SO MOLECULAR IMAGING LA English DT Article ID CELL LUNG-CANCER; SMALL-MOLECULE INHIBITOR; GROWTH-FACTOR RECEPTOR; GENE COPY NUMBER; SMALL-ANIMAL PET; SIGNALING PATHWAY; ANTIBODY ONARTUZUMAB; SELF-DISPLACEMENT; DOWN-REGULATION; IN-VIVO AB Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [Tc-99m] had high affinity in vitro (K-d = 3.3 nM) and detected relative changes in Met in human cancer cell lines. In vivo [Tc-99m]-Met peptide (AH-113018) was retained in Met-expressing tumors, and high-expressing Met tumors (MKN-45) were easily visualized and quantitated using single-photon emission computed tomography or optical imaging. In further studies, MKN-45 mouse xenografts treated with PHA 665752 (Met TKI) or vehicle were monitored weekly for tumor responses by [Tc-99m]-Met peptide imaging and measurement of tumor volumes. Tumor uptake of [Tc-99m]-Met peptide was significantly decreased as early as 1 week after PHA 665752 treatment, corresponding to decreases in tumor volumes. These results were comparable to Cy5**-Met peptide (AH-112543) fluorescence imaging using the same treatment model. [Tc-99m] or Cy5**-Met peptide tumor uptake was further validated by histologic (necrosis, apoptosis) and immunoassay (total Met, p Met, and plasma shed Met) assessments in imaged and nonimaged cohorts. These data suggest that [Tc-99m] or Cy5**-Met peptide imaging may have clinical diagnostic, prognostic, and therapeutic monitoring applications. C1 [Jagoda, Elaine M.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, ADRD, SAIC Frederick Inc, Frederick, MD USA. Leidos Biomed Res Inc, Small Anim Imaging Program, NCI, SAIC Frederick Inc, Frederick, MD USA. NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Jagoda, EM (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1088,BLG 10-RM B3B69, Bethesda, MD 20892 USA. EM ejagoda@mail.nih.gov FU National Cancer'Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer'Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 51 TC 0 Z9 0 U1 4 U2 9 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD NOV PY 2015 VL 14 BP 499 EP 515 DI 10.2310/7290.2015.00023 PG 17 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA CX3KR UT WOS:000365598200003 PM 26461980 ER PT J AU Statland, JM Barohn, RJ Dimachkie, MM Floeter, MK Mitsumoto, H AF Statland, Jeffrey M. Barohn, Richard J. Dimachkie, Mazen M. Floeter, Mary Kay Mitsumoto, Hiroshi TI Primary Lateral Sclerosis SO NEUROLOGIC CLINICS LA English DT Article DE Motor neuron disease; Upper motor neuron disease; Primary lateral sclerosis; Spastic quadriparesis; Pseudobulbar affect; Neuroimaging ID MOTOR-NEURON DISEASES; HEREDITARY SPASTIC PARAPLEGIA; CLINICAL-FEATURES; INVOLVEMENT; DYSFUNCTION; BRAIN; ALS; DISTINGUISH; CORTEX; PLS AB Primary lateral sclerosis is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs'of lower motor neuron involvement. Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical examination findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. Electromyogram is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Treatment is largely supportive. C1 [Statland, Jeffrey M.; Barohn, Richard J.; Dimachkie, Mazen M.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66160 USA. [Floeter, Mary Kay] NINDS, Human Spinal Physiol Unit, Bethesda, MD 20892 USA. [Mitsumoto, Hiroshi] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA. RP Statland, JM (reprint author), Univ Kansas, Med Ctr, Dept Neurol, 3901 Rainbow Blvd,Mailstop 2012, Kansas City, KS 66160 USA. EM jstatland@kumc.edu FU Institutional Clinical and Translational Science Award, NIH/NCATS [UL1TR000001]; CTSA grant from NCATS [KL2TR000119]; NIH, NINDS [Z01 NS002976] FX This publication was supported by an Institutional Clinical and Translational Science Award, NIH/NCATS Grant Number UL1TR000001. J.M. Statland's work on this project was supported by a CTSA grant from NCATS awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research #KL2TR000119. M.K Floeter's work on this project was supported by the intramural program of NIH, NINDS, grant # Z01 NS002976. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 48 TC 2 Z9 3 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8619 EI 1557-9875 J9 NEUROL CLIN JI Neurol. Clin. PD NOV PY 2015 VL 33 IS 4 BP 749 EP + DI 10.1016/j.ncl.2015.07.007 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CX1PA UT WOS:000365466900004 PM 26515619 ER PT J AU Grunseich, C Fischbeck, KH AF Grunseich, Christopher Fischbeck, Kenneth H. TI Spinal and Bulbar Muscular Atrophy SO NEUROLOGIC CLINICS LA English DT Article DE Spinal and bulbar muscular atrophy; Kennedy disease; Motor neuron disease; Androgen receptor ID TRANSGENIC MOUSE MODEL; AMYOTROPHIC-LATERAL-SCLEROSIS; ANDROGEN RECEPTOR; KENNEDY-DISEASE; CLINICAL-FEATURES; MEIOTIC STABILITY; CAG REPEAT; POLYGLUTAMINE; EXPRESSION; AUTOPHAGY AB Spinal and bulbar muscular atrophy, or Kennedy disease, is a slowly progressive X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Affected males typically develop weakness in their mid-40s as well as evidence of androgen insensitivity with reduced fertility and gynecomastia. Diagnosis is often delayed because of decreased awareness of the disease, although genetic testing allows for direct diagnosis. Therapeutic strategies to block the toxicity of the mutant androgen receptor have been unsuccessful thus far, and evaluation of additional candidate therapies is underway. C1 [Grunseich, Christopher; Fischbeck, Kenneth H.] Natl Inst Neurol Disorders & Stroke, NIH, Neurogenet Branch, Bethesda, MD 20892 USA. RP Grunseich, C (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Neurogenet Branch, 35 Convent Dr, Bethesda, MD 20892 USA. EM Christopher.grunseich@nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 43 TC 0 Z9 0 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8619 EI 1557-9875 J9 NEUROL CLIN JI Neurol. Clin. PD NOV PY 2015 VL 33 IS 4 BP 847 EP + DI 10.1016/j.ncl.2015.07.002 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CX1PA UT WOS:000365466900010 PM 26515625 ER PT J AU Bailit, JL Grobman, WA McGee, P Reddy, UM Wapner, RJ Varner, MW Thorp, JM Leveno, KJ Iams, JD Tita, ATN Saade, G Sorokin, Y Rouse, DJ Blackwell, SC AF Bailit, Jennifer L. Grobman, William A. McGee, Paula Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Thorp, John M. Leveno, Kenneth J. Iams, Jay D. Tita, Alan T. N. Saade, George Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. CA Eunice Kennedy Shriver Natl Inst C TI Does the Presence of a Condition-Specific Obstetric Protocol Lead to Detectable Improvements in Pregnancy Outcomes? EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Bailit, Jennifer L.] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Grobman, William A.] Northwestern Univ, Prentice Womens Hosp, Chicago, IL 60611 USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, John M.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Blackwell, Sean C.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Tita, Alan T. N.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Rouse, Dwight J.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [McGee, Paula] George Washington Univ, Ctr Biostat, Washington, DC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD NOV PY 2015 VL 70 IS 11 BP 679 EP 680 DI 10.1097/01.ogx.0000473082.76430.62 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CW9AE UT WOS:000365289900004 ER PT J AU Bayefsky, MJ Saylor, KW Berkman, BE AF Bayefsky, Michele J. Saylor, Katherine W. Berkman, Benjamin E. TI Parental Consent for the Use of Residual Newborn Screening Bloodspots: Respecting Individual Liberty vs Ensuring Public Health EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Bayefsky, Michele J.; Berkman, Benjamin E.] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Saylor, Katherine W.] NHGRI, Div Policy Commun & Educ, NIH, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. RP Bayefsky, MJ (reprint author), NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD NOV PY 2015 VL 70 IS 11 BP 686 EP 688 DI 10.1097/01.ogx.0000473446.49463.5b PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CW9AE UT WOS:000365289900008 ER PT J AU Nussinov, R Tsai, CJ AF Nussinov, Ruth Tsai, Chung-Jung TI Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle SO PLOS BIOLOGY LA English DT Editorial Material AB Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions but not single domains can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control. C1 [Nussinov, Ruth; Tsai, Chung-Jung] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth; Tsai, Chung-Jung] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU Intramural NIH HHS NR 10 TC 1 Z9 1 U1 8 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2015 VL 13 IS 11 AR e1002306 DI 10.1371/journal.pbio.1002306 PG 6 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA CX7RE UT WOS:000365898900016 PM 26618518 ER PT J AU Holzemer, A Thobakgale, CF Cruz, CAJ Garcia-Beltran, WF Carlson, JM van Teijlingen, NH Mann, JK Jaggernath, M Kang, SG Korner, C Chung, AW Schafer, JL Evans, DT Alter, G Walker, BD Goulder, PJ Carrington, M Hartmann, P Pertel, T Zhou, RH Ndung'u, T Altfeld, M AF Hoelzemer, Angelique Thobakgale, Christina F. Cruz, Camilo A. Jimenez Garcia-Beltran, Wilfredo F. Carlson, Jonathan M. van Teijlingen, Nienke H. Mann, Jaclyn K. Jaggernath, Manjeetha Kang, Seung-gu Koerner, Christian Chung, Amy W. Schafer, Jamie L. Evans, David T. Alter, Galit Walker, Bruce D. Goulder, Philip J. Carrington, Mary Hartmann, Pia Pertel, Thomas Zhou, Ruhong Ndung'u, Thumbi Altfeld, Marcus TI Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+Natural Killer Cells: Data from an Observational Cohort in South Africa SO PLOS MEDICINE LA English DT Article ID IMMUNOGLOBULIN-LIKE RECEPTOR; VIRUS TYPE-1 INFECTION; HLA CLASS-I; IMMUNE ESCAPE; NK CELLS; PHASE-1 TRIAL; FREE-ENERGY; KIR; RECOGNITION; PROTEINS AB Background Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. Methods and Findings Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 +/- 10.45 standard deviation [SD] and variant mean 44.67 +/- 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 +/- .07 standard error of the mean [SEM] and variant mean 0.63 +/- 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/ peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. Conclusions These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK C1 [Hoelzemer, Angelique; Thobakgale, Christina F.; Garcia-Beltran, Wilfredo F.; Koerner, Christian; Chung, Amy W.; Alter, Galit; Walker, Bruce D.; Carrington, Mary; Ndung'u, Thumbi; Altfeld, Marcus] MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA. [Hoelzemer, Angelique; Altfeld, Marcus] Heinrich Pette Inst, Leibniz Inst Expt Virol, Hamburg, Germany. [Hoelzemer, Angelique] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med 1, Hamburg, Germany. [Thobakgale, Christina F.; Mann, Jaclyn K.; Jaggernath, Manjeetha; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, HIV Pathogenesis Programme,Doris Duke Med Res Ins, Durban, South Africa. [Cruz, Camilo A. Jimenez; Kang, Seung-gu; Zhou, Ruhong] IBM Thomas J Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY USA. [Carlson, Jonathan M.] Microsoft Res, Los Angeles, CA USA. [van Teijlingen, Nienke H.] Univ Amsterdam, Acad Med Ctr, Expt Immunol, NL-1105 AZ Amsterdam, Netherlands. [Schafer, Jamie L.; Evans, David T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Schafer, Jamie L.; Evans, David T.] New England Primate Res Ctr, Div Microbiol, Southborough, MA USA. [Evans, David T.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Goulder, Philip J.] Univ Oxford, Dept Paediat, Oxford, England. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Hartmann, Pia] Univ Cologne, Div Infect Dis, Dept Internal Med 1, D-50931 Cologne, Germany. [Hartmann, Pia; Ndung'u, Thumbi] Univ Cologne, Inst Med Microbiol Immunol & Hyg, D-50931 Cologne, Germany. [Pertel, Thomas] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Pertel, Thomas] Harvard Univ, Sch Med, Boston, MA USA. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, Berlin, Germany. [Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Nelson R Mandela Sch Med, Durban, South Africa. RP Holzemer, A (reprint author), MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA. EM marcus.altfeld@hpi.uni-hamburg.de OI Chung, Amy/0000-0003-0020-9704; Korner, Christian/0000-0002-3431-7319 FU Ragon Institute of MGH, MIT and Harvard; Heinrich Pette Institute - Leibniz Institute for Experimental Virology; NIH [R01 AI066031, P30 AI060354, R01 AI095098, ROI-AI067073, NOI-AI-15422]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH; Harvard University Center for AIDS Research (CFAR); NIH Co-Funding and Participating Institutes and Centres: NIAID; NIH Co-Funding and Participating Institutes and Centres: NCI; NIH Co-Funding and Participating Institutes and Centres: NICHD; NIH Co-Funding and Participating Institutes and Centres: NHLBI; NIH Co-Funding and Participating Institutes and Centres: NIDA; NIH Co-Funding and Participating Institutes and Centres: NIMH; NIH Co-Funding and Participating Institutes and Centres: NIA; NIH Co-Funding and Participating Institutes and Centres: NCCAM; NIH Co-Funding and Participating Institutes and Centres: FIC; NIH Co-Funding and Participating Institutes and Centres: OAR; German Academic Exchange (DAAD); Koeln Fortune Program; Wellcome Trust [102468/Z/13/Z]; National Research Foundation; Victor Daitz Foundation; Howard Hughes Medical Institute; Federal Ministry of Education and Research [01KI1017]; DZIF (German Center for Infection Research) FX The work was supported by the Ragon Institute of MGH, MIT and Harvard (http://www.ragoninstitute.org/index.html), The Heinrich Pette Institute - Leibniz Institute for Experimental Virology (http://www.hpi-hamburg.de/en/), and the NIH (http://www.nih.gov/) (R01 AI066031). This project has partly been funded with federal funds from the Frederick National Laboratory for Cancer Research (http://web.ncifcrf.gov/, contract No. HHSN261200800001E), the Intramural Research Program of the NIH (Frederick National Lab, Center for Cancer Research), and Harvard University Center for AIDS Research (CFAR) (http://cfar.globalhealth.harvar-d.edu/icb/icb.do). CFAR is an NIH-funded program (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centres: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NCCAM, FIC, and OAR. AH was supported by a German Academic Exchange (DAAD) scholarship (www.daad.de) and the Koeln Fortune Program (http://www.medfak.uni-koeln.de/index.php?id=195&L=0). CT was supported by the Wellcome Trust (102468/Z/13/Z). DTE was supported by NIH R01 AI095098. JM was supported by a scholarship from the National Research Foundation. TN holds the South African Research Chair in Systems Biology of HIV/AIDS and is further supported by the Victor Daitz Foundation and an International Early Career Scientist award from the Howard Hughes Medical Institute. The Sinikithemba cohort was funded by the NIH (Grant ROI-AI067073 Contract NOI-AI-15422). PH is funded by the Federal Ministry of Education and Research grant 01KI1017 and supported by DZIF (German Center for Infection Research), www.dzif.de. JMC is an employee of Microsoft Corp; the employer was not involved in the research. The authors have no conflicting financial interests. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 10 Z9 10 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD NOV PY 2015 VL 12 IS 11 AR e1001900 DI 10.1371/journal.pmed.1001900 PG 25 WC Medicine, General & Internal SC General & Internal Medicine GA CX7UZ UT WOS:000365909700004 PM 26575988 ER PT J AU Dynlacht, JR Zeman, EM Held, KD Deye, J Vikram, B Joiner, MC AF Dynlacht, Joseph R. Zeman, Elaine M. Held, Kathryn D. Deye, James Vikram, Bhadrasain Joiner, Michael C. TI Education and Training Needs in the Radiation Sciences: Problems and Potential Solutions SO RADIATION RESEARCH LA English DT Article ID FUKUSHIMA RADIOLOGICAL EMERGENCY; ONCOLOGY RESIDENTS; AMERICAN SOCIETY; RADIOBIOLOGY; CONSENSUS; DOSIMETRY; FUTURE AB This article provides a summary of presentations focused on critical education and training issues in radiation oncology, radiobiology and medical physics from a workshop conducted as part of the 60th Annual Meeting of the Radiation Research Society held in Las Vegas, NV (September 21-24, 2014). Also included in this synopsis are pertinent comments and concerns raised by audience members, as well as recommendations for addressing ongoing and future challenges. (C) 2015 by Radiation Research Society C1 [Dynlacht, Joseph R.] Indiana Univ Sch Med, Dept Radiat Oncol, Indianapolis, IN 46202 USA. [Zeman, Elaine M.] Univ N Carolina, Dept Radiat Oncol, Sch Med, Chapel Hill, NC 27599 USA. [Held, Kathryn D.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Held, Kathryn D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Deye, James] NCI, Div Canc Treatment & Diag, Radiat Res Program, Bethesda, MD 20892 USA. [Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Joiner, Michael C.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48201 USA. RP Dynlacht, JR (reprint author), Indiana Univ, Dept Radiat Oncol, Indiana Canc Pavil,RT041,535 Barnhill Dr, Indianapolis, IN 46202 USA. EM jdynlach@iupui.edu FU National Cancer Institute's Center for Cancer Training [R25CA171971] FX Dr. Michael Joiner and the "Integrated course in Biology and Physics of Radiation Oncology" were supported by a grant from the National Cancer Institute's Center for Cancer Training (award no. R25CA171971). NR 19 TC 4 Z9 4 U1 0 U2 1 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2015 VL 184 IS 5 BP 449 EP 455 DI 10.1667/RR14199.1 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA CX6HB UT WOS:000365800700001 PM 26479274 ER PT J AU Thomason, ME Marusak, HA Tocco, MA Vila, AM McGarragle, O Rosenberg, DR AF Thomason, Moriah E. Marusak, Hilary A. Tocco, Maria A. Vila, Angela M. McGarragle, Olivia Rosenberg, David R. TI Altered amygdala connectivity in urban youth exposed to trauma SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE adolescent; child; maltreatment; resting-state; urban ID POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; NATIONAL COMORBIDITY SURVEY; INTRINSIC FUNCTIONAL CONNECTIVITY; ADVERSE CHILDHOOD EXPERIENCES; EARLY-LIFE STRESS; MALTREATED CHILDREN; PREFRONTAL CORTEX; INTERNALIZING SYMPTOMS; HOUSEHOLD DYSFUNCTION AB Early life trauma exposure represents a potent risk factor for the development of mental illnesses such as anxiety, depression and post-traumatic stress disorder. Moreover, deleterious consequences of trauma are exacerbated in youth living in impoverished, urban environments. A priori probability maps were used to examine resting-state functional connectivity (FC) of the amygdala in 21 trauma-exposed, and 21 age-and sex-matched urban children and adolescents (youth) without histories of trauma. Intrinsic FC analyses focused on amygdala-medial prefrontal circuitry, a key emotion regulatory pathway in the brain. We discovered reduced negative amygdala-subgenual cingulate connectivity in trauma-exposed youth. Differences between groups were also identified in anterior insula and dorsal anterior cingulate to amygdala connectivity. Overall, results suggest a model in which urban-dwelling trauma-exposed youth lack negative prefrontal to amygdala connectivity that may be critical for regulation of emotional responses. Functional changes in amygdala circuitry might reflect the biological embedding of stress reactivity in early life and mediate enhanced vulnerability to stress-related psychopathology. C1 [Thomason, Moriah E.; Marusak, Hilary A.; Vila, Angela M.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [Thomason, Moriah E.] Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA. [Thomason, Moriah E.] NICHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD USA. [Marusak, Hilary A.; McGarragle, Olivia; Rosenberg, David R.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI 48202 USA. [Tocco, Maria A.] Wayne State Univ, Sch Med, Detroit, MI 48202 USA. RP Thomason, ME (reprint author), Merrill Palmer Skillman Inst, 71 E Ferry St, Detroit, MI 48202 USA. EM moriah@wayne.edu FU Merrill Palmer Skillman Institute; Department of Pediatrics, WSU School of Medicine; National Alliance for Research on Schizophrenia and Depression (NARSAD); Lycaki-Young Funds; State of Michigan; Detroit Wayne Mental Health Authority; [R01MH59299]; [R01HD075806] FX This project was supported in part by the Merrill Palmer Skillman Institute and the Department of Pediatrics, WSU School of Medicine and by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (M.E.T.). Further support comes from Lycaki-Young Funds, State of Michigan, Detroit Wayne Mental Health Authority, and R01MH59299 (D.R.R.) and R01HD075806 (M.E.T). The authors would like to thank Pavan K. Jella, for his assistance in neuroimaging data acquisition; Rita Elias, Melissa Youmans, Mallory Gardner, Timothy Lozon and Ali Daher for assistance in participant recruitment, scanning and conducting structured behavioral interviews; Matthew Carroll for consultation on statistical analyses and are grateful to those families who volunteered their time to participate in this study. NR 83 TC 8 Z9 8 U1 5 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD NOV PY 2015 VL 10 IS 11 BP 1460 EP 1468 DI 10.1093/scan/nsv030 PG 9 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CX2RR UT WOS:000365544900003 PM 25836993 ER PT J AU Young, KD Bellgowan, PSF Bodurka, J Drevets, WC AF Young, Kymberly D. Bellgowan, Patrick S. F. Bodurka, Jerzy Drevets, Wayne C. TI Autobiographical deficits correlate with gray matter volume in depressed and high risk participants SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE depression; gray matter volume; hippocampus; autobiographical memory; familial risk; precuneus ID BRAINS DEFAULT NETWORK; MEMORY SPECIFICITY; SEX-DIFFERENCES; RETRIEVAL; DISORDER; METAANALYSIS; RELEVANCE; ANATOMY; RECALL; MOOD AB Autobiographical memory (AM) overgenerality is a consistent neuropsychological feature of major depressive disorder (MDD) and is present in individuals at high-familial risk (HR) of developing MDD. Structural changes have been found in brain regions implicated in AM recall in MDDs and HRs. However, the relationship between selective regional gray matter volume (GMV) differences and AM recall deficits has not been examined. We examined this relationship in 27 HR, 43 unmedicated MDD and 47 low-risk healthy control participants as they completed an AM task during functional magnetic resonance imaging. FreeSurfer was used for automated anatomical image processing and volumetric quantification. Anatomical regions of interest for GMV analysis were selected based on regions most commonly activated in controls as they recall specific AMs according to a recent meta-analysis. Pearson correlations were calculated among volumetric and AM recall data. In HRs and MDDs, left hippocampal volume correlated positively with specific (HRs r = 0.42; MDDs r = 0.60) and inversely with categorical AM recall (HRs r = -0.51; MDDs r = -0.35). In MDDs, left precuneus volume also correlated positively with specific (r = 0.49) and inversely with categorical (r = -0.35) AM recall. Our results suggest selective GMV alterations within the AM network may contribute to AM impairments observed in both HR and MDD individuals. C1 [Young, Kymberly D.; Bodurka, Jerzy; Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK 74136 USA. [Bellgowan, Patrick S. F.] NINDS, NIH, Bethesda, MD 20892 USA. [Bodurka, Jerzy] Univ Oklahoma, Norman, OK 73019 USA. [Drevets, Wayne C.] Johnson & Johnson Inc, Janssen Pharmaceut, Titusville, NJ USA. RP Young, KD (reprint author), Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. EM kyoung@laureateinstitute.org OI Young, Kymberly/0000-0001-5133-2142 FU Laureate Institute for Brain Research; William K. Warren Foundation FX This research was supported by the Laureate Institute for Brain Research and The William K. Warren Foundation. The funders had no influence on the design or conduct of the study, collection, management, analyses or interpretation of the data, or in the preparation, review or approval of the manuscript. NR 37 TC 1 Z9 3 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD NOV PY 2015 VL 10 IS 11 BP 1588 EP 1595 DI 10.1093/scan/nsv047 PG 8 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CX2RR UT WOS:000365544900016 PM 25925269 ER PT J AU Judson, RS Magpantay, FM Chickarmane, V Haskell, C Tania, N Taylor, J Xia, MH Huang, RL Rotroff, DM Filer, DL Houck, KA Martin, MT Sipes, N Richard, AM Mansouri, K Setzer, RW Knudsen, TB Crofton, KM Thomas, RS AF Judson, Richard S. Magpantay, Felicia Maria Chickarmane, Vijay Haskell, Cymra Tania, Nessy Taylor, Jean Xia, Menghang Huang, Ruili Rotroff, Daniel M. Filer, Dayne L. Houck, Keith A. Martin, Matthew T. Sipes, Nisha Richard, Ann M. Mansouri, Kamel Setzer, R. Woodrow Knudsen, Thomas B. Crofton, Kevin M. Thomas, Russell S. TI Integrated Model of Chemical Perturbations of a Biological Pathway Using 18 In Vitro High-Throughput Screening Assays for the Estrogen Receptor SO TOXICOLOGICAL SCIENCES LA English DT Article DE estrogen receptor; EDSP; high-throughput screening; In vitro; prioritization; biological modeling ID EPAS TOXCAST PROGRAM; ENVIRONMENTAL CHEMICALS; MOLECULAR-MECHANISMS; SELECTIVE LIGANDS; BREAST-CANCER; TOXICITY; EXPOSURE; PRIORITIZATION; IDENTIFICATION; TRANSCRIPTION AB We demonstrate a computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform ("assay interference"). The method is applied to a library of 1812 commercial and environmental chemicals, including 45 ER positive and negative reference chemicals. Among the reference chemicals, the network model correctly identified the agonists and antagonists with the exception of very weak compounds whose activity was outside the concentration range tested. The model agonist score also correlated with the expected potency class of the active reference chemicals. Of the 1812 chemicals evaluated, 111 (6.1%) were predicted to be strongly ER active in agonist or antagonist mode. This dataset and model were also used to begin a systematic investigation of assay interference. The most prominent cause of false-positive activity (activity in an assay that is likely not due to interaction of the chemical with ER) is cytotoxicity. The model provides the ability to prioritize a large set of important environmental chemicals with human exposure potential for additional in vivo endocrine testing. Finally, this model is generalizable to any molecular pathway for which there are multiple upstream and downstream assays available. C1 [Judson, Richard S.; Houck, Keith A.; Martin, Matthew T.; Richard, Ann M.; Setzer, R. Woodrow; Knudsen, Thomas B.; Crofton, Kevin M.; Thomas, Russell S.] US EPA, Res Triangle Pk, NC 27711 USA. [Magpantay, Felicia Maria] Univ Manitoba, Dept Math, Winnipeg, MB R3T 2N2, Canada. [Chickarmane, Vijay] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Haskell, Cymra] Univ So Calif, Dept Math, Los Angeles, CA 90089 USA. [Tania, Nessy] Smith Coll, Dept Math, Northampton, MA 01063 USA. [Taylor, Jean] NYU, Courant Inst, New York, NY 10012 USA. [Xia, Menghang; Huang, Ruili] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20892 USA. [Rotroff, Daniel M.] N Carolina State Univ, Dept Stat, Raleigh, NC 27607 USA. [Rotroff, Daniel M.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27607 USA. [Filer, Dayne L.; Mansouri, Kamel] US EPA, ORISE, Res Triangle Pk, NC 27711 USA. [Sipes, Nisha] NIH, Natl Toxicol Program, Res Triangle Pk, NC 27711 USA. RP Judson, RS (reprint author), US EPA, Res Triangle Pk, NC 27711 USA. EM judson.richard@epa.gov RI Crofton, Kevin/J-4798-2015; OI Crofton, Kevin/0000-0003-1749-9971; Mansouri, Kamel/0000-0002-6426-8036 FU American Institute of Mathematics; National Science Foundation; U.S. EPA FX The authors gratefully acknowledge the American Institute of Mathematics and National Science Foundation for support of this research through the "Modeling Problems Related to Our Environment" workshop held January 14-18, 2013 in Palo Alto, California. All other funding was provided by the U.S. EPA. NR 47 TC 24 Z9 24 U1 7 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2015 VL 148 IS 1 BP 137 EP 154 DI 10.1093/toxsci/kfv168 PG 18 WC Toxicology SC Toxicology GA CX2SU UT WOS:000365547900013 PM 26272952 ER PT J AU Bao, QY Hipp, M Hugo, A Lei, J Liu, Y Kehl, T Hechler, T Lochelt, M AF Bao, Qiuying Hipp, Michaela Hugo, Annette Lei, Janet Liu, Yang Kehl, Timo Hechler, Torsten Loechelt, Martin TI In Vitro Evolution of Bovine Foamy Virus Variants with Enhanced Cell-Free Virus Titers and Transmission SO VIRUSES-BASEL LA English DT Article DE bovine foamy virus; retrovirus; particle release; virus budding; Gag myristoylation; virus transmission ID TERMINAL GAG DOMAIN; ENV LEADER PROTEIN; SYNCYTIAL VIRUS; SPREAD; INFECTIVITY; RNA; MYRISTOYLATION; MORPHOGENESIS; REQUIREMENTS; SPUMAVIRUS AB Virus transmission is essential for spreading viral infections and is a highly coordinated process which occurs by cell-free transmission or cell-cell contact. The transmission of Bovine Foamy Virus (BFV) is highly cell-associated, with undetectable cell-free transmission. However, BFV particle budding can be induced by overexpression of wild-type (wt) BFV Gag and Env or artificial retargeting of Gag to the plasma membrane via myristoylation membrane targeting signals, closely resembling observations in other foamy viruses. Thus, the particle release machinery of wt BFV appears to be an excellent model system to study viral adaption to cell-free transmission by in vitro selection and evolution. Using selection for BFV variants with high cell-free infectivity in bovine and non-bovine cells, infectivity dramatically increased from almost no infectious units to about 10(5)-10(6) FFU (fluorescent focus forming units)/mL in both cell types. Importantly, the selected BFV variants with high titer (HT) cell-free infectivity could still transmit via cell-cell contacts and were neutralized by serum from naturally infected cows. These selected HT-BFV variants will shed light into virus transmission and potential routes of intervention in the spread of viral infections. It will also allow the improvement or development of new promising approaches for antiretroviral therapies. C1 [Bao, Qiuying; Hipp, Michaela; Hugo, Annette; Lei, Janet; Liu, Yang; Kehl, Timo; Hechler, Torsten; Loechelt, Martin] German Canc Res Ctr, Deutsch Krebsforschungszentrum, DKFZ, Div Molecuar Diagnost Oncogen Infect Res Focus In, D-69120 Heidelberg, Germany. [Lei, Janet] Univ Oxford, Dept Oncol, Oxford OX3 7DQ, England. [Liu, Yang] NCI, Dept Viral Recombinat, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Hechler, Torsten] Heidelberg Pharma GmbH, D-68526 Heidelberg, Germany. RP Lochelt, M (reprint author), German Canc Res Ctr, Deutsch Krebsforschungszentrum, DKFZ, Div Molecuar Diagnost Oncogen Infect Res Focus In, D-69120 Heidelberg, Germany. EM q.bao@dkfz.de; m.hipp@dkfz.de; a.hugo@dkfz.de; janet.lei@oncology.ox.ac.uk; liuy18@nih.gov; t.kehl@dkfz.de; t.hechler@hdpharma.com; m.loechelt@dkfz.de OI Lei, Janet/0000-0001-6486-9651 FU China Scholarship Council (CSC) FX We thank Lutz Gissmann for continuous support, Birgit Hub for electron microscopy and Juliane Hafermann for critically reading the manuscript (all Deutsches Krebsforschungszentrum, Heidelberg, Germany), Roland Riebe (Friedrich Loffler-Institut, Riems, Germany) for the BFV-Riems isolate and many helpful suggestions and discussions, Magdalena Materniak and Jacek Kuzmak (National Veterinary Research Institute, PIWet, Pulawy, Poland) for bovine and hyper-immune sera and Wentao Qiao (Nankai University, Tianjin, China) for providing the BICL cells. Q.B. is supported by an international PhD stipend from the China Scholarship Council (CSC). NR 51 TC 1 Z9 1 U1 2 U2 2 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2015 VL 7 IS 11 BP 5855 EP 5874 DI 10.3390/v7112907 PG 20 WC Virology SC Virology GA CX4GB UT WOS:000365656000015 PM 26569290 ER PT J AU Shchetinin, AM Lvov, DK Deriabin, PG Botikov, AG Gitelman, AK Kuhn, JH Alkhovsky, SV AF Shchetinin, Alexey M. Lvov, Dmitry K. Deriabin, Petr G. Botikov, Andrey G. Gitelman, Asya K. Kuhn, Jens H. Alkhovsky, Sergey V. TI Genetic and Phylogenetic Characterization of Tataguine and Witwatersrand Viruses and Other Orthobunyaviruses of the Anopheles A, Capim, Guama, Koongol, Mapputta, Tete, and Turlock Serogroups SO VIRUSES-BASEL LA English DT Article DE Anopheles A virus; bunyavirus; Capim virus; Guama virus; Koongol virus; orthobunyavirus; Tataguine virus; Tete virus; Turlock virus; Witwatersrand virus ID COMPLEX GENUS PHLEBOVIRUS; TICK-BORNE PHLEBOVIRUSES; FAMILY BUNYAVIRIDAE; ARBOVIRUS INFECTION; BUNYAMWERA-VIRUS; MOLECULAR CHARACTERIZATION; ANTIGENIC RELATIONSHIPS; NUCLEOTIDE-SEQUENCE; NORTH QUEENSLAND; TAXONOMIC STATUS AB The family Bunyaviridae has more than 530 members that are distributed among five genera or remain to be classified. The genus Orthobunyavirus is the most diverse bunyaviral genus with more than 220 viruses that have been assigned to more than 18 serogroups based on serological cross-reactions and limited molecular-biological characterization. Sequence information for all three orthobunyaviral genome segments is only available for viruses belonging to the Bunyamwera, Bwamba/Pongola, California encephalitis, Gamboa, Group C, Mapputta, Nyando, and Simbu serogroups. Here we present coding-complete sequences for all three genome segments of 15 orthobunyaviruses belonging to the Anopheles A, Capim, Guama, Kongool, Tete, and Turlock serogroups, and of two unclassified bunyaviruses previously not known to be orthobunyaviruses (Tataguine and Witwatersrand viruses). Using those sequence data, we established the most comprehensive phylogeny of the Orthobunyavirus genus to date, now covering 15 serogroups. Our results emphasize the high genetic diversity of orthobunyaviruses and reveal that the presence of the small nonstructural protein (NSs)-encoding open reading frame is not as common in orthobunyavirus genomes as previously thought. C1 [Shchetinin, Alexey M.; Lvov, Dmitry K.; Deriabin, Petr G.; Botikov, Andrey G.; Gitelman, Asya K.; Alkhovsky, Sergey V.] Minist Hlth Russian Federat, DI Ivanovskii Virol Inst, Gamaleya Fed Res Ctr Epidemiol & Microbiol, Moscow 123098, Russia. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Ft Detrick, MD 21702 USA. RP Alkhovsky, SV (reprint author), Minist Hlth Russian Federat, DI Ivanovskii Virol Inst, Gamaleya Fed Res Ctr Epidemiol & Microbiol, Moscow 123098, Russia. EM shchetinin.alexey@yandex.ru; dk_lvov@mail.ru; pg_deryabin@mail.ru; tessey@mail.ru; gitelman_ak@mail.ru; kuhnjens@mail.nih.gov; salkh@yandex.ru FU Russian Foundation for Basic Research (RFBR) [13-04-01749a]; Battelle Memorial Institute's prime; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX The authors thank Laura Bollinger (IRF-Frederick) for critically editing this paper. This work was funded by the Russian Foundation for Basic Research (RFBR) according to research project 13-04-01749a. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, or the institutions and companies affiliated with the authors. This work was supported in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I. A subcontractor to Battelle Memorial Institute who performed this work is: J.H.K., an employee of Tunnell Government Services, Inc. (Bethesda, MD, USA). NR 110 TC 4 Z9 4 U1 5 U2 7 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD NOV PY 2015 VL 7 IS 11 BP 5987 EP 6008 DI 10.3390/v7112918 PG 22 WC Virology SC Virology GA CX4GB UT WOS:000365656000023 PM 26610546 ER PT J AU Jha, A Ahuja, M Muallem, S AF Jha, Archana Ahuja, Malini Muallem, Shmuel TI Properties and function of the lysosomal channels TPCs and TRPML1 SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Jha, Archana; Ahuja, Malini; Muallem, Shmuel] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD NOV PY 2015 VL 215 SU 705 SI SI MA S11-2 BP 43 EP 43 PG 1 WC Physiology SC Physiology GA CW1XX UT WOS:000364786400093 ER PT J AU Hansen, M Smith, MC Crist, RM Clogston, JD McNeil, S AF Hansen, Matthew Smith, Mackensie C. Crist, Rachael M. Clogston, Jeffrey D. McNeil, Scott E. TI Analyzing the influence of PEG molecular weight on the separation of PEGylated gold nanoparticles by asymmetric-flow field-flow fractionation SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Polyethylene glycol; Surface characterization; Asymmetric-flow field-flow fractionation; Gold nanoparticles; Separation ID UV-VIS DETECTION; PROTEIN SURFACE INTERACTIONS; CAPILLARY-ELECTROPHORESIS; POLYETHYLENE OXIDE; GEL-ELECTROPHORESIS; NANOROD SEPARATION; AU NANOPARTICLES; SIZE; THERAPY; CHROMATOGRAPHY AB Polyethylene glycol (PEG) is an important tool for increasing the biocompatibility of nanoparticle therapeutics. Understanding how these potential nanomedicines will react after they have been introduced into the bloodstream is a critical component of the preclinical evaluation process. Hence, it is paramount that better methods for separating, characterizing, and analyzing these complex and polydisperse formulations are developed. We present a method for separating nominal 30-nm gold nanoparticles coated with various molecular weight PEG moieties that uses only phosphate-buffered saline as the mobile phase, without the need for stabilizing surfactants. The optimized asymmetric-flow field-flow fractionation technique using in-line multiangle light scattering, dynamic light scattering, refractive index, and UV-vis detectors allowed successful separation and detection of a mixture of nanoparticles coated with 2-, 5-, 10-, and 20-kDa PEG. The particles coated with the larger PEG species (10 and 20 kDa) were eluted at times significantly earlier than predicted by field-flow fractionation theory. This was attributed to a lower-density PEG shell for the higher molecular weight PEGylated nanoparticles, which allows a more fluid PEG surface that can be greater influenced by external forces. Hence, the apparent particle hydrodynamic size may fluctuate significantly depending on the overall density of the stabilizing surface coating when an external force is applied. This has considerable implications for PEGylated nanoparticles intended for in vivo application, as nanoparticle size is important for determining circulation times, accumulation sites, and routes of excretion, and highlights the importance and value of the use of secondary size detectors when one is working with complex samples in asymmetric-flow field-flow fractionation. C1 [Hansen, Matthew; Smith, Mackensie C.; Crist, Rachael M.; Clogston, Jeffrey D.; McNeil, Scott E.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. RP Clogston, JD (reprint author), Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc Res Technol Program, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. EM jeffrey.clogston@nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012; Crist, Rachael/K-7603-2012 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 47 TC 3 Z9 3 U1 3 U2 23 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD NOV PY 2015 VL 407 IS 29 BP 8661 EP 8672 DI 10.1007/s00216-015-9056-9 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CW7HS UT WOS:000365169500003 PM 26449845 ER PT J AU Thomas, A Giaccone, G AF Thomas, A. Giaccone, G. TI Why has active immunotherapy not worked in lung cancer? SO ANNALS OF ONCOLOGY LA English DT Review DE active immunotherapy; vaccines; nonsmall-cell lung cancer; immune checkpoint; tumor-mediated immunosuppression ID NONSMALL-CELL LUNG; BLP25 LIPOSOME VACCINE; MAJOR HISTOCOMPATIBILITY COMPLEX; TRANSFORMING-GROWTH-FACTOR; REGULATORY T-CELLS; CLASS-I; ANTIGEN PRESENTATION; IMMUNE-SYSTEM; PHASE-II; ANTITUMOR IMMUNITY AB This paper reviews the phase III trial results of antigen-specific immunotherapeutic approaches in nonsmall-cell lung cancer and explores in-depth the potential reasons behind their failure and discuss strategies for the future.Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC. C1 [Thomas, A.] NCI, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [Giaccone, G.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Res Bldg Room W503,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Intramural program, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural program, National Cancer Institute, National Institutes of Health. No grant numbers apply. NR 64 TC 12 Z9 12 U1 4 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2015 VL 26 IS 11 BP 2213 EP 2220 DI 10.1093/annonc/mdv323 PG 8 WC Oncology SC Oncology GA CW7DW UT WOS:000365159200003 PM 26232492 ER PT J AU Genkinger, JM Kitahara, CM Bernstein, L de Gonzalez, AB Brotzman, M Elena, JW Giles, GG Hartge, P Singh, PN Stolzenberg-Solomon, RZ Weiderpass, E Adami, HO Anderson, KE Beane-Freeman, LE Buring, JE Fraser, GE Fuchs, CS Gapstur, SM Gaziano, JM Helzlsouer, KJ Lacey, JV Linet, MS Liu, JJ Park, Y Peters, U Purdue, MP Robien, K Schairer, C Sesso, HD Visvanathan, K White, E Wolk, A Wolpin, BM Zeleniuch-Jacquotte, A Jacobs, EJ AF Genkinger, J. M. Kitahara, C. M. Bernstein, L. de Gonzalez, A. Berrington Brotzman, M. Elena, J. W. Giles, G. G. Hartge, P. Singh, P. N. Stolzenberg-Solomon, R. Z. Weiderpass, E. Adami, H. -O. Anderson, K. E. Beane-Freeman, L. E. Buring, J. E. Fraser, G. E. Fuchs, C. S. Gapstur, S. M. Gaziano, J. M. Helzlsouer, K. J. Lacey, J. V., Jr. Linet, M. S. Liu, J. J. Park, Y. Peters, U. Purdue, M. P. Robien, K. Schairer, C. Sesso, H. D. Visvanathan, K. White, E. Wolk, A. Wolpin, B. M. Zeleniuch-Jacquotte, A. Jacobs, E. J. TI Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies SO ANNALS OF ONCOLOGY LA English DT Review DE central adiposity; BMI; pancreatic cancer; pooled analysis ID BODY-MASS INDEX; LONGITUDINAL FOLLOW-UP; WAIST CIRCUMFERENCE; CARDIOVASCULAR-DISEASE; ABDOMINAL ADIPOSITY; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; BREAST-CANCER; RISK-FACTORS; HEALTH AB positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. Design: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity ( e. g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood ( ages 18- 21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later ( n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios ( HRs) and 95% confidence intervals ( CIs) were calculated using Cox proportional hazards regression models. Results: Higher waist-to-hip ratio ( HR = 1.09, 95% CI 1.02- 1.17 per 0.1 increment) and waist circumference ( HR = 1.07, 95% CI 1.00- 1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality ( HR = 1.18, 95% CI 1.11- 1.25 per 5 kg/ m2), with increased risk observed in both overweight and obese individuals ( compared with BMI of 21.0 to < 23 kg/ m(2), HR = 1.36, 95% CI 1.20- 1.55 for BMI 25.0 < 27.5 kg/ m2, HR = 1.48, 95% CI 1.20- 1.84 for BMI 27.5 to < 30 kg/ m2, HR = 1.43, 95% CI 1.11- 1.85 for BMI = 30 kg/ m2). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality ( HR = 1.05, 95% CI 1.01- 1.10 per 5 kg/ m2). Conclusions: Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life. C1 [Genkinger, J. M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Genkinger, J. M.] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Kitahara, C. M.; de Gonzalez, A. Berrington; Hartge, P.; Stolzenberg-Solomon, R. Z.; Beane-Freeman, L. E.; Linet, M. S.; Liu, J. J.; Park, Y.; Purdue, M. P.; Schairer, C.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD USA. [Bernstein, L.] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA 91010 USA. [Brotzman, M.] WESTAT Corp, Rockville, MD 20850 USA. [Elena, J. W.] NCI, Div Canc Control & Populat Sci, NIH, DHHS, Bethesda, MD 20892 USA. [Giles, G. G.] Univ Melbourne, Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, G. G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Singh, P. N.; Fraser, G. E.] Loma Linda Univ, Sch Med, Dept Epidemiol Biostat & Populat Med, Loma Linda, CA USA. [Singh, P. N.; Fraser, G. E.] Loma Linda Univ, Ctr Hlth Res, Loma Linda, CA USA. [Weiderpass, E.] Univ Tromso, Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, E.] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, E.; Adami, H. -O.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, E.] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Adami, H. -O.; Buring, J. E.; Sesso, H. D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Anderson, K. E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, K. E.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Buring, J. E.; Sesso, H. D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, J. E.; Fuchs, C. S.; Sesso, H. D.; Wolpin, B. M.] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, C. S.; Wolpin, B. M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, C. S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gapstur, S. M.; Jacobs, E. J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, J. M.; Sesso, H. D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Gaziano, J. M.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Ctr Geriatr Res Educ & Clin, Boston, MA USA. [Helzlsouer, K. J.] St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Helzlsouer, K. J.; Visvanathan, K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Park, Y.] Washington Univ, Div Publ Hlth Sci, Sch Med, St Louis, MO 63130 USA. [Peters, U.; White, E.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Peters, U.; White, E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Robien, K.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutr Sci, Washington, DC USA. [Visvanathan, K.] Johns Hopkins Sch Med, Sidney Kimmel Canc Ctr, Dept Med Oncol, Baltimore, MD USA. [Wolk, A.] Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-10401 Stockholm, Sweden. [Zeleniuch-Jacquotte, A.] NYU, Dept Populat Hlth, New York, NY USA. [Zeleniuch-Jacquotte, A.] NYU, Perlmutter Canc Ctr, New York, NY USA. RP Genkinger, JM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, 722 W 168th St,Rm 803, New York, NY 10032 USA. EM jg3081@columbia.edu RI Purdue, Mark/C-9228-2016; Weiderpass, Elisabete/M-4029-2016; Beane Freeman, Laura/C-4468-2015; Kitahara, Cari/R-8267-2016; OI Purdue, Mark/0000-0003-1177-3108; Weiderpass, Elisabete/0000-0003-2237-0128; Beane Freeman, Laura/0000-0003-1294-4124; Robien, Kim/0000-0002-2120-2280; Giles, Graham/0000-0003-4946-9099; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural NIH HHS; NCI NIH HHS [CA105069, CA 016087, CA 34944, CA 40360, CA 77398, CA 97193, CA047988, K05 CA154337, P01 CA055075, P01 CA87969, P30 CA015704, R01 CA 098661, R01 CA105069, R01 CA124908, R01 CA39742, R01 CA49449, R01-CA14703, UM1 CA167552, UM1 CA182913, UM1 CA182934, UM1 CA186107, Z99CA999999]; NHLBI NIH HHS [HL 26490, HL 34595, HL043851, HL080467, R01- HL26210]; NIA NIH HHS [5U01AG018033, U01 AG18033]; NIEHS NIH HHS [ES 000260, Z01 ES049030-11]; PHS HHS [Z01 P010119] NR 62 TC 5 Z9 5 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2015 VL 26 IS 11 BP 2257 EP 2266 DI 10.1093/annonc/mdv355 PG 10 WC Oncology SC Oncology GA CW7DW UT WOS:000365159200006 PM 26347100 ER PT J AU Cho, HY Kleeberger, S AF Cho, Hye-Youn Kleeberger, Steven R. TI Association of Nrf2 with airway pathogenesis: lessons learned from genetic mouse models SO ARCHIVES OF TOXICOLOGY LA English DT Review DE Nfe2l2; Lung; Knockout mice; Oxidative stress; Antioxidant response element ID RESPIRATORY SYNCYTIAL VIRUS; ACUTE LUNG INJURY; TRANSCRIPTION FACTOR NRF2; EXTRACELLULAR-SUPEROXIDE DISMUTASE; OBSTRUCTIVE PULMONARY-DISEASE; ANTIOXIDANT RESPONSE ELEMENTS; ERYTHROID 2-RELATED FACTOR-2; GLUTATHIONE-S-TRANSFERASE; DIESEL EXHAUST PARTICLES; SMOKE-INDUCED EMPHYSEMA AB Nrf2 is a key transcription factor for antioxidant response element (ARE)-bearing genes involved in diverse host defense functions including redox balance, cell cycle, immunity, mitochondrial biogenesis, energy metabolism, and carcinogenesis. Nrf2 in the airways is particularly essential as the respiratory system continuously interfaces with environmental stress. Since Nrf2 was determined to be a susceptibility gene for a model of acute lung injury, its protective capacity in the airways has been demonstrated in experimental models of human disorders using Nrf2 mutant mice which were susceptible to supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergens, virus, environmental pollutants, and fibrotic agents compared to wild-type littermates. Recent studies also determined that Nrf2 is indispensable in developmental lung injury. While association studies with genetic NRF2 polymorphisms supported a protective role for murine Nrf2 in oxidative airway diseases, somatic NRF2 mutations enhanced NRF2-ARE responses, and were favorable for lung carcinogenesis and chemoresistance. Bioinformatic tools have elucidated direct Nrf2 targets as well as Nrf2-interacting networks. Moreover, potent Nrf2-ARE agonists protected oxidant-induced lung phenotypes in model systems, suggesting a therapeutic or preventive intervention. Further investigations on Nrf2 should yield greater understanding of its contribution to normal and pathophysiological function in the airways. C1 [Cho, Hye-Youn; Kleeberger, Steven R.] NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, HY (reprint author), NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM cho2@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences, Department of Health and Human Services FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, Department of Health and Human Services. The authors thank Drs. Donald Cook and Michael Fessler for thoughtful comments on the manuscript. NR 203 TC 4 Z9 4 U1 4 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD NOV PY 2015 VL 89 IS 11 BP 1931 EP 1957 DI 10.1007/s00204-015-1557-y PG 27 WC Toxicology SC Toxicology GA CX0WK UT WOS:000365417800003 PM 26194645 ER PT J AU Rother, KI Sylvetsky, AC Schiffman, SS AF Rother, Kristina I. Sylvetsky, Allison C. Schiffman, S. S. TI Non-nutritive sweeteners in breast milk: perspective on potential implications of recent findings SO ARCHIVES OF TOXICOLOGY LA English DT Letter ID P-GLYCOPROTEIN; GUT MICROBIOTA; HEALTH; ONTOGENY; EXPRESSION; SUCRALOSE; OBESITY C1 [Rother, Kristina I.; Sylvetsky, Allison C.] NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Sylvetsky, Allison C.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutr Sci, Washington, DC USA. [Schiffman, S. S.] N Carolina State Univ, Dept Elect & Comp Engn, Raleigh, NC 27695 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab, NIH, 9000 Rockville Pike,Bldg 10,Room 8C-432A, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov FU Intramural NIH HHS [ZIA DK075093-01, ZIA DK075093-02, ZIA DK075093-03] NR 24 TC 3 Z9 3 U1 2 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD NOV PY 2015 VL 89 IS 11 BP 2169 EP 2171 DI 10.1007/s00204-015-1611-9 PG 3 WC Toxicology SC Toxicology GA CX0WK UT WOS:000365417800023 PM 26462668 ER PT J AU Makarova, KS Galperin, MY Koonin, EV AF Makarova, Kira S. Galperin, Michael Y. Koonin, Eugene V. TI Comparative genomic analysis of evolutionarily conserved but functionally uncharacterized membrane proteins in archaea: Prediction of novel components of secretion, membrane remodeling and glycosylation systems SO BIOCHIMIE LA English DT Article DE Archaeal genomes; arCOGs; Membrane proteins; Gene neighborhoods ID HORIZONTAL GENE-TRANSFER; HALOFERAX-VOLCANII; BACILLUS-SUBTILIS; N-GLYCOSYLATION; PHOSPHOLIPID BIOSYNTHESIS; STAPHYLOCOCCUS-AUREUS; ORTHOLOGOUS GENES; CELL-SURFACE; TTT FAMILY; COMPLEX AB A systematic comparative genomic analysis of all archaeal membrane proteins that have been projected to the last archaeal common ancestor gene set led to the identification of several novel components of predicted secretion, membrane remodeling, and protein glycosylation systems. Among other findings, most crenarchaea have been shown to encode highly diverged orthologs of the membrane insertase YidC, which is nearly universal in bacteria, eukaryotes, and euryarchaea. We also identified a vast family of archaeal proteins, including the C-terminal domain of N-glycosylation protein AglD, as membrane flippases homologous to the flippase domain of bacterial multipeptide resistance factor MprF, a bifunctional lysylphosphatidylglycerol synthase and flippase. Additionally, several proteins were predicted to function as membrane transporters. The results of this work, combined with our previous analyses, reveal an unexpected diversity of putative archaeal membrane-associated functional systems that remain to be functionally characterized. A more general conclusion from this work is that the currently available collection of archaeal (and bacterial) genomes could be sufficient to identify (almost) all widespread functional modules and develop experimentally testable predictions of their functions. (C) Published by Elsevier B.V. C1 [Makarova, Kira S.; Galperin, Michael Y.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Makarova, KS (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM makarova@ncbi.nlm.nih.gov FU NIH Intramural Research Program at the National Library of Medicine, US Department of Health and Human Services FX We thank Yuri Wolf for providing Perl scripts for genomic neighborhood analysis and other help. KSM, MYG and EVK are supported by the NIH Intramural Research Program at the National Library of Medicine, US Department of Health and Human Services. NR 81 TC 0 Z9 0 U1 3 U2 10 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 EI 1638-6183 J9 BIOCHIMIE JI Biochimie PD NOV PY 2015 VL 118 BP 302 EP 312 DI 10.1016/j.biochi.2015.01.004 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW5UN UT WOS:000365062200035 PM 25583072 ER PT J AU Peng, L Chen, XY AF Peng, Li Chen, Xiaoyuan TI Antibody-Drug Conjugates SO BIOCONJUGATE CHEMISTRY LA English DT Editorial Material C1 [Peng, Li] Medlmmune LLC, Antibody Discovery & Prot Engn, Gaithersburg, MD 20878 USA. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Peng, L (reprint author), Medlmmune LLC, Antibody Discovery & Prot Engn, One MedImmune Way, Gaithersburg, MD 20878 USA. EM pengl@medimmune.com; shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-07] NR 0 TC 1 Z9 1 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD NOV PY 2015 VL 26 IS 11 SI SI BP 2169 EP 2169 DI 10.1021/acs.bioconjchem.5b00515 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CW6ZX UT WOS:000365148700001 PM 26577284 ER PT J AU Qasba, PK AF Qasba, Pradman K. TI Glycans of Antibodies as a Specific Site for Drug Conjugation Using Glycosyltransferases SO BIOCONJUGATE CHEMISTRY LA English DT Review ID MUTANT GLYCOSYLTRANSFERASES; OLIGOSACCHARIDE MOIETIES; N-GLYCANS; BIOCONJUGATION; BIOMOLECULES; CHEMISTRY; RESIDUES; IMMUNOGLOBULINS; CYCLOADDITIONS; IDENTIFICATION AB The therapeutic cargo molecules conjugated to a specific site on a monoclonal antibody (mAb), called antibody drug conjugates (ADCs), are becoming powerful tools in cancer treatment. Generally, the cargo molecules conjugate at the cysteine or lysine residue of the mAb, which generally results in a highly heterogeneous ADC. Therapeutic cargo molecules need to be conjugated in a site-specific manner to the mAb so that the bioefficacy of these molecules is not compromised. The mAb (IgG1) are N-glycosylated at the conserved residue Asn(297), which is present in each heavy chain of the IgG1, near the CH2 domain of the Fc fragment. The mutant or wild-type glycosyltransferases transfer sugars with a chemical handle to the glycan molecule of IgG1, making the site-specific linking of cargo molecules possible via the chemical handle, and thus making the process an invaluable technique for the production of homogeneous ADCs. C1 [Qasba, Pradman K.] NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM qasbapr@helix.nih.gov FU National Cancer Institute, National Institutes of Health [BRL OOTC PID 001.015.0002.0001] FX The author thanks Ms. Ashley De Vine and Ms. Nancy Parish, Scientific Publications, Graphics & Media department at NCI-Frederick for editing the manuscript, which was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract BRL OOTC PID 001.015.0002.0001. The author also thanks all the coworkers who have contributed to this technology in particular Drs. Boopathy Ramakrishnan, Elizabeth Boeggeman, Martha Pasek and Natalia Mercer. NR 39 TC 5 Z9 5 U1 5 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD NOV PY 2015 VL 26 IS 11 SI SI BP 2170 EP 2175 DI 10.1021/acs.bioconjchem.5b00173 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CW6ZX UT WOS:000365148700002 PM 26065635 ER PT J AU Zhu, GZ Niu, G Chen, XY AF Zhu, Guizhi Niu, Gang Chen, Xiaoyuan TI Aptamer-Drug Conjugates SO BIOCONJUGATE CHEMISTRY LA English DT Review ID IN-VITRO SELECTION; PHOTODYNAMIC CANCER-THERAPY; NUCLEIC-ACID APTAMERS; STRANDED-DNA APTAMER; NEAR-INFRARED LIGHT; NF-KAPPA-B; RNA APTAMER; PHOTOTHERMAL THERAPY; TARGETED DELIVERY; LIVE CELLS AB Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited selectivity and the consequent "off-target" side effects. Targeted therapy aims to enhance the selectivity of therapeutic effects and reduce adverse side effects. One approach toward this goal is to utilize disease-specific ligands to guide the delivery of less-specific therapeutics, such that the therapeutic effects can be guided specifically to diseased tissues or organs. Among these ligands, aptamers, also known as chemical antibodies, have emerged over the past decades as a novel class of targeting ligands that are capable of specific binding to disease biomarkers. Compared with other types of targeting ligands, aptamers have an array of unique advantageous features, which make them promising for developing aptamer drug conjugates (ApDCs) for targeted therapy. In this Review, we will discuss ApDCs for targeted drug delivery in chemotherapy, gene therapy, immunotherapy, photodynamic therapy, and photothermal therapy, primarily of cancer. C1 [Zhu, Guizhi; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-06] NR 144 TC 17 Z9 17 U1 17 U2 72 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD NOV PY 2015 VL 26 IS 11 SI SI BP 2186 EP 2197 DI 10.1021/acs.bioconjchem.5b00291 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CW6ZX UT WOS:000365148700004 PM 26083153 ER PT J AU Lawler, M Siu, LL Rehm, HL Chanock, SJ Alterovitz, G Burn, J Calvo, F Lacombe, D Teh, BT North, KN Sawyers, CL AF Lawler, Mark Siu, Lillian L. Rehm, Heidi L. Chanock, Stephen J. Alterovitz, Gil Burn, John Calvo, Fabien Lacombe, Denis Teh, Bin Tean North, Kathryn N. Sawyers, Charles L. CA Global Alliance Genomics Hlth GA4G TI All the World's a Stage: Facilitating Discovery Science and Improved Cancer Care through the Global Alliance for Genomics and Health SO CANCER DISCOVERY LA English DT Editorial Material AB The recent explosion of genetic and clinical data generated from tumor genome analysis presents an unparalleled opportunity to enhance our understanding of cancer, but this opportunity is compromised by the reluctance of many in the scientific community to share datasets and the lack of interoperability between different data platforms. The Global Alliance for Genomics and Health is addressing these barriers and challenges through a cooperative framework that encourages "team science" and responsible data sharing, complemented by the development of a series of application program interfaces that link different data platforms, thus breaking down traditional silos and liberating the data to enable new discoveries and ultimately benefit patients. (C)2015 AACR. C1 [Lawler, Mark] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland. [Siu, Lillian L.] Univ Hlth Network, Toronto, ON, Canada. [Rehm, Heidi L.; Alterovitz, Gil] Harvard Univ, Sch Med, Boston, MA USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Washington, DC USA. [Burn, John] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Calvo, Fabien] Canc Core Europe, Villejuif, France. [Calvo, Fabien] Inst Gustave Roussy, Villejuif, France. [Lacombe, Denis] European Org Res Treatment Canc, Brussels, Belgium. [Teh, Bin Tean] Natl Canc Ctr Singapore, Singapore, Singapore. [North, Kathryn N.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Lawler, M (reprint author), Queens Univ Belfast, Ctr Canc Res & Cell Biol, CCRCB, Lisburn Rd 97, Belfast BT9 7AE, Antrim, North Ireland. EM mark.lawler@qub.ac.uk RI Sawyers, Charles/G-5327-2016; North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Burn, John/0000-0002-9823-2322 NR 17 TC 7 Z9 7 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD NOV PY 2015 VL 5 IS 11 BP 1133 EP 1136 DI 10.1158/2159-8290.CD-15-0821 PG 4 WC Oncology SC Oncology GA CX3KJ UT WOS:000365597400021 PM 26526696 ER PT J AU Bluemke, DA AF Bluemke, David A. TI Progress in the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia by Cardiac Magnetic Resonance Imaging Using Feature Tracking SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE Editorials; arrhythmogenic right ventricular cardiomyopathy; cardiac arrhythmias; dilatation; echocardiography magnetic resonance imaging C1 [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD 21287 USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, 10 Ctr Dr, Bethesda, MD 21287 USA. EM david.bluemke@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-06, ZIA EB000072-06] NR 10 TC 0 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD NOV PY 2015 VL 8 IS 11 AR e004167 DI 10.1161/CIRCIMAGING.115.004167 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CW6WU UT WOS:000365139900001 PM 26534933 ER PT J AU Thomas, C Avram, A Pierpaoli, C Baker, C AF Thomas, Cibu Avram, Alexandru Pierpaoli, Carlo Baker, Chris TI Diffusion MRI properties of the human uncinate fasciculus correlate with the ability to learn visual associations SO CORTEX LA English DT Article DE Uncinate fasciculus; Diffusion MRI; Tractography ID INFERIOR TEMPORAL CORTEX; ORBITAL PREFRONTAL CORTEX; CEREBRAL WHITE-MATTER; RHESUS-MONKEY; FRONTAL-CORTEX; LOBE EPILEPSY; NEURAL FRAMEWORK; FIBER TRACKING; HUMAN BRAIN; TRACTOGRAPHY AB The uncinate fasciculus (UF) is a cortico-cortico white matter pathway that links the anterior temporal and the orbitofrontal cortex (OFC). In the monkey, transection of the UP causes significant impairments in learning conditional visual visual associations, while object discrimination remains intact, suggesting an important role for the UP in mediating the learning of complex visual associations. Whether this functional role extends to the human UP has not been tested directly. Here, we used diffusion tensor magnetic resonance imaging (dMRI) and behavioral experiments to examine the relation between learning visual associations and the structural properties of the human UF. In a group of healthy adults, we segmented the UP and the inferior longitudinal fasciculus (ILF) and derived dMRI measures of the structural properties of the two pathways. We also used a behavioral experiment adapted from the monkey studies to characterize the ability of these individuals to learn to associate a person's face with a group of specific scenes (conditional visual visual association). We then tested whether the variability in the dMRI measures of the two pathways correlated with variability in the ability to rapidly learn the face place associations. Our study suggests that in the human, the left UF may be important for mediating the rapid learning of conditional visual visual associations whereas the right UP may play an important role in the immediate retrieval of visual-visual associations. These results provide preliminary evidence suggesting similarities and differences in the functional role of the UP in monkeys compared to humans. The findings presented here contribute to our understanding of the functional role of the UF in humans and the functional neuroanatomy of the brain networks involved in visual cognition. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Thomas, Cibu; Avram, Alexandru; Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Pediat Imaging & Tissue Sci, Bethesda, MD USA. [Thomas, Cibu] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Thomas, Cibu; Baker, Chris] NIMH, Sect Learning & Plast, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Thomas, C (reprint author), NIH, Room 3W16,13 South Dr, Bethesda, MD 20814 USA. EM thomascp@mail.nih.gov OI Baker, Chris/0000-0001-6861-8964 FU Intramural Research Programs of NICHD; NIMH [MH002909-07]; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX This work was supported by Intramural Research Programs of NICHD and NIMH (Grant Number MH002909-07). Salary support for CT was provided by funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine. We thank Dr. Joelle Sarlls for assistance with the diffusion MRI sequence design. NR 82 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD NOV PY 2015 VL 72 SI SI BP 65 EP 78 DI 10.1016/j.cortex.2015.01.023 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CW5SQ UT WOS:000365057300007 PM 25742710 ER PT J AU Simanek, AM Meier, HCS AF Simanek, Amanda M. Meier, Helen C. S. TI Association Between Prenatal Exposure to Maternal Infection and Offspring Mood Disorders: A Review of the Literature SO CURRENT PROBLEMS IN PEDIATRIC AND ADOLESCENT HEALTH CARE LA English DT Article ID TOXOPLASMA-GONDII INFECTION; HERPES-SIMPLEX-VIRUS; MAJOR AFFECTIVE-DISORDER; COMORBIDITY SURVEY REPLICATION; DEPRESSION-RELATED BEHAVIORS; GRAY-MATTER VOLUME; BIPOLAR DISORDER; UNITED-STATES; IMMUNE ACTIVATION; NERVOUS-SYSTEM AB The purpose of this article is to provide a systematic review of studies that have examined the association between prenatal exposure to maternal infection and development of mood disorders across the life course. Drawing from both human- and animal-based studies, we give an overview of hypothesized biological mechanisms by which exposure to maternal infection during critical periods of gestation may contribute to fetal programming of mood disorders in offspring. We discuss studies examining the association between prenatal exposure to maternal infection with pathogens including influenza as well as other respiratory viruses, herpesviruses, hepatitis viruses, and Toxoplasma gondii and mood disorders in human populations. Moreover, we outline strengths and limitations of the current body of evidence and make recommendations for future research. We also discuss findings in the context of well-documented gender and socioeconomic disparities in the prevalence and severity of mood disorders, particularly major depression, and the role that early exposure to infection may play in explaining the perpetuation of such disparities across generations. Overall, this review of the current knowledge on this topic has important implications for determining future research directions, designing interventions as well as prenatal care guidelines targeted at prevention or treatment of infection during pregnancy, and clinical practice for the identification of individuals that may be at increased risk for mood disorders beginning early in life. Importantly, such efforts may not only lower the overall burden of mood disorders but also serve to address social disparities in these adverse mental health conditions in the U.S. C1 [Simanek, Amanda M.] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. [Meier, Helen C. S.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Simanek, AM (reprint author), Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. FU National Institutes of Health, United States; National Institute of Environmental Health Sciences, United States FX H.C.S.M was supported by the intramural research program of the National Institutes of Health, United States and National Institute of Environmental Health Sciences, United States. NR 162 TC 6 Z9 6 U1 10 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-5442 EI 1538-3199 J9 CURR PROB PEDIATR AD JI Curr. Probl. Pediatr. Adolesc. Health Care PD NOV PY 2015 VL 45 IS 11 BP 325 EP 364 DI 10.1016/j.cppeds.2015.06.008 PG 40 WC Pediatrics SC Pediatrics GA CW4TU UT WOS:000364985800002 PM 26476880 ER PT J AU Cung, W Freedman, LA Khan, NE Romberg, E Gardner, PJ Bassim, CW Baldwin, AM Widemann, BC Stewart, DR AF Cung, Winnie Freedman, Laura A. Khan, Nicholas E. Romberg, Elaine Gardner, Pamela J. Bassim, Carol W. Baldwin, Andrea M. Widemann, Brigitte C. Stewart, Douglas R. TI Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the "NF1 facies" SO EUROPEAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Neurofibromatosis type 1; Cephalometery; Dysmorphology; Sphenoid wing dysplasia ID CRANIAL BASE; GROWTH; ABNORMALITIES AB Background: Neurofibromatosis type 1 (NF1) is a common, autosomal dominant tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Cephalometry is an inexpensive, readily available and non-invasive technique that is under-utilized in studying the NF1 craniofacial phenotype. An analysis of NF1 cephalometry was first published by Heerva et al. in 2011. We expand here on that first investigation with a larger cohort of adult and pediatric patients affected with NF1 and sought objective insight into the NF1 facies, said to feature hypertelorism and a broad nasal base, from cephalometric analysis. Methods: We obtained cephalograms from 101 patients with NF1 (78 adults and 23 children) from two NF1 protocols at the National Institutes of Health. Each subject had an age-, gender- and ethnicity-matched control. We used Dolphin software to make the cephalometric measurements. We assessed the normality of differences between paired samples using the Shapiro-Wilk test and evaluated the significance of mean differences using paired t-tests and adjusted for multiple testing. We explored the relationship between the cephalometric measurements and height, head circumference and interpupillary distance. Results: In this dataset of American whites with NF1, we confirmed in a modestly larger sample many of the findings found by Heerva et al. in an NF1 Finnish cohort. We found a shorter maxilla, mandible, cranial base, (especially anteriorly, p = 0.0001) and diminished facial height in adults, but not children, with NF1. Only one adult exhibited hypertelorism. Conclusions: The cephalometric differences in adults arise in part from cranial base shortening and thus result in a shorter face, mid-face hypoplasia, reduced facial projection, smaller jaw, and increased braincase globularity. In addition, we suggest that NF1 sphenoid bone shortening, a common event, is consistent with an intrinsic NF1 bone cell defect, which renders the bone more vulnerable to a random "second hit" in NF1, leading to sphenoid wing dysplasia, a rare event. Published by Elsevier Masson SAS. C1 [Cung, Winnie; Freedman, Laura A.; Romberg, Elaine] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. [Khan, Nicholas E.; Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Gardner, Pamela J.; Bassim, Carol W.] Natl Inst Dent & Craniofacial Res, Dent Consult Serv, NIH, Bethesda, MD USA. [Baldwin, Andrea M.; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Stewart, DR (reprint author), 9609 Med Ctr Dr Rm 6E450, Bethesda, MD 20892 USA. EM drstewart@mail.nih.gov FU Division of Cancer Epidemiology and Genetics (DCEG); Center for Cancer Research of the National Cancer Institute's Intramural Research Program FX This work was supported by the Division of Cancer Epidemiology and Genetics (DCEG) and the Center for Cancer Research of the National Cancer Institute's Intramural Research Program. We thank Janice Lee DDS, MD (NIDCR) for helpful discussions. NR 24 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1769-7212 EI 1878-0849 J9 EUR J MED GENET JI Eur. J. Med. Genet. PD NOV PY 2015 VL 58 IS 11 BP 584 EP 590 DI 10.1016/j.ejmg.2015.09.001 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CW9WP UT WOS:000365349200004 PM 26360873 ER PT J AU Elentner, A Ortner, D Clausen, BE Gonzalez, FJ Fernandez-Salguero, PM Schmuth, M Dubrac, S AF Elentner, Andreas Ortner, Daniela Clausen, Bjoern E. Gonzalez, Frank J. Fernandez-Salguero, Pedro M. Schmuth, Matthias Dubrac, Sandrine TI Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE DNA damage; H2AX; Langerhans cells; pregnane X receptor; skin ID POLYCYCLIC AROMATIC-HYDROCARBONS; SQUAMOUS-CELL CARCINOMA; IN-VITRO ALTERNATIVES; LANGERHANS CELLS; CONTACT HYPERSENSITIVITY; METABOLISM CAPACITIES; CHEMICAL CARCINOGENS; NUCLEAR RECEPTORS; HAIR FOLLICLE; DNA-DAMAGE AB Skin is in daily contact with potentially harmful molecules from the environment such as cigarette smoke, automobile emissions, industrial soot and groundwater. Pregnane X receptor (PXR) is a transcription factor expressed in liver and intestine that is activated by xenobiotic chemicals including drugs and environmental pollutants. Topical application of the tumor initiator 7,12-dimethylbenz(a)anthracene (DMBA) enhances Pxr, Cyp1a1, Cyp1b1 and Cyp3a11, but not Ahr expression in the skin. Surprisingly, DMBA-induced Pxr upregulation is largely impaired in Langerin(+) cell-depleted skin, suggesting that DMBA mainly triggers Pxr in Langerin(+) cells. Furthermore, PXR deficiency protects from DNA damage in epidermal cells but to a lesser extent than aryl hydrocarbon receptor (AHR) deficiency. Interestingly, skin exposure to low doses of DMBA induces migration of PXR-deficient but not of wild-type and AHR-deficient Langerhans cells (LCs). PXR-humanized mice show a marked increase in DNA damage to epidermal cells after topical application of DMBA, demonstrating relevance of these findings in human tissue. This is the first report suggesting that carcinogens might trigger PXR in epidermal cells, particularly in LCs, thus leading to DNA damage. Further studies are required to better delineate the role of PXR in cutaneous carcinogenesis. C1 [Elentner, Andreas; Ortner, Daniela; Schmuth, Matthias; Dubrac, Sandrine] Med Univ Innsbruck, Dept Dermatol & Venereol, A-6020 Innsbruck, Austria. [Clausen, Bjoern E.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Mol Med, D-55122 Mainz, Germany. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fernandez-Salguero, Pedro M.] Univ Extremadura, Fac Sci, Dept Biochem Mol Biol & Genet, Badajoz, Spain. RP Dubrac, S (reprint author), Med Univ Innsbruck, Dept Dermatol & Venereol, A-6020 Innsbruck, Austria. EM sandrine.dubrac@i-med.ac.at RI CLAUSEN, Bjorn/A-8229-2010; OI CLAUSEN, Bjorn/0000-0002-2484-7842; Fernandez-Salguero, Pedro M./0000-0003-2839-5027 FU Austrian Science Fund [FWF P-21449] FX This work was supported by a grant from the Austrian Science Fund to S.D. (FWF P-21449). AE, DO and SD performed assays; BC, FJG and PMF contributed essential mouse strains and participated in paper writing, MS and SD designed the research study, analysed the data and wrote the paper. NR 47 TC 4 Z9 4 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD NOV PY 2015 VL 24 IS 11 BP 835 EP 840 DI 10.1111/exd.12766 PG 6 WC Dermatology SC Dermatology GA CX0RL UT WOS:000365404300006 PM 26013842 ER PT J AU Almeida-Suhett, CP Prager, EM Pidoplichko, V Figueiredo, TH Marini, AM Li, Z Eiden, LE Braga, MFM AF Almeida-Suhett, Camila P. Prager, Eric M. Pidoplichko, Volodymyr Figueiredo, Taiza H. Marini, Ann M. Li, Zheng Eiden, Lee E. Braga, Maria F. M. TI GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CM region after mild traumatic brain injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Mild traumatic brain injury; CA1; Synaptic transmission; Controlled cortical impact; Cognitive impairment ID LONG-TERM POTENTIATION; CLOSED-HEAD-INJURY; PROFESSIONAL FOOTBALL PLAYERS; CONTROLLED CORTICAL IMPACT; FLUID PERCUSSION INJURY; GABA(A) RECEPTOR; COGNITIVE DEFICITS; RETROGRADE-AMNESIA; MEMORY IMPAIRMENT; NMDA RECEPTOR AB Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region. We investigated whether mTBI induces morphological and pathophysiological alterations in the CA1 using the controlled cortical impact (CCI) model. Seven days after CCI, animals subjected to mTBI showed cognitive impairment in the passive avoidance test and deficits to long-term potentiation (LTP) of synaptic transmission. Deficiencies in inducing or maintaining LTP were likely due to an observed reduction in the activation of NMDA but not AMPA receptors. Significant reductions in the frequency and amplitude of spontaneous and miniature GABA(A)-receptor mediated inhibitory postsynaptic currents (IPSCs) were also observed 7 days after CCI. Design-based stereology revealed that although the total number of neurons was unaltered, the number of GABAergic interneurons is significantly reduced in the CA1 region 7 days after CCI. Additionally, the surface expression of alpha 1, beta 2/3, and gamma 2 subunits of the GABA(A) receptor were reduced, contributing to a reduced mIPSC frequency and amplitude, respectively. Together, these results suggest that mTBI causes a significant reduction in GABAergic inhibitory transmission and deficits to NMDA receptor mediated currents in the CA1, which may contribute to changes in hippocampal excitability and subsequent cognitive impairments after mTBI. Published by Elsevier Inc. C1 [Almeida-Suhett, Camila P.; Prager, Eric M.; Marini, Ann M.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Program Neurosci, Bethesda, MD 20814 USA. [Pidoplichko, Volodymyr; Figueiredo, Taiza H.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Marini, Ann M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Neurol, Bethesda, MD 20814 USA. [Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Psychiat, Bethesda, MD 20814 USA. [Almeida-Suhett, Camila P.; Marini, Ann M.; Li, Zheng; Eiden, Lee E.; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Li, Zheng] NIMH, Sect Clin Studies, Intramural Res Program, Bethesda, MD 20892 USA. [Eiden, Lee E.] NIMH, Sect Mol Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Braga, MFM (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Psychiat, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM camila.almeida.ctr@usuhs.edu; eprager@wiley.com; volodymyr.pidoplichko.ctr@usuhs.edu; taiza.figueiredo.ctr@usuhs.edu; ann.marini@usuhs.edu; Lizheng2@mail.nih.gov; eidenl@mail.nih.gov; maria.braga@usuhs.edu FU Department of Defense in the Center for Neuroscience and Regenerative Medicine [G1702Z] FX The authors acknowledge the Department of Defense in the Center for Neuroscience and Regenerative Medicine for financially supporting the present work. Grant# G1702Z. URL of funder's website: http://www.usuhs.mil/cnrm/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 135 TC 10 Z9 10 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2015 VL 273 BP 11 EP 23 DI 10.1016/j.expneurol.2015.07.028 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CW7BB UT WOS:000365151800002 PM 26238734 ER PT J AU Eitan, E Hutchison, ER Greig, NH Tweedie, D Celik, H Ghosh, S Fishbein, KW Spencer, RG Sasaki, CY Ghosh, P Das, S Chigurapati, S Raymick, J Sarkar, S Chigurupati, S Seal, S Mattson, MP AF Eitan, Erez Hutchison, Emmette R. Greig, Nigel H. Tweedie, David Celik, Hasan Ghosh, Soumita Fishbein, Kenneth W. Spencer, Richard G. Sasaki, Carl Y. Ghosh, Paritosh Das, Soumen Chigurapati, Susheela Raymick, James Sarkar, Sumit Chigurupati, Srinivasulu Seal, Sudipta Mattson, Mark P. TI Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Cerebral ventricles; Cerium oxide nanoparticles; Demyelination; EAE; Multiple sclerosis ID CERIUM OXIDE NANOPARTICLES; PROGRESSIVE MULTIPLE-SCLEROSIS; GLATIRAMER ACETATE; MOUSE MODEL; THALIDOMIDE; ENCEPHALOMYELITIS; MECHANISM; DISEASE; NEURODEGENERATION; DEMYELINATION AB Objective: Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods: C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of the four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. Results: Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. Interpretation: By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. Published by Elsevier Inc. C1 [Eitan, Erez; Hutchison, Emmette R.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Greig, Nigel H.; Tweedie, David] NIA, Translat Gerontol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Celik, Hasan; Ghosh, Soumita; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. [Das, Soumen] Univ Cent Florida, Mat Sci & Engn Coll Med, Orlando, FL 32816 USA. [Sasaki, Carl Y.; Ghosh, Paritosh] NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Chigurapati, Susheela] US FDA, Arkansas Reg Lab, Off Regulatory Affairs, Jefferson, AR 72079 USA. [Raymick, James; Sarkar, Sumit; Chigurupati, Srinivasulu] US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Seal, Sudipta] Univ Cent Florida, Mech Mat Aerosp Engn, Nanosci Technol Ctr, Adv Mat Proc & Anal Ctr, Orlando, FL 32816 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 41 TC 4 Z9 4 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2015 VL 273 BP 151 EP 160 DI 10.1016/j.expneurol.2015.08.008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CW7BB UT WOS:000365151800014 PM 26277686 ER PT J AU Azoury, SC Aufforth, R He, M Yang, ZM Nilubol, N Kebebew, E AF Azoury, Said C. Aufforth, Rachel He, Mei Yang, Zhiming Nilubol, Naris Kebebew, Electron TI Quantitative reverse transcription polymerase chain reaction-based detection of thyroid-specific gene expression in fine-needle aspirate for thyroid cancer recurrence evaluation: A case report and review of the literature SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE thyroid cancer; fine-needle aspirate; polymerase chain reaction (PCR); recurrence; diagnosis ID SODIUM-IODIDE SYMPORTER; CERVICAL LYMPH-NODES; MEDIAN FOLLOW-UP; SERUM THYROGLOBULIN; NECK ULTRASONOGRAPHY; CARCINOMA; PAPILLARY; DIAGNOSIS; MANAGEMENT; DISEASE AB Background. Despite improved surveillance for patients after total thyroidectomy for cancer, there has yet to be a diagnostic method that detects recurrence with 100% accuracy. Methods. A 60-year-old woman with a family history of papillary thyroid cancer (PTC) underwent total thyroidectomy and radioactive iodine ablation. On postoperative surveillance, ultrasound examination of the neck demonstrated a focus concerning for recurrence and a fine-needle aspirate (FNA) was performed. The cytology report was nondiagnostic and, hence, RNA was extracted from the specimen followed by reverse transcription (cDNA), and quantitative real-time polymerase chain reaction (qRT-PCR) to detect thyroid-specific gene expression (thyroglobulin = Tg; sodium-iodide symporter = NIS; thyroperoxidase = TPO). Results. Expression of select thyroid-specific genes was demonstrated, and given the patient's remarkable cancer and family history, surgical resection was elected. Final pathology demonstrated follicular adenoma. Conclusion. This case demonstrates a novel approach used in the evaluation for recurrent thyroid cancer as an adjunct to FNA cytology. (C) 2015 Wiley Periodicals, Inc. C1 [Azoury, Said C.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Azoury, Said C.] Johns Hopkins Univ, Johns Hopkins Hosp, Sch Med, Dept Surg, Baltimore, MD 21287 USA. [Aufforth, Rachel; He, Mei; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yang, Zhiming] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Azoury, SC (reprint author), Johns Hopkins Univ, Johns Hopkins Hosp, Sch Med, Dept Surg, 600 N Wolfe St,Blalock 658, Baltimore, MD 21287 USA. EM sazoury1@jhmi.edu NR 38 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD NOV PY 2015 VL 37 IS 11 BP E165 EP E168 DI 10.1002/hed.24054 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CX0SD UT WOS:000365406100008 PM 25784309 ER PT J AU Ferencik, M Liu, T Mayrhofer, T Puchner, SB Lu, MT Maurovich-Horvat, P Pope, JH Truong, QA Udelson, JE Peacock, WF White, CS Woodard, PK Fleg, JL Nagurney, JT Januzzi, JL Hoffmann, U AF Ferencik, Maros Liu, Ting Mayrhofer, Thomas Puchner, Stefan B. Lu, Michael T. Maurovich-Horvat, Pal Pope, J. Hector Truong, Quynh A. Udelson, James E. Peacock, W. Frank White, Charles S. Woodard, Pamela K. Fleg, Jerome L. Nagurney, John T. Januzzi, James L. Hoffmann, Udo TI hs-Troponin I Followed by CT Angiography Improves Acute Coronary Syndrome Risk Stratification Accuracy and Work-Up in Acute Chest Pain Patients Results From ROMICAT II Trial SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE acute coronary syndrome; coronary computed tomography angiography; coronary plaque; emergency department; highly sensitive troponin; risk stratification ID SENSITIVITY CARDIAC TROPONIN; ACUTE MYOCARDIAL-INFARCTION; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; EARLY-DIAGNOSIS; EMERGENCY-DEPARTMENT; SERIAL CHANGES; ASSAY; RULE; RECLASSIFICATION; ASSOCIATION AB OBJECTIVES This study compared diagnostic accuracy of conventional troponin/traditional coronary artery disease (CAD) assessment and highly sensitive troponin (hsTn) I/advanced CAD assessment for acute coronary syndrome (ACS) during the index hospitalization. BACKGROUND hsTnI and advanced assessment of CAD using coronary computed tomography angiography (CTA) are promising candidates to improve the accuracy of emergency department evaluation of patients with suspected ACS. METHODS We performed an observational cohort study in patients with suspected ACS enrolled in the ROMICAT II (Rule Out Myocardial Infarction/Ischemia using Computer Assisted Tomography) trial and randomized to coronary CTA who also had hsTnI measurement at the time of the emergency department presentation. We assessed coronary CTA for traditional (no CAD, nonobstructive CAD, >= 50% stenosis) and advanced features of CAD (>= 50% stenosis, high-risk plaque features: positive remodeling, low <30-Hounsfield units plaque, napkin-ring sign, spotty calcium). RESULTS Of 160 patients (mean age: 53 +/- 8 years, 40% women) 10.6% were diagnosed with ACS. The ACS rate in patients with hsTnI below the limit of detection (n = 9, 5.6%), intermediate (n = 139, 86.9%), and above the 99th percentile (n = 12, 7.5%) was 0%, 8.6%, and 58.3%, respectively. Absence of >= 50% stenosis and high-risk plaque ruled out ACS in patients with intermediate hsTnI (n = 87, 54.4%; ACS rate 0%), whereas patients with both >= 50% stenosis and high-risk plaque were at high risk (n = 13, 8.1%; ACS rate 69.2%) and patients with either >= 50% stenosis or high-risk plaque were at intermediate risk for ACS (n = 39, 24.4%; ACS rate 7.7%). hsTnI/advanced coronary CTA assessment significantly improved the diagnostic accuracy for ACS as compared to conventional troponin/traditional coronary CTA (area under the curve 0.84, 95% confidence interval [CI]: 0.80 to .88 vs. 0.74, 95% CI: 0.70 to 0.78; p < 0.001). CONCLUSIONS hsTnI at the time of presentation followed by early advanced coronary CTA assessment improves the risk stratification and diagnostic accuracy for ACS as compared to conventional troponin and traditional coronary CTA assessment. (C) 2015 by the American College of Cardiology Foundation. C1 [Ferencik, Maros] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97239 USA. [Ferencik, Maros; Liu, Ting; Mayrhofer, Thomas; Puchner, Stefan B.; Lu, Michael T.; Truong, Quynh A.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ferencik, Maros; Liu, Ting; Mayrhofer, Thomas; Puchner, Stefan B.; Lu, Michael T.; Truong, Quynh A.; Nagurney, John T.; Januzzi, James L.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Ferencik, Maros; Liu, Ting; Mayrhofer, Thomas; Puchner, Stefan B.; Lu, Michael T.; Truong, Quynh A.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Liu, Ting] China Med Univ, Dept Radiol, Affiliated Hosp 1, Shenyang 110001, Peoples R China. [Puchner, Stefan B.] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Maurovich-Horvat, Pal] Semmelweis Univ, Heart & Vasc Ctr, TA SE Lendulet Cardiovasc Imaging Res Grp, H-1085 Budapest, Hungary. [Pope, J. Hector] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Truong, Quynh A.] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY USA. [Truong, Quynh A.] Weill Cornell Med Coll, New York, NY USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Houston, TX 77030 USA. [White, Charles S.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Januzzi, James L.; Hoffmann, Udo] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Ferencik, M (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3180 Sam Jackson Pk Rd,Mail Code UHN62, Portland, OR 97239 USA. EM ferencik@ohsu.edu FU National Institutes of Health, ACRIN [NIH U01HL092040, U01HL092022]; American Heart Association [13FTF16450001]; NIH/NHLBI [K23HL098370, L30HL093896]; St. Jude Medical; American College of Radiology Imaging Network; Duke Clinical Research; Abbott; Alere; Banyan; Cardiorentis; Portola; Roche; Medicines Company; Siemens; Thermo Fisher; Singulex; NIH [U01HL092022, U01HL092040]; Siemens Medical Solutions; Heart Flow Inc.; Alere/Biosite; Brahms Ltd/Thermo-Fisher; Nanosphere FX The ROMICAT II trial is supported by the National Institutes of Health grant numbers NIH U01HL092040 and U01HL092022, ACRIN. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the views of the National Institutes of Health or the Department of Health and Human Services. Dr. Ferencik has received a research grant from the American Heart Association Fellow to Faculty Award 13FTF16450001. Dr. Truong has received research grants from NIH/NHLBI K23HL098370 and L30HL093896, St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research. Dr. Peacock has received research grants from Abbott, Alere, Banyan, Cardiorentis, Portola, Roche, and The Medicines Company; has ownership of Comprehensive Research Associates LLC and Emergencies in Medicine LLC; is a consultant with and on advisory boards for BG Medicine, Beckman, Boehringer-Ingelheim, Instrument Labs, Prevencio, The Medicines Company, ZS Pharma, Alere, Cardiorentis, and Janssen. Dr. Nagumey has received research grants from Alere/Biosite, Brahms Ltd/Thermo-Fisher, Nanosphere; is a consultant for and on advisory board at CardioDx. Dr. Januzzi received research grants from Siemens, Thermo Fisher, and Singulex; is a consultant with and on advisory board of Critical Diagnostics, Sphingotec, and Roche. Dr. Hoffmann received research grants from NIH U01HL092040, U01HL092022, Siemens Medical Solutions, Heart Flow Inc.; and is a consultant for and on advisory board of Heart Flow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ferencik and Liu contributed equally to this work. NR 26 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 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD NOV PY 2015 VL 8 IS 11 BP 1272 EP 1281 DI 10.1016/j.jcmg.2015.06.016 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CW7AS UT WOS:000365150900007 PM 26476506 ER PT J AU Guy, GP Berkowitz, Z Holman, DM Hartman, AM AF Guy, Gery P., Jr. Berkowitz, Zahava Holman, Dawn M. Hartman, Anne M. TI Recent Changes in the Prevalence of and Factors Associated With Frequency of Indoor Tanning Among US Adults SO JAMA DERMATOLOGY LA English DT Letter C1 [Guy, Gery P., Jr.; Berkowitz, Zahava; Holman, Dawn M.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA 30341 USA. [Hartman, Anne M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Guy, GP (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Hwy NE,Mail Stop F76, Atlanta, GA 30341 USA. EM irm2@cdc.gov FU Intramural CDC HHS [CC999999] NR 7 TC 12 Z9 12 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD NOV PY 2015 VL 151 IS 11 BP 1256 EP 1259 DI 10.1001/jamadermatol.2015.1568 PG 5 WC Dermatology SC Dermatology GA CW9GD UT WOS:000365305900024 PM 26131768 ER PT J AU Konc, J Miller, BT Stular, T Lesnik, S Woodcock, HL Brooks, BR Janezic, D AF Konc, Janez Miller, Benjamin T. Stular, Tanja Lesnik, Samo Woodcock, H. Lee Brooks, Bernard R. Janezic, Dusanka TI ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID GENERAL FORCE-FIELD; LOCAL-STRUCTURE ALIGNMENT; REPLICA-EXCHANGE METHOD; MOLECULAR-DYNAMICS; EXPLICIT SOLVENT; DOCKING SCREENS; USER-INTERFACE; DRUG DESIGN; SIMULATION; ALGORITHM AB Proteins often exist only as apo structures (unligated) in the Protein Data Bank, with their corresponding holo structures (with ligands) unavailable. However, apoproteins may not represent the amino-acid residue arrangement upon ligand binding well, which is especially problematic for molecular docking. We developed the ProBiS-CHARMMing web interface by connecting the ProBiS (http://probis.cmm.ki.si) and CHARMMing (http://www.charmining.org) web servers into one functional unit that enables prediction of protein-ligand complexes and allows for their geometry optimization and interaction energy calculation. The ProBiS web server predicts ligands (small compounds, proteins, nucleic acids, and single-atom ligands) that may bind to a query protein. This is achieved by comparing its surface structure against a nonredundant database of protein structures and finding those that have binding sites similar to that of the query protein. Existing ligands found in the similar binding sites are then transposed to the query according to predictions from ProBiS. The CHARMMing web server enables, among other things, minimization and potential energy calculation for a wide variety of biomolecular systems, and it is used here to optimize the geometry of the predicted protein ligand complex structures using the CHARMM force field and to calculate their interaction energies with the corresponding query proteins. We show how ProBiS-CHARMMing can be used to predict ligands and their poses for a particular binding site, and minimize the predicted protein ligand complexes to obtain representations of holoproteins. The ProBiS-CHA_RMMing web interface is freely available for academic users at http://probis. nih.gov. C1 [Konc, Janez; Lesnik, Samo] Natl Inst Chem, Lab Mol Modeling, SI-1000 Ljubljana, Slovenia. [Konc, Janez; Stular, Tanja; Janezic, Dusanka] Univ Primorska, Fac Math Nat Sci & Informat Technol, SI-6000 Koper, Slovenia. [Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Woodcock, H. Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. RP Janezic, D (reprint author), Univ Primorska, Fac Math Nat Sci & Informat Technol, Glagoljaska 8, SI-6000 Koper, Slovenia. EM dusanka.janezic@upr.si FU Slovenian Research Agency [P1-0002, J1-6743]; DOE [DE-SC0011297]; NSF [CHE-1464946]; National Heart, Lung, and Blood Institute, NIH FX The financial support through Grant Nos. P1-0002 and J1-6743 of the Slovenian Research Agency is acknowledged. J.K. acknowledges the Fulbright Scholarship at the National Heart, Lung, and Blood Institute, NIH. H.L.W. would like to acknowledge the DOE (No. DE-SC0011297) and NSF (No. CHE-1464946) for Funding. Support by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH, is also acknowledged. NR 42 TC 6 Z9 6 U1 2 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD NOV PY 2015 VL 55 IS 11 BP 2308 EP 2314 DI 10.1021/acs.jcim.5b00534 PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA CX1OL UT WOS:000365465400002 PM 26509288 ER PT J AU Briggs-Gowan, MJ Pollak, SD Grasso, D Voss, J Mian, ND Zobel, E McCarthy, KJ Wakschlag, LS Pine, DS AF Briggs-Gowan, Margaret J. Pollak, Seth D. Grasso, Damion Voss, Joel Mian, Nicholas D. Zobel, Elvira McCarthy, Kimberly J. Wakschlag, Lauren S. Pine, Daniel S. TI Attention bias and anxiety in young children exposed to family violence SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Attention bias; violence; harsh parenting; early childhood; anxiety; fear ID DIAGNOSTIC-OBSERVATION-SCHEDULE; PRESCHOOL DISRUPTIVE BEHAVIOR; CONFLICT-TACTICS-SCALES; MALTREATED CHILDREN; PSYCHOMETRIC DATA; DISORDERS; SYMPTOMS; STRESS; THREAT; PSYCHOPATHOLOGY AB Background: Attention bias toward threat is associated with anxiety in older youth and adults and has been linked with violence exposure. Attention bias may moderate the relationship between violence exposure and anxiety in young children. Capitalizing on measurement advances, this study examines these relationships at a younger age than previously possible. Methods: Young children (mean age 4.7, +/- 0.8) from a cross-sectional sample oversampled for violence exposure (N = 218) completed the dot-probe task to assess their attention biases. Observed fear/anxiety was characterized with a novel observational paradigm, the Anxiety Dimensional Observation Scale. Mother-reported symptoms were assessed with the Preschool Age Psychiatric Assessment and Trauma Symptom Checklist for Young Children. Violence exposure was characterized with dimensional scores reflecting probability of membership in two classes derived via latent class analysis from the Conflict Tactics Scales: Abuse and Harsh Parenting. Results: Family violence predicted greater child anxiety and trauma symptoms. Attention bias moderated the relationship between violence and anxiety. Conclusions: Attention bias toward threat may strengthen the effects of family violence on the development of anxiety, with potentially cascading effects across childhood. Such associations may be most readily detected when using observational measures of childhood anxiety. C1 [Briggs-Gowan, Margaret J.; Grasso, Damion; McCarthy, Kimberly J.] Univ Connecticut, Sch Med, Dept Psychiat, Farmington, CT 06030 USA. [Pollak, Seth D.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Pollak, Seth D.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Voss, Joel; Zobel, Elvira; Wakschlag, Lauren S.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Mian, Nicholas D.] Boston Univ, Dept Psychol, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. [Wakschlag, Lauren S.] Northwestern Univ, Inst Policy Res, Chicago, IL 60611 USA. [Pine, Daniel S.] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. RP Briggs-Gowan, MJ (reprint author), Univ Connecticut, Ctr Hlth, Dept Psychiat, 263 Farmington Ave,MC-1410, Farmington, CT 06030 USA. EM mbriggsgowan@uchc.edu FU National Institute of Mental Health [U01MH090301, R01MH082830] FX Financial support for the study was provided by grants from the National Institute of Mental Health (U01MH090301; R01MH082830). The authors thank Jackie Kestler and Kimberly McCarthy for their hard work and dedication to supporting this study. The authors have declared that they have no competing or potential conflicts of interest. NR 37 TC 6 Z9 6 U1 10 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD NOV PY 2015 VL 56 IS 11 BP 1194 EP 1201 DI 10.1111/jcpp.12397 PG 8 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA CX0UA UT WOS:000365411200007 PM 26716142 ER PT J AU Schwartz, AV Chen, HY Ambrosius, WT Sood, A Josse, RG Bonds, DE Schnall, AM Vittinghoff, E Bauer, DC Banerji, MA Cohen, RM Hamilton, BP Isakova, T Sellmeyer, DE Simmons, DL Shibli-Rahhal, A Williamson, JD Margolis, KL AF Schwartz, Ann V. Chen, Haiying Ambrosius, Walter T. Sood, Ajay Josse, Robert G. Bonds, Denise E. Schnall, Adrian M. Vittinghoff, Eric Bauer, Douglas C. Banerji, Mary Ann Cohen, Robert M. Hamilton, Bruce P. Isakova, Tamara Sellmeyer, Deborah E. Simmons, Debra L. Shibli-Rahhal, Amal Williamson, Jeff D. Margolis, Karen L. TI Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; IMPAIRED GLUCOSE-TOLERANCE; MINERAL DENSITY; POSTMENOPAUSAL WOMEN; DIABETES-MELLITUS; ROSIGLITAZONE; PIOGLITAZONE; RISK; THIAZOLIDINEDIONES; METAANALYSIS AB Context: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown. Objective: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men. Design: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2-4 months at clinic visits, were modeled as timevarying covariates in proportional hazards models for occurrence of first non-spine fracture. Participants: We studied a total of 6865 participants in ACCORD BONE. Main Outcome Measures: Main outcome measures were centrally adjudicated non-spine fracture. Results: Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1-2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or > 2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1-2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men. Conclusions: TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated. C1 [Schwartz, Ann V.; Vittinghoff, Eric; Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chen, Haiying; Ambrosius, Walter T.; Williamson, Jeff D.] Wake Forest Sch Med, Winston Salem, NC 27157 USA. [Sood, Ajay] Louis Stokes VA Med Ctr, Cleveland, OH 44106 USA. [Sood, Ajay; Schnall, Adrian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Josse, Robert G.] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Bonds, Denise E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Banerji, Mary Ann] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Banerji, Mary Ann] Kings Cty Hosp, Brooklyn, NY 11203 USA. [Cohen, Robert M.] Univ Cincinnati, Coll Med, Cincinnati, OH 45267 USA. [Hamilton, Bruce P.] VA Med Ctr, Baltimore, MD 21201 USA. [Hamilton, Bruce P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Isakova, Tamara] Univ Miami, Miami, FL 33124 USA. [Sellmeyer, Deborah E.] Johns Hopkins Sch Med, Div Endocrinol, Baltimore, MD 21205 USA. [Simmons, Debra L.] Univ Utah, Salt Lake City, UT 84148 USA. [Simmons, Debra L.] Salt Lake City Vet Hosp, Salt Lake City, UT 84148 USA. [Shibli-Rahhal, Amal] Univ Iowa, Carver Coll Med, Iowa City, IA 52242 USA. [Margolis, Karen L.] Hlth Partners Inst Educ & Res, Minneapolis, MN 55425 USA. RP Schwartz, AV (reprint author), Univ Calif San Francisco, Mission Hall,550 16th St,Second Floor, San Francisco, CA 94158 USA. EM aschwartz@psg.ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01DK069514]; National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01- HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01- HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, National Institute on Aging; National Institutes of Health, National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers FX The ACCORD BONE ancillary study was funded by a grant (R01DK069514) from the National Institute of Diabetes and Digestive and Kidney Diseases. The ACCORD study was supported by grants (N01-HC-95178, N01-HC-95179, N01- HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01- HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough. NR 27 TC 6 Z9 7 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2015 VL 100 IS 11 BP 4059 EP 4066 DI 10.1210/jc.2015-1215 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW3XM UT WOS:000364925700033 PM 26305617 ER PT J AU Zarek, SM Mitchell, EM Sjaarda, LA Mumford, SL Silver, RM Stanford, JB Galai, N White, MV Schliep, KC DeCherney, AH Schisterman, EF AF Zarek, Shvetha M. Mitchell, Emily M. Sjaarda, Lindsey A. Mumford, Sunni L. Silver, Robert M. Stanford, Joseph B. Galai, Noya White, Mark V. Schliep, Karen C. DeCherney, Alan H. Schisterman, Enrique F. TI Is Anti-Mullerian Hormone Associated With Fecundability? Findings From the EAGeR Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; REVISED 2003 CONSENSUS; ANTIMULLERIAN HORMONE; DIAGNOSTIC-CRITERIA; EUMENORRHEIC WOMEN; OOCYTE QUALITY; PREGNANCY; AGE; RESERVE; TIME AB Objective: The objective of the study was to evaluate whether anti-Mullerian hormone (AMH) is associated with fecundability among women with proven fecundity and a history of pregnancy loss. Design: This was a prospective cohort study within a multicenter, block-randomized, double-blind, placebo-controlled clinical trial (clinicaltrials.gov, number NCT00467363). Setting: The study was conducted at four US medical centers (2006-2012). Participants: Participating women were aged 18-40 years, with a history of one to two pregnancy losses who were actively attempting pregnancy. Main Outcome Measures: Time to human chorionic gonadotropin detected and clinical pregnancy were assessed using Cox proportional hazard regression models to estimate fecundability odds ratios (fecundability odds ratios with 95% confidence interval [CI]) adjusted for age, race, body mass index, income, low-dose aspirin treatment, parity, number of previous losses, and time since most recent loss. Analyses examined by preconception AMH levels: low (<1.00 ng/mL, n = 124); normal (referent 1.00-3.5 ng/mL, n = 595); and high (>3.5 ng/mL, n = 483). Results: Of the 1202 women with baseline AMH levels, 82 women with low AMH (66.1%) achieved an human chorionic gonadotropin detected pregnancy, compared with 383 with normal AMH (65.2%) and 315 with high AMH level (65.2%). Low or high AMH levels relative to normal AMH (referent) were not associated with fecundability (low AMH: fecundability odds ratios 1.13, 95% CI 0.85-1.49; high AMH: FOR 1.04, 95% CI 0.87-1.24). Conclusions: Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women. C1 [Zarek, Shvetha M.; Mitchell, Emily M.; Sjaarda, Lindsey A.; Mumford, Sunni L.; Schliep, Karen C.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20854 USA. [Zarek, Shvetha M.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20982 USA. [Silver, Robert M.; Stanford, Joseph B.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84111 USA. Intermt HealthCare, Salt Lake City, UT 84111 USA. [Galai, Noya] Univ Haifa, Dept Stat, IL-3498838 Haifa, Israel. [White, Mark V.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA 18509 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Executive Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contracts HHSN267200603423, HHSN267200603424, and HHSN267200603426). NR 43 TC 4 Z9 4 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2015 VL 100 IS 11 BP 4215 EP 4221 DI 10.1210/jc.2015-2474 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW3XM UT WOS:000364925700052 PM 26406293 ER PT J AU Shen, J Poole, JC Topel, ML Bidulescu, A Morris, AA Patel, RS Binongo, JG Dunbar, SB Phillips, L Vaccarino, V Gibbons, GH Quyyumi, AA AF Shen, Jia Poole, Joseph C. Topel, Matthew L. Bidulescu, Aurelian Morris, Alanna A. Patel, Riyaz S. Binongo, Jose G. Dunbar, Sandra B. Phillips, Lawrence Vaccarino, Viola Gibbons, Gary H. Quyyumi, Arshed A. TI Subclinical Vascular Dysfunction Associated with Metabolic Syndrome in African Americans and Whites SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ALL-CAUSE MORTALITY; ARTERIAL STIFFNESS; NITRIC-OXIDE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; CORONARY ATHEROSCLEROSIS; ENDOTHELIAL DYSFUNCTION; ESSENTIAL-HYPERTENSION; REACTIVE HYPEREMIA; INSULIN-RESISTANCE AB Context: The diagnosis of metabolic syndrome (MetS) identifies individuals at risk for developing diabetes and cardiovascular disease. African Americans (AAs) have high rates of cardiovascular disease and subclinical vascular disease including arterial stiffness and microvascular dysfunction but have relatively low rates of MetS. Objective: The objective of the study was to evaluate the relationship between MetS and vascular function in a biracial cohort with the hypothesis that the diagnosis of MetS underestimates sub-clinical vascular disease in AAs. Design: We measured components of MetS in a community-based cohort of 951 AAs and white subjects (aged 48.8 +/- 11 y, 47% AA, 55% female). Main Outcome Measures: Using digital pulse amplitude tonometry, we estimated the reactive hyperemia index (RHI), a measure of microvascular endothelial function. Using applanation tonometry (Sphygmocor), central augmentation index (CAIx) and pulse wave velocity (PWV) were measured as indices of wave reflections and arterial stiffness, respectively. Results: MetS was present in 24.0% of subjects and was associated with increased PWV (P < .001) and CAIx (P < .001) and a trend to lower RHI (P = .068) in both races. However, in subjects without MetS, AAs had lower RHI (P < .001) and higher PWV (P = .003) and CAIx (P = .002) compared with white subjects. Addition of an extra MetS criterion point for AAs with hypertension eliminated the racial differences in PWV and CAIx but not RHI. Conclusion: Although MetS is associated with microvascular dysfunction and increased arterial stiffness in both racial groups, AAs without MetS have greater vascular dysfunction compared with whites. Additional weighting for hypertension in AAs attenuated the racial differences in sub-clinical disease associated with MetS. C1 [Shen, Jia; Poole, Joseph C.; Morris, Alanna A.; Vaccarino, Viola; Quyyumi, Arshed A.] Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA. [Topel, Matthew L.; Phillips, Lawrence] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Binongo, Jose G.] Emory Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Dunbar, Sandra B.] Emory Univ, Sch Nursing, Atlanta, GA 30322 USA. [Bidulescu, Aurelian] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Patel, Riyaz S.] UCL, Inst Cardiovasc Sci, London WC1 6BT, England. [Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20824 USA. RP Quyyumi, AA (reprint author), Div Cardiol, Med, 1462 Clifton Rd NE,Suite 510, Atlanta, GA 30322 USA. EM aquyyum@emory.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute Grant [1 U01 HL079156-01, 1 U01 HL79214-01]; National Institutes of Health from the Clinical and Translational Science Award program for the Emory Clinical Interaction Unit [UL1 RR025008]; National Institutes of Health/National Center for Research Resources [5P20RR11104]; Woodruff Fund FX This work was supported by funding from National Institutes of Health/National Heart, Lung, and Blood Institute Grant 1 U01 HL079156-01 (to A.A.Q.) and Grant 1 U01 HL79214-01 (to G.H.G.); in part by National Institutes of Health Grant UL1 RR025008 from the Clinical and Translational Science Award program for the Emory Clinical Interaction Unit; National Institutes of Health/National Center for Research Resources Grant 5P20RR11104 (to the Morehouse Clinical Research Center); and the Woodruff Fund (to the Emory Predictive Health Initiative). NR 45 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2015 VL 100 IS 11 BP 4231 EP 4239 DI 10.1210/jc.2014-4344 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW3XM UT WOS:000364925700054 PM 26151335 ER PT J AU Gourgari, E Lodish, M Shamburek, R Keil, M Wesley, R Walter, M Sampson, M Bernstein, S Khurana, D Lyssikatos, C Ten, S Dobs, A Remaley, AT Stratakis, CA AF Gourgari, E. Lodish, M. Shamburek, R. Keil, M. Wesley, R. Walter, M. Sampson, M. Bernstein, S. Khurana, D. Lyssikatos, C. Ten, S. Dobs, A. Remaley, A. T. Stratakis, C. A. TI Lipoprotein Particles in Adolescents and Young Women With PCOS Provide Insights Into Their Cardiovascular Risk SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; LOW-DENSITY-LIPOPROTEIN; C-REACTIVE PROTEIN; INSULIN-RESISTANCE; CAROTID ATHEROSCLEROSIS; ADIPOSE-TISSUE; ATHEROGENIC DYSLIPIDEMIA; METABOLIC SYNDROME; ADIPONECTIN LEVELS; OBESE ADOLESCENTS AB Context: Adult women with polycystic ovarian syndrome (PCOS) have an increased risk for cardiovascular disease, but the evidence for this is controversial in adolescents and young women with PCOS. Measurement of low-density lipoprotein (LDL) particle number, measured by nuclear magnetic resonance spectroscopy is a novel technology to assess cardiovascular risk. Objective: The objective of the study was to evaluate lipoprotein particle number and size in young women with PCOS and its relationship with insulin resistance and hyperandrogenism. Design: This was a cross-sectional case control study. Setting: The study was conducted at a clinical research center. Participants: Women with PCOS (n = 35) and normal controls (n = 20) participated in the study. Interventions: Blood samples and anthropometric measures were obtained. Main Outcome Measures: LDL particle size and number were measured using nuclear magnetic resonance spectroscopy. A secondary outcome was to investigate the correlation of LDL particle number with high-sensitivity C-reactive protein, waist to hip ratio, hyperandrogenism, insulin resistance, and adiponectin. Results: Women with PCOS had higher LDL particle number when compared with healthy controls (935 +/- 412 vs 735 +/- 264, P = .032); LDL particle number correlated strongly with high-sensitivity C-reactive protein (r = 0.37, P = .006) and waist-to-hip (r = 0.57, P = .0003). The higher LDL particle number was driven mainly due to differences in the small LDL particle number (sLDLp), with PCOS patients having more sLDLp (348 +/- 305 vs 178 +/- 195, P = .015). The sLDLp correlated with the Matsuda index (r = -0.51, P = .0001), homeostasis model assessment index of insulin resistance (r = 0.41, P = .002), and adiponectin (r = -0.46, P = .0004) but not with T. Conclusion: Adolescent and young women with PCOS have an atherogenic lipoprotein profile suggestive of increased cardiovascular risk that appears to be driven by the degree of visceral adiposity and insulin resistance. C1 [Gourgari, E.; Lodish, M.; Keil, M.; Bernstein, S.; Lyssikatos, C.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Walter, M.] NIDDK, Sect Clin Lab Serv, Bethesda, MD 20892 USA. [Gourgari, E.] Georgetown Univ, Med Ctr, Div Pediat Endocrinol, Washington, DC 20057 USA. [Shamburek, R.; Sampson, M.; Remaley, A. T.] NHLBI, Sect Lipoprot Metab, Bethesda, MD 20824 USA. [Wesley, R.] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20814 USA. [Walter, M.] SUNY, Infants & Childrens Hosp Brooklyn Maimonides, Div Pediat Endocrinol, Brooklyn, NY 11219 USA. SUNY, Children & Hosp Downstate, Brooklyn, NY 11219 USA. [Khurana, D.; Ten, S.; Dobs, A.] Johns Hopkins Univ, Sch Med, Dept Endocrinol, Baltimore, MD 21205 USA. RP Gourgari, E (reprint author), MedStar Georgetown Univ Hosp, Div Pediat Endocrinol, 4200 Wisconsin Ave NW,Fourth Floor, Washington, DC 20016 USA. EM evgenia.gourgari@gunet.georgetown.edu FU Eunice Kennedy Shriver National Institute of Child and Health and Human Development, the National Institutes of Health Clinical Center; Bench-to-Bedside Program of the National Institutes of Health; Office of Research on Women's Health, Office of the Director, National Institutes of Health FX This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child and Health and Human Development, the National Institutes of Health Clinical Center, the Bench-to-Bedside Program of the National Institutes of Health, and the Office of Research on Women's Health, Office of the Director, National Institutes of Health. NR 41 TC 2 Z9 3 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2015 VL 100 IS 11 BP 4291 EP 4298 DI 10.1210/jc.2015-2566 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW3XM UT WOS:000364925700061 PM 26371381 ER PT J AU Masur, H Read, SW AF Masur, Henry Read, Sarah W. TI Opportunistic Infections and Mortality: Still Room for Improvement SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE HIV; opportunistic infections; pneumocystis pneumonia; life expectancy; mortality ID COMBINATION ANTIRETROVIRAL THERAPY; UNITED-STATES; ERA; ASSOCIATION; ILLNESSES; SURVIVAL; OUTCOMES; COHORT; CARE C1 [Masur, Henry] NIAID, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Read, Sarah W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Masur, H (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Rm 2C145, Bethesda, MD 20892 USA. EM hmasur@nih.gov NR 15 TC 3 Z9 3 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 NOV 1 PY 2015 VL 212 IS 9 BP 1348 EP 1350 DI 10.1093/infdis/jiv236 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW1QX UT WOS:000364767500002 PM 26044290 ER PT J AU Pombo, C Wherry, EJ Gostick, E Price, DA Betts, MR AF Pombo, Carolina Wherry, E. John Gostick, Emma Price, David A. Betts, Michael R. TI Elevated Expression of CD160 and 2B4 Defines a Cytolytic HIV-Specific CD8(+) T-Cell Population in Elite Controllers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; elite controllers; T-cell exhaustion; PD-1; CD160; 2B4; CD8(+) T cells ID POLYCHROMATIC FLOW-CYTOMETRY; HERPESVIRUS ENTRY MEDIATOR; CHRONIC VIRAL-INFECTION; INHIBITORY RECEPTORS; CYTOKINE PRODUCTION; UP-REGULATION; EXHAUSTION; ACTIVATION; PD-1; NONPROGRESSORS AB During chronic human immunodeficiency virus (HIV) infection, virus-specific CD8(+) T cells become functionally exhausted. Unlike most chronically infected individuals, elite controllers of HIV retain CD8(+) T-cell polyfunctionality and cytolytic capacity. It remains unclear whether elite controllers manifest T-cell exhaustion similar to subjects with chronic progression of HIV infection. Here we assessed coexpression of PD-1, Lag-3, CD160, and 2B4 as a measure of T-cell exhaustion in a cohort of elite controllers and in chronic progressors. We found that elite controllers have a high proportion of potentially exhausted (PD1(+)CD160(+)2B4(+)) HIV-specific CD8(+) T cells that is comparable to the proportion in chronic progressors. However, elite controllers also harbor a population of HIV-specific CD160(+)2B4(+) CD8(+) T cells that correlates with cytolytic capacity, as measured by perforin expression, a population not commonly present in chronic progressors. We therefore propose that coexpression of CD160 and 2B4 delineates a population of cytolytic CD8(+) T cells important for the control of HIV. C1 [Pombo, Carolina; Wherry, E. John; Betts, Michael R.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wherry, E. John] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. RP Betts, MR (reprint author), Univ Penn, Microbiol, 522E Johnson Pavil,3610 Hamilton Walk, Philadelphia, PA 19104 USA. EM betts@mail.med.upenn.edu RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU National Institutes of Health [R01 A1076066]; National Institutes of Health (HIV training grant) [T32 AI 07632]; Wellcome Trust FX This work was supported by the National Institutes of Health (grant R01 A1076066 to M. R. B. and C. P. and HIV training grant T32 AI 07632 to C. P.) and the Wellcome Trust (to D. A. P.). NR 50 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2015 VL 212 IS 9 BP 1376 EP 1386 DI 10.1093/infdis/jiv226 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW1QX UT WOS:000364767500006 PM 25883386 ER PT J AU Sciaranghella, G Wang, CW Hu, HH Anastos, K Merhi, Z Nowicki, M Stanczyk, FZ Greenblatt, RM Cohen, M Golub, ET Watts, DH Alter, G Young, MA Tsibris, AMN AF Sciaranghella, Gaia Wang, Cuiwei Hu, Haihong Anastos, Kathryn Merhi, Zaher Nowicki, Marek Stanczyk, Frank Z. Greenblatt, Ruth M. Cohen, Mardge Golub, Elizabeth T. Watts, D. Heather Alter, Galit Young, Mary A. Tsibris, Athe M. N. TI CCR5 Expression Levels in HIV-Uninfected Women Receiving Hormonal Contraception SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV-1; hormonal contraception; CCR5; medroxyprogesterone acetate; levonorgestrel; oral contraceptive pills; peripheral blood mononuclear cells; CD4; CXCR4 ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTRAUTERINE SYSTEM; RISK; RADIOIMMUNOASSAY; FITNESS; COHORT; ENTRY AB Human immunodeficiency virus (HIV) infectivity increases as receptor/coreceptor expression levels increase. We determined peripheral CD4, CCR5, and CXCR4 expression levels in HIV-uninfected women who used depot medroxyprogesterone acetate (DMPA; n = 32), the levonorgestrel-releasing intrauterine device (LNG-IUD; n = 27), oral contraceptive pills (n = 32), or no hormonal contraception (n = 33). The use of LNG-IUD increased the proportion of CD4(+) and CD8(+) T cells that expressed CCR5; increases in the magnitude of T-cell subset CCR5 expression were observed with DMPA and LNG-IUD use (P < .01 for all comparisons). LNG-IUD and, to a lesser extent, DMPA use were associated with increased peripheral T-cell CCR5 expression. C1 [Sciaranghella, Gaia; Alter, Galit] MIT, Ragon Inst MGH, Boston, MA USA. [Sciaranghella, Gaia; Alter, Galit] Harvard Univ, Boston, MA 02115 USA. [Tsibris, Athe M. N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wang, Cuiwei; Hu, Haihong; Tsibris, Athe M. N.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Cuiwei; Hu, Haihong; Young, Mary A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Merhi, Zaher] NYU, Sch Med, Dept Obstet & Gynecol, Div Reprod Biol, New York, NY 10016 USA. [Nowicki, Marek] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Greenblatt, Ruth M.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Cohen, Mardge] Stroger Hosp, Dept Med, Chicago, IL USA. [Cohen, Mardge] Rush Univ, Dept Med, Chicago, IL 60612 USA. [Cohen, Mardge] CORE Ctr, Chicago, IL USA. [Golub, Elizabeth T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Tsibris, AMN (reprint author), Harvard Univ, Sch Med, Dept Med, Div Infect Dis,Brigham & Womens Hosp, 65 Landsdowne St,Rm 422, Cambridge, MA 02139 USA. EM atsibris@partners.org FU NIH; National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI034994]; NIAID; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institute on Drug Abuse; National Institute on Mental Health; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and other Communication Disorders; NIH Office of Research on Women's Health; NIH Clinical and Translation Science Award [UL1-TR000004] FX This work was supported by the NIH and the National Institute of Allergy and Infectious Diseases (NIAID) (through a subcontract of U01 AI034994 [to A. M. N. T.]). The WIHS is funded primarily by the NIAID, with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the NIH Office of Research on Women's Health. WIHS data collection is also supported by the NIH Clinical and Translation Science Award UL1-TR000004 to the University of California-San Francisco. NR 15 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2015 VL 212 IS 9 BP 1397 EP 1401 DI 10.1093/infdis/jiv233 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW1QX UT WOS:000364767500008 PM 25895986 ER PT J AU Gilbert, PB Gabriel, EE Hudgens, MG Miao, XP Li, XM Su, SC Parrino, J Chan, ISF AF Gilbert, Peter B. Gabriel, Erin E. Hudgens, Michael G. Miao, Xiaopeng Li, Xiaoming Su, Shu-Chih Parrino, Janie Chan, Ivan S. F. TI Ifit1 Protects Against Lipopolysaccharide and D-galactosamine-Induced Fatal Hepatitis by Inhibiting Activation of the JNK Pathway Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID VACCINE; TRIALS C1 [Gilbert, Peter B.] Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98195 USA. [Gilbert, Peter B.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, Xiaoming] Gilead Sci Inc, Biostat, Seattle, WA USA. [Gabriel, Erin E.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Hudgens, Michael G.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA. [Miao, Xiaopeng] Biogen Inc, Biostat, Cambridge, MA 02142 USA. [Su, Shu-Chih; Parrino, Janie; Chan, Ivan S. F.] Merck & Co Inc, Whitehouse Stn, NJ USA. RP Gilbert, PB (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM pgilbert@scharp.org FU NIAID NIH HHS [UM1 AI068635] NR 5 TC 0 Z9 0 U1 0 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 NOV 1 PY 2015 VL 212 IS 9 BP 1521 EP 1523 DI 10.1093/infdis/jiv287 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CW1QX UT WOS:000364767500021 PM 25985906 ER PT J AU Moore, E Tycko, R AF Moore, Eric Tycko, Robert TI Micron-scale magnetic resonance imaging of both liquids and solids SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE MRI; Solid state NMR; Lee-Goldburg decoupling; Constant-time imaging; Microcoil ID DYNAMIC NUCLEAR-POLARIZATION; VACANCY SPIN SENSOR; NMR MICROSCOPY; STATE NMR; PULSE SEQUENCES; SINGLE-CELL; RESOLUTION; FIELD; SENSITIVITY; NUTATION AB We describe and demonstrate a novel apparatus for magnetic resonance imaging (MRI), suitable for imaging of both liquid and solid samples with micron-scale isotropic resolution. The apparatus includes a solenoidal radio-frequency microcoil with 170 mu m inner diameter and a set of planar gradient coils, all wound by hand and supported on a series of stacked sapphire plates. The design ensures efficient heat dissipation during gradient pulses and also facilitates disassembly, sample changes, and reassembly. To demonstrate liquid state H-1 MRI, we present an image of polystyrene beads within CuSO4-doped water, contained within a capillary tube with 100 mu m inner diameter, with 5.0 mu m isotropic resolution. To demonstrate solid state H-1 MRI, we present an image of NH4Cl particles within the capillary tube, with 8.0 mu m isotropic resolution. High-resolution solid state MRI is enabled by frequency-switched Lee-Goldburg decoupling, with an effective rotating frame field amplitude of 289 kHz. At room temperature, pulsed gradients of 4 T/m (i.e., 170 Hz/mu m for H-1 MRI) are achievable in all three directions with currents of 10 A or less. The apparatus is contained within a variable-temperature liquid helium cryostat, which will allow future efforts to obtain MRI images at low temperatures with signal enhancement by dynamic nuclear polarization. Published by Elsevier Inc. C1 [Moore, Eric; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health. NR 55 TC 1 Z9 1 U1 6 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD NOV PY 2015 VL 260 BP 1 EP 9 DI 10.1016/j.jmr.2015.09.001 PG 9 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA CW4SK UT WOS:000364982200001 PM 26397215 ER PT J AU Basheer, WA Harris, BS Mentrup, HL Abreha, M Thames, EL Lea, JB Swing, DA Copeland, NG Jenkins, NA Price, RL Matesic, LE AF Basheer, Wassim A. Harris, Brett S. Mentrup, Heather L. Abreha, Measho Thames, Elizabeth L. Lea, Jessica B. Swing, Deborah A. Copeland, Neal G. Jenkins, Nancy A. Price, Robert L. Matesic, Lydia E. TI Cardiomyocyte-specific overexpression of the ubiquitin ligase Wwp1 contributes to reduction in Connexin 43 and arrhythmogenesis SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Connexin; Gap junction; Wwp1; Ubiquitin; Arrhythmogenesis ID GAP-JUNCTION PROTEIN; POTENTIAL MOLECULAR TARGET; E3 LIGASE; ADULT-RAT; HEART; CANCER; GROWTH; GENE; CONDUCTION; EXPRESSION AB Gap junctions (GJ) are intercellular channels composed of connexin subunits that play a critical role in a diverse number of cellular processes in all tissue types. In the heart, GJs mediate electrical coupling between cardiomyocytes and display mislocalization and/or downregulation in cardiac disease (a process known as GJ remodeling), producing an arrhythmogenic substrate. The main constituent of GJs in the ventricular myocardium is Connexin 43 (Cx43), an integral membrane protein that is rapidly turned over and shows decreased expression or function with age. We hypothesized that Wwp1, an ubiquitin ligase whose expression in known to increase in aging-related pathologies, may regulate Cx43 in vivo by targeting it for ubiquitylation and degradation and yield tissue-specific Cx43 loss of function phenotypes. When Wwp1 was globally overexpressed in mice under the control of a beta-actin promoter, the highest induction of Wwp1 expression was observed in the heart which was associated with a 90% reduction in cardiac Cx43 protein levels, left ventricular hypertrophy (LVH), and the development of lethal ventricular arrhythmias around 8 weeks of age. This phenotype was completely penetrant in two independent founder lines. Cardiomyocyte-specific overexpression of Wwp1 confirmed that this phenotype was cell autonomous and delineated Cx43-dependent and independent roles for Wwp1 in arrhythmogenesis and LVH, respectively. Using a cell-based system, it was determined that Wwp1 co-immunoprecipitates with and ubiquitylates Cx43, causing a decrease in the steady state levels of Cx43 protein. These findings offer new mechanistic insights into the regulation of Cx43 which may be exploitable in various gap junctionopathies. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Basheer, Wassim A.; Mentrup, Heather L.; Abreha, Measho; Thames, Elizabeth L.; Lea, Jessica B.; Matesic, Lydia E.] Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. [Harris, Brett S.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Swing, Deborah A.; Copeland, Neal G.; Jenkins, Nancy A.] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Price, Robert L.] Univ S Carolina, Sch Med, Dept Cell Biol & Anat, Columbia, SC 29209 USA. RP Matesic, LE (reprint author), 715 Sumter St, Columbia, SC 29208 USA. EM lmatesic@biol.sc.edu FU National Institutes of Health [R01HL104030]; American Heart Association [10SDG2650005]; intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the National Institutes of Health [R01HL104030 to L.E.M.], the American Heart Association [10SDG2650005 to L.E.M.], and the intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [N.G.C. and N.A.J.]. NR 53 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD NOV PY 2015 VL 88 BP 1 EP 13 DI 10.1016/j.yjmcc.2015.09.004 PG 13 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA CW5TK UT WOS:000365059300001 PM 26386426 ER PT J AU Boylston, JA Sun, JH Chen, Y Gucek, M Sack, MN Murphy, E AF Boylston, Jennifer A. Sun, Junhui Chen, Yong Gucek, Marjan Sack, Michael N. Murphy, Elizabeth TI Characterization of the cardiac succinylome and its role in ischemia-reperfusion injury SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Sirt5; Ischemia-reperfusion; Cardiac; Succinylation; Succinate ID LYSINE SUCCINYLATION; POSTTRANSLATIONAL MODIFICATION; PROTEIN; ACETYLATION; SIRT5; DEGRADATION; CARDIOMYOCYTES; IDENTIFICATION; PROTEASOME; TURNOVER AB Succinylation refers to modification of lysine residues with succinyl groups donated by succinyl-CoA. Sirtuin5 (Sirt5) is a mitochondrial NAD(+)-dependent deacylase that catalyzes the removal of succinyl groups from proteins. Sirt5 and protein succinylation are conserved across species, suggesting functional importance of the modification. Sirt5 loss impacts liver metabolism but the role of succinylation in the heart has not been explored. We combined affinity enrichment with proteomics and mass spectrometry to analyze total succinylated lysine content of mitochondria isolated from WT and Sirt5(-/-) mouse hearts. We identified 887 succinylated lysine residues in 184 proteins. 44 peptides (5 proteins) occurred uniquely in WT samples, 289 (46 proteins) in Sirt5(-/-) samples, and 554 (133 proteins) were common to both groups. The 46 unique proteins in Sirt5(-/-) heart participate in metabolic processes such as fatty add beta-oxidation (Eci2) and branched chain amino acid catabolism, and include respiratory chain proteins (Ndufa7, 12, 13, Dhsa). We performed label-free analysis of the peptides common to WT and Sirt5(-/-) hearts. 16 peptides from 9 proteins were significantly increased in Sirt5(-/-) by at least 30%. The adenine nucleotide transporter 1 showed the highest increase in succinylation in Sirt5(-/-) (108.4 fold). The data indicate that succinylation is widespread in the heart and enriched in metabolic pathways. We examined whether the loss of Sirt5 would impact ischemia-reperfusion (I/R) injury and we found an increase in infarct size in Sirt5(-/-) hearts compared to WT littermates (68.5(+)/_ 1.1% Sirt5(-/-) vs 39.6(+)/(-) 6.8% WT) following 20 min of ischemia and 90-min reperfusion. We further demonstrate that I/R injury in Sirt5(-/-) heart is restored to WT levels by pretreatment with dimethyl malonate, a competitive inhibitor of succinate dehydrogenase (SDH), implicating alteration in SDEI activity as causative of the injury. Published by Elsevier Ltd. C1 [Boylston, Jennifer A.; Sun, Junhui; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [ZIA HL002066] FX This work was funded by the National Heart, Lung, and Blood Institute (NHLBI) Intramural Program (ZIA HL002066). We thank Dr. Christian Combs and the NHLBI Light Microscopy Core for their assistance with the Mito Sox measurements. NR 30 TC 11 Z9 11 U1 3 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD NOV PY 2015 VL 88 BP 73 EP 81 DI 10.1016/j.yjmcc.2015.09.005 PG 9 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA CW5TK UT WOS:000365059300007 PM 26388266 ER PT J AU Farber, A Tan, TW Hu, B Dember, LM Beck, GJ Dixon, BS Kusek, JW Feldman, HI AF Farber, Alik Tan, Tze-Woei Hu, Bo Dember, Laura M. Beck, Gerald J. Dixon, Bradley S. Kusek, John W. Feldman, Harold I. CA DAC Study Grp TI The effect of location and configuration on forearm and upper arm hemodialysis arteriovenous grafts SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID TRANSPOSED BRACHIOBASILIC FISTULAS; VASCULAR ACCESS; BRACHIOCEPHALIC FISTULAS; RANDOMIZED MULTICENTER; DIALYSIS-ACCESS; CLINICAL-TRIAL; LOOP; PATENCY; POLYTETRAFLUOROETHYLENE; SURVIVAL AB Objective: The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG. Methods: Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted. Results: A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P=. 03), African American (62% vs 78%; P <.001), and receiving dialysis at the time of surgery (62% vs 80%; P <.001). Participants with fAVG had a higher mean body mass index (33 vs 29; P <.001). The LPUP (fAVG 70% vs uAVG 78%; P =. 07) and CGF (33% vs 36%; P =.91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P =.20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P =.10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P =.16). Conclusions: Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft. C1 [Farber, Alik] Boston Univ, Med Ctr, Div Vasc & Endovasc Surg, Boston, MA USA. [Tan, Tze-Woei] Louisiana State Univ, Shreveport Hlth Sci Ctr, Div Vasc Surg, Shreveport, LA 71105 USA. [Hu, Bo; Beck, Gerald J.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Dember, Laura M.; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Feldman, Harold I.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Dixon, Bradley S.] Univ Iowa, Nephrol Sect, Iowa City, IA USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Farber, A (reprint author), Boston Med Ctr, Div Vasc & Endovasc Surg, 88 E Newton St,Collamore 5,Ste D506, Boston, MA 02118 USA. EM alik.farber@bmc.org NR 43 TC 1 Z9 1 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD NOV PY 2015 VL 62 IS 5 BP 1258 EP 1264 DI 10.1016/j.jvs.2015.06.132 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CW8IF UT WOS:000365242000022 PM 26254823 ER PT J AU Fabbri, E An, Y Schrack, JA Gonzalez-Freire, M Zoli, M Simonsick, EM Guralnik, JM Boyd, CM Studenski, SA Ferrucci, L AF Fabbri, Elisa An, Yang Schrack, Jennifer A. Gonzalez-Freire, Marta Zoli, Marco Simonsick, Eleanor M. Guralnik, Jack M. Boyd, Cynthia M. Studenski, Stephanie A. Ferrucci, Luigi TI Energy Metabolism and the Burden of Multimorbidity in Older Adults: Results From the Baltimore Longitudinal Study of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Multimorbidity; Resting metabolic rate; Aging; Health status; Metabolism ID X-RAY ABSORPTIOMETRY; BODY-COMPOSITION; INDIRECT CALORIMETRY; HEALTH; EXPENDITURE; LIFE; POPULATION; LONGEVITY; CACHEXIA; WEIGHT AB Excessively elevated resting metabolic rate ( RMR) for persons of a certain age, sex, and body composition is a mortality risk factor. Whether elevated RMR constitutes an early marker of health deterioration in older adult has not been fully investigated. Using data from the Baltimore Longitudinal Study of Aging, we hypothesized that higher RMR ( i) was cross-sectionally associated with higher multimorbidity and ( ii) predicted higher multimorbidity in subsequent follow-ups. The analysis included 695 Baltimore Longitudinal Study of Aging participants, aged 60 or older at baseline, of whom 248 had follow-up data available 2 years later and 109 four years later. Multimorbidity was assessed as number of chronic diseases. RMR was measured by indirect calorimetry and was tested in regression analyses adjusted for covariates age, sex, and dual-energy x-ray absorptiometrymeasured total body fat mass and lean mass. Baseline RMR and multimorbidity were positively associated, independent of covariates ( p =.002). Moreover, in a three-wave bivariate autoregressive cross-lagged model adjusted for covariates, higher prior RMR predicted greater future multimorbidity above and beyond the cross-sectional and autoregressive associations ( p = .034). RMR higher than expected, given age, sex, and body composition, predicts future higher multimorbidity in older adults and may be used as early biomarker of impending health deterioration. Replication and the development of normative data are required for clinical translation. C1 [Fabbri, Elisa; An, Yang; Schrack, Jennifer A.; Gonzalez-Freire, Marta; Simonsick, Eleanor M.; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Intramural Res Branch, NIH, Baltimore, MD 21224 USA. [Fabbri, Elisa; Zoli, Marco] Univ Bologna, Dept Med & Surg Sci, I-40126 Bologna, Italy. [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Boyd, Cynthia M.] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Dept Med, Baltimore, MD USA. RP Fabbri, E (reprint author), NIA, Intramural Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM elisa.fabbri@nih.gov FU Intramural Research Program of National Institutes of Health, National Institute on Aging [03-AG-0325]; Paul Beeson Career Development Award Program [NIA K23 AG032910]; Paul Beeson Career Development Award Program (AFAR); Paul Beeson Career Development Award Program (John A. Hartford Foundation); Paul Beeson Career Development Award Program (Atlantic Philanthropies); Paul Beeson Career Development Award Program (Starr Foundation) FX This research was supported by the Intramural Research Program of National Institutes of Health, National Institute on Aging (03-AG-0325). Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. Dr. C.M.B. was supported by the Paul Beeson Career Development Award Program (NIA K23 AG032910, AFAR, The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation, and an anonymous donor). NR 38 TC 12 Z9 12 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2015 VL 70 IS 11 BP 1297 EP 1303 DI 10.1093/gerona/glu209 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CW1QF UT WOS:000364765700001 PM 25409892 ER PT J AU Kritchevsky, SB de Cabo, R AF Kritchevsky, Stephen B. de Cabo, Rafael TI Energy - A Hallmark of Physical Function SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material C1 [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [de Cabo, Rafael] NIA, Expt Gerontol Sect, Baltimore, MD 21224 USA. RP Kritchevsky, SB (reprint author), Wake Forest Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM skritche@wakehealth.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 1 TC 1 Z9 1 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2015 VL 70 IS 11 BP 1333 EP 1333 DI 10.1093/gerona/glv131 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CW1QF UT WOS:000364765700005 PM 26273026 ER PT J AU Gonzalez-Freire, M de Cabo, R Bernier, M Sollott, SJ Fabbri, E Navas, P Ferrucci, L AF Gonzalez-Freire, Marta de Cabo, Rafael Bernier, Michel Sollott, Steven J. Fabbri, Elisa Navas, Placido Ferrucci, Luigi TI Reconsidering the Role of Mitochondria in Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mitochondria; Aging; Lifespan ID FATTY-ACID UNSATURATION; SKELETAL-MUSCLE MITOCHONDRIA; OXIDATIVE STRESS; ELECTRON-TRANSPORT; DELETION MUTATIONS; LON PROTEASE; LIFE-SPAN; PERMEABILITY TRANSITION; ENDOPLASMIC-RETICULUM; AEROBIC CAPACITY AB Background: Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases. Harman's Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. Harman's hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy. The purpose of this review is to scan the ever-growing literature on mitochondria from the perspective of aging research and try to identify priority questions that should be addressed in future research.Methods: A systematic search of peer-reviewed studies was performed using PubMed. Search terms included (i) mitochondria or mitochondrial; (ii) aging, ageing, older adults or elderly; and (iii) reactive oxygen species, mitochondria dynamics, mitochondrial proteostasis, cytosol, mitochondrial-associated membranes, redox homeostasis, electron transport chain, electron transport chain efficiency, epigenetic regulation, DNA heteroplasmy.Results: The importance of mitochondrial biology as a trait d'union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics. Conclusions: Mitochondria could play a key role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging. C1 [Gonzalez-Freire, Marta; de Cabo, Rafael; Bernier, Michel; Fabbri, Elisa; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Sollott, Steven J.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Fabbri, Elisa] Univ Bologna, Dept Med & Surg Sci, I-40126 Bologna, Italy. [Navas, Placido] Univ Pablo de Olavide, CSIC, Inst Salud Carlos 3, Ctr Andaluz Biol Desarrollo,CIBERER, Seville 41013, Spain. RP Gonzalez-Freire, M (reprint author), NIA, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM marta.gonzalezfreire@nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural Research Program of NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of NIH, National Institute on Aging. NR 101 TC 24 Z9 24 U1 18 U2 60 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2015 VL 70 IS 11 BP 1334 EP 1342 DI 10.1093/gerona/glv070 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CW1QF UT WOS:000364765700006 PM 25995290 ER PT J AU Santanasto, AJ Glynn, NW Jubrias, SA Conley, KE Boudreau, RM Amati, F Mackey, DC Simonsick, EM Strotmeyer, ES Coen, PM Goodpaster, BH Newman, AB AF Santanasto, Adam J. Glynn, Nancy W. Jubrias, Sharon A. Conley, Kevin E. Boudreau, Robert M. Amati, Francesca Mackey, Dawn C. Simonsick, Eleanor M. Strotmeyer, Elsa S. Coen, Paul M. Goodpaster, Bret H. Newman, Anne B. TI Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mitochondrial function; Fatigability; Aerobic capacity; Skeletal muscle ID OXIDATIVE CAPACITY; EXERCISE INTOLERANCE; AEROBIC CAPACITY; FATIGUE; AGE; DECLINE; ASSOCIATION; PERFORMANCE; DISABILITY; ENERGETICS AB Background. Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults. Methods. The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 +/- 5.0 years ( 47% female, 93% white), with a body mass index of 25.9 +/- 2.7 kg/ m(2) and usual gait-speed of 1.2 +/- 0.2 m/s. Fatigability was defined using rating of perceived exertion ( 6-20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using P-31 magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax ( mM ATP/s) and oxidative capacity of the quadriceps ( ATPmax center dot Quadriceps volume) were calculated. Peak aerobic capacity ( VO2 peak) was measured using a modified Balke protocol. Results. ATPmax center dot Quadriceps volume was associated with VO2 peak and was 162.61 mM ATP center dot mL/s lower ( p =.03) in those with high ( rating of perceived exertion >= 10) versus low ( rating of perceived exertion <= 9) fatigability. Participants with high fatigability required a significantly higher proportion of VO 2 peak to walk at 0.72 m/s compared with those with low fatigability ( 58.7 +/- 19.4% vs 44.9 +/- 13.2%, p <.05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability ( odds ratio: 0.34, 95% CI: 0.11- 1.01, p =.05). C1 [Santanasto, Adam J.; Glynn, Nancy W.; Boudreau, Robert M.; Strotmeyer, Elsa S.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Amati, Francesca; Coen, Paul M.; Goodpaster, Bret H.] Univ Pittsburgh, Sch Med, Div Endocrinol & Metab, Pittsburgh, PA 15260 USA. [Jubrias, Sharon A.; Conley, Kevin E.] Univ Washington, Translat Ctr Metab Imaging, Seattle, WA 98195 USA. [Mackey, Dawn C.] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Simonsick, Eleanor M.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Coen, Paul M.] Univ Pittsburgh, Sch Educ, Dept Hlth & Phys Act, Pittsburgh, PA 15260 USA. RP Glynn, NW (reprint author), 130 DeSoto St,A531 Crabtree Hall, Pittsburgh, PA 15261 USA. EM glynnn@edc.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036; Boudreau, Robert/0000-0003-0162-5187; Amati, Francesca/0000-0002-1731-0262; Coen, Paul/0000-0002-2805-2115; Glynn, Nancy/0000-0003-2265-0162 FU National Institute on Aging at the National Institutes of Health [1RC2AG036594-01, 1RC2AG036606] FX This work was supported by the National Institute on Aging at the National Institutes of Health (1RC2AG036594-01 and 1RC2AG036606) NR 39 TC 11 Z9 11 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2015 VL 70 IS 11 BP 1379 EP 1385 DI 10.1093/gerona/glu134 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CW1QF UT WOS:000364765700011 PM 25167867 ER PT J AU Katzman, SM Strotmeyer, ES Nalls, MA Zhao, YQ Mooney, S Schork, N Newman, AB Harris, TB Yaffe, K Cummings, SR Liu, YM Tranah, GJ AF Katzman, Shana M. Strotmeyer, Elsa S. Nalls, Michael A. Zhao, Yiqiang Mooney, Sean Schork, Nik Newman, Anne B. Harris, Tamara B. Yaffe, Kristine Cummings, Steven R. Liu, Yongmei Tranah, Gregory J. CA Hlth Aging Body Composition Study TI Mitochondrial DNA Sequence Variation Associated With Peripheral Nerve Function in the Elderly SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Sensory; Genetics; Epidemiology; Functional Performance ID AMYLOID PRECURSOR PROTEIN; CYCLIC VOMITING SYNDROME; ALZHEIMERS-DISEASE; BODY-COMPOSITION; CALORIE RESTRICTION; MUTATIONAL ANALYSIS; ENERGY-EXPENDITURE; DIABETES-MELLITUS; POLG MUTATIONS; RETT-SYNDROME AB Background. Mitochondrial dysfunction is a prominent hallmark of many sensory neuropathies. The purpose of this study was to assess the influence of mitochondrial DNA sequence variation on peripheral nerve function in the population-based Health, Aging, and Body Composition Study. Methods. We investigated the role of common mitochondrial DNA variation ( n = 1,580) and complete mitochondrial DNA sequences ( n = 138) on peroneal motor nerve conduction velocity and amplitude, average vibration detection threshold, and monofilament sensitivity. Results. Nominal associations among common mitochondrial DNA variants and haplogroups were identified but were not statistically significant after adjustment for multiple comparisons. Sequence-based approaches were used to identify aggregate variant associations across the 16S rRNA ( weighted- sum, p = 2E-05 and variable threshold, p = 9E-06) for nerve conduction velocity. Several of these rare 16S variants occurred at or near sites with earlier disease associations and are also in close proximity to the peptidyl transferase center, which is the catalytic center of the 16S rRNA Conclusions. These results suggest that sequence variation related to mitochondrial protein synthesis/ assembly is associated with peripheral nerve function and may provide insight into targets for intervention or new clinical strategies to preserve nerve function in late life. C1 [Katzman, Shana M.] Univ Calif San Francisco, Dept Innovat Technol & Alliances, San Francisco, CA 94143 USA. [Strotmeyer, Elsa S.; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Zhao, Yiqiang] China Agr Univ, State Key Lab Agrobiotechnol, Beijing 100094, Peoples R China. [Mooney, Sean] Buck Inst Res Aging, Dept Bioinformat, Novato, CA USA. [Schork, Nik] J Craig Venter Inst, Dept Human Biol, La Jolla, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, Dept Geriatr Psychiat, San Francisco, CA USA. [Cummings, Steven R.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. RP Tranah, GJ (reprint author), UCSF, San Francisco Coordinating Ctr, Calif Pacific Med Ctr, Res Inst, 185 Berry St,Lobby 5,Suite 5700, San Francisco, CA 94107 USA. EM gtranah@sfcc-cpmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, R01-AG032098, R03-AG032498]; NINR [R01-NR012459, Z01A6000932]; National Institutes of Health [HHSN268200782096C]; NLM [LM009722]; NIH, National Institute on Aging FX This research was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; NIA grants R01-AG028050, R01-AG032098, and R03-AG032498; NINR grant R01-NR012459 and Z01A6000932. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Y.Z. was supported by NLM grant LM009722. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 85 TC 1 Z9 1 U1 2 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2015 VL 70 IS 11 BP 1400 EP 1408 DI 10.1093/gerona/glu175 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CW1QF UT WOS:000364765700014 PM 25394619 ER PT J AU Burkle, A Grune, T Gonos, ES Bohr, VA AF Buerkle, Alexander Grune, Tilman Gonos, Efstathios S. Bohr, Vilhelm A. TI Special Issue Biomarkers of Human Ageing SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Editorial Material C1 [Buerkle, Alexander] Univ Konstanz, Dept Biol, D-78457 Constance, Germany. [Grune, Tilman] German Inst Nutr Potsdam Rehbruecke DIfE, D-14558 Nuthetal, Germany. [Gonos, Efstathios S.] Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens 11635, Greece. [Bohr, Vilhelm A.] NIA, Dept Mol Gerontol, Baltimore, MD 21224 USA. RP Burkle, A (reprint author), Univ Konstanz, Dept Biol, D-78457 Constance, Germany. EM alexander.buerkle@uni-konstanz.de FU Intramural NIH HHS [Z01 AG000726-15] NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD NOV PY 2015 VL 151 SI SI BP 1 EP 1 DI 10.1016/j.mad.2015.08.008 PG 1 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CX0CH UT WOS:000365364000001 PM 26348899 ER PT J AU Lynn, GM Laga, R Darrah, PA Ishizuka, AS Balaci, AJ Dulcey, AE Pechar, M Pola, R Gerner, MY Yamamoto, A Buechler, CR Quinn, KM Smelkinson, MG Vanek, O Cawood, R Hills, T Vasalatiy, O Kastenmuller, K Francica, JR Stutts, L Tom, JK Ryu, KA Esser-Kahn, AP Etrych, T Fisher, KD Seymour, LW Seder, RA AF Lynn, Geoffrey M. Laga, Richard Darrah, Patricia A. Ishizuka, Andrew S. Balaci, Alexandra J. Dulcey, Andres E. Pechar, Michal Pola, Robert Gerner, Michael Y. Yamamoto, Ayako Buechler, Connor R. Quinn, Kylie M. Smelkinson, Margery G. Vanek, Ondrej Cawood, Ryan Hills, Thomas Vasalatiy, Olga Kastenmueller, Kathrin Francica, Joseph R. Stutts, Lalisa Tom, Janine K. Ryu, Keun Ah Esser-Kahn, Aaron P. Etrych, Tomas Fisher, Kerry D. Seymour, Leonard W. Seder, Robert A. TI In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity SO NATURE BIOTECHNOLOGY LA English DT Article ID T-CELL IMMUNITY; DENDRITIC CELLS; INNATE IMMUNITY; LYMPH-NODES; ADJUVANT; RESPONSES; ANTIGEN; PROTECTION; ACTIVATION; COPOLYMERS AB The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens. C1 [Lynn, Geoffrey M.; Darrah, Patricia A.; Ishizuka, Andrew S.; Balaci, Alexandra J.; Yamamoto, Ayako; Buechler, Connor R.; Quinn, Kylie M.; Kastenmueller, Kathrin; Francica, Joseph R.; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lynn, Geoffrey M.; Laga, Richard; Cawood, Ryan; Hills, Thomas; Fisher, Kerry D.; Seymour, Leonard W.] Univ Oxford, Dept Oncol, Oxford, England. [Laga, Richard; Pechar, Michal; Pola, Robert; Etrych, Tomas] Acad Sci Czech Republic, Inst Macromol Chem, Prague, Czech Republic. [Dulcey, Andres E.; Vasalatiy, Olga] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD USA. [Gerner, Michael Y.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Smelkinson, Margery G.] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Vanek, Ondrej] Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic. [Stutts, Lalisa; Tom, Janine K.; Ryu, Keun Ah; Esser-Kahn, Aaron P.] Univ Calif Irvine, Dept Chem, Irvine, CA 92717 USA. RP Seder, RA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Pechar, Michal/G-6423-2014; Laga, Richard/G-3627-2014; Etrych, Tomas/G-3420-2014; Pola, Robert/G-5723-2014; Vanek, Ondrej/I-7022-2016; OI Etrych, Tomas/0000-0001-5908-5182; Vanek, Ondrej/0000-0003-1190-8535; Ishizuka, Andrew/0000-0002-3024-7536 FU BIOPOL project (Ministry of Education, Youth and Sports of the Czech Republic) [EE2.3.30.0029]; Czech Science Foundation [15-15181S]; Charles University [UNCE 204025/2012]; Cancer Research UK [C552/A17720]; Office of AIDS Research of the US National Institutes of Health; National Institute of Allergy and Infectious Diseases of the US National Institutes of Health FX The authors wish to acknowledge M. Dillon, K. Wuddie and C. Chiedi at the Vaccine Research Center and B. Klaunberg and V. Diaz at the Mouse Imaging Facility (MIF) for their valuable support and assistance with the animal studies. We would also like to thank K. Ulbrich, R. Swenson and G. Griffiths for their support and helpful insights. This work was supported in part by the BIOPOL project (Grant of the Ministry of Education, Youth and Sports of the Czech Republic, no. EE2.3.30.0029); by the Czech Science Foundation (15-15181S); by Charles University (UNCE 204025/2012); by a Cancer Research UK grant (C552/A17720); and by the Office of AIDS Research and the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. NR 58 TC 25 Z9 26 U1 21 U2 63 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD NOV PY 2015 VL 33 IS 11 BP 1201 EP + DI 10.1038/nbt.3371 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CW3TY UT WOS:000364916000028 PM 26501954 ER PT J AU Mankodi, A Grunseich, C Skov, M Cook, L Aue, G Purev, E Bakar, D Lehky, T Jurkat-Rott, K Pedersen, TH Childs, RW AF Mankodi, Ami Grunseich, Christopher Skov, Martin Cook, Lisa Aue, Georg Purev, Enkhtsetseg Bakar, Dara Lehky, Tanya Jurkat-Rott, Karin Pedersen, Thomas H. Childs, Richard W. TI Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy SO NEUROMUSCULAR DISORDERS LA English DT Article DE Myotonia; Paramyotonia congenita; Periodic paralysis; Muscle weakness; Sodium channel; Magnesium ID CALCIUM REDUCE MYOTONIA; EXTRACELLULAR MAGNESIUM; PARAMYOTONIA-CONGENITA; PERIODIC PARALYSIS; MUTATION; GENOTYPE AB We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.4 channel activation and a faster recovery from slow channel inactivation. A further shift in the Nav1.4 channel activation in the hyperpolarizing direction as expected with low divalent cations resulted in myotonia that progressed to membrane inexcitability. Shifting the channel activation in the depolarizing direction as would be anticipated from magnesium supplementation abolished the myotonia. These observations provide clinical and biophysical evidence that the muscle symptoms in sodium channelopathy are sensitive to divalent cations. Exploration of the role of magnesium administration in therapy or prophylaxis is warranted with a randomized clinical trial. Published by Elsevier B.V. C1 [Mankodi, Ami; Grunseich, Christopher; Bakar, Dara] NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. [Skov, Martin; Pedersen, Thomas H.] Univ Aarhus, Dept Biomed, DK-8000 Aarhus, Denmark. [Cook, Lisa; Aue, Georg; Purev, Enkhtsetseg; Childs, Richard W.] NHLBI, Sect Transplantat Imnzunotherapy, Bethesda, MD 20892 USA. [Lehky, Tanya] NINDS, Clin Neurophysiol Program, EMG Sect, Bethesda, MD 20892 USA. [Jurkat-Rott, Karin] Univ Ulm, Div Nettrophysiol, D-89069 Ulm, Germany. RP Mankodi, A (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35,Room 2A-1002, Bethesda, MD 20892 USA. EM Ami.Mankodi@nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 14 TC 0 Z9 0 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD NOV PY 2015 VL 25 IS 11 BP 908 EP 912 DI 10.1016/j.nmd.2015.08.007 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CX0BP UT WOS:000365362200012 PM 26494408 ER PT J AU Grunho, M Sonies, B Frattali, CM Litvan, I AF Grunho, M. Sonies, B. Frattali, C. M. Litvan, I. TI Swallowing disturbances in the corticobasal syndrome SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Corticobasal syndrome; Swallowing; Dysphagia; Atypical parkinsonism ID PROGRESSIVE SUPRANUCLEAR PALSY; PARKINSONS-DISEASE; DEGENERATION; DYSPHAGIA; APRAXIA; DISORDERS; ABNORMALITIES; DYSARTHRIA; DIAGNOSIS; FEATURES AB Objectives: To determine the characteristics of swallowing and speech disturbances in patients with corticobasal syndrome (CBS) compared to healthy controls, and whether a subjective swallowing questionnaire, the NIH-Speech Pathology swallowing questionnaire (NIH-SQ), can predict swallowing impairment. Methods: Twenty-four consecutive CBS patients underwent a swallowing assessment comprised of the NIH-SQ ultrasound swallow study (US) and modified barium swallow (MBS) study. Healthy controls (n = 28) completed the NIH-SQ and the US. Results: Ninety-six percent of the patients with CBS reported at least one complaint in the NIH-SQ 59% had abnormal dry swallow duration and 10% abnormal wet swallow duration. Twenty-three patients with CBS had some abnormality on the MBS. The MBS category "piecemeal deglutition" (excessive lingual gestures causing multiple swallows required to clear a single bolus) was characteristic of CBS patients. No aspiration was detected. No NIH-SQ cutoff score or combination of subjective complaints predicted an abnormal MBS. Fifty-two percent of the patients had speech apraxia. Conclusions: Swallowing and speech disturbances are common in patients with CBS and differ from those previously reported in patients with PSP syndrome. Piecemeal deglutition and speech apraxia are characteristic features of our CBS patients. Although the NIH-SQ cannot predict the results of the more objective MBS in this population, it characterizes the patients' major subjective swallowing complaints. Published by Elsevier Ltd. C1 [Grunho, M.; Litvan, I.] Univ Calif San Diego, Dept Neurosci, Movement Disorders Ctr, La Jolla, CA 92037 USA. [Sonies, B.; Frattali, C. M.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Litvan, I (reprint author), Univ Calif San Diego, Dept Neurosci, Movement Disorders Ctr, Tasch Endowed Prof Parkinson Dis Res, 8950 Villa La Jolla Dr,Suite C112, La Jolla, CA 92037 USA. EM ilitvan@ucsd.edu OI Litvan, Irene/0000-0002-3485-3445 NR 30 TC 0 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD NOV PY 2015 VL 21 IS 11 BP 1342 EP 1348 DI 10.1016/j.parkreldis.2015.09.043 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CW5RS UT WOS:000365054900008 PM 26456115 ER PT J AU Su, XZ Miller, LH AF Su Xin-Zhuan Miller, Louis H. TI The discovery of artemisinin and the Nobel Prize in Physiology or Medicine SO SCIENCE CHINA-LIFE SCIENCES LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM MALARIA; RESISTANCE C1 [Su Xin-Zhuan; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov; lmiller@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 7 TC 8 Z9 9 U1 0 U2 7 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1674-7305 EI 1869-1889 J9 SCI CHINA LIFE SCI JI Sci. China-Life Sci. PD NOV PY 2015 VL 58 IS 11 BP 1175 EP 1179 DI 10.1007/s11427-015-4948-7 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CW6TF UT WOS:000365130000022 PM 26481135 ER PT J AU Clyne, B Smith, SM Hughes, CM Boland, F Bradley, MC Cooper, JA Fahey, T AF Clyne, Barbara Smith, Susan M. Hughes, Carmel M. Boland, Fiona Bradley, Marie C. Cooper, Janine A. Fahey, Tom CA OPTI-SCRIPT Study Team TI Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study) SO ANNALS OF FAMILY MEDICINE LA English DT Article DE randomized controlled trial; potentially inappropriate prescribing; primary health care; prescription drugs; practice-based research ID ELDERLY-PATIENTS; GENERAL-PRACTICE; NURSING-HOMES; PEOPLE; OUTCOMES; RISK; BENZODIAZEPINES; QUESTIONNAIRE; POPULATION; MEDICATION AB PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care. METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression. RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15-0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50-1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14-0.68; P = .04). CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally. C1 [Clyne, Barbara; Smith, Susan M.; Boland, Fiona; Cooper, Janine A.; Fahey, Tom] Royal Coll Surgeons Ireland, HRB Ctr Primary Care Res, Dept Gen Practice, Dublin 2, Ireland. [Hughes, Carmel M.; Cooper, Janine A.] Queens Univ Belfast, Sch Pharm, Belfast, Antrim, North Ireland. [Bradley, Marie C.] NCI, Rockville, MD USA. RP Clyne, B (reprint author), Royal Coll Surgeons Ireland, HRB Ctr Primary Care Res, Dept Gen Practice, 123 St Stephens Green, Dublin 2, Ireland. EM barbaraclyne@rcsi.ie RI Fahey, Tom/C-9367-2012; OI Fahey, Tom/0000-0002-5896-5783; smith, susan/0000-0001-6027-2727; Clyne, Barbara/0000-0002-1186-9495 FU Health Research Board (HRB) PhD Scholars Programme in Health Services Research [PHD/2007/16]; HRB Centre for Primary Care Research [HRC/2007/1] FX This study is independent research, funded by the Health Research Board (HRB) PhD Scholars Programme in Health Services Research under grant PHD/2007/16 and the HRB Centre for Primary Care Research under grant HRC/2007/1. NR 42 TC 11 Z9 11 U1 2 U2 11 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD NOV-DEC PY 2015 VL 13 IS 6 BP 545 EP 553 DI 10.1370/afm.1838 PG 9 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA CW2SN UT WOS:000364843100008 PM 26553894 ER PT J AU Arkenau, HT Kelly, K Patel, MR Neuteboom, B Speit, I Chin, K Heery, CR Gulley, JL AF Arkenau, H. -T. Kelly, K. Patel, M. R. Neuteboom, B. Speit, I. Chin, K. Heery, C. R. Gulley, J. L. TI Phase I JAVELIN solid tumor trial of avelumab (MSB0010718C), an anti-PD-L1 antibody: Safety and pharmacokinetics SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT Meeting of the European-Society-for-Medical-Oncology (ESMO) CY NOV 20-21, 2015 CL Lausanne, SWITZERLAND SP European Soc Med Oncol, Bristol Myers Squibb, MSD, Merck, Pfizer, Roche, Celldex Therapeut C1 [Arkenau, H. -T.] Sarah Cannon Res Inst, Drug Dev Unit, London, England. [Kelly, K.] Univ Calif Davis, Ctr Comprehens Canc, Dept Hematol & Oncol, Sacramento, CA 95817 USA. [Patel, M. R.] Florida Canc Specialists, Sarah Cannon Res Inst, Med Oncol, Sarasota, FL USA. [Neuteboom, B.] EMD Serono Inc, Quantitat Pharmacol & Drug Disposit Dept, Billerica, MA USA. [Speit, I.] Merck KGaA, Global Drug Safety, Darmstadt, Germany. [Chin, K.] EMD Serono Inc, Inst Res & Dev, Billerica, MA USA. [Heery, C. R.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, J. L.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Genitourinary Malignancies Branch,NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 1 Z9 1 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2015 VL 26 SU 8 MA 8PD BP 3 EP 3 PG 1 WC Oncology SC Oncology GA CW7EH UT WOS:000365160300009 ER PT J AU Dueck, AC Basch, E Mitchell, SA AF Dueck, Amylou C. Basch, Ethan Mitchell, Sandra A. TI Development of the US NCI patient-reported outcomes version of the common terminology criteria for adverse events SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Japanese-Society-of-Medical-Oncology (JSMO) CY JUL 16-18, 2015 CL Sapporo, JAPAN SP Japanese Soc Med Oncol C1 [Dueck, Amylou C.] Mayo Clin, Div Hlth Sci Res, Rochester, MN USA. [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA. [Mitchell, Sandra A.] Natl Canc Inst, Div Canc Control & Populat Sci, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2015 VL 26 SU 7 MA SY1-3 BP 26 EP 26 PG 1 WC Oncology SC Oncology GA CW7ED UT WOS:000365159900066 ER PT J AU Pol, HH Brouwer, R Glahn, D Hibar, D Hua, X Jahanshad, N Abramovic, L Franz, C Hansell, N Koenis, M Mather, K Panizzon, M Strike, L Swagerman, S Wen, W Boomsma, D Gilmore, J Gogtay, N Kahn, RS Kremen, W Sachdev, P Wright, M Thompson, P AF Pol, Hilleke Hulshoff Brouwer, Rachel Glahn, David Hibar, Derrek Hua, Xue Jahanshad, Neda Abramovic, Lucija Franz, Carol Hansell, Narelle Koenis, Marinka Mather, Karen Panizzon, Matthew Strike, Lachlan Swagerman, Suzanne Wen, Wei Boomsma, Dorret Gilmore, John Gogtay, Nitin Kahn, Rene S. Kremen, William Sachdev, Perminder Wright, Margaret Thompson, Paul TI Genetic influences on longitudinal changes in subcortical volumes: results of the ENIGMA Plasticity Working Group SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 45th Annual Meeting of the Behavior-Genetics-Association CY JUN 20, 2015 CL San Diego, CA SP Behav Genet Assoc C1 [Pol, Hilleke Hulshoff; Brouwer, Rachel; Abramovic, Lucija; Koenis, Marinka] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Glahn, David] Yale Univ Med, Dept Psychiat, New Haven, CT USA. [Hibar, Derrek; Hua, Xue; Jahanshad, Neda; Thompson, Paul] USC, Keck Sch Med, Imaging Genet Ctr, Los Angeles, CA USA. [Franz, Carol; Panizzon, Matthew; Kremen, William] Univ Calif San Diego, La Jolla, CA 92093 USA. [Hansell, Narelle; Wright, Margaret] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Mather, Karen; Wen, Wei] Univ New S Wales, Ctr Hlth Brain Ageing, Psychiat, Sydney, NSW, Australia. [Strike, Lachlan] QIMR Berghofer Med Res Inst, Neuroimaging Genet, Brisbane, Qld, Australia. [Swagerman, Suzanne] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Boomsma, Dorret] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Gilmore, John] Univ North Carolina Chapel Hill, Dept Psychiat, Chapel Hill, NC USA. [Gogtay, Nitin] NIMH, NIH, Bethesda, MD USA. [Kahn, Rene S.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. [Kremen, William] VA SD Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Sachdev, Perminder] Univ New S Wales, Sydney, NSW 2052, Australia. RI Karen, Mather/O-9795-2016; Hansell, Narelle/A-4553-2016 OI Karen, Mather/0000-0003-4143-8941; Hansell, Narelle/0000-0002-8229-9741 NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2015 VL 45 IS 6 SI SI BP 662 EP 663 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA CW4RI UT WOS:000364978800079 ER PT J AU Machiela, MJ Chanock, SJ AF Machiela, Mitchell J. Chanock, Stephen J. TI LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants SO BIOINFORMATICS LA English DT Article ID ANNOTATION; GENOMES AB A Summary: Assessing linkage disequilibrium (LD) across ancestral populations is a powerful approach for investigating population-specific genetic structure as well as functionally mapping regions of disease susceptibility. Here, we present LDlink, a web-based collection of bioinformatic modules that query single nucleotide polymorphisms (SNPs) in population groups of interest to generate haplotype tables and interactive plots. Modules are designed with an emphasis on ease of use, query flexibility, and interactive visualization of results. Phase 3 haplotype data from the 1000 Genomes Project are referenced for calculating pairwise metrics of LD, searching for proxies in high LD, and enumerating all observed haplotypes. LDlink is tailored for investigators interested in mapping common and uncommon disease susceptibility loci by focusing on output linking correlated alleles and highlighting putative functional variants. C1 [Machiela, Mitchell J.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Machiela, MJ (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. OI Machiela, Mitchell/0000-0001-6538-9705 FU National Cancer Institute's Intramural Research Program; Division of Cancer Epidemiology and Genetics Informatics Tool Challenge FX Support comes from the National Cancer Institute's Intramural Research Program and the Division of Cancer Epidemiology and Genetics Informatics Tool Challenge. NR 7 TC 25 Z9 25 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 1 PY 2015 VL 31 IS 21 BP 3555 EP 3557 DI 10.1093/bioinformatics/btv402 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CW6UT UT WOS:000365134400024 PM 26139635 ER PT J AU Kerridge, BT Saha, TD Chou, SP Zhang, HT Jung, JS Ruan, WJ Smith, SM Huang, BJ Hasin, DS AF Kerridge, Bradley T. Saha, Tulshi D. Chou, S. Patricia Zhang, Haitao Jung, Jeesun Ruan, W. June Smith, Sharon M. Huang, Boji Hasin, Deborah S. TI Gender and nonmedical prescription opioid use and DSM-5 nonmedical prescription opioid use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions - III SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Opioid use disorder; Gender differences; Comorbidity; Disability; Treatment ID SUBSTANCE USE DISORDERS; GENERAL-POPULATION SAMPLE; CHRONIC NONCANCER PAIN; DRUG-USE DISORDERS; CHRONIC BACK-PAIN; UNITED-STATES; OLDER-ADULTS; PSYCHIATRIC-DISORDERS; PROCEDURAL VALIDITY; CLINICAL-TRIAL AB Background: Little is known about sex-specific risk for nonmedical prescription opioid use (NMPOU) and DSM-5 nonmedical prescription opioid use disorder (NMPOUD). The objective of the present study was to present prevalence, correlates, psychiatric comorbidity, treatment and disability of NMPOU and DSM-5 NMPOUD among men and women. Methods: Nationally representative sample of the U.S. Results: Prevalences of 12-month and lifetime NMPOU were greater among men (4.4%, 13.0%) than women (3.9%, 9.8%), while corresponding rates of DSM-5 NMPOUD did not differ between men (0.9%, 2.2%) and women (0.9%, 1.9%). Regardless of time frame and sex, NMPOU and NMPOUD generally decreased with age and were lower among Blacks, Asians/Pacific Islanders and Hispanics, and respondents with lower socioeconomic status. Among men with NMPOU, rates were lower among respondents in the Northeast and South and among those previously married (lifetime). Across time frames and gender, NMPOU and NMPOUD were generally associated with other substance use disorders, posttraumatic stress and borderline, schizotypal and antisocial personality disorders, but associated with major depressive disorder, persistent depression and bipolar I disorder only among men. Disability increased with NMPOU frequency and NMPOUD severity. Only 7.6% and 8.2% of men and women with NMPOU ever received treatment, while 26.8% and 31.1% ever received treatment for NMPOUD. Conclusions: NMPOU and NMPOUD are highly disabling, associated with a broad array of sex-specific and shared correlates and comorbidities and largely go untreated in the U.S. Valid assessment tools are needed that include gender as a stratification variable to identify NMPOU and NMPOUD. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Kerridge, Bradley T.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Saha, Tulshi D.; Chou, S. Patricia; Zhang, Haitao; Jung, Jeesun; Ruan, W. June; Smith, Sharon M.; Huang, Boji] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Hasin, Deborah S.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ, Hlth, New York, NY 10032 USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Kerridge, BT (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. EM BradleyKerridge@gmail.com FU National Institute on Alcohol Abuse and Alcoholism FX The NESARC-III was funded and sponsored by the National Institute on Alcohol Abuse and Alcoholism, with supplemented support from the National Institute on Drug Abuse. The sponsors had no involvement in the study design, collection, analysis and interpretation of the data, in the writing of the report and in the decision to submit the article for publication. NR 85 TC 4 Z9 4 U1 3 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD NOV 1 PY 2015 VL 156 BP 47 EP 56 DI 10.1016/j.drugalcdep.2015.08.026 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CW5SN UT WOS:000365057000006 PM 26374990 ER PT J AU Wu, LT Ghitza, UE Batch, BC Pencina, MJ Rojas, LF Goldstein, BA Schibler, T Dunham, AA Rusincovitch, S Brady, KT AF Wu, Li-Tzy Ghitza, Udi E. Batch, Bryan C. Pencina, Michael J. Rojas, Leoncio Flavio Goldstein, Benjamin A. Schibler, Tony Dunham, Ashley A. Rusincovitch, Shelley Brady, Kathleen T. TI Substance use and mental diagnoses among adults with and without type 2 diabetes: Results from electronic health records data SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Anxiety disorder; Comorbidity; Diabetes mellitus; Electronic health records; Mood disorder; Substance use disorder ID PRIMARY-CARE; COLLABORATIVE CARE; GENERAL-PRACTICE; MEDICAL-RECORDS; USE DISORDERS; DEPRESSION; METAANALYSIS; ANXIETY; ALCOHOL; ABUSE AB Background: Comorbid diabetes and substance use diagnoses (SUD) represent a hazardous combination, both in terms of healthcare cost and morbidity. To date, there is limited information about the association of SUD and related mental disorders with type 2 diabetes mellitus (T2DM). Methods: We examined the associations between T2DM and multiple psychiatric diagnosis categories, with a focus on SUD and related psychiatric comorbidities among adults with T2DM. We analyzed electronic health record (EHR) data on 170,853 unique adults aged >= 18 years from the EHR warehouse of a large academic healthcare system. Logistic regression analyses were conducted to estimate the strength of an association for comorbidities. Results: Overall, 9% of adults (n = 16,243) had T2DM. Blacks, Hispanics, Asians, and Native Americans had greater odds of having T2DM than whites. All 10 psychiatric diagnosis categories were more prevalent among adults with T2DM than among those without T2DM. Prevalent diagnoses among adults with T2MD were mood (21.22%), SUD (17.02%: tobacco 13.25%, alcohol 4.00%, drugs 4.22%), and anxiety diagnoses (13.98%). Among adults with T2DM, SUD was positively associated with mood, anxiety, personality, somatic, and schizophrenia diagnoses. Conclusions: We examined a large diverse sample of individuals and found clinical evidence of SUD and psychiatric comorbidities among adults with T2DM. These results highlight the need to identify feasible collaborative care models for adults with T2DM and SUD related psychiatric comorbidities, particularly in primary care settings, that will improve behavioral health and reduce health risk. (C) 2015 The Authors. Published by Elsevier Ireland Ltd. C1 [Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Wu, Li-Tzy; Pencina, Michael J.; Rojas, Leoncio Flavio; Goldstein, Benjamin A.; Schibler, Tony] Duke Univ, Duke Clin Res Inst, Durham, NC 27710 USA. [Ghitza, Udi E.] NIDA, Bethesda, MD 20892 USA. [Batch, Bryan C.] Duke Univ, Med Ctr, Div Endocrinol, Durham, NC 27710 USA. [Pencina, Michael J.; Goldstein, Benjamin A.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Dunham, Ashley A.; Rusincovitch, Shelley] Duke Univ, Duke Translat Res Inst, Durham, NC 27710 USA. [Brady, Kathleen T.] Med Univ S Carolina, South Carolina Clin & Translat Res Inst, Charleston, SC 29425 USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Sch Med, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institutes of Health [U10DA013727, R01MD007658, UG1DA040317]; Centers for Medicare and Medicaid Services [1C1CMS331018]; Bristol-Myers Squibb Foundation FX This work was made possible by research support from the U.S. National Institutes of Health (U10DA013727; R01MD007658; UG1DA040317), the Centers for Medicare and Medicaid Services (1C1CMS331018), and the Bristol-Myers Squibb Foundation. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors and do not represent the official position of the U.S. government and the Bristol-Myers Squibb Foundation. NR 62 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD NOV 1 PY 2015 VL 156 BP 162 EP 169 DI 10.1016/j.drugalcdep.2015.09.003 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CW5SN UT WOS:000365057000022 PM 26392231 ER PT J AU Pilkonis, PA Yu, L Dodds, NE Johnston, KL Lawrence, SM Hilton, TF Daley, DC Patkar, AA McCarty, D AF Pilkonis, Paul A. Yu, Lan Dodds, Nathan E. Johnston, Kelly L. Lawrence, Suzanne M. Hilton, Thomas F. Daley, Dennis C. Patkar, Ashwin A. McCarty, Dennis TI Item banks for substance use from the Patient-Reported Outcomes Measurement Information System (PROMIS (R)): Severity of use and positive appeal of use SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance use; Drug use; Item response theory; Measurement ID NATIONAL EPIDEMIOLOGIC SURVEY; RESPONSE THEORY ANALYSIS; CLINICAL-TRIALS-NETWORK; SCREENING-TEST ASSIST; DRUG-ABUSE-TREATMENT; USE DISORDERS; DSM-IV; ALCOHOL-USE; TREATMENT PROGRAMS; SHORT FORMS AB Background: Two item banks for substance use were developed as part of the Patient-Reported Outcomes Measurement Information System (PROMIS (R)): severity of substance use and positive appeal of substance use. Methods: Qualitative item analysis (including focus groups, cognitive interviewing, expert review, and item revision) reduced an initial pool of more than 5300 items for substance use to 119 items included in field testing. Items were written in a first-person, past-tense format, with 5 response options reflecting frequency or severity. Both 30-day and 3-month time frames were tested. The calibration sample of 1336 respondents included 875 individuals from the general population (ascertained through an internet panel) and 461 patients from addiction treatment centers participating in the National Drug Abuse Treatment Clinical Trials Network. Results: Final banks of 37 and 18 items were calibrated for severity of substance use and positive appeal of substance use, respectively, using the two-parameter graded response model from item response theory (IRT). Initial calibrations were similar for the 30-day and 3-month time frames, and final calibrations used data combined across the time frames, making the items applicable with either interval. Seven-item static short forms were also developed from each item bank. Conclusions: Test information curves showed that the PROMIS item banks provided substantial information in a broad range of severity, making them suitable for treatment, observational, and epidemiological research in both clinical and community settings. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Pilkonis, Paul A.; Yu, Lan; Dodds, Nathan E.; Johnston, Kelly L.; Lawrence, Suzanne M.; Daley, Dennis C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Yu, Lan] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Hilton, Thomas F.] NIDA, Indian Harbor Beach, FL 32937 USA. [Patkar, Ashwin A.] Duke Univ, Sch Med, Dept Psychiat, Durham, NC 27705 USA. [Patkar, Ashwin A.] Duke Univ, Sch Med, Dept Community & Family Med, Durham, NC 27705 USA. [McCarty, Dennis] Oregon Hlth & Sci Univ, Publ Hlth & Prevent Med, Portland, OR 97239 USA. RP Pilkonis, PA (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM pilkonispa@upmc.edu FU National Institutes of Health (NIH) Common Fund Initiative (Northwestern University) [U54AR057951, U01AR052177]; Northwestern University [U54AR057943]; American Institutes for Research [U54AR057926]; State University of New York, Stony Brook [U01AR057948, U01AR052170]; University of Washington, Seattle [U01AR057954, U01AR052171]; University of North Carolina, Chapel Hill [U01AR052181]; Children's Hospital of Philadelphia [U01AR057956]; Stanford University [U01AR052158]; Boston University [U01AR057929]; University of California, Los Angeles; MSHS [U01AR057936]; University of Pittsburgh [U01AR052155]; Georgetown University [U01AR057971]; Children's Hospital Medical Center, Cincinnati [U01AR057940]; University of Maryland, Baltimore [U01AR057967]; Duke University [U01AR052186]; National Institute on Drug Abuse [UG1 DA015815] FX PROMIS (R) was funded with cooperative agreements from the National Institutes of Health (NIH) Common Fund Initiative (Northwestern University, PI: David Cella, PhD, U54AR057951, U01AR052177; Northwestern University, PI: Richard C. Gershon, PhD, U54AR057943; American Institutes for Research, PI: Susan (San) D. Keller, PhD, U54AR057926; State University of New York, Stony Brook, PIs: Joan E. Broderick, PhD and Arthur A. Stone, PhD, U01AR057948, U01AR052170; University of Washington, Seattle, PIs: Heidi M. Crane, MD, MPH, Paul K. Crane, MD, MPH, and Donald L. Patrick, PhD, U01AR057954; University of Washington, Seattle, PI: Dagmar Amtmann, PhD, U01AR052171; University of North Carolina, Chapel Hill, PI: Harry A. Guess, MD, PhD (deceased), Darren A. DeWalt, MD, MPH, U01AR052181; Children's Hospital of Philadelphia, PI: Christopher B. Forrest, MD, PhD, U01AR057956; Stanford University, PI: James F. Fries, MD, U01AR052158; Boston University, PIs: Alan Jette, PT, PhD, Stephen M. Haley, PhD (deceased), and David Scott Tulsky, PhD (University of Michigan, Ann Arbor), U01AR057929; University of California, Los Angeles, PIs: Dinesh Khanna, MD (University of Michigan, Ann Arbor) and Brennan Spiegel, MD, MSHS, U01AR057936; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, U01AR052155; Georgetown University, PIs: Carol. M. Moinpour, PhD (Fred Hutchinson Cancer Research Center, Seattle) and Arnold L. Potosky, PhD, U01AR057971; Children's Hospital Medical Center, Cincinnati, PI: Esi M. Morgan DeWitt, MD, MSCE, U01AR057940; University of Maryland, Baltimore, PI: Lisa M. Shulman, MD, U01AR057967; and Duke University, PI: Kevin P. Weinfurt, PhD, U01AR052186). NIH Science Officers on this project have included Deborah Ader, PhD, Vanessa Ameen, MD (deceased), Susan Czajkowski, PhD, Basil Eldadah, MD, PhD, Lawrence Fine, MD, DrPH, Lawrence Fox, MD, PhD, Lynne Haverkos, MD, MPH, Thomas Hilton, PhD, Laura Lee Johnson, PhD, Michael Kozak, PhD, Peter Lyster, PhD, Donald Mattison, MD, Claudia Moy, PhD, Louis Quatrano, PhD, Bryce Reeve, PhD, William Riley, PhD, Peter Scheidt, MD, Ashley Wilder Smith, PhD, MPH, Susana Serrate-Sztein, MD, William Phillip Tonkins, DrPH, Ellen Werner, PhD, Tisha Wiley, PhD, and James Witter, MD, PhD. An award from the National Institute on Drug Abuse (UG1 DA015815) provided additional support for Dennis McCarty's participation. This article uses data developed under PROMIS. These contents do not necessarily represent an endorsement by the US Government or PROMIS. See www.nihpromis.org for additional information on the PROMIS (R) initiative. NR 48 TC 2 Z9 2 U1 4 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD NOV 1 PY 2015 VL 156 BP 184 EP 192 DI 10.1016/j.drugalcdep.2015.09.008 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CW5SN UT WOS:000365057000025 PM 26423364 ER PT J AU Kleiner, DE Bedossa, P AF Kleiner, David E. Bedossa, Pierre TI Liver Histology and Clinical Trials for Nonalcoholic Steatohepatitis-Perspectives From 2 Pathologists SO GASTROENTEROLOGY LA English DT Editorial Material ID FATTY LIVER; FOLLOW-UP; SCORING SYSTEM; DISEASE; PROGRESSION; FIBROSIS; BIOPSIES; NAFLD; PIOGLITAZONE; MULTICENTER C1 [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Bedossa, Pierre] Univ Paris Diderot, UFR Med, Paris, France. RP Kleiner, DE (reprint author), NCI, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 26 TC 7 Z9 7 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2015 VL 149 IS 6 BP 1305 EP 1308 DI 10.1053/j.gastro.2015.09.015 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CW6GN UT WOS:000365095800010 PM 26409177 ER PT J AU Schoen, RE Razzak, A Yu, KJ Berndt, SI Firl, K Riley, TL Pinsky, PF AF Schoen, Robert E. Razzak, Anthony Yu, Kelly J. Berndt, Sonja I. Firl, Kevin Riley, Thomas L. Pinsky, Paul F. TI Incidence and Mortality of Colorectal Cancer in Individuals With a Family History of Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Adenomatous Polyps; Colon Cancer; Genetic Risk Factors; Screening ID AMERICAN-COLLEGE; SURVEILLANCE COLONOSCOPY; RISK; GASTROENTEROLOGY; METAANALYSIS; PREVENTION; ENDOSCOPY; GUIDELINE; DATABASE; SOCIETY AB BACKGROUND & AIMS: Little is known about the change in risk conferred by family history of colorectal cancer (CRC) as a person ages. We evaluated the effect of family history on CRC incidence and mortality after 55 years of age, when the risk of early onset cancer had passed. METHODS: We collected data from participants in the randomized, controlled Prostate, Lung, Colorectal and Ovarian cancer screening trial of flexible sigmoidoscopy versus usual care (55-74 years old, no history of CRC), performed at 10 US centers from 1993 to 2001. A detailed family history of colorectal cancer was obtained at enrollment, and subjects were followed for CRC incidence and mortality for up to 13 years. RESULTS: Among 144,768 participants, 14,961 subjects (10.3%) reported a family of CRC. Of 2090 incident cases, 273 cases (13.1%) had a family history of CRC; among 538 deaths from CRC, 71 (13.2%) had a family history of CRC. Overall, family history of CRC was associated with an increased risk of CRC incidence (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.50; P<.0001) and increased mortality (HR, 1.31; 95% CI, 1.02-1.69; P=.03). Subjects with 1 first degree relative (FDR) with CRC (n = 238; HR, 1.23; 95% CI, 1.07-1.42) or >= 2 FDRs with CRC (n = 35; HR, 2.04; 95% CI, 1.44-2.86) were at increased risk for incident CRC. However, among individuals with 1 FDR with CRC, there were no differences in risk based on age at diagnosis in the FDR (for FDR <60 years of age: HR, 1.27; 95% CI, 0.97-1.63; for FDR 60-70 years of age: HR, 1.33; 95% CI, 1.06-1.62; for FDR >70 years of age: HR, 1.14; 95% CI, 0.93-1.45; P trend = .59). CONCLUSIONS: After 55 years of age, subjects with 1 FDR with CRC had only a modest increase in risk for CRC incidence and death; age of onset in the FDR was not significantly associated with risk. Individuals with >= 2 FDRs with CRC had continued increased risk in older age. Guidelines and clinical practice for subjects with a family history of CRC should be modified to align CRC testing to risk. C1 [Schoen, Robert E.; Razzak, Anthony] Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Yu, Kelly J.; Pinsky, Paul F.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Berndt, Sonja I.; Firl, Kevin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Riley, Thomas L.] Informat Management Serv Inc, Rockville, MD USA. RP Schoen, RE (reprint author), Div Gastroenterol Hepatol & Nutr, Mezzanine Level,C Wing,PUH 200 Lothrop St, Pittsburgh, PA 15213 USA. EM rschoen@pitt.edu OI Firl, Kevin/0000-0002-7598-0299 FU Division of Cancer Prevention, National Cancer Institute [N01-CN-25511] FX This work was supported by the Division of Cancer Prevention, National Cancer Institute contract N01-CN-25511 to the University of Pittsburgh Cancer Institute. NR 27 TC 8 Z9 8 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2015 VL 149 IS 6 BP 1438 EP + DI 10.1053/j.gastro.2015.07.055 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CW6GN UT WOS:000365095800032 PM 26255045 ER PT J AU Huang, CR Haritunians, T Okou, DT Cutler, DJ Zwick, ME Taylor, KD Datta, LW Maranville, JC Liu, ZQ Ellis, S Chopra, P Alexander, JS Baldassano, RN Cross, RK Dassopoulos, T Dhere, TA Duerr, RH Hanson, JS Hou, JK Hussain, SZ Isaacs, KL Kachelries, KE Kader, H Kappelman, MD Katz, J Kellermayer, R Kirschner, BS Kuemmerle, JF Kumar, A Kwon, JH Lazarev, M Mannon, P Moulton, DE Osuntokun, BO Patel, A Rioux, JD Rotter, JI Saeed, S Scherl, EJ Silverberg, MS Silverman, A Targan, SR Valentine, JF Wang, MH Simpson, CL Bridges, SL Kimberly, RP Rich, SS Cho, JH Di Rienzo, A Kao, LWH McGovern, DPB Brant, SR Kugathasan, S AF Huang, Chengrui Haritunians, Talin Okou, David T. Cutler, David J. Zwick, Michael E. Taylor, Kent D. Datta, Lisa W. Maranville, Joseph C. Liu, Zhenqiu Ellis, Shannon Chopra, Pankaj Alexander, Jonathan S. Baldassano, Robert N. Cross, Raymond K. Dassopoulos, Themistocles Dhere, Tanvi A. Duerr, Richard H. Hanson, John S. Hou, Jason K. Hussain, Sunny Z. Isaacs, Kim L. Kachelries, Kelly E. Kader, Howard Kappelman, Michael D. Katz, Jeffrey Kellermayer, Richard Kirschner, Barbara S. Kuemmerle, John F. Kumar, Archana Kwon, John H. Lazarev, Mark Mannon, Peter Moulton, Dedrick E. Osuntokun, Bankole O. Patel, Ashish Rioux, John D. Rotter, Jerome I. Saeed, Shehzad Scherl, Ellen J. Silverberg, Mark S. Silverman, Ann Targan, Stephan R. Valentine, John F. Wang, Ming-Hsi Simpson, Claire L. Bridges, S. Louis Kimberly, Robert P. Rich, Stephen S. Cho, Judy H. Di Rienzo, Anna Kao, Linda W. H. McGovern, Dermot P. B. Brant, Steven R. Kugathasan, Subra TI Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans SO GASTROENTEROLOGY LA English DT Article DE Race; Ethnicity; Genetic Variant; Intestinal Inflammation ID GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; JAPANESE POPULATION; ULCERATIVE-COLITIS; RISK; CAUCASIANS; ADMIXTURE; PREVALENCE; PREDICTORS; ANCESTRY AB BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 x 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 x 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 x 10(-6)). Additional suggestive associations (P < 4.2 x 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 x 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 x 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate < 1 x 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study. C1 [Huang, Chengrui; Kao, Linda W. H.; Brant, Steven R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21231 USA. [Haritunians, Talin; Liu, Zhenqiu; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA 90048 USA. [Okou, David T.; Kumar, Archana; Kugathasan, Subra] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Div Genom Outcomes, Torrance, CA 90509 USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Med, Torrance, CA 90509 USA. [Cutler, David J.; Zwick, Michael E.; Chopra, Pankaj] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Datta, Lisa W.; Ellis, Shannon; Lazarev, Mark; Wang, Ming-Hsi; Brant, Steven R.] Johns Hopkins Univ, Sch Med, Meyerhoff Inflammatory Bowel Dis Ctr, Dept Med, Baltimore, MD 21231 USA. [Maranville, Joseph C.; Di Rienzo, Anna] Univ Chicago, Comm Clin Pharmacol & Pharmacogen, Chicago, IL 60637 USA. [Maranville, Joseph C.; Di Rienzo, Anna] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Alexander, Jonathan S.] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71105 USA. [Baldassano, Robert N.; Kachelries, Kelly E.] Childrens Hosp Philadelphia, Div Gastroenterol & Nutr, Philadelphia, PA 19104 USA. [Cross, Raymond K.] Univ Maryland, Div Gastroenterol, Baltimore, MD 21201 USA. [Dassopoulos, Themistocles] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Dhere, Tanvi A.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Duerr, Richard H.] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. [Duerr, Richard H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Hanson, John S.] PLLC, Charlotte Gastroenterol & Hepatol, Charlotte, NC USA. [Hou, Jason K.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Hou, Jason K.] Michael E DeBakey VA Med Ctr, VA HSR&D Ctr Innovat Qual Effectiveness & Safety, Houston, TX USA. [Hussain, Sunny Z.] Willis Knighton Phys Network, Dept Pediat, Shreveport, LA USA. [Isaacs, Kim L.] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Kader, Howard] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Kappelman, Michael D.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Katz, Jeffrey] Case Western Reserve Univ, Div Gastroenterol, Cleveland, OH 44106 USA. [Kellermayer, Richard] Baylor Coll Med, Sect Pediat Gastroenterol, Houston, TX 77030 USA. [Kirschner, Barbara S.] Univ Chicago, Comer Childrens Hosp, Dept Pediat, Chicago, IL 60637 USA. [Kuemmerle, John F.] Virginia Commonwealth Univ, Dept Med, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Kuemmerle, John F.] Virginia Commonwealth Univ, Med Coll Virginia Campus, Dept Physiol & Biophys, VCU Program Enter Neuromuscular Sci, Richmond, VA 23298 USA. [Kwon, John H.] Univ Chicago, Dept Med, Gastroenterol Sect, Chicago, IL 60637 USA. [Mannon, Peter] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Moulton, Dedrick E.] Vanderbilt Childrens Hosp, Div Gastroenterol, Nashville, TN USA. [Osuntokun, Bankole O.] Cook Childrens Med Ctr, Dept Pediat, Ft Worth, TX USA. [Patel, Ashish] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Rioux, John D.] Univ Montreal, Montreal, PQ, Canada. [Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Saeed, Shehzad] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Scherl, Ellen J.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Silverberg, Mark S.] Univ Toronto, Samuel Lunenfeld Res Inst, Dept Med, Dept Surg,Dept Publ Hlth Sci,Dept Immunol, Toronto, ON, Canada. [Silverberg, Mark S.] Univ Toronto, Samuel Lunenfeld Res Inst, Dept Mol & Med Genet, Toronto, ON, Canada. [Silverberg, Mark S.] Toronto Gen Hosp, Mt Sinai Hosp, Res Inst, Toronto, ON, Canada. [Silverman, Ann] Henry Ford Hlth Syst, Dept Gastroenterol, Detroit, MI USA. [Valentine, John F.] Univ Utah, Div Gastroenterol Hepatol & Nutr, Salt Lake City, UT USA. [Simpson, Claire L.] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Bridges, S. Louis; Kimberly, Robert P.] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Rich, Stephen S.] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Cho, Judy H.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Brant, SR (reprint author), Johns Hopkins Univ, Sch Med, Meyerhoff Inflammatory Bowel Dis Ctr, 1501 E Jefferson St,B136, Baltimore, MD 21231 USA. EM sbrant@jhmi.edu RI Rioux, John/A-9599-2015; Silverberg, Mark/B-4183-2008; OI Rioux, John/0000-0001-7560-8326; Ellis, Shannon/0000-0002-9231-0481; Kimberly, Robert/0000-0002-5330-3086 FU National Institutes of Health (NIH) [DK062431, DK087694, DK062413, DK046763-19, AI067068, U54DE023789-01, DK062429, DK062422, DK062420, DK062432, DK062423]; Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center; Morton Hyatt Family; Buford and Linda Lewis family; Marcus foundation; Joshua L and Lisa Z Greer Endowed Chair; Agency for Healthcare Research and Quality [HS021747]; European Union [305479]; Leona M. and Harry B. Helmsley Charitable Trust; Veterans Administration HSR&D Center for Innovations in Quality, Effectiveness and Safety [CIN 13-413]; Michael E. DeBakey VA Medical Center; NIH/National Heart, Lung, and Blood Institute [HL06957]; Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR); NIH [N01-AR-02247, AR-62278, P01-AR49084, M01-RR-00032]; University of Alabama General Clinical Research Center [M01-RR-00032]; PROFILE Study group coordinated at the University of Alabama Birmingham; Type 1 Diabetes Genetics Consortium [U01 DK062418]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Center for Human Genome Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work supported by National Institutes of Health (NIH) grants DK062431 (S.R.B.), DK087694 (S.K.), DK062413 (D.P.B.M and K.T), DK046763-19, AI067068, and U54DE023789-01 (D.P.B.M.), DK062429 and DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), and DK062423 (M.S.S.). Additional support from Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center, the Morton Hyatt Family, the Buford and Linda Lewis family (S.R.B.); endowed professorship from Marcus foundation (S.K.); The Joshua L and Lisa Z Greer Endowed Chair, HS021747 from the Agency for Healthcare Research and Quality, grant 305479 from the European Union, and The Leona M. and Harry B. Helmsley Charitable Trust (D.P.B.M.); from the Veterans Administration HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413) and the Michael E. DeBakey VA Medical Center (J.K.H.). PARC control samples supported by NIH/National Heart, Lung, and Blood Institute grant HL06957 (Ronald M. Krauss, principal investigator). Rheumatoid arthritis control samples recruited and supported by the Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR), NIH grants N01-AR-02247 and AR-62278 (S.L.B.) and the University of Alabama General Clinical Research Center (M01-RR-00032); systemic lupus erythematosus control samples recruited and supported by the PROFILE Study group coordinated at the University of Alabama Birmingham and supported by NIH grants P01-AR49084 (R.P.K.) and M01-RR-00032; type 1 diabetes control samples recruited and supported by the Type 1 Diabetes Genetics Consortium U01 DK062418 (S.S.R.), and sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Center for Human Genome Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Juvenile Diabetes Research Foundation. C.L.S. is supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 37 TC 13 Z9 13 U1 2 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2015 VL 149 IS 6 BP 1575 EP 1586 DI 10.1053/j.gastro.2015.07.065 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CW6GN UT WOS:000365095800046 PM 26278503 ER PT J AU Park, JE Vanegas-Arroyave, N Hallett, M Lungu, C AF Park, Jung E. Vanegas-Arroyave, Nora Hallett, Mark Lungu, Codrin TI A Woman With a Novel Mutation of THAP1 With a Prominent Response to Deep Brain Stimulation of the Globus Pallidus Internus SO JAMA NEUROLOGY LA English DT Editorial Material ID DYSTONIA C1 [Park, Jung E.; Vanegas-Arroyave, Nora; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Vanegas-Arroyave, Nora; Lungu, Codrin] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Park, JE (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,Bldg 10,Room 7D42, Bethesda, MD 20892 USA. EM junge.park@nih.gov FU Intramural NIH HHS NR 4 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD NOV PY 2015 VL 72 IS 11 BP 1369 EP 1369 DI 10.1001/jamaneurol.2015.1954 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CW1ZO UT WOS:000364790900023 PM 26415042 ER PT J AU Freeman, WD Brazis, PW Biller, J Masdeu, JC Merrilees, GR Olson, S AF Freeman, William David Brazis, Paul W. Biller, Jose Masdeu, Joseph C. Merrilees, G. Robert Olson, Sandra TI In Memoriam: Frank A. Rubino, MD SO JAMA NEUROLOGY LA English DT Biographical-Item C1 [Freeman, William David; Brazis, Paul W.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Biller, Jose] Loyola Univ Chicago, Stritch Sch Med, Dept Neurol, Maywood, IL USA. [Masdeu, Joseph C.] NIMH, Clin Brain Disorders Branch, Sect Integrat Neuroimaging, Intramural Res Program,Dept Neurol,NIH, Bethesda, MD 20892 USA. [Merrilees, G. Robert] US Coast Guard, Natl Aeronaut & Space Adm, Merritt Isl, FL USA. [Olson, Sandra] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Freeman, WD (reprint author), Mayo Clin, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM freeman.william1@mayo.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD NOV PY 2015 VL 72 IS 11 BP 1384 EP 1385 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CW1ZO UT WOS:000364790900032 PM 26551966 ER PT J AU Takeuchi, M Kastner, DL Remmers, EF AF Takeuchi, Masaki Kastner, Daniel L. Remmers, Elaine F. TI The immunogenetics of Behcet's disease: A comprehensive review SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Behcet's disease; GWAS; HLA-B*51; ERAP1; Disease-associated genetic variants ID GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; FAMILIAL MEDITERRANEAN FEVER; HLA CLASS-I; PSORIASIS SUSCEPTIBILITY LOCI; MHC CLASS-I; ANKYLOSING-SPONDYLITIS; GENETIC ASSOCIATION; JAPANESE PATIENTS; CHINESE HAN AB Behcet's disease is a chronic multisystem inflammatory disorder characterized mainly by recurrent oral ulcers, ocular involvement, genital ulcers, and skin lesions, presenting with remissions and exacerbations. It is thought that both environmental and genetic factors contribute to its onset and development. Although the etiology of Behget's disease remains unclear, recent immunogenetic findings are providing clues to its pathogenesis. In addition to the positive association of HLA-B*51, which was identified more than four decades ago, and which has since been confirmed in multiple populations, recent studies report additional independent associations in the major histocompatibility complex class I region. HLA-B*15, -B*27, -B*57, and -A*26 are independent risk factors for Behget's disease, while HLA-B*49 and -A*03 are independent class I alleles that are protective for Behcet's disease. Genome-wide association studies have identified associations with genome-wide significance (P < 5 x 10(-8)) in the IL23R-1L12RB2, STAT4, CCR1-CCR3, KLRC4, ERAP1, TNFAIP3, and FUT2 loci. In addition, targeted next-generation sequencing has revealed the involvement of rare nonsynonymous variants of IL23R, TLR4, NOD2, and MEW in Behcet's disease pathogenesis. Significant differences in gene function or mRNA expression associated with the risk alleles of the disease susceptibility loci suggest which genes in a disease-associated locus influence disease pathogenesis. These genes encompass both innate and adaptive immunity and confirm the importance of the predominant polarization towards helper T cell (Th) 1 versus Th2 cells, and the involvement of Th17 cells. In addition, epistasis observed between HLA-B*51 and the risk coding haplotype of the endoplasmic reticulum-associated protease, ERAPI, provides a clue that an HLA class I-peptide presentation-based mechanism contributes to this complex disease. Published by Elsevier Ltd. C1 [Takeuchi, Masaki; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, Bethesda, MD 20892 USA. [Takeuchi, Masaki] Yokohama City Univ, Grad Sch Med, Ophthalmol & Visual Sci, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. RP Remmers, EF (reprint author), NHGRI, Inflammatory Dis Sect, Metab Cardiovasc & Inflammatory Dis Genom Branch, NIH, Bethesda, MD 20892 USA. EM elaine.remmers@nih.gov FU Intramural NIH HHS [Z99 HG999999, Z01 AR041083-19] NR 134 TC 18 Z9 19 U1 2 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD NOV PY 2015 VL 64 SI SI BP 137 EP 148 DI 10.1016/j.jaut.2015.08.013 PG 12 WC Immunology SC Immunology GA CW3LT UT WOS:000364894500013 PM 26347074 ER PT J AU Glaser, R Dimitrakakis, C AF Glaser, R. Dimitrakakis, C. TI Testosterone and breast cancer prevention SO MATURITAS LA English DT Review DE Testosterone; Breast cancer; Prevention; Aromatase; Anastrozole; Therapy ID AROMATASE EXPRESSION; ANDROGEN RECEPTOR; HORMONE-THERAPY; WOMEN; TISSUE; INFLAMMATION; ANASTROZOLE; INHIBITOR AB Testosterone (T) is the most abundant biologically active hormone in women. Androgen receptors (AR) are located throughout the body including the breast where T decreases tissue proliferation. However, T can be aromatized to estradiol (E2), which increases proliferation and hence, breast cancer (BCA) risk. Increased aromatase expression and an imbalance in the ratio of stimulatory estrogens to protective androgens impacts breast homeostasis. Recent clinical data supports a role for T in BCA prevention. Women with symptoms of hormone deficiency treated with pharmacological doses of T alone or in combination with anastrozole (A), delivered by subcutaneous implants, had a reduced incidence of BCA. In addition, T combined with A effectively treated symptoms of hormone deficiency in BCA survivors and was not associated with recurrent disease. Most notably, T+A implants placed in breast tissue surrounding malignant tumors significantly reduced BCA tumor size, further supporting T direct antiproliferative, protective and therapeutic effect. (C) 2015 The Authors. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Glaser, R.] Millennium Wellness Ctr, Dayton, OH 45458 USA. [Glaser, R.] Wright State Univ, Boonshoft Sch Med, Dept Surg, Dayton, OH 45435 USA. [Dimitrakakis, C.] Univ Athens, Sch Med, Dept Ob Gyn 1, Athens 11528, Greece. [Dimitrakakis, C.] NICHD, NIH, Bethesda, MD 20892 USA. RP Glaser, R (reprint author), Millennium Wellness Ctr, 228 E Spring Valley Rd, Dayton, OH 45458 USA. EM rglaser@woh.rr.com; rglasermd@gmail.com NR 30 TC 4 Z9 4 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 EI 1873-4111 J9 MATURITAS JI Maturitas PD NOV PY 2015 VL 82 IS 3 BP 291 EP 295 DI 10.1016/j.maturitas.2015.06.002 PG 5 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA CW3HQ UT WOS:000364883000009 PM 26160683 ER PT J AU Blanchard, H Chang, LS Rezvani, AH Rapoport, SI Taha, AY AF Blanchard, Helene Chang, Lisa Rezvani, Amir H. Rapoport, Stanley I. Taha, Ameer Y. TI Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression SO NEUROCHEMICAL RESEARCH LA English DT Article DE Depression model; Arachidonic acid; Turnover; Metabolism; Flinders Sensitive Line rat; Fatty acids; Brain lipid concentrations; Kinetic ID POSITRON-EMISSION-TOMOGRAPHY; CHRONIC ANTIDEPRESSANT TREATMENT; THIN-LAYER CHROMATOGRAPHY; GENETIC ANIMAL-MODEL; PHOSPHOLIPASE A(2); UNANESTHETIZED RATS; SEROTONIN TRANSPORTER; RECEPTOR-BINDING; REUPTAKE TRANSPORTER; SIGNAL-TRANSDUCTION AB Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A(2). Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, C-14-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague-Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA. C1 [Blanchard, Helene; Chang, Lisa; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. [Rezvani, Amir H.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Taha, Ameer Y.] Univ Calif Davis, Coll Agr & Environm Sci, Dept Food Sci & Technol, Davis, CA 95616 USA. RP Taha, AY (reprint author), Univ Calif Davis, Coll Agr & Environm Sci, Dept Food Sci & Technol, RMI North,Room 3162, Davis, CA 95616 USA. EM ataha@ucdavis.edu FU National Institute on Aging FX Research was supported by the Intramural Research Program of the National Institute on Aging. NR 50 TC 0 Z9 0 U1 2 U2 5 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 NOV PY 2015 VL 40 IS 11 BP 2293 EP 2303 DI 10.1007/s11064-015-1719-6 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CW6CQ UT WOS:000365085500014 PM 26404538 ER PT J AU Song, SB Garrido, L Nagy, Z Mohammadi, S Steel, A Driver, J Dolan, RJ Duchaine, B Furl, N AF Song, Sunbin Garrido, Lucia Nagy, Zoltan Mohammadi, Siawoosh Steel, Adam Driver, Jon Dolan, Ray J. Duchaine, Bradley Furl, Nicholas TI Local but not long-range microstructural differences of the ventral temporal cortex in developmental prosopagnosia SO NEUROPSYCHOLOGIA LA English DT Article DE Diffusion-weighted imaging; Inferior longitudinal fasciculus; Inferior fronto-occipital fasciculus; Prosopagnosia; Face perception; Individual differences ID DIFFUSION TENSOR TRACTOGRAPHY; FACE PROCESSING NETWORK; CONGENITAL PROSOPAGNOSIA; DETAILED EXPLORATION; ALZHEIMERS-DISEASE; WEIGHTED MRI; SPIN-ECHO; CONNECTIVITY; RECOGNITION; SUBJECT AB Individuals with developmental prosopagnosia (DP) experience face recognition impairments despite normal intellect and low-level vision and no history of brain damage. Prior studies using diffusion tensor imaging in small samples of subjects with DP (n=6 or n=8) offer conflicting views on the neurobiological bases for DP, with one suggesting white matter differences in two major long-range tracts running through the temporal cortex, and another suggesting white matter differences confined to fibers local to ventral temporal face-specific functional regions of interest (fROIs) in the fusiform gyrus. Here, we address these inconsistent findings using a comprehensive set of analyzes in a sample of DP subjects larger than both prior studies combined (n=16). While we found no microstructural differences in long-range tracts between DP and age-matched control participants, we found differences local to face-specific fROIs, and relationships between these microstructural measures with face recognition ability. We conclude that subtle differences in local rather than long-range tracts in the ventral temporal lobe are more likely associated with developmental prosopagnosia. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Song, Sunbin; Steel, Adam] NIH, Human Cort Physiol Sect, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Garrido, Lucia] Brunel Univ, Div Psychol, Dept Life Sci, Uxbridge UB8 3PH, Middx, England. [Nagy, Zoltan] Univ Zurich, Lab Social & Neural Syst Res SNS Lab, CH-8091 Zurich, Switzerland. [Nagy, Zoltan; Mohammadi, Siawoosh; Driver, Jon; Dolan, Ray J.] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Mohammadi, Siawoosh] Univ Med Ctr Hamburg Eppendorf, Dept Syst Neurosci, Hamburg, Germany. [Driver, Jon] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Duchaine, Bradley] Dartmouth Coll, Psychol & Brain Sci, Hanover, NH 03755 USA. [Furl, Nicholas] Univ London, Royal Holloway & Bedford New Coll, Dept Psychol, Egham TW20 0EX, Surrey, England. RP Song, SB (reprint author), NIH, Human Cort Physiol Sect, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. EM songss@mail.nih.gov RI Mohammadi, Siawoosh/H-9539-2012; OI Mohammadi, Siawoosh/0000-0003-1311-9636; furl, nicholas/0000-0003-2488-1343; Steel, Adam/0000-0001-8876-933X; Nagy, Zoltan/0000-0001-6611-6362 FU ESRC [RES-061-23-0040]; Deutsche Forschungsgemeinschaft (DFG) [MO 2397/1-1]; Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/22580/2005]; Wellcome Trust [079866/Z/06/Z] FX We are grateful to our DP participants for their involvement in the study. Funding was provided by ESRC (RES-061-23-0040) to B. D., by the Deutsche Forschungsgemeinschaft (DFG, MO 2397/1-1) to S.M., and by the Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BD/22580/2005) to L.G. The Wellcome Trust (079866/Z/06/Z) to Z.N., N.F., S.M. covered scanning costs. NR 60 TC 10 Z9 10 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD NOV PY 2015 VL 78 BP 195 EP 206 DI 10.1016/j.neuropsychologia.2015.10.010 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA CW5RH UT WOS:000365053800020 PM 26456436 ER PT J AU Svetkey, LP Batch, BC Lin, PH Intille, SS Corsino, L Tyson, CC Bosworth, HB Grambow, SC Voils, C Loria, C Gallis, JA Schwager, J Bennett, GB AF Svetkey, Laura P. Batch, Bryan C. Lin, Pao-Hwa Intille, Stephen S. Corsino, Leonor Tyson, Crystal C. Bosworth, Hayden B. Grambow, Steven C. Voils, Corrine Loria, Catherine Gallis, John A. Schwager, Jenifer Bennett, Gary B. TI Cell phone intervention for you (CITY): A randomized, controlled trial of behavioral weight loss intervention for young adults using mobile technology SO OBESITY LA English DT Article ID BODY-MASS INDEX; CLINICAL-TRIALS; PHYSICAL-ACTIVITY; BLOOD-PRESSURE; RISK; DIET; OVERWEIGHT; PREVENTION; STRATEGIES; SUCCESS AB ObjectiveTo determine the effect on weight of two mobile technology-based (mHealth) behavioral weight loss interventions in young adults. MethodsRandomized, controlled comparative effectiveness trial in 18- to 35-year-olds with BMI25 kg/m(2) (overweight/obese), with participants randomized to 24 months of mHealth intervention delivered by interactive smartphone application on a cell phone (CP); personal coaching enhanced by smartphone self-monitoring (PC); or Control. ResultsThe 365 randomized participants had mean baseline BMI of 35 kg/m(2). Final weight was measured in 86% of participants. CP was not superior to Control at any measurement point. PC participants lost significantly more weight than Controls at 6 months (net effect -1.92 kg [CI -3.17, -0.67], P=0.003), but not at 12 and 24 months. ConclusionsDespite high intervention engagement and study retention, the inclusion of behavioral principles and tools in both interventions, and weight loss in all treatment groups, CP did not lead to weight loss, and PC did not lead to sustained weight loss relative to Control. Although mHealth solutions offer broad dissemination and scalability, the CITY results sound a cautionary note concerning intervention delivery by mobile applications. Effective intervention may require the efficiency of mobile technology, the social support and human interaction of personal coaching, and an adaptive approach to intervention design. C1 [Svetkey, Laura P.; Lin, Pao-Hwa; Tyson, Crystal C.; Schwager, Jenifer] Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. [Svetkey, Laura P.; Lin, Pao-Hwa; Schwager, Jenifer] Duke Mol Physiol Inst, Sarah W Stedman Nutr & Metab Ctr, Durham, NC USA. [Batch, Bryan C.; Corsino, Leonor] Duke Univ, Med Ctr, Dept Med, Div Endocrinol Metab & Nutr, Durham, NC 27710 USA. [Intille, Stephen S.] Northeastern Univ, Coll Comp & Informat Sci, Boston, MA 02115 USA. [Intille, Stephen S.] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Bosworth, Hayden B.; Voils, Corrine] Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC 27710 USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Sch Nursing, Durham, NC 27710 USA. [Bosworth, Hayden B.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Grambow, Steven C.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Gallis, John A.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Bennett, Gary B.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27710 USA. [Bennett, Gary B.] Duke Univ, Med Ctr, Duke Obes Prevent Program, Durham, NC 27710 USA. RP Svetkey, LP (reprint author), Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. EM svetk001@mc.duke.edu RI Emchi, Karma/Q-1952-2016 FU National Heart, Lung, and Blood Institute, a component of the National Institutes of Health (NIH) [U01HL096720] FX The CITY study was sponsored by grant number U01HL096720 from the National Heart, Lung, and Blood Institute, a component of the National Institutes of Health (NIH). NR 37 TC 9 Z9 9 U1 5 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2015 VL 23 IS 11 BP 2133 EP 2141 DI 10.1002/oby.21226 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CV9SG UT WOS:000364626300001 PM 26530929 ER PT J AU Gluck, ME Alonso-Alonso, M Piaggi, P Weise, CM Jumpertz-von Schwartzenberg, R Reinhardt, M Wassermann, EM Venti, CA Votruba, SB Krakoff, J AF Gluck, Marci E. Alonso-Alonso, Miguel Piaggi, Paolo Weise, Christopher M. Jumpertz-von Schwartzenberg, Reiner Reinhardt, Martin Wassermann, Eric M. Venti, Colleen A. Votruba, Susanne B. Krakoff, Jonathan TI Neuromodulation targeted to the prefrontal cortex induces changes in energy intake and weight loss in obesity SO OBESITY LA English DT Article ID DIRECT-CURRENT STIMULATION; BRAIN POLARIZATION; FOOD-CONSUMPTION; LESS ACTIVATION; SELF-CONTROL; LEAN WOMEN; HUMANS; MEAL; SATIATION; SYSTEM AB ObjectiveObesity is associated with decreased activity in the prefrontal cortex. Transcranial direct current stimulation (tDCS) modifies cortical excitability and may facilitate improved control of eating. The energy intake (EI) and body weight in subjects who received cathodal versus sham (study 1) and subsequent anodal versus sham (study 2) tDCS aimed at the left dorsolateral prefrontal cortex (LDLPFC) were measured. MethodsNine (3m, 6f) healthy volunteers with obesity (9415 kg [MSD]; 42 +/- 8 y) were admitted as inpatients for 9 days to participate in a double-blind, randomized, placebo-controlled crossover experiment. Study 1: following 5 days of a weight-maintaining diet, participants received cathodal or sham tDCS (2mA, 40min) on three consecutive mornings and then ate ad libitum from a computerized vending machine, which recorded EI. Weight was measured daily. Study 2: participants repeated the study, maintaining original assignment to active (this time anodal) and sham. ResultsParticipants tended to consume fewer kilocalories per day (P=0.07), significantly fewer kilocalories from soda (P=0.02) and fat (P=0.03), and had a greater % weight loss (P=0.009) during anodal versus cathodal tDCS. ConclusionsThe results indicated a role for the LDLPFC in obesity and food intake. This proof of concept study suggested, for the first time, the potential application of anodal tDCS to facilitate weight loss. C1 [Gluck, Marci E.; Piaggi, Paolo; Weise, Christopher M.; Jumpertz-von Schwartzenberg, Reiner; Reinhardt, Martin; Venti, Colleen A.; Votruba, Susanne B.; Krakoff, Jonathan] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Alonso-Alonso, Miguel] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Lab Bariatr & Nutr Neurosci,Ctr Study Nutr Med, Boston, MA USA. [Weise, Christopher M.] Univ Leipzig, Dept Neurol, D-04109 Leipzig, Germany. [Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. RP Gluck, ME (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM gmarci@mail.nih.gov FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Boston Nutrition and Obesity Research Center [P30 DK046200]; Nutrition Obesity Research Center at Harvard [P30 DK040561]; Center for Nutritional Research Charitable Trust FX This research was funded by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Alonso-Alonso is a recipient of grants from the Boston Nutrition and Obesity Research Center, P30 DK046200, the Nutrition Obesity Research Center at Harvard, P30 DK040561, and the Center for Nutritional Research Charitable Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 9 Z9 9 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2015 VL 23 IS 11 BP 2149 EP 2156 DI 10.1002/oby.21313 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CV9SG UT WOS:000364626300003 PM 26530931 ER PT J AU Solomon, SB Cortes-Puch, I Sun, JF Remy, KE Wang, D Feng, J Khan, SS Sinchar, D Kim-Shapiro, DB Klein, HG Natanson, C AF Solomon, Steven B. Cortes-Puch, Irene Sun, Junfeng Remy, Kenneth E. Wang, Dong Feng, Jing Khan, Sameena S. Sinchar, Derek Kim-Shapiro, Daniel B. Klein, Harvey G. Natanson, Charles TI Transfused older stored red blood cells improve the clinical course and outcome in a canine lethal hemorrhage and reperfusion model SO TRANSFUSION LA English DT Article ID INHALED NITRIC-OXIDE; STORAGE DURATION; CARDIAC-SURGERY; FREE HEMOGLOBIN; SHOCK; IRON; RESUSCITATION; TRIAL; INFLAMMATION; INJURY AB BACKGROUNDIn canine models, transfused older stored red blood cells (RBCs) hemolyze in vivo resulting in significantly increased intravascular cell-free hemoglobin (CFH) and non-transferrin-bound iron (NTBI). During canine bacterial pneumonia with septic shock, but not in controls, older stored RBCs were associated with significantly increased lung injury and mortality. It is unknown if in shock without infection transfusion of older RBCs will result in similar adverse effects. STUDY DESIGN AND METHODSTwo-year-old purpose-bred beagles (n=12) were transfused similar quantities of either older (42-day) or fresher (7-day) stored universal donor canine RBCs 2.5 hours after undergoing controlled hemorrhage (55 mL/kg). RESULTSWith older transfused RBCs, CFH (p<0.0001) and NTBI (p=0.004) levels increased, but lung injury (p=0.01) and C-reactive protein levels (p=0.002) declined and there was a trend toward lower mortality (18% vs. 50%). All three deaths after transfused fresher RBCs resulted from hepatic fractures. Lowered exogenous norepinephrine requirements (p<0.05) and cardiac outputs (p<0.05) after older transfused RBCs were associated with increased CFH levels that have known vasoconstrictive nitric oxide scavenging capability. CONCLUSIONSIn hemorrhagic shock, older RBCs altered resuscitation physiology but did not worsen clinical outcomes. Elevated CFH may lower norepinephrine requirements and cardiac outputs ameliorating reperfusion injuries. With hemorrhagic shock, NTBI levels persist in contrast to the increased clearance, lung injury, and mortality in the previously reported infection model. These preclinical data suggest that whereas iron derived from older RBCs promotes bacterial growth, worsening septic shock mortality during infection, release of CFH and NTBI during hemorrhagic shock is not necessarily harmful. C1 [Solomon, Steven B.; Cortes-Puch, Irene; Sun, Junfeng; Remy, Kenneth E.; Wang, Dong; Feng, Jing; Khan, Sameena S.; Natanson, Charles] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Khan, Sameena S.] Univ Coll Dublin, Dublin 2, Ireland. [Sinchar, Derek] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Klein, Harvey G.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Solomon, SB (reprint author), NIH, Ctr Clin, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM SSolomon@cc.nih.gov FU US government; NIH [HL058091, HL098032] FX The work by the authors was done as part of US government-funded research; however, the opinions expressed are not necessarily those of the National Institutes of Health.; Supported by intramural NIH funds. NIH external grants HL058091 and HL098032 were used to support this study. NR 44 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2015 VL 55 IS 11 BP 2552 EP 2563 DI 10.1111/trf.13213 PG 12 WC Hematology SC Hematology GA CW3EZ UT WOS:000364876100006 PM 26175134 ER PT J AU Cortes-Puch, I Remy, KE Solomon, SB Sun, JF Wang, D Al-Hamad, M Kelly, SM Sinchar, D Bellavia, L Kanias, T Popovsky, MA Kim-Shapiro, DB Klein, HG Natanson, C AF Cortes-Puch, Irene Remy, Kenneth E. Solomon, Steven B. Sun, Junfeng Wang, Dong Al-Hamad, Mariam Kelly, Seth M. Sinchar, Derek Bellavia, Landon Kanias, Tamir Popovsky, Mark A. Kim-Shapiro, Daniel B. Klein, Harvey G. Natanson, Charles TI In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome SO TRANSFUSION LA English DT Article ID IN-HOSPITAL MORTALITY; STORED-BLOOD; STAPHYLOCOCCUS-AUREUS; STORAGE DURATION; CARDIAC-SURGERY; FREE HEMOGLOBIN; NITRIC-OXIDE; IRON; ASSOCIATION; FRESH AB BACKGROUNDMassive exchange transfusion of 42-day-old red blood cells (RBCs) in a canine model of Staphylococcus aureus pneumonia resulted in in vivo hemolysis with increases in cell-free hemoglobin (CFH), transferrin-bound iron (TBI), non-transferrin-bound iron (NTBI), and mortality. We have previously shown that washing 42-day-old RBCs before transfusion significantly decreased NTBI levels and mortality, but washing 7-day-old RBCs increased mortality and CFH levels. We now report the results of altering volume, washing, and age of RBCs. STUDY DESIGN AND METHODSTwo-year-old purpose-bred infected beagles were transfused with increasing volumes (5-10, 20-40, or 60-80 mL/kg) of either 42- or 7-day-old RBCs (n=36) or 80 mL/kg of either unwashed or washed RBCs with increasing storage age (14, 21, 28, or 35 days; n=40). RESULTSAll volumes transfused (5-80 mL/kg) of 42-day-old RBCs resulted in alike (i.e., not significantly different) increases in TBI during transfusion as well as in CFH, lung injury, and mortality rates after transfusion. Transfusion of 80 mL/kg RBCs stored for 14, 21, 28, and 35 days resulted in increased CFH and NTBI in between levels found at 7 and 42 days of storage. However, washing RBCs of intermediate ages (14-35 days) does not alter NTBI and CFH levels or mortality rates. CONCLUSIONSPreclinical data suggest that any volume of 42-day-old blood potentially increases risks during established infection. In contrast, even massive volumes of 7-day-old blood result in minimal CFH and NTBI levels and risks. In contrast to the extremes of storage, washing blood stored for intermediate ages does not alter risks of transfusion or NTBI and CFH clearance. C1 [Cortes-Puch, Irene; Remy, Kenneth E.; Solomon, Steven B.; Sun, Junfeng; Wang, Dong; Al-Hamad, Mariam; Kelly, Seth M.; Natanson, Charles] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Klein, Harvey G.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Sinchar, Derek; Kanias, Tamir] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Bellavia, Landon; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Bellavia, Landon; Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Bellavia, Landon] Univ Findlay, Dept Phys, Findlay, OH USA. [Popovsky, Mark A.] Haemonet Corp, Braintree, MA USA. RP Cortes-Puch, I (reprint author), NIH, Ctr Clin, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM irene.cortes-puch@nih.gov RI Kanias, Tamir/K-2384-2016 OI Kanias, Tamir/0000-0001-6558-0913 FU Haemonetics (Braintree, MA) FX Haemonetics (Braintree, MA) funded 10% of the study costs and provided the ACP215 (automated cell processing system) as well as the disposable kits (RBC deglycerol set 325 mL BMB Ref. 236) used throughout the experiments. NR 51 TC 7 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2015 VL 55 IS 11 BP 2564 EP 2575 DI 10.1111/trf.13275 PG 12 WC Hematology SC Hematology GA CW3EZ UT WOS:000364876100007 PM 26469998 ER PT J AU Flegel, WA Gottschall, JL Denomme, GA AF Flegel, Willy A. Gottschall, Jerome L. Denomme, Gregory A. TI Implementing mass-scale red cell genotyping at a blood center SO TRANSFUSION LA English DT Article ID APPLYING MOLECULAR IMMUNOHEMATOLOGY; DONORS; TIME; STRATEGY; PLATFORM; ALLELES AB BACKGROUNDWhen problems with compatibility beyond ABO and D arise, currently transfusion services search their inventories and perform time-consuming serologic testing to locate antigen-negative blood. These clinically important blood group antigens can be detected reliably by red cell genotyping, which is a technology whereby DNA-based techniques are used to evaluate gene polymorphisms that determine the expression of blood group antigens. We introduced mass-scale genotyping and measured availability of genotyped blood. STUDY DESIGN AND METHODSAll non-Caucasian donors qualified for genotyping along with donors who had a history of repeat donation. Mass-scale red cell genotyping, performed on an electronic interfaced open array platform, was implemented to screen blood donors for 32 single-nucleotide polymorphisms that predicted 42 blood group antigens. Genotype screening results were confirmed by phenotyping, when needed for antigen-negative transfusion, before release of the red blood cell (RBC) unit. RESULTSApproximately 22,000 donors were red cell genotyped within 4 months and a total of 43,066 donors in 4 years. There were 463 discordances (0.52% of 89,596 genotypes with a phenotype). Among the 307 resolved discordances, approximate equal numbers represented historical serologic or genotyping discrepancies (n=151 and n=156, respectively). In the final year of the study, a mean of 29% of the daily inventory had a genotype. CONCLUSIONSRed cell genotyping of blood donors using an electronic interface created a large and stable supply of RBC units with historical genotypes. The database served the needs of antigen-negative blood requests for a large regional blood center and allowed us to abandon screening by serology. C1 [Flegel, Willy A.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Gottschall, Jerome L.] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI USA. [Gottschall, Jerome L.; Denomme, Gregory A.] BloodCtr Wisconsin, Diagnost Labs, Milwaukee, WI 53201 USA. RP Denomme, GA (reprint author), BloodCtr Wisconsin, Diagnost Labs, 638 N 18th St,POB 2178, Milwaukee, WI 53201 USA. EM greg.denomme@bcw.edu OI Denomme, Gregory/0000-0001-8727-1679 FU BloodCenter of Wisconsin Diagnostic Laboratories Strategic Initiative; NIH Clinical Center FX This work was supported by a BloodCenter of Wisconsin Diagnostic Laboratories Strategic Initiative and the Intramural Research Program of the NIH Clinical Center. NR 27 TC 5 Z9 5 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD NOV PY 2015 VL 55 IS 11 BP 2610 EP 2615 DI 10.1111/trf.13168 PG 6 WC Hematology SC Hematology GA CW3EZ UT WOS:000364876100013 PM 26094790 ER PT J AU Peters, JM Gonzalez, FJ Muller, R AF Peters, Jeffrey M. Gonzalez, Frank J. Mueller, Rolf TI Establishing the Role of PPAR beta/delta in Carcinogenesis SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID ACTIVATED-RECEPTOR-BETA/DELTA; ANGIOPOIETIN-LIKE 4; CANCER-CELL-LINES; PROMOTES VENOUS INVASION; COLON-CANCER; VASCULAR-PERMEABILITY; EXPRESSION PATTERNS; SIGNALING PATHWAY; MICROARRAY DATA; RETINOIC ACID AB The role of the nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in carcinogenesis is controversial because conflicting studies indicate that it both inhibits and promotes tumorigenesis. In this review, we focus on recent studies on PPAR beta/delta including the significance of increased or decreased PPAR beta/delta expression in cancers; a range of opposing mechanisms describing how PPAR beta/delta agonists, antagonists, and inverse agonists regulate tumorigenesis and/or whether there may be cell context-specific mechanisms; and whether activating or inhibiting PPAR beta/delta is feasible for cancer chemoprevention and/or therapy. Research questions that need to be addressed are highlighted to establish whether PPAR beta/delta can be effectively targeted for cancer chemoprevention. C1 [Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Mueller, Rolf] Univ Marburg, Ctr Tumor Biol & Immunol, Inst Mol Biol & Tumor Res, D-35043 Marburg, Germany. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Muller, Rolf/L-4997-2016 OI Muller, Rolf/0000-0003-3339-4248 FU National Cancer Institute [CA124533, CA141029]; Intramural Research Program of the National Institutes of Health [1ZIAB0005561, 1ZIABC005562, 1ZIABC005708]; Deutsche Forschungsgemeinschaft [MU601/13] FX The authors gratefully acknowledge Till Adhikary for constructive comments, and apologize to all scientists whose relevant work was not cited owing to the space limitations of this review. This work was supported by the National Cancer Institute grants CA124533, CA141029 to J.M.P., by the Intramural Research Program of the National Institutes of Health (1ZIAB0005561, 1ZIABC005562, 1ZIABC005708) to F.J.G., and a grant from the Deutsche Forschungsgemeinschaft (MU601/13) to R.M. NR 87 TC 8 Z9 8 U1 3 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD NOV PY 2015 VL 26 IS 11 BP 595 EP 607 DI 10.1016/j.tem.2015.09.004 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CW3LR UT WOS:000364894300005 PM 26490384 ER PT J AU Birger, RB Kouyos, RD Cohen, T Griffiths, EC Huijben, S Mina, MJ Volkova, V Grenfell, B Metcalf, CJE AF Birger, Ruthie B. Kouyos, Roger D. Cohen, Ted Griffiths, Emily C. Huijben, Silvie Mina, Michael J. Volkova, Victoriya Grenfell, Bryan Metcalf, C. Jessica E. TI The potential impact of coinfection on antimicrobial chemotherapy and drug resistance (vol 23, pg 537, 2015) SO TRENDS IN MICROBIOLOGY LA English DT Correction C1 [Birger, Ruthie B.; Mina, Michael J.; Grenfell, Bryan; Metcalf, C. Jessica E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Kouyos, Roger D.] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Kouyos, Roger D.] Univ Zurich, Inst Med Virol, Zurich, Switzerland. [Cohen, Ted] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Griffiths, Emily C.] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Huijben, Silvie] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain. [Mina, Michael J.] Emory Univ, Sch Med, Med Scientist Training Program, Atlanta, GA USA. [Volkova, Victoriya] Kansas State Univ, Coll Vet Med, Inst Computat Comparat Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. [Grenfell, Bryan; Metcalf, C. Jessica E.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Birger, RB (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM rbirger@princeton.edu NR 1 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD NOV PY 2015 VL 23 IS 11 BP 742 EP 742 DI 10.1016/j.tim.2015.09.001 PG 1 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA CW3IA UT WOS:000364884200009 ER PT J AU Brenner, P Mayr, T Guethoff, S Buchholz, S Poettinger, T Lutzmann, I Werner, F Bauer, A Klymiuk, N Wolf, E Reimann, K Mohiuddin, M Hermanns, W Ayares, D McGregor, C Lambris, JD Hagl, C Reichart, B Abicht, JM AF Brenner, Paolo Mayr, Tanja Guethoff, Sonja Buchholz, Stefan Poettinger, Thomas Lutzmann, Isabelle Werner, Fabian Bauer, Andreas Klymiuk, Nikolai Wolf, Eckhard Reimann, Keith Mohiuddin, Muhammad Hermanns, Walter Ayares, David McGregor, Christopher Lambris, John D. Hagl, Christian Reichart, Bruno Abicht, Jan-Michael TI CD40mAb costimulation blockade in (life-supporting) heterotopic and orthotopic cardiac xenotransplantation models with GalT-KO/hCD46/hTM transgenic donor pigs into the baboon SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT IPITA/IXA/CTS Joint Congress CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP IPITA, IXA, CTS C1 [Brenner, Paolo; Mayr, Tanja; Guethoff, Sonja; Buchholz, Stefan; Poettinger, Thomas; Lutzmann, Isabelle; Werner, Fabian; Hagl, Christian] Univ Munich, Dept Cardiac Surg, Munich, Germany. [Brenner, Paolo; Mayr, Tanja; Guethoff, Sonja; Poettinger, Thomas; Lutzmann, Isabelle; Werner, Fabian; Reichart, Bruno; Abicht, Jan-Michael] Univ Munich, Walter Brendel Ctr, Munich, Germany. [Bauer, Andreas; Abicht, Jan-Michael] Univ Munich, Dept Anaesthesiol, Munich, Germany. [Klymiuk, Nikolai; Wolf, Eckhard] Univ Munich, Dept Mol Anim Breeding & Biotechnol, Munich, Germany. [Reimann, Keith] Univ Massachusetts, Sch Med, MassBiol, Boston, MA 02125 USA. [Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Lab, NIH, Bethesda, WA USA. [Hermanns, Walter] Univ Munich, Dept Vet Pathol, Munich, Germany. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. [McGregor, Christopher] UCL, Dept Cardiothorac Surg, London, England. [Lambris, John D.] Univ Penn, Pathol & Lab Med, Philadelphia, PA 19104 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV PY 2015 VL 22 SU 1 SI SI MA 815 BP S146 EP S146 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA CV9FY UT WOS:000364594100351 ER PT J AU Miller, J Singh, A Eckhaus, M Corcoran, P Thomas, M Lewis, B Reimann, K Ayares, D Horvath, K Mohiuddin, M AF Miller, Justin Singh, Avneesh Eckhaus, Michael Corcoran, Philip Thomas, Marvin Lewis, Billeta Reimann, Keith Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Histological evidence of acute rejection after terminating anti CD40 antibody (2C10R4) treatment in GTKO.hCD46.htbm pig to baboon cardiac xenografts surviving for over one year SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT IPITA/IXA/CTS Joint Congress CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP IPITA, IXA, CTS C1 [Miller, Justin; Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael; Thomas, Marvin; Lewis, Billeta] NIH, Div Vet Resources ORS, Bethesda, MD 20892 USA. [Reimann, Keith] Univ Massachusetts, Boston, MD USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV PY 2015 VL 22 SU 1 SI SI MA 811 BP S145 EP S145 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA CV9FY UT WOS:000364594100347 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Thomas, M Lewis, B Clark, T Eckhaus, M Belli, A Reimann, K Klymuik, N Wolf, E Ayares, D Horvath, K AF Mohiuddin, Muhammad Singh, Avneesh Corcoran, Philip Thomas, Marvin Lewis, Billeta Clark, Tannia Eckhaus, Michael Belli, Aaron Reimann, Keith Klymuik, Nikolai Wolf, Eckhard Ayares, David Horvath, Keith TI Critical need of continuous co-stimulation blockade with anti CD40 antibody (2C10.R4) for long-term maintenance of GTKO.HCD46.hTBM pig cardiac xenograft survival in baboons SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT IPITA/IXA/CTS Joint Congress CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP IPITA, IXA, CTS C1 [Mohiuddin, Muhammad; Singh, Avneesh; Corcoran, Philip; Horvath, Keith] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Thomas, Marvin; Lewis, Billeta; Clark, Tannia; Eckhaus, Michael] NIH, DVR ORS, Bethesda, MD 20892 USA. [Belli, Aaron; Reimann, Keith] Univ Massachusetts, Boston, MA 02125 USA. [Klymuik, Nikolai; Wolf, Eckhard] LMU, Munich, Germany. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV PY 2015 VL 22 SU 1 SI SI MA 810 BP S144 EP S145 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA CV9FY UT WOS:000364594100346 ER PT J AU Singh, A Corcoran, P Lewis, B Thomas, M Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Lewis, Billeta Thomas, Marvin Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Cardiac xenotransplantation: role of CD4+CD25hiFoxP3+T regulatory cells in long-term cardiac xenograft survivors SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT IPITA/IXA/CTS Joint Congress CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP IPITA, IXA, CTS C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DVR, ORS, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV PY 2015 VL 22 SU 1 SI SI MA 1058 BP S196 EP S196 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA CV9FY UT WOS:000364594100481 ER PT J AU Singh, A Corcoran, P Lewis, B Thomas, M Ayares, D Horvath, K Mohiuddin, M AF Singh, Avneesh Corcoran, Philip Lewis, Billeta Thomas, Marvin Ayares, David Horvath, Keith Mohiuddin, Muhammad TI Cardiac xenotransplantation: Re-emerged b cells after transient depletion by Rituxan treatment maintains their repertoire but have a muted immune response SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT IPITA/IXA/CTS Joint Congress CY NOV 15-19, 2015 CL Melbourne, AUSTRALIA SP IPITA, IXA, CTS C1 [Singh, Avneesh; Corcoran, Philip; Horvath, Keith; Mohiuddin, Muhammad] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Lewis, Billeta; Thomas, Marvin] NIH, DvR ORS, Bethesda, MD 20892 USA. [Ayares, David] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV PY 2015 VL 22 SU 1 SI SI MA 812 BP S145 EP S145 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA CV9FY UT WOS:000364594100348 ER PT J AU Dauter, Z Wlodawer, A AF Dauter, Zbigniew Wlodawer, Alexander TI On the accuracy of unit-cell parameters in protein crystallography SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE protein crystallography; unit-cell parameter accuracy; symmetry ID CRYSTAL-STRUCTURE; DIFFRACTION DATA; RADIATION-DAMAGE; STRUCTURAL BASIS; BINDING; INSIGHTS; DIMER; CRYOCRYSTALLOGRAPHY; REFINEMENT; PEPTIDE AB The availability in the Protein Data Bank (PDB) of a number of structures that are presented in space group P1 but in reality possess higher symmetry allowed the accuracy and precision of the unit-cell parameters of the crystals of macromolecules to be evaluated. In addition, diffraction images from crystals of several proteins, previously collected as part of in-house projects, were processed independently with three popular software packages. An analysis of the results, augmented by published serial crystallography data, suggests that the apparent precision of the presentation of unit-cell parameters in the PDB to three decimal points is not justified, since these parameters are subject to errors of not less than 0.2%. It was also noticed that processing data including full crystallographic symmetry does not lead to deterioration of the refinement parameters; thus, it is not beneficial to treat the crystals as belonging to space group P1 when higher symmetry can be seen. C1 [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. [Wlodawer, Alexander] NCI, Prot Struct Sect, MCL, Ft Detrick, MD 21702 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, MCL, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov; wlodawer@nih.gov FU Intramural Research Program of National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 42 TC 0 Z9 0 U1 0 U2 6 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD NOV PY 2015 VL 71 BP 2217 EP 2226 DI 10.1107/S1399004715015503 PN 11 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CV8QT UT WOS:000364553500005 PM 26527139 ER PT J AU Jakob, M Lubkowski, J O'Keefe, BR Wlodawer, A AF Jakob, Michal Lubkowski, Jacek O'Keefe, Barry R. Wlodawer, Alexander TI Structure of a lectin from the sea mussel Crenomytilus grayanus (CGL) SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE lectin; molecular replacement; carbohydrate binding; structure comparison; beta-trefoil ID GALNAC/GAL-SPECIFIC LECTIN; AMINO-ACID-SEQUENCE; MOLECULAR REPLACEMENT; PROTEIN-STRUCTURE; PREDICTION; CLONING; SUITE AB CGL is a 150 amino-acid residue lectin that was originally isolated from the sea mussel Crenomytilus grayanus. It is specific for binding GalNAc/Gal-containing carbohydrate moieties and in general does not share sequence homology with other known galectins or lectins. Since CGL displays antibacterial, antifungal and antiviral activities, and interacts with high affinity with mucin-type receptors, which are abundant on some cancer cells, knowledge of its structure is of significant interest. Conditions have been established for the expression, purification and crystallization of a recombinant variant of CGL. The crystal structure of recombinant CGL was determined and refined at a resolution of 2.12 angstrom. The amino-acid sequence of CGL contains three homologous regions (73% similarity) and the folded protein has a beta-trefoil topology. Structural comparison of CGL with the closely related lectin MytiLec allowed description of the glycan-binding pockets. C1 [Jakob, Michal; Lubkowski, Jacek; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Jakob, Michal; O'Keefe, Barry R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [O'Keefe, Barry R.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM wlodawer@nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH Intramural AIDS Targeted Antiviral Program FX We would like to thank Mr Mi Li for assistance with X-ray data collection. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SERCAT) located at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by funds from the NIH Intramural AIDS Targeted Antiviral Program (to AW, BRO and MJ). NR 28 TC 4 Z9 4 U1 1 U2 5 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD NOV PY 2015 VL 71 BP 1429 EP 1436 DI 10.1107/S2053230X15019858 PN 11 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CV8SJ UT WOS:000364557700011 PM 26527272 ER PT J AU Hiruy, H Fuchs, EJ Marzinke, MA Bakshi, RP Breakey, JC Aung, WS Manohar, M Yue, C Caffo, BS Du, Y Abebe, KZ Spiegel, HML Rohan, LC McGowan, I Hendrix, CW AF Hiruy, Hiwot Fuchs, Edward J. Marzinke, Mark A. Bakshi, Rahul P. Breakey, Jennifer C. Aung, Wutyi S. Manohar, Madhuri Yue, Chen Caffo, Brian S. Du, Yong Abebe, Kaleab Z. Spiegel, Hans M. L. Rohan, Lisa C. McGowan, Ian Hendrix, Craig W. TI A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ANTIRETROVIRAL PROPHYLAXIS; HIV TRANSMISSION; ORAL TENOFOVIR; MEN; PREVENTION; EPIDEMIC; ACCEPTABILITY; HYPEROSMOLAR; PREVALENCE; SURROGATES AB CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development. C1 [Hiruy, Hiwot; Fuchs, Edward J.; Marzinke, Mark A.; Bakshi, Rahul P.; Breakey, Jennifer C.; Aung, Wutyi S.; Manohar, Madhuri; Yue, Chen; Hendrix, Craig W.] Johns Hopkins Univ, Dept Med Clin Pharmacol, Baltimore, MD 21287 USA. [Yue, Chen; Caffo, Brian S.] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Du, Yong] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Abebe, Kaleab Z.; Rohan, Lisa C.; McGowan, Ian] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Spiegel, Hans M. L.] NIAID, HJF DAIDS, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Rohan, Lisa C.; McGowan, Ian] Magee Womens Res Inst, Pittsburgh, PA USA. RP Hendrix, CW (reprint author), Johns Hopkins Univ, Sch Med, 600 North Wolfe St,Blalock 569, Baltimore, MD 21287 USA. EM chendrix@jhmi.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Abebe, Kaleab/0000-0002-3644-8419; Bakshi, Rahul/0000-0003-1478-1031 FU U19 grant under the Integrated Preclinical-Clinical Program for HV Topical Microbicides (IPCP-HTM), Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [AI082637]; National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX The study was funded by a U19 grant under the Integrated Preclinical-Clinical Program for HV Topical Microbicides (IPCP-HTM), Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (AI082637). This project has also been funded in part with federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200800014C. NR 36 TC 3 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2015 VL 31 IS 11 BP 1098 EP 1108 DI 10.1089/aid.2015.0098 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CV5SJ UT WOS:000364331100006 PM 26227279 ER PT J AU Weinberg, A Muresan, P Richardson, K Fenton, T Dominguez, T Bloom, A Watts, DH Abzug, MJ Nachman, SA Levin, MJ AF Weinberg, Adriana Muresan, Petronella Richardson, Kelly Fenton, Terence Dominguez, Teresa Bloom, Anthony Watts, D. Heather Abzug, Mark J. Nachman, Sharon A. Levin, Myron J. CA P1086 Study Team TI Heterogeneity of T Cell Responses to Pandemic pH1N1 Monovalent Vaccine in HIV-Infected Pregnant Women SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID INACTIVATED INFLUENZA VACCINES; VIRUS-INFECTION; ANTIBODY-RESPONSES; PROTECTION; SAFETY; CHILDREN; IMMUNOGENICITY; CORRELATE; ADULTS; ASSOCIATION AB We investigated the Th1 protective and regulatory T and B cell (Treg and Breg) responses to pH1N1 monovalent influenza vaccine (IIV1) in HIV-infected pregnant women on combination antiretroviral therapy (cART). Peripheral blood mononuclear cells (PBMCs) from 52 study participants were cryopreserved before and after vaccination and analyzed by flow cytometry. pH1N1-specific Th1, Treg, and Breg responses were measured in PBMCs after in vitro stimulation with pH1N1 and control antigen. The cohort analysis did not detect changes in pH1N1-Th1, Treg, or Breg subsets postvaccination. However, individual analyses distinguished subjects who mounted vigorous Th1 responses postvaccination from others who did not. Postvaccination, high pH1N1-Th1 correlated with high pH1N1-Treg and Breg responses, suggesting that low influenza effector responses did not result from excessive vaccine-induced immune regulation. High postvaccination pH1N1-Th1 responses correlated with baseline high PHA- and pH1N1-IFN-gamma ELISpot and circulating CD4(+)CD39(+)% and CD8(+)CD39(+)% Treg, with low CD8(+) cell numbers and CD19(+)FOXP3(+)% Breg, but not with CD4(+) cell numbers or HIV viral load. These data highlight the heterogeneity of T cell responses to vaccines in HIV-infected individuals on cART. Predictors of robust Th1 responses to IIV include CD8(+) cell numbers, T cell functionality, and circulating Breg and Treg. C1 [Weinberg, Adriana; Richardson, Kelly; Dominguez, Teresa; Abzug, Mark J.; Levin, Myron J.] Univ Colorado Anschutz Med Campus, Aurora, CO USA. [Muresan, Petronella; Fenton, Terence] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Bloom, Anthony] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Nachman, Sharon A.] SUNY Stony Brook, Hlth Sci Ctr Stony Brook, Stony Brook, NY 11794 USA. RP Weinberg, A (reprint author), Mail Stop 8604,12700 East 19th Ave,Room 11126, Aurora, CO 80045 USA. EM adriana.weinberg@ucdenver.edu FU NIH/NCATS Colorado CTSI Grant [UL1 TR000154]; National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; National Institute of Allergy and Infectious Diseases (NIAID); NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network - NICHD [N01-DK-9-001/HHSN267200800001C]; [N01HD33162 (97-07)] FX Participating sites and site personnel: University of Miami Pediatric/Perinatal HIV/AIDS CRS (Amanda Cotter, MD; Gwendolyn B. Scott, MD; Erika Lopez-Bertiery, MD; Safia Khan, MD); University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (Irma L. Febo, MD; Carmen D. Zorrilla, MD; Vivian Tamayo-Agrait, MD; Ruth Santos, RN, MPH); University of Southern California, LA NICHD CRS (Alice Stek, MD; Michael Neely, MD; LaShonda Spencer, MD; Andrea Kovacs, MD); Washington Hospital Center NICHD CRS (Sara Parker, MD; Patricia Tanjutco, MD; Vanessa Emmanuel, BA; Liv Thulin); Texas Children's Hospital CRS (Shelly Buschur, RN, CNM; Mary Paul, MD; Filiz Seeborg, MD; Kathy Pitts, PhD); Chicago Children's CRS (Jessica Shore, RN; Sarah Sutton, MD); UCSD Maternal, Child, and Adolescent HIV CRS (Stephen A. Spector, MD; Andrew Hull, MD; Mary Caffery, RN, MSN; Jean Manning, RN, BSN); DUMC Pediatric CRS (Margaret Donnelly, PA; Mary Jo Hassett, RN; Elizabeth Livingston, MD; Julieta Giner, RN); Rush University Cook County Hospital, Chicago NICHD CRS (Mariam Aziz, MD; Latania Logan, MD; Julie Schmidt, MD; Helen Cejtin, MD); The Children's Hospital of Philadelphia IMPAACT CRS (Samuel Parry, MD; Rita Leite, MD); University of South Florida, Tampa NICHD CRS (Karen L. Bruder, MD; Gail Lewis, RN; Patricia Emmanuel, MD; Tampa General Hospital); San Juan City Hospital PR NICHD CRS (Elvia Perez, MPH, MA; Rodrigo Diaz, MD; Dalila Guzman, RPh; Midnela Acevedo-Flores, MD); South Florida CDC, Ft. Lauderdale NICHD CRS; Johns Hopkins University, Baltimore NCHD CRS (Allison Agwu, MD, ScM; Todd Noletto, MPH; Jennifer Chang, BS; Andi Weiss, PharmD); Tulane University, New Orleans NICHD CRS (Chi Dola, MD; Thomas Alchediak, MD; Yvette Luster, RN; Sheila Bradford, RN); Bronx-Lebanon Hospital IMPAACT CRS (Jenny Gutierrez, MD; Mahboobullah Mirza Baig, MD; Stefan Hagmann, MD; Murli Purswani, MD); NJ Medical School CRS (Arlene D. Bardeguez, MD, MPH; Charmane Calilap-Bernardo, RN; Linda Bettica, RN); Columbia IMPAACT CRS (Andrea Jurgrau, CNP; Gina Silva, RN; Alice Higgins, RN; Marc Foca, MD); Metropolitan Hospital NICHD CRS (Mahrukh Bamji, MD; Santa Paul, MD; Siobhan Riley, MPH; Deepali Jain, MD); Children's Hospital of Boston NICHD CRS (Sandra K. Burchett, MD, MS; Ruth Tuomala, MD; Arlene Buck, RN; Catherine Kneut, RN, CPNP); University of Colorado, Denver NICHD CRS (Jennifer Dunn, FNP-C; Paul Harding, MS; Kay Kinzie, FNP-C; Jenna Wallace, MSW; Supported by NIH/NCATS Colorado CTSI Grant Number UL1 TR000154); St. Jude/UTHSC CRS (L. Jill Utech, RN, MSN, CCRP; Edwin Thorpe, Jr., MD; Nina Sublette, RN, FNP, PhD; Pam Finnie, MSN); WNE Maternal Pediatric Adolescent AIDS CRS; UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS (Jaime G. Deville, MD; Karin Nielsen-Saines, MD; Nicole Falgout, RN; Joseph Geffen); Boston Medical Center Pediatric HIV Program NICHD CRS; Jacobi Medical Center Bronx NICHD CRS; Seattle Children's Hospital CRS; SUNY Stony Brook NICHD CRS (Denise Ferraro, FNP; Erin Infanzon; Michele Kelly, NP; Jennifer Griffin, CNM); Miller Children's Hospital Long Beach, CA NICHD CRS (Audra Deveikis, MD; Janielle Jackson-Alvarez, RN; Tempe K. Chen, MD; Jagmohan S. Batra, MD); University of Florida College of Medicine, Jacksonville NICHD CRS (Mobeen Rathore, MD; Ayesha Mirza, MD; Nizar Maraqa, MD; Kathleen Thoma, MA, CCRP); University of California, San Francisco NICHD CRS Diane Wara, MD; Nicole Tilton, PNP; Mica Muscat, PNP).; Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [AI068632]. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). The laboratory work was supported by N01HD33162 (97-07) and the statistical work by the Statistical and Data Analysis Center at Harvard School of Public Health under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, the United States Government, or the U.S. Department of State. NR 31 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2015 VL 31 IS 11 BP 1170 EP 1177 DI 10.1089/aid.2015.0151 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CV5SJ UT WOS:000364331100014 PM 26322930 ER PT J AU Sarafin, K Durazo-Arvizu, R Tian, L Phinney, KW Tai, S Camara, JE Merkel, J Green, E Sempos, CT Brooks, SPJ AF Sarafin, Kurtis Durazo-Arvizu, Ramon Tian, Lu Phinney, Karen W. Tai, Susan Camara, Johanna E. Merkel, Joyce Green, Evan Sempos, Christopher T. Brooks, Stephen P. J. TI Standardizing 25-hydroxyvitamin D values from the Canadian Health Measures Survey SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE standardization; vitamin D; immunoassay; population survey; adequacy; CHMS ID TANDEM MASS-SPECTROMETRY; VITAMIN-D INSUFFICIENCY; D ASSAYS; CIRCULATING 25-HYDROXYVITAMIN-D; D METABOLITES; HUMAN SERUM; ACCURACY; D-3 AB Background: The Canadian Health Measures Survey (CHMS) is an ongoing cross-sectional national survey that includes a measure of 25-hydroxyvitamin D [25(OH)D] by immunoassay. For cycles 1 and 2, the collection period occurred approximately every 2 y, with a new sample of similar to 5600 individuals. Objective: The goal was to standardize the original 25(OH)D CHMS values in cycles 1 and 2 to the internationally recognized reference measurement procedures (RMPs) developed by the US National Institute for Standards and Technology (NIST) and Ghent University, Belgium. Design: Standardization was accomplished by using a 2-step procedure. First, serum samples corresponding to the original plasma samples were remeasured by using the currently available immunoassay method. Second, 50 serum samples with known 25(OH)D values assigned by the NIST and Ghent reference method laboratories were measured by using the currently available immunoassay method. The mathematical models for each step-i.e., 1) Y-Current = X-Original and 2) YNIST-Ghent = X-Current -were estimated by using Deming regression, and the 2 models were solved to obtain a single equation for converting the "original" values to NIST-Ghent RMP values. Results: After standardization (cycles 1 and 2 combined), the percentage of Canadians with 25(OH)D values <40 nmol/L increased from 16.4% (original) to 19.4% (standardized), and values <50 nmol/L increased from 29.0% (original) to 36.8% (standardized). The 25(OH)D standardized distributions (cycles 1 and 2 analyzed separately) were similar across age and sex groups; slightly higher values were associated with cycle 2 in the young and old. This finding contrasts with the original data, which indicated that cycle 2 values were lower for all age groups. Conclusion: The shifts in 25(OH)D distribution brought about by standardization indicate its importance in drawing correct conclusions about potential population deficiencies and insufficiencies and in permitting the comparison of distributions between national surveys. C1 [Sarafin, Kurtis; Brooks, Stephen P. J.] Hlth Canada, Bur Nutr Sci, Ottawa, ON K1A 0L2, Canada. [Durazo-Arvizu, Ramon] Loyola Univ, Stritch Sch Med, Dept Publ Hlth Sci, Chicago, IL 60611 USA. [Tian, Lu] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Phinney, Karen W.] Natl Inst Stand & Technol, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [Tai, Susan; Camara, Johanna E.] Natl Inst Stand & Technol, Div Chem Sci, Gaithersburg, MD 20899 USA. [Merkel, Joyce; Sempos, Christopher T.] Off Dietary Supplements, NIH, Bethesda, MD USA. [Green, Evan] STAT Canada, Ottawa, ON, Canada. RP Brooks, SPJ (reprint author), Hlth Canada, Bur Nutr Sci, Ottawa, ON K1A 0L2, Canada. EM steve.brooks@hc-sc.gc.ca FU Health Canada; NIH; National Institute of Standards and Technology; Statistics Canada FX Supported by Health Canada (SPJB and KS), the NIH (JM and CTS), the National Institute of Standards and Technology (KWP, ST, and JEC), and Statistics Canada (EG). NR 36 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2015 VL 102 IS 5 BP 1044 EP 1050 DI 10.3945/ajcn.114.103689 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CV4YV UT WOS:000364273300012 PM 26423385 ER PT J AU Key, TJ Appleby, PN Travis, RC Albanes, D Alberg, AJ Barricarte, A Black, A Boeing, H Bueno-de-Mesquita, HB Chan, JM Chen, C Cook, MB Donovan, JL Galan, P Gilbert, R Giles, GG Giovannucci, E Goodman, GE Goodman, PJ Gunter, MJ Hamdy, FC Heliovaara, M Helzlsouer, KJ Henderson, BE Hercberg, S Hoffman-Bolton, J Hoover, RN Johansson, M Khaw, KT King, IB Knekt, P Kolonel, LN Le Marchand, L Mannisto, S Martin, RM Meyer, HE Mondul, AM Moy, KA Neal, DE Neuhouser, ML Palli, D Platz, EA Pouchieu, C Rissanen, H Schenk, JM Severi, G Stampfer, MJ Tjonneland, A Touvier, M Trichopoulou, A Weinstein, SJ Ziegler, RG Zhou, CK Allen, NE AF Key, Timothy J. Appleby, Paul N. Travis, Ruth C. Albanes, Demetrius Alberg, Anthony J. Barricarte, Aurelio Black, Amanda Boeing, Heiner Bueno-de-Mesquita, H. Bas Chan, June M. Chen, Chu Cook, Michael B. Donovan, Jenny L. Galan, Pilar Gilbert, Rebecca Giles, Graham G. Giovannucci, Edward Goodman, Gary E. Goodman, Phyllis J. Gunter, Marc J. Hamdy, Freddie C. Heliovaara, Markku Helzlsouer, Kathy J. Henderson, Brian E. Hercberg, Serge Hoffman-Bolton, Judy Hoover, Robert N. Johansson, Mattias Khaw, Kay-Tee King, Irena B. Knekt, Paul Kolonel, Laurence N. Le Marchand, Loic Mannisto, Satu Martin, Richard M. Meyer, Haakon E. Mondul, Alison M. Moy, Kristin A. Neal, David E. Neuhouser, Marian L. Palli, Domenico Platz, Elizabeth A. Pouchieu, Camille Rissanen, Harri Schenk, Jeannette M. Severi, Gianluca Stampfer, Meir J. Tjonneland, Anne Touvier, Mathilde Trichopoulou, Antonia Weinstein, Stephanie J. Ziegler, Regina G. Zhou, Cindy Ke Allen, Naomi E. CA Endogenous Hormones Nutr TI Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE prostate cancer; carotenoids; retinol; tocopherols; vitamin E; vitamin A; pooled analysis; nested case-control study; biomarkers ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; SERUM VITAMIN-A; BETA-CAROTENE; ALPHA-TOCOPHEROL; FOLLOW-UP; PREVENTION TRIAL; SCREENING TRIAL; DISEASE RISK; PLASMA AB Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear. C1 [Key, Timothy J.; Appleby, Paul N.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, Dept Surg, Oxford, England. [Allen, Naomi E.] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England. [Albanes, Demetrius; Black, Amanda; Cook, Michael B.; Hoover, Robert N.; Mondul, Alison M.; Moy, Kristin A.; Weinstein, Stephanie J.; Ziegler, Regina G.; Zhou, Cindy Ke] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Alberg, Anthony J.; Platz, Elizabeth A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Barricarte, Aurelio] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Barcelona, Spain. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas; Gunter, Marc J.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Chan, June M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Chan, June M.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. [Chen, Chu] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [King, Irena B.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Core Labs, Seattle, WA 98104 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Schenk, Jeannette M.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Donovan, Jenny L.; Gilbert, Rebecca; Martin, Richard M.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Galan, Pilar; Hercberg, Serge; Touvier, Mathilde] Univ Paris 07, INSERM,Epidemiol & Biostatist Res Ctr, Inra,Cnam,Univ Paris 13,Univ Paris 5,U1153,U1125, Nutr Epidemiol Res Team,Sorbonne Paris Cite, Bobigny, France. [Giles, Graham G.; Pouchieu, Camille; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Goodman, Gary E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Goodman, Gary E.] Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. [Heliovaara, Markku; Knekt, Paul; Mannisto, Satu; Rissanen, Harri] Natl Inst Hlth & Welf, Helsinki, Finland. [Helzlsouer, Kathy J.] St Johns Mercy Med Ctr, Prevent Res Ctr, Baltimore, MD USA. [Henderson, Brian E.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Hoffman-Bolton, Judy] George W Comstock Ctr Publ Hlth Res & Prevent, Hagerstown, MD USA. [Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Johansson, Mattias] Umea Univ, Dept Biobank Res, Umea, Sweden. [Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Neal, David E.] Univ Cambridge, Dept Oncol, Cambridge, England. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Martin, Richard M.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Martin, Richard M.] Bristol Biomed Res Unit Nutr, Natl Inst Hlth Res, Bristol, Avon, England. [Meyer, Haakon E.] Univ Oslo, Dept Community Med, Fac Med, Oslo, Norway. [Meyer, Haakon E.] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulou, Antonia] Acad Athens, Hellen Hlth Fdn & Bur Epidemiol Res, Athens, Greece. [King, Irena B.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. RP Key, TJ (reprint author), Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Populat Hlth, Oxford, England. EM titn.key@ceu.ox.ac.uk RI Cook, Michael/A-5641-2009; Zhou, Cindy /H-2165-2015; OI Cook, Michael/0000-0002-0533-7302; Zhou, Cindy /0000-0003-4814-4305; Johansson, Mattias/0000-0002-3116-5081; PALLI, Domenico/0000-0002-5558-2437; Mondul, Alison/0000-0002-8843-1416; Mannisto, Satu/0000-0002-8668-3046; Giles, Graham/0000-0003-4946-9099 FU Cancer Research UK [C8221/A19170, C570/A11691]; Intramural Research Program of the NIH; US Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; NIH, Department of Health and Human Services [U01 CA63673, R01 CA96789, N01 PC35142]; National Cancer Institute, NIH [CA 94028]; Hellenic Health Foundation; Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch Zorg Onderzoek Nederland; World Cancer Research Fund; Statistics Netherlands; National Cancer Institute [CA 55075, CA 72036, P01 CA 33619, R37 CA 54281, 1-UM1-CA164973]; NIH [CA37429, P01 CA108964]; Norwegian Cancer Society; Throne Hoist Foundation; VicHealth; Cancer Council Victoria; Australian National Health and Medical Research Council [209057, 251553, 504711]; United Kingdom National Institute for Health Research Health Technology Assessment Programme [96/20/06, 96/20/99]; Medical Research Council; University of Bristol; National Institute for Health Research FX Supported by Cancer Research UK grants C8221/A19170 and C570/A11691, Funding for the collaborating studies was as follows. Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: Supported in part by the Intramural Research Program of the NIH and the National Cancer Institute; also, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. beta-Carotene and Retinol Efficacy Trial: Supported by U01 CA63673, R01 CA96789, and N01 PC35142, all from the NIH, Department of Health and Human Services. CLUE I and II: Supported by CA 94028 from the National Cancer Institute, NIH. European Prospective Investigation into Cancer and Nutrition Greece: Supported by the Hellenic Health Foundation. European Prospective Investigation into Cancer and Nutrition Netherlands: Supported by the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands. Health Professionals Follow-Up Study: Supported by CA 55075 and CA 72036 from the National Cancer Institute and the NIH. Janus: The serum analysis of vitamins was supported by a grant from the Norwegian Cancer Society and the Throne Hoist Foundation. Melbourne Collaborative Cohort Study (MCCS): Cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Multiethnic Cohort: Supported by National Cancer Institute grants P01 CA 33619, R37 CA 54281, and 1-UM1-CA164973. Prostate Cancer Prevention Trial: Supported by National Cancer Institute and NIH, CA37429 and P01 CA108964. Prostate testing for cancer and Treatment trial: Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme (projects 96/20/06, 96/20/99, www.hta/1230); the views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. The University of Bristol Integrated Epidemiology Unit is supported by the Medical Research Council and the University of Bristol. The Bristol Nutrition Biomedical Research Unit is funded by the National Institute for Health Research and is a partnership between the University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. SU.VI.MAX, SUpplementation en VItamines et Mineraux Anti-oXydants trial: Supported by the Direction Generale de la Sante (French Ministry of Health) for laboratory assays. NR 53 TC 11 Z9 11 U1 1 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2015 VL 102 IS 5 BP 1142 EP 1157 DI 10.3945/ajcn.115.114306 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CV4YV UT WOS:000364273300023 PM 26447150 ER PT J AU Fretts, AM Follis, JL Nettleton, JA Lemaitre, RN Ngwa, JS Wojczynski, MK Kalafati, IP Varga, TV Frazier-Wood, AC Houston, DK Lahti, J Ericson, U van den Hooven, EH Mikkila, V Kiefte-de Jong, JC Mozaffarian, D Rice, K Renstrom, F North, KE McKeown, NM Feitosa, MF Kanoni, S Smith, CE Garcia, ME Tiainen, AM Sonestedt, E Manichaikul, A Van Rooij, FJA Dimitriou, M Raitakari, O Pankow, JS Djousse, L Province, MA Hu, FB Lai, CQ Keller, MF Perala, MM Rotter, JI Hofman, A Graff, M Kahonen, M Mukamal, K Johansson, I Ordovas, JM Liu, YM Mannisto, S Uitterlinden, AG Deloukas, P Seppala, I Psaty, BM Cupples, LA Borecki, IB Franks, PW Arnett, DK Nalls, MA Eriksson, JG Orho-Melander, M Franco, OH Lehtimaki, T Dedoussis, GV Meigs, JB Siscovick, DS AF Fretts, Amanda M. Follis, Jack L. Nettleton, Jennifer A. Lemaitre, Rozenn N. Ngwa, Julius S. Wojczynski, Mary K. Kalafati, Ioanna Panagiota Varga, Tibor V. Frazier-Wood, Alexis C. Houston, Denise K. Lahti, Jari Ericson, Ulrika van den Hooven, Edith H. Mikkilae, Vera Kiefte-de Jong, Jessica C. Mozaffarian, Dariush Rice, Kenneth Renstroem, Frida North, Kari E. McKeown, Nicola M. Feitosa, Mary F. Kanoni, Stavroula Smith, Caren E. Garcia, Melissa E. Tiainen, Anna-Maija Sonestedt, Emily Manichaikul, Ani van Rooij, Frank J. A. Dimitriou, Maria Raitakari, Olli Pankow, James S. Djousse, Luc Province, Michael A. Hu, Frank B. Lai, Chao-Qiang Keller, Margaux F. Peraelae, Mia-Maria Rotter, Jerome I. Hofman, Albert Graff, Misa Kaehoenen, Mika Mukamal, Kenneth Johansson, Ingegerd Ordovas, Jose M. Liu, Yongmei Maennistoe, Satu Uitterlinden, Andre G. Deloukas, Panos Seppaelae, Ilkka Psaty, Bruce M. Cupples, L. Adrienne Borecki, Ingrid B. Franks, Paul W. Arnett, Donna K. Nalls, Mike A. Eriksson, Johan G. Orho-Melander, Marju Franco, Oscar H. Lehtimaeki, Terho Dedoussis, George V. Meigs, James B. Siscovick, David S. TI Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE gene-diet interaction; glucose; insulin; meat intake; diet; meta-analysis ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; DIABETES-MELLITUS; SUSCEPTIBILITY LOCI; CHARGE CONSORTIUM; UNPROCESSED RED; OLDER-ADULTS; TYPE-2; WOMEN AB Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined l) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-1n-pmon (95% CI: 0.035, 0.063-1n-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. Conclusion: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. C1 [Fretts, Amanda M.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lemaitre, Rozenn N.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Fretts, Amanda M.; Lemaitre, Rozenn N.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Frazier-Wood, Alexis C.] Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, USDA ARS, Houston, TX 77030 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Follis, Jack L.] Univ St Thomas, Dept Math Comp Sci & Cooperat Engn, Houston, TX 77006 USA. [Ngwa, Julius S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Wojczynski, Mary K.; Feitosa, Mary F.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Gen, Dept Genet, St Louis, MO USA. [Kalafati, Ioanna Panagiota; Dimitriou, Maria; Dedoussis, George V.] Harokopio Univ Athens, Dept Nutr & Dietet, Athens, Greece. [Varga, Tibor V.; Renstroem, Frida; Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Ericson, Ulrika; Sonestedt, Emily; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Renstroem, Frida] Umea Univ, Dept Biobank Res, Umea, Sweden. [Johansson, Ingegerd] Umea Univ, Dept Odontol, Umea, Sweden. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Houston, Denise K.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27103 USA. [Lahti, Jari] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Mikkilae, Vera] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [van den Hooven, Edith H.; Kiefte-de Jong, Jessica C.; van Rooij, Frank J. A.; Hofman, Albert; Uitterlinden, Andre G.; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Mikkilae, Vera; Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Djousse, Luc] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Mozaffarian, Dariush] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [North, Kari E.; Graff, Misa] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [McKeown, Nicola M.] Tufts Univ, Nutr Epidemiol Program, Boston, MA 02111 USA. [McKeown, Nicola M.; Lai, Chao-Qiang; Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Smith, Caren E.; Lai, Chao-Qiang; Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Boston, MA 02111 USA. [Kanoni, Stavroula; Deloukas, Panos] Barts, William Harvey Res Inst, London, England. [Kanoni, Stavroula] Queen Mary Univ London, London Sch Med & Dent, London, England. [Garcia, Melissa E.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Keller, Margaux F.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Tiainen, Anna-Maija; Peraelae, Mia-Maria; Maennistoe, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA. [van Rooij, Frank J. A.] Netherlands Genom Initiat, Leiden, Netherlands. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Keller, Margaux F.] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Seppaelae, Ilkka; Lehtimaeki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Seppaelae, Ilkka; Lehtimaeki, Terho] Univ Tampere, Fimlab Labs, FIN-33101 Tampere, Finland. [Kaehoenen, Mika; Seppaelae, Ilkka; Lehtimaeki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Kaehoenen, Mika] Univ Tampere, Tampere Univ Hosp, FIN-33101 Tampere, Finland. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Ordovas, Jose M.] Cardiovasc Res Ctr, Dept Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] IMDEA Food Inst, Madrid, Spain. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Gen Practice Unit, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Diabet Res Unit, Boston, MA 02114 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. RP Fretts, AM (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. EM amfretts@uw.edu RI Sonestedt, Emily/I-3814-2016; Deloukas, Panos/B-2922-2013; Feitosa, Mary/K-8044-2012; Djousse, Luc/F-5033-2017; OI Sonestedt, Emily/0000-0002-0747-4562; Deloukas, Panos/0000-0001-9251-070X; Feitosa, Mary/0000-0002-0933-2410; Djousse, Luc/0000-0002-9902-3047; Mannisto, Satu/0000-0002-8668-3046; Kiefte-de Jong, Jessica/0000-0002-8136-0918; Lahti, Jari/0000-0002-4310-5297 FU National Heart, Lung, and Blood Institute (NHLBI) [R01HL105756]; Institute of Translational Health Sciences [5KL2TR000421-08]; NHLBI [T32HL007902] FX Infrastructure for the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium is supported in part by National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756. This meta-analysis was supported by the Institute of Translational Health Sciences (5KL2TR000421-08) and NHLBI (T32HL007902). Sources of support for the participating cohorts are provided in Supplemental Table 12. Funders had no role in the design, implementation, analysis, and interpretation of the data for the studies. NR 65 TC 6 Z9 6 U1 4 U2 23 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2015 VL 102 IS 5 BP 1266 EP 1278 DI 10.3945/ajcn.114.101238 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CV4YV UT WOS:000364273300036 PM 26354543 ER PT J AU Klauzinska, M McCurdy, D Rangel, MC Vaidyanath, A Castro, NP Shen, MM Gonzales, M Bertolette, D Bianco, C Callahan, R Salomon, DS Raafat, A AF Klauzinska, Malgorzata McCurdy, David Rangel, Maria Cristina Vaidyanath, Arun Castro, Nadia P. Shen, Michael M. Gonzales, Monica Bertolette, Daniel Bianco, Caterina Callahan, Robert Salomon, David S. Raafat, Ahmed TI Cripto-1 Ablation Disrupts Alveolar Development in the Mouse Mammary Gland through a Progesterone Receptor-Mediated Pathway SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; PLURIPOTENT STEM-CELLS; TRANSGENIC MICE; BRANCHING MORPHOGENESIS; RETINOIC ACID; KNOCKOUT MICE; KEY STAGES; LINE T-47D; KAPPA-B; EXPRESSION AB Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelialmesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-kappa B/receptor activator NF-kappa B ligand, and NF-kappa B signaling pathways. C1 [Klauzinska, Malgorzata; Rangel, Maria Cristina; Castro, Nadia P.; Gonzales, Monica; Bertolette, Daniel; Bianco, Caterina; Salomon, David S.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [McCurdy, David; Vaidyanath, Arun; Callahan, Robert; Raafat, Ahmed] NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. [Shen, Michael M.] Columbia Univ, Med Ctr, Dept Med Genet & Dev, New York, NY USA. [Shen, Michael M.] Columbia Univ, Med Ctr, Dept Urol, New York, NY USA. [Shen, Michael M.] Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY USA. RP Raafat, A (reprint author), NCI, Basic Res Lab, NIH, 37 Convent Dr,Bldg 37,Room 1118, Bethesda, MD 20892 USA. EM raafata@mail.nih.gov RI Shen, Michael/C-7546-2009 OI Shen, Michael/0000-0002-4042-1657 FU Intramural Research Program of the NIH, National Cancer Institute (Bethesda, MD) FX Supported by Intramural Research Program of the NIH, National Cancer Institute (Bethesda, MD). NR 78 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2015 VL 185 IS 11 BP 2907 EP 2922 DI 10.1016/j.ajpath.2015.07.023 PG 16 WC Pathology SC Pathology GA CV7FY UT WOS:000364439000006 PM 26429739 ER PT J AU Jain, S Chen, J Nicolae, A Wang, HS Shin, DM Adkins, EB Sproule, TJ Leeth, CM Sakai, T Kovalchuk, AL Raffeld, M Ward, JM Rehg, JE Waldmann, TA Jaffe, ES Roopenian, DC Morse, HC AF Jain, Shweta Chen, Jing Nicolae, Alina Wang, Hongsheng Shin, Dong-Mi Adkins, Elisabeth B. Sproule, Thomas J. Leeth, Caroline M. Sakai, Tomomi Kovalchuk, Alexander L. Raffeld, Mark Ward, Jerrold M. Rehg, Jerold E. Waldmann, Thomas A. Jaffe, Elaine S. Roopenian, Derry C. Morse, Herbert C., III TI IL-21-Driven Neoplasms in SJL Mice Mimic Some Key Features of Human Angioimmunoblastic T-Cell Lymphoma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID FOLLICULAR-HELPER-CELLS; REVERSE IMMUNE SURVEILLANCE; MURINE LEUKEMIA VIRUSES; GERMINAL CENTER; B-CELLS; GROWTH; SUPERANTIGEN; AUTOIMMUNITY; EXPRESSION; EXPANSION AB SJL/J mice exhibit a high incidence of mature B-cell lymphomas that require CD4(+) T cells for their development. We found that their spleens and lymph nodes contained increased numbers of germinal centers and T follicular helper (T-FH) cells. Microarray analyses revealed high levels of transcripts encoding IL-21 associated with high levels of serum IL-21. We developed IL-21 receptor (IL21R)-deficient Swiss Jim Lambart (SJL) mice to determine the role of IL-21 in disease. These mice had reduced numbers of T-FH cells, lower serum Levels of IL-21, and few germinal center B cells, and they did not develop B-cell tumors, suggesting IL-21-dependent B-cell lymphomagenesis. We also noted a series of features common to SJL disease and human angioimmunoblastic T-cell lymphoma (AITL), a malignancy of T-FH cells. Gene expression analyses of AITL showed that essentially all cases expressed elevated Levels of transcripts for IL21, IL21R, and a series of genes associated with T-FH cell development and function. These results identify a mouse model with features of AITL and suggest that patients with the disease might benefit from therapeutic interventions that interrupt IL-21 signaling. C1 [Jain, Shweta; Wang, Hongsheng; Shin, Dong-Mi; Sakai, Tomomi; Kovalchuk, Alexander L.; Ward, Jerrold M.; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, Rockville, MD 20852 USA. [Chen, Jing; Waldmann, Thomas A.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nicolae, Alina; Raffeld, Mark; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shin, Dong-Mi] Seoul Natl Univ, Dept Food & Nutr, Seoul, South Korea. [Adkins, Elisabeth B.; Sproule, Thomas J.; Roopenian, Derry C.] Jackson Lab, Bar Harbor, ME 04609 USA. [Adkins, Elisabeth B.; Leeth, Caroline M.; Roopenian, Derry C.] Tufts Univ, Sackler Sch Grad Biomed Sci, Genet Program, Boston, MA 02111 USA. [Leeth, Caroline M.] Virginia Polytech Inst & State Univ, Coll Agr & Life Sci, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA. [Rehg, Jerold E.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. RP Morse, HC (reprint author), NIAID, Virol & Cellular Immunol Sect, NIH, Room 1421,Twinbrook Bldg 1,MSC 8152, Rockville, MD 20852 USA. EM hmorse@niaid.nih.gov FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases; National Cancer Institute; Alliance for Lupus Research; Lakeside Foundation; Seoul National University; NIH; Jackson Laboratory's Education Program FX Supported, in part, by the Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Diseases (H.C.M., H.W., A.L.K., S.J., T.S., D.-M.S., and J.M.W.), and the National Cancer Institute (J.C., E.S.J., AN., and T.A.W.), in part by the Alliance for Lupus Research (D.C.R.) and the Lakeside Foundation (D.C.R.), and in part by Seoul National University (D.-M.S.). C.M.L. was supported in part by an NIH training grant. E.B.A. was supported by The Jackson Laboratory's Education Program. NR 50 TC 3 Z9 3 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2015 VL 185 IS 11 BP 3102 EP 3114 DI 10.1016/j.ajpath.2015.07.021 PG 13 WC Pathology SC Pathology GA CV7FY UT WOS:000364439000021 PM 26363366 ER PT J AU Miller, AH Vayttaden, SJ Al-Khodor, S Fraser, IDC AF Miller, Alexandra H. Vayttaden, Sharat J. Al-Khodor, Souhaila Fraser, Iain D. C. TI Assay Development for Image-Based Quantification of Intracellular Bacterial Replication and Analysis of the Innate Immune Response to Infection SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article; Proceedings Paper CT 2nd Annual Conference of the Society-for-Biomolecular-Imaging-and-Informatics CY SEP 15-17, 2015 CL Harvard Med Sch, Boston, MA SP Soc Biomolecular Imaging & Informat HO Harvard Med Sch ID BURKHOLDERIA-CEPACIA COMPLEX; CYSTIC-FIBROSIS; AUTOPHAGY; MACROPHAGES; MECHANISMS; MITOPHAGY AB Severe bacterial infection can lead to inflammation, host tissue damage, and ultimately disseminated septic shock. The mammalian innate immune system responds to microbial infection through the detection of invariant pathogen-associated molecular patterns (PAMPs) by a range of pattern recognition receptors (PRRs) expressed by the host cell. A successful immune response involves tightly coordinated signaling from these receptors, leading to a robust transcriptional response producing cytokines and antimicrobial effectors. While the PRR-expressing phagocytes of the host innate immune system function to contain and degrade internalized bacteria through pathways such as selective autophagy, pathogenic bacteria may subvert this process to replicate in the host cell. We describe the development of imaging assays to investigate these host-pathogen interactions through gene perturbation screens, which could lead to the identification of novel effectors of the host response to bacterial infection. We identify markers of coordinated initial signaling in macrophages challenged with ligands to PRRs of the toll-like receptor (TLR) family and compare this response to that induced by intact bacteria of the Burkholderia cenocepacia complex (Bcc), an opportunistic pathogen that causes life-threatening infections in patients with cystic fibrosis and chronic granulomatous disease. Bcc has been shown to escape the endocytic pathway, activate selective autophagy, and replicate within human macrophages. We demonstrate robust image-based quantification of multiple stages of Bcc infection of macrophages: ubiquitin tagging of cytosolic bacteria, recruitment of selective autophagy effector proteins, and intracellular bacterial replication, and we show perturbation of bacterial replication using drug treatment or siRNA-based gene knockdown. The described panel of imaging assays can be extended to other bacterial infections and pathogenic ligand combinations where high-content siRNA screening could provide significant new insight into regulation of the innate immune response to infection. C1 [Miller, Alexandra H.; Vayttaden, Sharat J.; Fraser, Iain D. C.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Al-Khodor, Souhaila] Sidra Med & Res Ctr, Div Translat Med, Infect Dis Unit, Doha, Qatar. RP Fraser, IDC (reprint author), NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, 9000 Rockville Pike,Bldg 4,Rm 109A,MSC 0421, Bethesda, MD 20892 USA. EM fraseri@niaid.nih.gov OI Al Khodor, Souhaila/0000-0003-4858-7130 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (A.H.M., S.J.V., and I.D.C.F). NR 22 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X EI 1557-8127 J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD NOV 1 PY 2015 VL 13 IS 9 SI SI BP 515 EP 528 DI 10.1089/adt.2015.664 PG 14 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA CW2NZ UT WOS:000364830500003 PM 26505731 ER PT J AU Ann, J Jung, A Kim, MY Kim, HM Ryu, H Kim, S Kang, DW Hong, S Cui, M Choi, S Blumberg, PM Frank-Foltyn, R Bahrenberg, G Stockhausen, H Christoph, T Lee, J AF Ann, Jihyae Jung, Aeran Kim, Mi-Yeon Kim, Hyuk-Min Ryu, HyungChul Kim, Sunjoo Kang, Dong Wook Hong, Sunhye Cui, Minghua Choi, Sun Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Stockhausen, Hannelore Christoph, Thomas Lee, Jeewoo TI Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonists; Analgesic ID VANILLOID CAPSAICIN RECEPTORS; ANALGESIC AGENTS; AGONIST ACTIVITY; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES AB A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 445 antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K-i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 445 in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ann, Jihyae; Jung, Aeran; Kim, Mi-Yeon; Kim, Hyuk-Min; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. [Ryu, HyungChul; Kim, Sunjoo] J2H Biotech, Ansan, Gyeonggi Do, South Korea. [Kang, Dong Wook] Catholic Univ Deagu, Dept Pharmaceut Sci & Technol, Coll Hlth & Med Sci, Gyongsan 712702, Gyeongsangbuk D, South Korea. [Hong, Sunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Hong, Sunhye; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Grunenthal in Germany; Korea Science and Engineering Foundation (KOSEF) [NRF-2007-0057057]; National Leading Research Lab (NLRL) program in South Korea [2011-0028885]; NIH, Center for Cancer Research, NCI in the USA [Z1A BC 005270] FX This research was supported by research Grants from Grunenthal in Germany, grants from the Korea Science and Engineering Foundation (KOSEF) (NRF-2007-0057057) and the National Leading Research Lab (NLRL) program (2011-0028885) in South Korea, and in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA. NR 25 TC 2 Z9 2 U1 2 U2 3 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 NOV 1 PY 2015 VL 23 IS 21 BP 6844 EP 6854 DI 10.1016/j.bmc.2015.10.001 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CV7FI UT WOS:000364437400007 PM 26474664 ER PT J AU Stone, EL Citossi, F Singh, R Kaur, B Gaskell, M Farmer, PB Monks, A Hose, C Stevens, MFG Leong, CO Stocks, M Kellam, B Marlow, M Bradshaw, TD AF Stone, Erica L. Citossi, Francesca Singh, Rajinder Kaur, Balvinder Gaskell, Margaret Farmer, Peter B. Monks, Anne Hose, Curtis Stevens, Malcolm F. G. Leong, Chee-Onn Stocks, Michael Kellam, Barrie Marlow, Maria Bradshaw, Tracey D. TI Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Antitumour benzothiazoles; GW 610; 5F 203; DNA adducts; DNA double strand breaks; Low molecular weight gelators (LMWGs) ID MOLECULAR-WEIGHT HYDROGELS; CYTOCHROME P450S 1A1; AMINO-ACID PRODRUGS; CANCER CELL-LINES; IN-VITRO; DRUG-DELIVERY; COLORECTAL-CANCER; BIOLOGICAL-PROPERTIES; TUMOR-CELLS; NSC 721648 AB Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R-2 > 0.7). Time-dependent appearance of gamma-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Stone, Erica L.; Citossi, Francesca; Stevens, Malcolm F. G.; Stocks, Michael; Kellam, Barrie; Marlow, Maria; Bradshaw, Tracey D.] Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England. [Singh, Rajinder; Kaur, Balvinder; Gaskell, Margaret; Farmer, Peter B.] Univ Leicester, Bioctr, Leicester LE1 7RH, Leics, England. [Monks, Anne; Hose, Curtis] NCI, Frederick, MD 21702 USA. [Leong, Chee-Onn] Int Med Univ, Sch Pharm & Hlth Sci, Kuala Lumpur 57000, Malaysia. RP Bradshaw, TD (reprint author), Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England. OI Stocks, Michael/0000-0003-3046-137X; Marlow, Maria/0000-0002-0333-5290 FU University of Nottingham, UK FX Authors thanks the University of Nottingham, UK for studentships (E.L.S. and F.C.) funding, and are grateful to colleagues at NCI and the University of Leicester for collaborations. NR 44 TC 6 Z9 6 U1 4 U2 11 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 NOV 1 PY 2015 VL 23 IS 21 BP 6891 EP 6899 DI 10.1016/j.bmc.2015.09.052 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CV7FI UT WOS:000364437400012 PM 26474663 ER PT J AU Hamano, R Wu, XQ Wang, YT Oppenheim, JJ Chen, X AF Hamano, Ryoko Wu, Xueqiang Wang, Yitao Oppenheim, Joost J. Chen, Xin TI Characterization of MT-2 cells as a human regulatory T cell-like cell line SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Editorial Material C1 [Hamano, Ryoko; Wu, Xueqiang; Oppenheim, Joost J.; Chen, Xin] NCI, Mol Immunoregulat Lab, Canc Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Hamano, Ryoko] Kanazawa Univ, Div Rheumatol, Kanazawa, Ishikawa, Japan. [Wang, Yitao; Chen, Xin] Univ Macau, State Key Lab Qual Res Chinese Med, Inst Chinese Med Sci, Macau, Peoples R China. RP Chen, X (reprint author), Univ Macau, Rm 7039,Bldg N22,Ave Univ, Taipa, Macau, Peoples R China. EM xchen@umac.mo RI Chen, Xin/I-6601-2015; Wang, Yitao/O-5184-2016 OI Chen, Xin/0000-0002-2628-4027; FU Intramural NIH HHS NR 10 TC 4 Z9 4 U1 1 U2 3 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD NOV PY 2015 VL 12 IS 6 BP 780 EP 782 DI 10.1038/cmi.2014.123 PG 3 WC Immunology SC Immunology GA CV8HO UT WOS:000364523600015 PM 25544500 ER PT J AU Cooper, LB Mentz, RJ Sun, JL Schulte, PJ Fleg, JL Cooper, LS Pina, IL Leifer, ES Kraus, WE Whellan, DJ Keteyian, SJ O'Connor, CM AF Cooper, Lauren B. Mentz, Robert J. Sun, Jie-Lena Schulte, Phillip J. Fleg, Jerome L. Cooper, Lawton S. Pina, Ileana L. Leifer, Eric S. Kraus, William E. Whellan, David J. Keteyian, Steven J. O'Connor, Christopher M. TI Psychosocial Factors, Exercise Adherence, and Outcomes in Heart Failure Patients Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) SO CIRCULATION-HEART FAILURE LA English DT Article DE exercise; exercise therapy; heart failure; patients; social support ID RANDOMIZED CONTROLLED-TRIAL; PERCEIVED SOCIAL SUPPORT; DEPRESSIVE SYMPTOMS; CLINICAL-OUTCOMES; HEALTH-STATUS; MYOCARDIAL-INFARCTION; PHYSICAL-ACTIVITY; 1ST YEAR; MORTALITY; HOSPITALIZATION AB Background-Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. Methods and Results-Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS (r= 0.09 and r= 0.13, respectively) and BTES (r=-0.11 and r=-0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P<0.005). For cardiovascular death or HF hospitalization, there was a significant interaction between the randomization group and BTES (P=0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). Conclusions-Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. C1 [Cooper, Lauren B.; Mentz, Robert J.; Sun, Jie-Lena; Schulte, Phillip J.; O'Connor, Christopher M.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Cooper, Lauren B.; Mentz, Robert J.; Kraus, William E.; O'Connor, Christopher M.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Fleg, Jerome L.; Cooper, Lawton S.; Leifer, Eric S.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Div Cardiol, Bronx, NY 10467 USA. [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Div Cardiol, Philadelphia, PA 19107 USA. [Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. RP Cooper, LB (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM lauren.b.cooper@duke.edu FU National Institutes of Health; National Institute of Health [T32HL069749-11A1] FX HF-ACTION was funded by the National Institutes of Health. Dr Cooper is supported by grant T32HL069749-11A1 from the National Institute of Health. NR 30 TC 4 Z9 4 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD NOV PY 2015 VL 8 IS 6 BP 1044 EP 1051 DI 10.1161/CIRCHEARTFAILURE.115.002327 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW1SQ UT WOS:000364772000005 PM 26578668 ER PT J AU Shah, AM Claggett, B Sweitzer, NK Shah, SJ Deswal, A Anand, IS Fleg, JL Pitt, B Pfeffer, MA Solomon, SD AF Shah, Amil M. Claggett, Brian Sweitzer, Nancy K. Shah, Sanjiv J. Deswal, Anita Anand, Inder S. Fleg, Jerome L. Pitt, Bertram Pfeffer, Marc A. Solomon, Scott D. TI Prognostic Importance of Changes in Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone SO CIRCULATION-HEART FAILURE LA English DT Article DE clinical trial; echocardiography; heart failure with preserved ejection fraction; spironolactone ID RANDOMIZED CONTROLLED-TRIAL; ALDOSTERONE ANTAGONIST TRIAL; PULMONARY-HYPERTENSION; EXERCISE CAPACITY; PHOSPHODIESTERASE-5 INHIBITION; EUROPEAN-ASSOCIATION; DIASTOLIC FUNCTION; AMERICAN-SOCIETY; TOPCAT TRIAL; DYSFUNCTION AB Background-Limited data exist regarding the impact of aldosterone antagonist therapy on cardiac structure and function in heart failure with preserved ejection fraction and on the prognostic relevance of changes in cardiac structure and function in heart failure with preserved ejection fraction. Methods and Results-Cardiac structure and function were assessed by quantitative echocardiography at baseline and at 12- to 18-month follow-up in 239 patients with heart failure with preserved ejection fraction (left ventricular [LV] ejection fraction [LVEF] 45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. The impact of spironolactone therapy on measures of cardiac structure and function was assessed in the study population overall, and change in echocardiographic measures was associated with the subsequent occurrence of the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. Spironolactone was not associated with alterations in cardiac structure and function compared with placebo. Decrease in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary outcome. Conclusions-Twelve to 18 months of spironolactone therapy was not associated with alterations in cardiac structure or function in patients with heart failure with preserved ejection fraction. Reduction in left atrial volume at follow-up was associated with a lower risk of subsequent occurrence of the primary composite outcome. C1 [Shah, Amil M.; Claggett, Brian; Pfeffer, Marc A.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Sweitzer, Nancy K.] Univ Arizona, Coll Med, Div Cardiol, Sarver Heart Ctr, Tucson, AZ USA. [Shah, Sanjiv J.] Northwestern Univ, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Div Cardiol, Houston, TX USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Anand, Inder S.] VA Med Ctr, Div Cardiovasc, Minneapolis, MN USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Pitt, Bertram] Univ Michigan, Sch Med, Div Cardiol, Ann Arbor, MI USA. RP Shah, AM (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boson, MA 02445 USA. EM ashah11@partners.org FU National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (Bethesda, MD) [HHSN268200425207C]; NHLBI [1K08HL116792]; American Heart Association grant [14CRP20380422] FX TOPCAT was funded by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (Bethesda, MD), Contract Number HHSN268200425207C. The content of this article does not necessarily represent the views of the sponsor or of the Department of Health and Human Services. The work for this article was also supported by NHLBI grant 1K08HL116792 (A.M. Shah) and American Heart Association grant 14CRP20380422 (A.M. Shah). NR 26 TC 8 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD NOV PY 2015 VL 8 IS 6 BP 1052 EP 1058 DI 10.1161/CIRCHEARTFAILURE.115.002249 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW1SQ UT WOS:000364772000006 PM 26475142 ER PT J AU Kennedy, DJ Shrestha, K Sheehey, B Li, XS Guggilam, A Wu, YP Finucan, M Gabi, A Medert, CM Westfall, K Borowski, A Fedorova, O Bagrov, AY Tang, WHW AF Kennedy, David J. Shrestha, Kevin Sheehey, Brendan Li, Xinmin S. Guggilam, Anuradha Wu, Yuping Finucan, Michael Gabi, Alaa Medert, Charles M. Westfall, Kristen Borowski, Allen Fedorova, Olga Bagrov, Alexei Y. Tang, W. H. Wilson TI Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE cardiac fibrosis; cardiotonic steroids; heart failure; nitrative stress; outcome ID ACUTE MYOCARDIAL-INFARCTION; EXPERIMENTAL UREMIC CARDIOMYOPATHY; DIGOXIN-LIKE IMMUNOREACTIVITY; NACL-SENSITIVE HYPERTENSION; SODIUM-PUMP; CARDIAC-HYPERTROPHY; ATPASE INHIBITION; RENAL-FAILURE; OUABAIN; DIGITALIS AB Background-Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes. Methods and Results-We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383-812) pM. Higher MBG was associated with higher myeloperoxidase (r=0.42, P<0.0001), B-type natriuretic peptide (r=0.25, P=0.001), and asymmetrical dimethylarginine (r=0.32, P<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s', r=-0.39, P<0.0001) and predicted increased risk of adverse clinical outcomes (MBG574 pmol/L: hazard ratio 1.58 [1.10-2.31], P=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis. Conclusions-In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis. C1 [Kennedy, David J.; Shrestha, Kevin; Sheehey, Brendan; Li, Xinmin S.; Guggilam, Anuradha; Wu, Yuping; Finucan, Michael; Gabi, Alaa; Medert, Charles M.; Westfall, Kristen; Borowski, Allen; Tang, W. H. Wilson] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Tang, W. H. Wilson] Cleveland Clin, Ctr Cardiovasc Diagnost & Prevent, Lerner Res Inst, Cleveland, OH 44106 USA. [Kennedy, David J.] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Hypertens & Nephrol, Cleveland, OH 44106 USA. [Tang, W. H. Wilson] Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Fedorova, Olga; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, Hypertens Unit, NIH, Baltimore, MD 21224 USA. RP Tang, WHW (reprint author), 9500 Euclid Ave,Desk J3-4, Cleveland, OH 44195 USA. EM tangw@ccf.org FU National Institutes of Health (NIH) [R01HL103931]; NIH/Office of Dietary Supplements [P20HL113452]; Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA [UL1TR 000439]; American Heart Association Scientist Development Grant [14SDG18650010]; Intramural Research Program, National Institute on Aging, National Institutes of Health FX This research was supported by grants from the National Institutes of Health (NIH, R01HL103931) and the NIH/Office of Dietary Supplements (P20HL113452) and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA (UL1TR 000439). Dr Kennedy was supported by an American Heart Association Scientist Development Grant 14SDG18650010. Drs Fedorova and Bagrov are supported by Intramural Research Program, National Institute on Aging, National Institutes of Health. Mass spectrometry studies were performed on instruments housed in a facility supported in part by a Center of Innovations Award by AB SCIEX. NR 49 TC 2 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD NOV PY 2015 VL 8 IS 6 BP 1068 EP 1076 DI 10.1161/CIRCHEARTFAILURE.114.001976 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW1SQ UT WOS:000364772000008 PM 26276886 ER PT J AU Olanich, ME Sun, W Hewitt, SM Abdullaev, Z Pack, SD Barr, FG AF Olanich, Mary E. Sun, Wenyue Hewitt, Stephen M. Abdullaev, Zied Pack, Svetlana D. Barr, Frederic G. TI CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma SO CLINICAL CANCER RESEARCH LA English DT Article ID ALVEOLAR RHABDOMYOSARCOMA; CELL-CYCLE; TARGET GENES; IN-VITRO; TUMOR; CANCER; E2F; RESISTANCE; SENESCENCE; EXPRESSION AB Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS. Experimental Design: We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts. Results: Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and nonamplified fusion-positive-RMS cells viaG1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distribution, proliferation, or transformation were not observed in RMS cells over expressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell-cycle arrest. Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models ofCDK4-amplified and nonamplified fusion-positive RMS. Conclusions: Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F-mediated G1-phase cell-cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition. (C) 2015 AACR. C1 [Olanich, Mary E.; Sun, Wenyue; Barr, Frederic G.] NCI, Canc Mol Pathol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Appl Mol Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Abdullaev, Zied; Pack, Svetlana D.] NCI, Chromosome Pathol Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Barr, FG (reprint author), NCI, Pathol Lab, Ctr Canc Res, 10 Ctr Dr,Room 3B55, Bethesda, MD 20892 USA. EM barrfg@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the National Cancer Institute; Joanna McAfee Childhood Cancer Foundation FX This research was supported by the Intramural Research Program of the National Cancer Institute and by the Joanna McAfee Childhood Cancer Foundation. NR 50 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2015 VL 21 IS 21 BP 4947 EP 4959 DI 10.1158/1078-0432.CCR-14-2955 PG 13 WC Oncology SC Oncology GA CV7WW UT WOS:000364488100023 PM 25810375 ER PT J AU Wang, BD Ceniccola, K Yang, Q Andrawis, R Patel, V Ji, Y Rhim, J Olender, J Popratiloff, A Latham, P Lai, Y Patierno, SR Lee, NH AF Wang, Bi-Dar Ceniccola, Kristin Yang, Qi Andrawis, Ramez Patel, Vyomesh Ji, Youngmi Rhim, Johng Olender, Jacqueline Popratiloff, Anastas Latham, Patricia Lai, Yinglei Patierno, Steven R. Lee, Norman H. TI Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; BREAST-CANCER; EXPRESSION; MIR-96; TARGETS; GROWTH; LOCUS; DEREGULATION; ASSOCIATION; PATHWAYS AB Purpose: African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to prostate cancer disparities. Experimental Design: Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA-mRNA interactions associated with prostate cancer disparities. Results: We identified 22 AA-specific and 18 EA-specific miRNAs in prostate cancer versus patient-matched normal prostate, and 10 "AA-enriched/-depleted" miRNAs in AA prostate cancer versus EA prostate cancer comparisons. Manyof these populationspecific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA-mRNApairings. Novel miRNA-mRNApairings were validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2, and miR-34a/PPP2R2A as critical miRNA-mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells. Conclusions: Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1, and miR-96/FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer. (C) 2015 AACR. C1 [Wang, Bi-Dar; Ceniccola, Kristin; Yang, Qi; Olender, Jacqueline; Lee, Norman H.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol & Physiol, Washington, DC 20037 USA. [Andrawis, Ramez] George Washington Univ, Sch Med & Hlth Sci, Med Fac Associates, Washington, DC 20037 USA. [Patel, Vyomesh] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Ji, Youngmi] NIAMSD, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD 20892 USA. [Rhim, Johng] Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Bethesda, MD 20814 USA. [Popratiloff, Anastas] George Washington Univ, Sch Med & Hlth Sci, Dept Anat & Regenerat Biol, Washington, DC 20037 USA. [Latham, Patricia] George Washington Univ, Sch Med & Hlth Sci, Dept Pathol, Washington, DC 20037 USA. [Lai, Yinglei] George Washington Univ, Dept Stat, Washington, DC 20037 USA. [Patierno, Steven R.] George Washington Univ, Med Ctr, GW Canc Inst, Washington, DC 20037 USA. [Patierno, Steven R.] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. RP Lee, NH (reprint author), George Washington Univ, Sch Med & Hlth Sci, 2300 I St North West, Washington, DC 20037 USA. EM nhlee@gwu.edu FU NCI grant [R01 CA120316]; DOD grant [PC121975]; Affymetrix Collaborations in Cancer Research Award; NCI supplement grant [U01 CA116937]; American Cancer Society grant [IRG-08-091-01] FX This work was supported by NCI grant R01 CA120316 (to N.H. Lee), DOD grant PC121975 (to N.H. Lee), Affymetrix Collaborations in Cancer Research Award (to N.H. Lee), NCI supplement grant U01 CA116937 (to S.R. Patierno), and American Cancer Society grant IRG-08-091-01 (to B.-D. Wang). NR 50 TC 5 Z9 5 U1 2 U2 7 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 NOV 1 PY 2015 VL 21 IS 21 BP 4970 EP 4984 DI 10.1158/1078-0432.CCR-14-1566 PG 15 WC Oncology SC Oncology GA CV7WW UT WOS:000364488100025 PM 26089375 ER PT J AU Schoenbaum, M AF Schoenbaum, Michael TI INCREASING SUPPLY OF AND DEMAND FOR EVIDENCE-BASED PSYCHOTHERAPY: NEAR-TERM OPTIONS FOR PAYERS AND POLICYMAKERS SO DEPRESSION AND ANXIETY LA English DT Editorial Material C1 NIMH, Off Sci Policy Planning & Commun, Bethesda, MD 20892 USA. RP Schoenbaum, M (reprint author), NIMH, Off Sci Policy Planning & Commun, 6001 Execut Blvd,MSC 9669, Bethesda, MD 20892 USA. EM schoenbaumm@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD NOV PY 2015 VL 32 IS 11 BP 809 EP 810 DI 10.1002/da.22442 PG 2 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CV6PM UT WOS:000364392300010 PM 26502366 ER PT J AU Thievessen, I Fakhri, N Steinwachs, J Kraus, V McIsaac, RS Gao, L Chen, BC Baird, MA Davidson, MW Betzig, E Oldenbourg, R Waterman, CM Fabry, B AF Thievessen, Ingo Fakhri, Nikta Steinwachs, Julian Kraus, Viola McIsaac, R. Scott Gao, Liang Chen, Bi-Chang Baird, Michelle A. Davidson, Michael W. Betzig, Eric Oldenbourg, Rudolf Waterman, Clare M. Fabry, Ben TI Vinculin is required for cell polarization, migration, and extracellular matrix remodeling in 3D collagen SO FASEB JOURNAL LA English DT Article DE 3D cell migration; cell morphodynamics; traction force generation; integrin ID BIOPOLYMER NETWORKS; ADHESION; FORCE; TISSUE; MORPHOGENESIS; FIBRONECTIN; TENSION; RECRUITMENT; MOVEMENT; DYNAMICS AB Vinculin is filamentous (F)-actin-binding protein enriched in integrin-based adhesions to the extracellular matrix (ECM). Whereas studies in 2-dimensional (2D) tissue culture models have suggested that vinculin negatively regulates cell migration by promoting cytoskeleton-ECM coupling to strengthen and stabilize adhesions, its role in regulating cell migration in more physiologic, 3-dimensional (3D) environments is unclear. To address the role of vinculin in 3D cell migration, we analyzed the morphodynamics, migration, and ECM remodeling of primary murine embryonic fibroblasts (MEFs) with cre/loxP-mediated vinculin gene disruption in 3D collagen I cultures. We found that vinculin promoted 3D cell migration by increasing directional persistence. Vinculin was necessary for persistent cell protrusion, cell elongation, and stable cell orientation in 3D collagen, but was dispensable for lamellipodia formation, suggesting that vinculin-mediated cell adhesion to the ECM is needed to convert actin-based cell protrusion into persistent cell shape change and migration. Consistent with this finding, vinculin was necessary for efficient traction force generation in 3D collagen without affecting myosin II activity and promoted 3D collagen fiber alignment and macroscopical gel contraction. Our results suggest that vinculin promotes directionally persistent cell migration and tension-dependent ECM remodeling in complex 3D environments by increasing cell-ECM adhesion and traction force generation. C1 [Thievessen, Ingo; Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Thievessen, Ingo; Steinwachs, Julian; Kraus, Viola; Fabry, Ben] Univ Erlangen Nurnberg, Biophys Grp, Dept Phys, D-91054 Erlangen, Germany. [Thievessen, Ingo; Fakhri, Nikta; McIsaac, R. Scott; Gao, Liang; Chen, Bi-Chang; Baird, Michelle A.; Davidson, Michael W.; Betzig, Eric; Waterman, Clare M.] Marine Biol Lab, Physiol Course, Woods Hole, MA 02543 USA. [Oldenbourg, Rudolf] Marine Biol Lab, Cellular Dynam Program, Woods Hole, MA 02543 USA. [Fakhri, Nikta] Univ Gottingen, Phys Inst Biophys 3, D-37073 Gottingen, Germany. [Fakhri, Nikta] MIT, Dept Phys, Phys Living Syst, Cambridge, MA 02139 USA. [McIsaac, R. Scott] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [McIsaac, R. Scott] Calif Life Co, San Francisco, CA USA. [Gao, Liang; Chen, Bi-Chang; Betzig, Eric] Howard Hughes Med Inst, Ashburn, VA USA. [Gao, Liang] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. [Chen, Bi-Chang] Acad Sinica, Res Ctr Appl Sci, Taipei 115, Taiwan. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Natl High Magnet Field Lab, Tallahassee, FL 32306 USA. RP Thievessen, I (reprint author), Univ Erlangen Nurnberg, Biophys Grp, Dept Phys, Henkestr 91, D-91054 Erlangen, Germany. EM ithievessen@biomed.uni-erlangen.de RI Chen , Bi-Chang /F-3480-2014; Fakhri, Nikta/B-4657-2008; Fabry, Ben/C-5496-2013 OI Fakhri, Nikta/0000-0003-1261-7465; Fabry, Ben/0000-0003-1737-0465 FU NIH NHLBI Division of Intramural Research; Deutsche Forschungsgemeinschaft; Human Frontier Science Program Fellowship; U.S. National Science Foundation Graduate Research Fellowship Program FX The authors thank the U.S. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) Flow Cytometry Core Facility, for fluorescence-activated cell sorting, Silvio Gutkind for adenovirus, and Robert Fischer for helpful discussion. This work was supported by the NIH NHLBI Division of Intramural Research (C.M.W. and I.T.), Deutsche Forschungsgemeinschaft (B.F., I.T., and J.S.), the Human Frontier Science Program Fellowship (N.F.), and the U.S. National Science Foundation Graduate Research Fellowship Program (R.S.M.). NR 41 TC 8 Z9 8 U1 3 U2 23 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD NOV PY 2015 VL 29 IS 11 BP 4555 EP 4567 DI 10.1096/fj.14-268235 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CV8EZ UT WOS:000364514700015 PM 26195589 ER PT J AU Kirkby, NS Reed, DM Edin, ML Rauzi, F Mataragka, S Vojnovic, I Bishop-Bailey, D Milne, GL Longhurst, H Zeldin, DC Mitchell, JA Warner, TD AF Kirkby, Nicholas S. Reed, Daniel M. Edin, Matthew L. Rauzi, Francesca Mataragka, Stefania Vojnovic, Ivana Bishop-Bailey, David Milne, Ginger L. Longhurst, Hilary Zeldin, Darryl C. Mitchell, Jane A. Warner, Timothy D. TI Inherited human group IVA cytosolic phospholipase A(2) deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation SO FASEB JOURNAL LA English DT Article DE cardiovascular; thromboxane A(2); prostacyclin; inflammation ID 12-HYDROXYEICOSATETRAENOIC ACID; CARDIOVASCULAR-SYSTEM; ARACHIDONIC-ACID; GLYCOPROTEIN-VI; BLOOD; 12-LIPOXYGENASE; BIOSYNTHESIS; PROSTACYCLIN; ACTIVATION; RECEPTOR AB Eicosanoids are important vascular regulators, but the phospholipase A(2) (PLA(2)) isoforms supporting their production within the cardiovascular system are not fully understood. To address this, we have studied platelets, endothelial cells, and leukocytes from 2 siblings with a homozygous loss-of-function mutation in group IVA cytosolic phospholipase A(2) (cPLA(2)alpha). Chromatography/mass spectrometry was used to determine levels of a broad range of eicosanoids produced by isolated vascular cells, and in plasma and urine. Eicosanoid release data were paired with studies of cellular function. Absence of cPLA(2)alpha almost abolished eicosanoid synthesis in platelets (e.g., thromboxane A(2), control 20.5 +/- 1.4 ng/ml vs. patient 0.1 ng/ml) and leukocytes [e.g., prostaglandin E-2 (PGE(2)), control 21.9 +/- 7.4 ng/ml vs. patient 1.9 ng/ml], and this was associated with impaired platelet activation and enhanced inflammatory responses. cPLA(2)alpha-deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I-2 (prostacyclin; control 956 +/- 422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation. In the urine, prostaglandin metabolites were selectively influenced by cPLA(2)alpha deficiency. For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA(2)alpha, whereas PGE(2) metabolites (77.8% of control) were similar to healthy volunteer levels. These studies constitute a definitive account, demonstrating the fundamental role of cPLA(2)alpha to eicosanoid formation and cellular responses within the human circulation. C1 [Kirkby, Nicholas S.; Reed, Daniel M.; Mataragka, Stefania; Mitchell, Jane A.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Kirkby, Nicholas S.; Rauzi, Francesca; Vojnovic, Ivana; Warner, Timothy D.] Queen Mary Univ London, William Harvey Res Inst, London, England. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Bishop-Bailey, David] Univ London Royal Vet Coll, Dept Comparat Biomed Sci, London, England. [Milne, Ginger L.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Milne, Ginger L.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Longhurst, Hilary] Barts Hlth, Immunol Dept, London, England. [Longhurst, Hilary] London Natl Hlth Serv Trust, London, England. RP Warner, TD (reprint author), Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England. EM t.d.warner@qmul.ac.uk RI Warner, Timothy/A-1980-2009; Milne, Ginger/D-7648-2014; OI Warner, Timothy/0000-0003-3988-4408; Milne, Ginger/0000-0003-3890-151X; Edin, Matthew/0000-0002-7042-500X FU Imperial College Junior Research Fellowship; Wellcome Trust program grant [0852551Z108/Z]; British Heart Foundation Ph.D. studentship [FS/10/033/28271]; British Heart Foundation project grant [PG/11/39/28890]; Intramural Research Program of the U.S. National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES025034] FX The authors acknowledge the cytosolic phospholipase A2-deficient individuals who made these studies possible by volunteering to provide blood samples. This research was supported by an Imperial College Junior Research Fellowship (to N.S.K.), Wellcome Trust program grant (0852551Z108/Z to J.A.M. and T.D.W.), British Heart Foundation Ph.D. studentship (FS/10/033/28271 to F.R.), British Heart Foundation project grant (PG/11/39/28890 to D.B.-B.), and by the Intramural Research Program of the U.S. National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES025034 to D.C.Z.). NR 46 TC 3 Z9 3 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD NOV PY 2015 VL 29 IS 11 BP 4568 EP 4578 DI 10.1096/fj.15-275065 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CV8EZ UT WOS:000364514700016 PM 26183771 ER PT J AU Cho, HY Marzec, J Kleeberger, SR AF Cho, Hye-Youn Marzec, Jacqui Kleeberger, Steven R. TI Functional polymorphisms in Nrf2: implications for human disease SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Somatic; Mutations; Complex disease; Genetic; Promoter; Antioxidant response element; Mouse; Genome-wide association ID NRF2-ENCODING NFE2L2 HAPLOTYPES; ANTIOXIDANT RESPONSE ELEMENTS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENE PROMOTER POLYMORPHISM; TRANSCRIPTION FACTOR NRF2; SQUAMOUS-CELL CARCINOMAS; ACUTE LUNG INJURY; ANNUAL DECLINE; BREAST-CANCER; E3 LIGASE AB Nuclear factor (erythroid derived)-2 like 2 (NFE2L2), also known as nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), is a ubiquitous transcription factor essential for protecting cells and tissues from oxidative stress-induced injury. Positional cloning and studies with Nrf2 knockout mice have identified important roles for this transcription factor in disease phenotypes for many organ systems. Studies have also characterized the means through which human Nrf2 is regulated and the mechanisms of interaction with antioxidant response elements (ARE) in promoters of effector genes. Moreover, single nucleotide polymorphisms (SNPs) in Nrf2 have been identified and evaluated for effects on gene expression and function, and translational investigations have sought to determine whether loss of function SNPs associate with disease progression. In this review, we present 1) an overview of the human Nrf2 gene and protein domain, 2) identification of genetic mutations in Nrf2 and associations of the mutations with multiple diseases, and 3) the role of somatic mutations in Nrf2 in diseases, primarily various cancers. C1 [Cho, Hye-Youn; Marzec, Jacqui; Kleeberger, Steven R.] NIEHS, Inflammat Immun & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kleeberger, SR (reprint author), NIEHS, Inflammat Immun & Dis Lab, NIH, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM kleeber1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) FX The research related to the manuscript was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS). Drs. Michael Fessler and Donald Cook at the N1EHS provided excellent critical review of the manuscript. NR 80 TC 6 Z9 6 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV PY 2015 VL 88 BP 362 EP 372 DI 10.1016/j.freeradbiomed.2015.06.012 PN B PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CV0TN UT WOS:000363966300024 PM 26117318 ER PT J AU Lacher, SE Lee, JS Wang, XT Campbell, MR Bell, DA Slattery, M AF Lacher, Sarah E. Lee, Joslynn S. Wang, Xuting Campbell, Michelle R. Bell, Douglas A. Slattery, Matthew TI Beyond antioxidant genes in the ancient Nrf2 regulatory network SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nrf2; Keap1; ARE; Drosophila; Human; Genomics; Transcriptional regulation; Enhancer; Free radicals ID TRANSCRIPTION FACTOR NRF2; OXIDATIVE STRESS-ADAPTATION; HUMAN NEUROBLASTOMA-CELLS; DIET-INDUCED OBESITY; DROSOPHILA-MELANOGASTER; PYRUVATE-CARBOXYLASE; TERT-BUTYLHYDROQUINONE; ENRICHMENT ANALYSIS; SIGNALING PATHWAY; FEEDBACK LOOP AB Nrf2, a basic leucine zipper transcription factor encoded by the gene NFE2L2, is a master regulator of the transcriptional response to oxidative stress. Nrf2 is structurally and functionally conserved from insects to humans, and it heterodimerizes with the small MAF transcription factors to bind a consensus DNA sequence (the antioxidant response element, or ARE) and regulate gene expression. We have used genome-wide chromatin immunoprecipitation and gene expression data to identify direct Nrf2 target genes in Drosophila and humans. These data have allowed us to construct the deeply conserved ancient Nrf2 regulatory network target genes that are conserved from Drosophila to human. The ancient network consists of canonical antioxidant genes, as well as genes related to proteasomal pathways and metabolism and a number of less expected genes. We have also used enhancer reporter assays and electrophoretic mobility-shift assays to confirm Nrf2-mediated regulation of ARE activity at a number of these novel target genes. Interestingly, the ancient network also highlights a prominent negative feedback loop; this, combined with the finding that Nrf2-mediated regulatory output is tightly linked to the quality of the ARE it is targeting, suggests that precise regulation of nuclear Nrf2 concentration is necessary to achieve proper quantitative regulation of distinct gene sets. Together, these findings highlight the importance of balance in the Nrf2-ARE pathway and indicate that Nrf2-mediated regulation of xenobiotic metabolism, glucose metabolism, and proteostasis has been central to this pathway since its inception. (C) 2015 Published by Elsevier Inc. C1 [Lacher, Sarah E.; Lee, Joslynn S.; Slattery, Matthew] Univ Minnesota, Sch Med, Dept Biomed Sci, Duluth, MN 55812 USA. [Wang, Xuting; Campbell, Michelle R.; Bell, Douglas A.] NIEHS, Environm Genom Sect, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Slattery, Matthew] Univ Minnesota, Ctr Dev Biol, Minneapolis, MN 55455 USA. RP Slattery, M (reprint author), Univ Minnesota, Sch Med, Dept Biomed Sci, Duluth, MN 55812 USA. EM mslatter@umn.edu OI Lee, Joslynn/0000-0001-9363-6013; Wang, Xuting/0000-0001-6781-8008 FU University of Minnesota Foundation; Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES-100475, ES065079] FX The authors thank Evan Odean (University of Minnesota), Lijia Ma (University of Chicago), Anshul Kundaje (Stanford), and Katherine Harris (SwitchGear Genomics) for technical assistance. This work was supported by funding from the University of Minnesota Foundation (M.S.) and the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01-ES-100475 and ES065079 to D.A.B.). NR 75 TC 5 Z9 7 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV PY 2015 VL 88 BP 452 EP 465 DI 10.1016/j.freeradbiomed.2015.06.044 PN B PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CV0TN UT WOS:000363966300032 PM 26163000 ER PT J AU Shen, F Mao, L Zhu, W Lawton, MT Pechan, P Colosi, P Wu, Z Scaria, A Su, H AF Shen, F. Mao, L. Zhu, W. Lawton, M. T. Pechan, P. Colosi, P. Wu, Z. Scaria, A. Su, H. TI Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1 SO GENE THERAPY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; HEREDITARY HEMORRHAGIC TELANGIECTASIA; ADULT-MOUSE BRAIN; ADENOASSOCIATED VIRUS; GENE-TRANSFER; ARTERIOVENOUS-MALFORMATION; VASCULAR MALFORMATIONS; IMMUNE-RESPONSES; VEGF; THERAPY AB The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example, age-related macular degeneration. We hypothesized that adeno-associated viral vector (AAV)mediated sFLT1 expression could be used to inhibit abnormal brain angiogenesis. We tested the anti-angiogenic effect of sFLT1 and the feasibility of using AAV serotype 9 to deliver sFLT1 through intravenous injection (IV) to the brain angiogenic region. AAVs were packaged in AAV serotypes 1 and 2 (stereotactic injection) and 9 (IV injection). Brain angiogenesis was induced in adult mice through stereotactic injection of AAV1-VEGF. AAV2-sFLT02 containing sFLT1 VEGF-binding domain (domain 2) was injected into the brain angiogenic region, and AAV9-sFLT1 was injected into the jugular vein at the time of or 4 weeks after AAV1-VEGF injection. We showed that AAV2-sFLT02 inhibited brain angiogenesis at both time points. IV injection of AAV9-sFLT1 inhibited angiogenesis only when the vector was injected 4 weeks after angiogenic induction. Neither lymphocyte infiltration nor neuron loss was observed in AAV9-sFLT1-treated mice. Our data show that systemically delivered AAV9-sFLT1 inhibits angiogenesis in the mouse brain, which could be utilized to treat brain angiogenic diseases such as brain arteriovenous malformation. C1 [Shen, F.; Mao, L.; Zhu, W.; Su, H.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Ctr Cerebrovasc Res, San Francisco, CA 94110 USA. [Shen, F.] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurol, Shanghai, Peoples R China. [Lawton, M. T.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94110 USA. [Pechan, P.; Scaria, A.] Sanofi Genzyme R&D Ctr, Framingham, MA USA. [Colosi, P.; Wu, Z.] NEI, Ocular Gene Therapy Core, NIH, Bethesda, MD 20892 USA. RP Su, H (reprint author), Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, 1001 Potrero Ave Box 1368, San Francisco, CA 94110 USA. EM hua.su@ucsf.edu FU National Institutes of Health [R01 NS027713, R01 HL122774, R21 NS070153]; Michael Ryan Zodda Foundation; UCSF Research Evaluation and Allocation Committee (REAC); National Natural Science Foundation of China [81471177] FX We thank the members of the UCSF BAVM Study Project (http://avm.ucsf.edu) for their support, and Voltaire Gungab for assistance with manuscript preparation. This study was supported by grants to H. Su from the National Institutes of Health (R01 NS027713, R01 HL122774, and R21 NS070153) and from the Michael Ryan Zodda Foundation and UCSF Research Evaluation and Allocation Committee (REAC), and by a grant to F Shen from the National Natural Science Foundation of China (No 81471177). NR 60 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD NOV PY 2015 VL 22 IS 11 BP 893 EP 900 DI 10.1038/gt.2015.57 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CV8YO UT WOS:000364574500007 PM 26090874 ER PT J AU Singh, PK Plumb, MR Ferris, AL Iben, JR Wu, XL Fadel, HJ Luke, BT Esnault, C Poeschla, EM Hughes, SH Kvaratskhelia, M Levin, HL AF Singh, Parmit Kumar Plumb, Matthew R. Ferris, Andrea L. Iben, James R. Wu, Xiaolin Fadel, Hind J. Luke, Brian T. Esnault, Caroline Poeschla, Eric M. Hughes, Stephen H. Kvaratskhelia, Mamuka Levin, Henry L. TI LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes SO GENES & DEVELOPMENT LA English DT Article DE HIV-1; integration; mRNA splicing; LEDGF; p75; retrovirus ID LEUKEMIA-VIRUS INTEGRATION; HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSCRIPTION START SITES; DNA INTEGRATION; HUMAN-CELLS; LENTIVIRAL INTEGRATION; RETROVIRAL INTEGRATION; STRUCTURAL BASIS; MLV INTEGRATION; COACTIVATOR P75 AB The host chromatin-binding factor LEDGF/p75 interacts with HIV-1 integrase and directs integration to active transcription units. To understand how LEDGF/p75 recognizes transcription units, we sequenced 1 million HIV-1 integration sites isolated from cultured HEK293T cells. Analysis of integration sites showed that cancer genes were preferentially targeted, raising concerns about using lentivirus vectors for gene therapy. Additional analysis led to the discovery that introns and alternative splicing contributed significantly to integration site selection. These correlations were independent of transcription levels, size of transcription units, and length of the introns. Multivariate analysis with five parameters previously found to predict integration sites showed that intron density is the strongest predictor of integration density in transcription units. Analysis of previously published HIV-1 integration site data showed that integration density in transcription units in mouse embryonic fibroblasts also correlated strongly with intron number, and this correlation was absent in cells lacking LEDGF. Affinity purification showed that LEDGF/p75 is associated with a number of splicing factors, and RNA sequencing (RNA-seq) analysis of HEK293T cells lacking LEDGF/p75 or the LEDGF/p75 integrase-binding domain (IBD) showed that LEDGF/p75 contributes to splicing patterns in half of the transcription units that have alternative isoforms. Thus, LEDGF/p75 interacts with splicing factors, contributes to exon choice, and directs HIV-1 integration to transcription units that are highly spliced. C1 [Singh, Parmit Kumar; Esnault, Caroline; Levin, Henry L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Plumb, Matthew R.; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Ferris, Andrea L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Iben, James R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Wu, Xiaolin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Fadel, Hind J.] Mayo Clin, Coll Med, Dept Mol Med, Rochester, MN 55905 USA. [Luke, Brian T.] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD USA. [Poeschla, Eric M.] Univ Colorado, Div Infect Dis, Sch Med, Aurora, CO 80045 USA. RP Levin, HL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM henry_levin@nih.gov FU Intramural Research Programs of the National Institutes of Health from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; National Institutes of Health Intramural AIDS Targeted Antiviral Program; National Institutes of Health [AI062520, AI77344]; National Cancer Institute [HHSN261200800001E] FX P.K.S. dedicates this article to his parents, Shri Dhurandhar Singh and Smt. Sushila Devi. We thank Anthony Hickey for computational assistance. We are grateful to Allen Kane for help in preparing the figures. This research was supported by the Intramural Research Programs of the National Institutes of Health from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (H.L.L.) and the National Cancer Institute (S.H.H.). This research also received support from the National Institutes of Health Intramural AIDS Targeted Antiviral Program (H.L.L. and S.H.H.). The present study was also supported by National Institutes of Health grants AI062520 (to M.K.) and AI77344 (to E.M.P.). Funds from the National Cancer Institute under contract number HHSN261200800001E to the Frederick National Laboratory for Cancer Research (B.T.L.) were also used. P.K.S., M.R.P., A.L.F., and H.J.F. designed and performed experiments and analyzed data. J.R.I., C.E., and X.W. provided computational expertise and analysis. E.M.P., S.H.H., M.K., and H.L.L. designed, supervised, and analyzed experiments. B.T.L. and P.K.S. conducted the multivariate analyses. P.K.S. and H.L.L. conceived the study and wrote the paper. All authors contributed to editing of the paper. NR 57 TC 10 Z9 10 U1 0 U2 2 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 NOV 1 PY 2015 VL 29 IS 21 BP 2287 EP 2297 DI 10.1101/gad.267609.115 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CW2WJ UT WOS:000364853500007 PM 26545813 ER PT J AU Decker, B Davis, BW Rimbault, M Long, AH Karlins, E Jagannathan, V Reiman, R Parker, HG Drogemuller, C Corneveaux, JJ Chapman, ES Trent, JM Leeb, T Huentelman, MJ Wayne, RK Karyadi, DM Ostranderl, EA AF Decker, Brennan Davis, Brian W. Rimbault, Maud Long, Adrienne H. Karlins, Eric Jagannathan, Vidhya Reiman, Rebecca Parker, Heidi G. Droegemueller, Cord Corneveaux, Jason J. Chapman, Erica S. Trent, Jeffery M. Leeb, Tosso Huentelman, Matthew J. Wayne, Robert K. Karyadi, Danielle M. Ostranderl, Elaine A. TI Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor SO GENOME RESEARCH LA English DT Article ID CLASS-I MOLECULES; ANTIGEN PRESENTATION; GRANZYME-B; IFN-GAMMA; CANCER; ACTIVATION; APOPTOSIS; ORIGIN; AMINOPEPTIDASE; SUBSTITUTIONS AB Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world. C1 [Decker, Brennan; Davis, Brian W.; Rimbault, Maud; Karlins, Eric; Parker, Heidi G.; Chapman, Erica S.; Karyadi, Danielle M.; Ostranderl, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Decker, Brennan] Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Long, Adrienne H.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jagannathan, Vidhya; Droegemueller, Cord; Leeb, Tosso] Univ Bern, Inst Genet, CH-3001 Bern, Switzerland. [Reiman, Rebecca; Corneveaux, Jason J.; Trent, Jeffery M.; Huentelman, Matthew J.] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. RP Ostranderl, EA (reprint author), NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Davis, Brian/0000-0002-6121-135X; Decker, Brennan/0000-0003-4516-7421; Drogemuller, Cord/0000-0001-9773-522X; Ostrander, Elaine/0000-0001-6075-9738 FU NSF; Biowulf Linux cluster at the National Institutes of Health; Intramural Program of the National Human Genome Research Institute; Intramural Program of the National Cancer Institute; National Institutes of Health Cambridge Scholars Program; National Cancer Institute [UC2CA148149] FX We thank the dog owners for donating blood samples to research. We thank Adam Boyko for additional information about published canid genomes. We also thank the National Intramural Sequencing Program, the Next Generation Sequencing Platform of the University of Bern, Wayne Pfeiffer at the San Diego Supercomputer Center with support from NSF, and the Biowulf Linux cluster at the National Institutes of Health. This work was supported by the Intramural Program of the National Human Genome Research Institute (E.A.O., B.D., B.W.D., M.R., E.K., D.M.K., H.G.P., E.S.C.), the Intramural Program of the National Cancer Institute (A.H.L.), the National Institutes of Health Cambridge Scholars Program (B.D.), and UC2CA148149 from the National Cancer Institute (M.J.H., J.M.T., R.R., J.J.C., awarded to J.M.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 9 Z9 9 U1 1 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2015 VL 25 IS 11 BP 1646 EP 1655 DI 10.1101/gr.190314.115 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CV6BL UT WOS:000364355600006 PM 26232412 ER PT J AU Resnik, DB AF Resnik, David B. TI The Censor's Hand: The Misregulation of Human-Subject Research SO HASTINGS CENTER REPORT LA English DT Book Review AB Very few people who read Carl Schneider's The Censor's Hand: The Misregulation of Human-Subject Research (MIT Press, 2015) will have a neutral opinion of his book. Schneider defends the radical thesis that the system of regulating human subjects research is not just broken but deeply misguided and therefore needs to be abolished. While some researchers who are frustrated with the current regime will welcome Schneider's scathing critiques of institutional review boards and the regulations they enforce, those who view the status quo as a necessary, though perhaps flawed, means of protecting human subjects will recoil from his arguments and conclusions. Schneider rejects reform efforts, such as the proposed revisions to the Common Rule, as likely to be short-lived and ineffective. He argues that professional self-regulation and tort law can do a better job of protecting human subjects and advancing research than government regulation. C1 [Resnik, David B.] Natl Inst Environm Hlth Sci, Inst Review Board, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), Natl Inst Environm Hlth Sci, Inst Review Board, Res Triangle Pk, NC 27709 USA. FU National Institute for Environmental Health Sciences at the National Institutes of Health FX This research was supported by the intramural program of the National Institute for Environmental Health Sciences at the National Institutes of Health. It does not represent the views of the NIEHS, NIH, or U.S. government. NR 1 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD NOV-DEC PY 2015 VL 45 IS 6 BP 49 EP 50 DI 10.1002/hast.517 PG 2 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA CW1YD UT WOS:000364787000015 PM 26556146 ER PT J AU Arem, H Matthews, CE Lee, IM AF Arem, Hannah Matthews, Charles E. Lee, I-Min TI Physical Activity and Successful Aging: Even a Little Is Good Reply SO JAMA Internal Medicine LA English DT Letter C1 [Arem, Hannah; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lee, I-Min] Harvard Univ, Sch Med, Boston, MA USA. RP Arem, H (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E314,MSC 9768, Bethesda, MD 20892 USA. EM Aremhe2@mail.nih.gov NR 3 TC 1 Z9 1 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD NOV PY 2015 VL 175 IS 11 BP 1863 EP 1863 DI 10.1001/jamainternmed.2015.4750 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CV7BO UT WOS:000364427200037 PM 26524743 ER PT J AU Hingson, R Zha, WX White, A Simons-Morton, B AF Hingson, Ralph Zha, Wenxing White, Aaron Simons-Morton, Bruce TI Screening and Brief Alcohol Counseling of College Students and Persons Not in School SO JAMA Pediatrics LA English DT Letter ID INTERVENTIONS; ADOLESCENTS C1 [Hingson, Ralph; Zha, Wenxing] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [White, Aaron] NIAAA, Off Director, Bethesda, MD 20892 USA. [Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. RP Hingson, R (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Ln,Room 2074, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS; NICHD NIH HHS [HHSN267200800009C, HHSN275201200001I]; PHS HHS [HHSN267200800009C] NR 6 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD NOV PY 2015 VL 169 IS 11 BP 1068 EP 1070 DI 10.1001/jamapediatrics.2015.2231 PG 4 WC Pediatrics SC Pediatrics GA CV7CM UT WOS:000364430000021 PM 26414397 ER PT J AU Bonilla, FA Khan, DA Ballas, ZK Chinen, J Frank, MM Hsu, JT Keller, M Kobrynski, LJ Komarow, HD Mazer, B Nelson, RP Orange, JS Routes, JM Shearer, WT Sorensen, RU Verbsky, JW Bernstein, DI Blessing-Moore, J Lang, D Nicklas, RA Oppenheimer, J Portnoy, JM Randolph, CR Schuller, D Spector, SL Tilles, S Wallace, D AF Bonilla, Francisco A. Khan, David A. Ballas, Zuhair K. Chinen, Javier Frank, Michael M. Hsu, Joyce T. Keller, Michael Kobrynski, Lisa J. Komarow, Hirsh D. Mazer, Bruce Nelson, Robert P., Jr. Orange, Jordan S. Routes, John M. Shearer, William T. Sorensen, Ricardo U. Verbsky, James W. Bernstein, David I. Blessing-Moore, Joann Lang, David Nicklas, Richard A. Oppenheimer, John Portnoy, Jay M. Randolph, Christopher R. Schuller, Diane Spector, Sheldon L. Tilles, Stephen Wallace, Dana TI Practice parameter for the diagnosis and management of primary immunodeficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material AB The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency.'' This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. C1 [Bonilla, Francisco A.] Boston Childrens Hosp, Boston, MA 02115 USA. [Bonilla, Francisco A.] Harvard Univ, Sch Med, Pediat, Boston, MA USA. [Khan, David A.] Univ Texas SW Med Ctr Dallas, Internal Med, Dallas, TX 75390 USA. [Bernstein, David I.] Univ Cincinnati, Coll Med, Div Immunol Allergy & Rheumatol, Clin Med & Environm Hlth, Cincinnati, OH USA. [Blessing-Moore, Joann] Stanford Univ, Med Ctr, Dept Immunol, Med & Pediat, Palo Alto, CA 94304 USA. [Lang, David] Cleveland Clin Fdn, Allergy Immunol Sect Resp Inst, Cleveland, OH 44195 USA. [Lang, David] Cleveland Clin Fdn, Allergy & Immunol Fellowship Training Program, Cleveland, OH 44195 USA. [Nicklas, Richard A.] George Washington Med Ctr, Med, Washington, DC USA. [Oppenheimer, John] Univ Med & Dent New Jersey, Pulm & Allergy Associates, Dept Internal Med, Morristown, NJ USA. [Portnoy, Jay M.] Childrens Mercy Hosp, Sect Allergy Asthma & Immunol, Kansas City, MO 64108 USA. [Portnoy, Jay M.] Univ Missouri, Kansas City Sch Med, Pediat, Kansas City, MO 64110 USA. [Randolph, Christopher R.] Yale Affiliated Hosp, Pediat Allergy Immunol, Ctr Allergy Asthma & Immunol, Waterbury, CT USA. [Schuller, Diane] Penn State Univ, Milton S Hershey Med Coll, Pediat, Hershey, PA USA. [Schuller, Diane] Penn State Univ, Milton S Hershey Med Coll, Allergy & Immunol, Hershey, PA USA. [Spector, Sheldon L.] Univ Calif Los Angeles, Sch Med, Med, Los Angeles, CA USA. [Tilles, Stephen] Univ Washington, Sch Med, Med, Redmond, WA USA. [Wallace, Dana] Nova SE Univ, Coll Osteopath Med, Med, Davie, FL USA. [Ballas, Zuhair K.] Univ Iowa, Dept Internal Med, Div Immunol, Iowa City, IA 52242 USA. [Ballas, Zuhair K.] Iowa City Vet Adm Med Ctr, Iowa City, IA USA. [Chinen, Javier] Lake Houston Allergy & Immunol, Allergy & Immunol, Humble, TX USA. [Frank, Michael M.] Duke Univ, Med Ctr, Dept Pediat, Pediat,Childrens Hlth Ctr, Durham, NC 27710 USA. [Frank, Michael M.] Duke Univ, Med Ctr, Dept Pediat, Immunol & Med,Childrens Hlth Ctr, Durham, NC 27710 USA. [Hsu, Joyce T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Hsu, Joyce T.] Harvard Univ, Sch Med, Pediat, Boston, MA 02115 USA. [Keller, Michael] Childrens Natl Med Ctr, Pediat, Washington, DC 20010 USA. [Kobrynski, Lisa J.] Emory Univ, Sch Med, Pediat, Atlanta, GA USA. [Komarow, Hirsh D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Mazer, Bruce] McGill Univ, Montreal Childrens Hosp, Hlth Ctr, Allergy & Immunol, Montreal, PQ H3H 1P3, Canada. [Mazer, Bruce] McGill Univ, Pediat, Montreal, PQ, Canada. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Div Hematol & Oncol, Med & Pediat, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Div Stem Cell Transplantat, Med & Pediat, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Riley Hosp, Pediat Immunodeficiency Clin, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] IU Melvin & Bren Simon Canc Ctr, Indianapolis, IN USA. [Orange, Jordan S.] Texas Childrens Hosp, Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Orange, Jordan S.] Texas Childrens Hosp, Ctr Human Immunobiol, Houston, TX 77030 USA. [Orange, Jordan S.] Baylor Coll Med, Pathol & Immunol, Houston, TX 77030 USA. [Orange, Jordan S.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Routes, John M.] Med Coll Wisconsin, Allergy & Clin Immunol, Milwaukee, WI 53226 USA. [Routes, John M.] Med Coll Wisconsin, Pediat & Med, Milwaukee, WI 53226 USA. [Shearer, William T.] Texas Childrens Hosp, Allergy & Immunol Serv, Houston, TX 77030 USA. [Shearer, William T.] Baylor Coll Med, Pediat & Immunol, Houston, TX 77030 USA. [Sorensen, Ricardo U.] Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA USA. [Verbsky, James W.] Med Coll Wisconsin, Pediat & Microbiol & Med Genet, Milwaukee, WI 53226 USA. RP Bonilla, FA (reprint author), Boston Childrens Hosp, Boston, MA 02115 USA. EM francisco.bonilla@childrens.harvard.edu FU Intramural NIH HHS NR 1 TC 27 Z9 27 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1186 EP 1205 DI 10.1016/j.jaci.2015.04.049 PG 20 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200006 PM 26371839 ER PT J AU Holzinger, D Fassl, SK de Jager, W Lohse, P Rohrig, UF Gattorno, M Omenetti, A Chiesa, S Schena, F Austermann, J Vogl, T Kuhns, DB Holland, SM Rodriguez-Gallego, C Lopez-Almaraz, R Arostegui, JI Colino, E Roldan, R Fessatou, S Isidor, B Poignant, S Ito, K Epple, HJ Bernstein, JA Jeng, M Frankovich, J Lionetti, G Church, JA Ong, PY LaPlant, M Abinun, M Skinner, R Bigley, V Sachs, UJ Hinze, C Hoppenreijs, E Ehrchen, J Foell, D Chae, JJ Ombrello, A Aksentijevich, I Sunderkoetter, C Roth, J AF Holzinger, Dirk Fassl, Selina Kathleen de Jager, Wilco Lohse, Peter Roehrig, Ute F. Gattorno, Marco Omenetti, Alessia Chiesa, Sabrina Schena, Francesca Austermann, Judith Vogl, Thomas Kuhns, Douglas B. Holland, Steven M. Rodriguez-Gallego, Carlos Lopez-Almaraz, Ricardo Arostegui, Juan I. Colino, Elena Roldan, Rosa Fessatou, Smaragdi Isidor, Bertrand Poignant, Sylvaine Ito, Koichi Epple, Hans-Joerg Bernstein, Jonathan A. Jeng, Michael Frankovich, Jennifer Lionetti, Geraldina Church, Joseph A. Ong, Peck Y. LaPlant, Mona Abinun, Mario Skinner, Rod Bigley, Venetia Sachs, Ulrich J. Hinze, Claas Hoppenreijs, Esther Ehrchen, Jan Foell, Dirk Chae, Jae Jin Ombrello, Amanda Aksentijevich, Ivona Sunderkoetter, Cord Roth, Johannes TI Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Hyperzincemia and hypercalprotectinemia; myeloid-related protein 8/14; calprotectin; S100 proteins; zinc; proline-serine-threonine phosphatase-interacting protein 1; pyogenic arthritis; pyoderma gangrenosum, and acne syndrome; genotype; phenotype; autoinflammation ID JUVENILE IDIOPATHIC ARTHRITIS; PAPA SYNDROME; PYODERMA-GANGRENOSUM; ZINC-METABOLISM; RECEPTOR 4; PYOGENIC ARTHRITIS; INTERFERON-GAMMA; GENE-EXPRESSION; IN-VITRO; T-CELLS AB Background: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). Objective: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Methods: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Results: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p. E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 +/- 1300 mu g/mL) compared with those with PAPA syndrome (116 +/- 74 mu g/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. Conclusion: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E -> K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family. C1 [Holzinger, Dirk; Fassl, Selina Kathleen; Austermann, Judith; Vogl, Thomas; Roth, Johannes] Univ Munster, Inst Immunol, D-48149 Munster, Germany. [Holzinger, Dirk; Austermann, Judith; Vogl, Thomas; Hinze, Claas; Ehrchen, Jan; Foell, Dirk; Sunderkoetter, Cord; Roth, Johannes] Univ Munster, Univ Hosp Muenster, Interdisciplinary Ctr Clin Res IZKF, D-48149 Munster, Germany. [Holzinger, Dirk; Foell, Dirk] Univ Munster, Univ Childrens Hosp Muenster, Dept Paediat Rheumatol & Immunol, D-48149 Munster, Germany. [de Jager, Wilco; Hinze, Claas] Univ Med Ctr Utrecht, Dept Paediat Immunol, Lab Translat Immunol, Utrecht, Netherlands. [Lohse, Peter] Univ Munich, Dept Clin Chem Grosshadern, D-81377 Munich, Germany. [Roehrig, Ute F.] Swiss Inst Bioinformat, Mol Modeling Grp, Lausanne, Switzerland. [Gattorno, Marco; Omenetti, Alessia; Chiesa, Sabrina; Schena, Francesca] G Gaslini Sci Inst, Div Pediat 2, Genoa, Italy. [Kuhns, Douglas B.] Leidos Biomed Res, Frederick, MD USA. [Holland, Steven M.] NIAID, NIH, Bethesda, MD USA. [Rodriguez-Gallego, Carlos] Hosp Univ Son Espases, Dept Immunol, Palma De Mallorca, Spain. [Lopez-Almaraz, Ricardo] Hosp Univ Canarias, Dept Pediat, San Cristobal la Laguna, Spain. [Arostegui, Juan I.] Hosp Clin IDIBAPS, Dept Immunol CDB, Barcelona, Spain. [Colino, Elena] Complejo Hosp Univ Insular Materno Infant, Dept Paediat, Las Palmas Gran Canaria, Spain. [Roldan, Rosa] Hosp Univ Reina Sofia, Dept Pediat Rheumatol, Cordoba, Spain. [Fessatou, Smaragdi] Univ Athens, Sch Med, ATTIKON Hosp, Dept Pediat 3, GR-10679 Athens, Greece. [Isidor, Bertrand] Ctr Hosp Univ, Serv Genet Med, Nantes, France. [Poignant, Sylvaine] CH Cholet, Serv Pediat, Cholet, France. [Ito, Koichi] Nagoya City Univ, Grad Sch Med Sci, Dept Pediat & Neonatol, Nagoya, Aichi, Japan. [Epple, Hans-Joerg] Charite, Dept Gastroenterol Infect Dis & Rheumatol, D-13353 Berlin, Germany. [Bernstein, Jonathan A.; Jeng, Michael; Frankovich, Jennifer] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Lionetti, Geraldina] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Church, Joseph A.; Ong, Peck Y.] Univ So Calif, Keck Sch Med, Div Clin Immunol & Allergy, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. [Church, Joseph A.; Ong, Peck Y.] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90033 USA. [LaPlant, Mona] Childrens Hosp & Clin Minnesota, St Paul, MN USA. [Abinun, Mario] Great North Childrens Hosp, Dept Paediat Immunol, Newcastle Upon Tyne, Tyne & Wear, England. [Abinun, Mario] Great North Childrens Hosp, Childrens BMT Unit, Newcastle Upon Tyne, Tyne & Wear, England. [Abinun, Mario] Newcastle Univ, Inst Clin Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Skinner, Rod] Royal Victoria Infirm, Great North Childrens Hosp, Dept Paediat & Adolescent Haematol & Oncol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Skinner, Rod] Royal Victoria Infirm, Great North Childrens Hosp, Childrens BMT Unit, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Skinner, Rod] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Bigley, Venetia] Newcastle Univ, Sch Med, Human Dendrit Cell Lab, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Sachs, Ulrich J.] Univ Giessen, Inst Clin Immunol & Transfus Med, Giessen, Germany. [Hinze, Claas] Deutsch Zentrum Kinder & Jugendrheumatol, Garmisch Partenkirchen, Germany. [Hoppenreijs, Esther] St Maartens Clin, Dept Paediat Paediat Rheumatol, Nijmegen, Netherlands. [Hoppenreijs, Esther] Radboud Univ Nijmegen, Ctr Med, NL-6525 ED Nijmegen, Netherlands. [Ehrchen, Jan; Sunderkoetter, Cord] Univ Hosp Muenster, Dept Dermatol, Munster, Germany. [Chae, Jae Jin; Ombrello, Amanda; Aksentijevich, Ivona] NHGRI, NIH, Bethesda, MD 20892 USA. [Ehrchen, Jan; Sunderkoetter, Cord] Univ Hosp Muenster, Dept Translat Dermatoinfectiol, Munster, Germany. RP Roth, J (reprint author), Univ Munster, Inst Immunol, D-48149 Munster, Germany. EM rothj@uni-muenster.de RI Omenetti, Alessia/K-5975-2016; OI Omenetti, Alessia/0000-0002-8220-0385; Fassl, Selina/0000-0002-6356-5012; Arostegui, Juan Ignacio/0000-0003-4757-504X; Hinze, Claas/0000-0001-9247-4729; Roehrig, Ute/0000-0002-4676-4087 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; "Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad [PI06/1031, PI10/01718]; European Regional Development Fund European Social Fund FEDER-FSE; Interdisciplinary Centre for Clinical Research University of Munster; German Research Foundation [SFB1009]; Bundesministerium fur Bildung und Forschung (AID-NET) [01GM08100] FX Supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Instituters of Health, Department of Health and Haman Services (to S.M.H.) and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Also supported by "Fondo de Investigaciones Sanitarias,'' Ministerio de Economia y Competitividad (PI06/1031, PI10/01718), with the funding of European Regional Development Fund European Social Fund FEDER-FSE, the Interdisciplinary Centre for Clinical Research University of Munster, the German Research Foundation (SFB1009), and the Bundesministerium fur Bildung und Forschung (AID-NET, project 01GM08100). NR 54 TC 5 Z9 5 U1 1 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1337 EP 1345 DI 10.1016/j.jaci.2015.04.016 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200024 PM 26025129 ER PT J AU Mueller, GA Pedersen, LC Glesner, J Edwards, LL Zakzuk, J London, RE Arruda, LK Chapman, MD Caraballo, L Pomes, A AF Mueller, Geoffrey A. Pedersen, Lars C. Glesner, Jill Edwards, Lori L. Zakzuk, Josefina London, Robert E. Arruda, L. Karla Chapman, Martin D. Caraballo, Luis Pomes, Anna TI Analysis of glutathione S-transferase allergen cross-reactivity in a North American population: Relevance for molecular diagnosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Cockroach; house dust mite; helminth; glutathione S-transferases (GST); cross-reactivity; diagnosis ID HOUSE-DUST-MITE; IGE ANTIBODY-RESPONSES; GERMAN-COCKROACH; DERMATOPHAGOIDES-PTERONYSSINUS; ASCARIS-LUMBRICOIDES; BLOMIA-TROPICALIS; ASTHMA; IDENTIFICATION; SENSITIZATION; EXPOSURE AB Background: It is not clear whether cross-reactivity or cosensitization to glutathione S-transferases (GSTs) occurs in tropical and subtropical environments. In the United States, Bla g 5 is the most important GST allergen and lack of coexposure to GSTs from certain species allows a better assessment of cross-reactivity. Objectives: To examine the molecular structure of GST allergens from cockroach (Bla g 5), dust mites (Der p 8 and Blo t 8), and helminth (Asc s 13) for potential cross-reactive sites, and to assess the IgE cross-reactivity of sensitized patients from a temperate climate for these allergens for molecular diagnostic purposes. Methods: Four crystal structures were determined. Sera from patients allergic to cockroach and mite were tested for IgE reactivity to these GSTs. A panel of 6 murine anti-Bla g 5 mAb was assessed for cross-reactivity with the other 3 GSTs using antibody binding assays. Results: Comparisons of the allergen structures, formed by 2-domain monomers that dimerize, revealed few contiguous regions of similar exposed residues, rendering cross-reactivity unlikely. Accordingly, anti-Bla g 5 or anti-Der p 8 IgE from North American patients did not recognize Der p 8 or Bla g 5, respectively, and neither showed binding to Blo t 8 or Asc s 13. A weaker binding of anti-Bla g 5 IgE to Der p 8 versus Bla g 5 (similar to 100-fold) was observed by inhibition assays, similar to a weak recognition of Der p 8 by anti-Bla g 5 mAb. Patients from tropical Colombia had IgE to all 4 GSTs. Conclusions: The lack of significant IgE cross-reactivity among the 4 GSTs is in agreement with the low shared amino acid identity at the molecular surface. Each GST is needed for accurate molecular diagnosis in different geographic areas. C1 [Mueller, Geoffrey A.; Pedersen, Lars C.; Edwards, Lori L.; London, Robert E.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Glesner, Jill; Chapman, Martin D.; Pomes, Anna] Indoor Biotechnol Inc, Charlottesville, VA 22903 USA. [Zakzuk, Josefina; Caraballo, Luis] Univ Cartagena, Inst Immunol Res, Cartagena, Colombia. [Zakzuk, Josefina; Caraballo, Luis] Fdn Dev Med & Biol Sci, Cartagena, Colombia. [Arruda, L. Karla] Univ Sao Paulo, Ribeirao Preto Med Sch, Sao Paulo, Brazil. RP Pomes, A (reprint author), Indoor Biotechnol Inc, 1216 Harris St, Charlottesville, VA 22903 USA. EM apomes@inbio.com RI Arruda, L. Karla /D-5845-2013; OI Arruda, L. Karla /0000-0002-7505-210X; Pomes, Anna/0000-0002-8729-1829 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01- ES102885-01, ZIA- ES102645]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI077653]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Administrative Department of Science, Technology and Innovation (Colciencias) (Colombia) [406-2011, 201-2015] FX This study was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Research Project nos. Z01- ES102885-01 to R.E.L. and ZIA- ES102645 to L.C.P.), and in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (under Award no. R01AI077653 to A.P. and M.D.C.). Use of the Advance Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences (contract no. W-31-109-Eng-38). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research was also supported by the Administrative Department of Science, Technology and Innovation (Colciencias) Contract 406-2011 and 201-2015 (Colombia). NR 37 TC 5 Z9 5 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1369 EP 1377 DI 10.1016/j.jaci.2015.03.015 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200027 PM 25930195 ER PT J AU Fernandez-Boyanapalli, RF Falcone, EL Zerbe, CS Marciano, BE Frasch, SC Henson, PM Holland, SM Bratton, DL AF Fernandez-Boyanapalli, Ruby F. Falcone, Emilia Liana Zerbe, Christa S. Marciano, Beatriz E. Frasch, S. Courtney Henson, Peter M. Holland, Steven M. Bratton, Donna L. TI Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID STERILE INFLAMMATION; MACROPHAGE; CGD C1 [Fernandez-Boyanapalli, Ruby F.; Frasch, S. Courtney; Henson, Peter M.; Bratton, Donna L.] Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA. [Falcone, Emilia Liana; Zerbe, Christa S.; Marciano, Beatriz E.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Fernandez-Boyanapalli, RF (reprint author), Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA. EM brattond@njhealth.org FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL114381, HL114381, P01 HL034303]; NIAID NIH HHS [AI058228, R01 AI110408, AI110408, R01 AI058228, R56 AI058228] NR 10 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1399 EP 1401 DI 10.1016/j.jaci.2015.07.034 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200031 PM 26386811 ER PT J AU Crestani, E Volpi, S Candotti, F Giliani, S Notarangelo, LD Chu, J Becerra, JCA Buchbinder, D Chou, J Geha, RS Kanariou, M King, A Mazza, C Moratto, D Sokolic, R Garabedian, E Porta, F Putti, MC Wakim, RH Tsitsikov, E Pai, SY Notarangelo, LD AF Crestani, Elena Volpi, Stefano Candotti, Fabio Giliani, Silvia Notarangelo, Lucia Dora Chu, Julia Becerra, Juan Carlos Aldave Buchbinder, David Chou, Janet Geha, Raif S. Kanariou, Maria King, Alejandra Mazza, Cinzia Moratto, Daniele Sokolic, Robert Garabedian, Elizabeth Porta, Fulvio Putti, Maria Caterina Wakim, Rima H. Tsitsikov, Erdyni Pai, Sung-Yun Notarangelo, Luigi D. TI Broad spectrum of autoantibodies in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID SYNDROME PROTEIN-DEFICIENCY; AUTOIMMUNITY; HUMANS; CELLS C1 [Crestani, Elena; Volpi, Stefano; Chou, Janet; Geha, Raif S.; Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Chu, Julia; Pai, Sung-Yun] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Tsitsikov, Erdyni] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA. [Volpi, Stefano] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy. [Candotti, Fabio; Sokolic, Robert; Garabedian, Elizabeth] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Giliani, Silvia; Mazza, Cinzia; Moratto, Daniele] Univ Brescia, Angelo Nocivelli Inst Mol Med, Brescia, Italy. [Notarangelo, Lucia Dora; Porta, Fulvio] Spedali Civil Brescia, Pediat Hematol Oncol Unit, I-25125 Brescia, Italy. [Becerra, Juan Carlos Aldave] Rebagliati Martins Natl Hosp, Div Allergy & Clin Immunol, Lima, Peru. [Buchbinder, David] Univ Calif Irvine, Childrens Hosp Orange Cty, Div Pediat Hematol, Irvine, CA USA. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Dept Immunol, Athens, Greece. [King, Alejandra] Hosp Ninos Luis Calvo Mackenna, Div Pediat Immunol, Santiago, Chile. [Putti, Maria Caterina] Univ Hosp, Dept Woman & Child Hlth, Clin Pediat Hematol Oncol, Padua, Italy. [Wakim, Rima H.] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut, Lebanon. RP Crestani, E (reprint author), Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu RI Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Candotti, Fabio/0000-0001-6399-6042 FU NHLBI NIH HHS [5P01HL059561-13, 5T32HL007574-33, P01 HL059561]; NIAID NIH HHS [5T32AI007512, T32 AI007512] NR 12 TC 3 Z9 4 U1 3 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1401 EP 1404 DI 10.1016/j.jaci.2015.08.010 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200032 PM 26409660 ER PT J AU Odio, CD Milligan, KL McGowan, K Spergel, AKR Bishop, R Boris, L Urban, A Welch, P Heller, T Kleiner, D Jackson, MA Holland, SM Freeman, AF AF Odio, Camila D. Milligan, Ki Lee McGowan, Katherine Spergel, Amanda K. Rudman Bishop, Rachel Boris, Lisa Urban, Amanda Welch, Pamela Heller, Theo Kleiner, David Jackson, Mary Anne Holland, Steven M. Freeman, Alexandra F. TI Endemic mycoses in patients with STAT3-mutated hyper-IgE (Job) syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID INHALED CORTICOSTEROIDS; ASTHMA; ADHERENCE C1 [Odio, Camila D.; Milligan, Ki Lee; McGowan, Katherine; Spergel, Amanda K. Rudman; Holland, Steven M.; Freeman, Alexandra F.] NIAID, NIH, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Boris, Lisa; Urban, Amanda; Welch, Pamela] Leidos Biomed Res Inc, Clin Monitoring Res Program, Clin Res Directorate, Bethesda, MD USA. [Heller, Theo] NIDDK, NIH, Bethesda, MD 20892 USA. [Kleiner, David] NCI, NIH, Bethesda, MD 20892 USA. [Jackson, Mary Anne] Childrens Mercy Hosp, Bethesda, MD USA. RP Odio, CD (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov OI McGowan, Katherine/0000-0002-4128-5722; Kleiner, David/0000-0003-3442-4453 FU CCR NIH HHS [HHSN261200800001C]; Howard Hughes Medical Institute; Intramural NIH HHS [Z99 AI999999]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 13 TC 4 Z9 5 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1411 EP 1413 DI 10.1016/j.jaci.2015.07.003 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200036 PM 26292779 ER PT J AU Hox, V Metcalfe, DD Olivera, A AF Hox, Valerie Metcalfe, Dean D. Olivera, Ana TI Impact of sex on anaphylaxis severity-data from the Anaphylaxis Registry Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID MENOPAUSE C1 [Hox, Valerie; Metcalfe, Dean D.; Olivera, Ana] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Hox, V (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Ana.Olivera@nih.gov FU Intramural NIH HHS NR 7 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 BP 1426 EP 1426 DI 10.1016/j.jaci.2015.08.002 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200043 PM 26392053 ER PT J AU Bonilla, FA Khan, DA Ballas, ZK Chinen, J Frank, MM Hsu, JT Keller, M Kobrynski, LJ Komarow, HD Mazer, B Nelson, RP Orange, JS Routes, JM Shearer, WT Sorensen, RU Verbsky, JW Bernstein, DI Blessing-Moore, J Lang, D Nicklas, RA Oppenheimer, J Portnoy, JM Randolph, CR Schuller, D Spector, SL Tilles, S Wallace, D AF Bonilla, Francisco A. Khan, David A. Ballas, Zuhair K. Chinen, Javier Frank, Michael M. Hsu, Joyce T. Keller, Michael Kobrynski, Lisa J. Komarow, Hirsh D. Mazer, Bruce Nelson, Robert P., Jr. Orange, Jordan S. Routes, John M. Shearer, William T. Sorensen, Ricardo U. Verbsky, James W. Bernstein, David I. Blessing-Moore, Joann Lang, David Nicklas, Richard A. Oppenheimer, John Portnoy, Jay M. Randolph, Christopher R. Schuller, Diane Spector, Sheldon L. Tilles, Stephen Wallace, Dana TI Practice parameter for the diagnosis and management of primary immunodeficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material ID COMMON-VARIABLE-IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; STEM-CELL TRANSPLANTATION; HYPER-IGE SYNDROME; X-LINKED AGAMMAGLOBULINEMIA; WISKOTT-ALDRICH-SYNDROME; PULMONARY ALVEOLAR PROTEINOSIS; BONE-MARROW-TRANSPLANTATION; CHRONIC MUCOCUTANEOUS CANDIDIASIS; HEMOLYTIC-UREMIC SYNDROME AB The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency.'' This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. C1 [Bonilla, Francisco A.] Boston Childrens Hosp, Boston, MA 02115 USA. [Bonilla, Francisco A.] Harvard Univ, Sch Med, Pediat, Boston, MA USA. [Khan, David A.] Univ Texas SW Med Ctr Dallas, Internal Med, Dallas, TX 75390 USA. [Bernstein, David I.] Univ Cincinnati, Coll Med, Div Immunol Allergy & Rheumatol, Clin Med & Environm Hlth, Cincinnati, OH USA. [Blessing-Moore, Joann] Stanford Univ, Med Ctr, Dept Immunol, Med & Pediat, Palo Alto, CA 94304 USA. [Lang, David] Cleveland Clin Fdn, Allergy Immunol Sect, Resp Inst, Cleveland, OH 44195 USA. [Lang, David] Cleveland Clin Fdn, Allergy & Immunol Fellowship Training Program, Cleveland, OH 44195 USA. [Nicklas, Richard A.] George Washington Med Ctr, Med, Washington, DC USA. [Oppenheimer, John] Univ Med & Dent New Jersey, Pulm & Allergy Associates, Dept Internal Med, Morristown, NJ USA. [Portnoy, Jay M.] Childrens Mercy Hosp, Sect Allergy Asthma & Immunol, Kansas City, MO 64108 USA. [Portnoy, Jay M.] Univ Missouri, Kansas City Sch Med, Pediat, Kansas City, MO 64110 USA. [Randolph, Christopher R.] Yale Affiliated Hosp, Pediat Allergy Immunol, Ctr Allergy Asthma & Immunol, Waterbury, CT USA. [Schuller, Diane] Penn State Univ, Milton S Hershey Med Coll, Pediat, Hershey, PA USA. [Schuller, Diane] Penn State Univ, Milton S Hershey Med Coll, Allergy & Immunol, Hershey, PA USA. [Spector, Sheldon L.] Univ Calif Los Angeles, Sch Med, Med, Los Angeles, CA USA. [Tilles, Stephen] Univ Washington, Sch Med, Med, Redmond, WA USA. [Wallace, Dana] Nova SE Univ, Coll Osteopath Med, Med, Davie, FL USA. [Ballas, Zuhair K.] Univ Iowa, Dept Internal Med, Div Immunol, Iowa City, IA 52242 USA. [Ballas, Zuhair K.] Iowa City Vet Adm Med Ctr, Iowa City, IA USA. [Chinen, Javier] Lake Houston Allergy & Immunol, Allergy & Immunol, Humble, TX USA. [Frank, Michael M.] Duke Univ, Med Ctr, Pediat, Durham, NC USA. [Frank, Michael M.] Duke Univ, Med Ctr, Dept Pediat, Immunol & Med, Durham, NC 27710 USA. [Hsu, Joyce T.] Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Sch Med, Boston, MA 02115 USA. [Hsu, Joyce T.] Harvard Univ, Sch Med, Pediat, Boston, MA USA. [Keller, Michael] Childrens Natl Med Ctr, Pediat, Washington, DC 20010 USA. [Kobrynski, Lisa J.] Emory Univ, Sch Med, Atlanta, GA USA. [Komarow, Hirsh D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Mazer, Bruce] McGill Univ, Montreal Childrens Hosp, Hlth Ctr, Allergy & Immunol, Montreal, PQ H3H 1P3, Canada. [Mazer, Bruce] McGill Univ, Pediat, Montreal, PQ, Canada. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Div Hematol & Oncol, Med & Pediat, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Div Stem Cell Transplantat, Med & Pediat, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] Indiana Univ Sch Med, Riley Hosp, Pediat Immunodeficiency Clin, Indianapolis, IN 46202 USA. [Nelson, Robert P., Jr.] IU Melvin & Bren Simon Canc Ctr, Indianapolis, IN USA. [Orange, Jordan S.] Texas Childrens Hosp, Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Orange, Jordan S.] Texas Childrens Hosp, Ctr Human Immunobiol, Houston, TX 77030 USA. [Orange, Jordan S.] Baylor Coll Med, Pediat Pathol & Immunol, Houston, TX 77030 USA. [Orange, Jordan S.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Routes, John M.] Med Coll Wisconsin, Allergy & Clin Immunol, Milwaukee, WI 53226 USA. [Routes, John M.] Med Coll Wisconsin, Pediat & Med, Milwaukee, WI 53226 USA. [Shearer, William T.] Texas Childrens Hosp, Allergy & Immunol Serv, Houston, TX 77030 USA. [Shearer, William T.] Baylor Coll Med, Pediat & Immunol, Houston, TX 77030 USA. [Sorensen, Ricardo U.] Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA USA. [Verbsky, James W.] Med Coll Wisconsin, Pediat & Microbiol & Med Genet, Milwaukee, WI 53226 USA. RP Bonilla, FA (reprint author), Boston Childrens Hosp, Boston, MA 02115 USA. EM francisco.bonilla@childrens.harvard.edu NR 770 TC 0 Z9 0 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2015 VL 136 IS 5 PG 78 WC Allergy; Immunology SC Allergy; Immunology GA CW1YE UT WOS:000364787200007 ER PT J AU Ekman, C Elgzyri, T Strom, K Almgren, P Parikh, H Nitert, MD Ronn, T Koivula, FM Ling, C Tornberg, AB Wollmer, P Eriksson, KF Groop, L Hansson, O AF Ekman, C. Elgzyri, T. Strom, K. Almgren, P. Parikh, H. Nitert, Marloes Dekker Ronn, T. Koivula, Fiona Manderson Ling, C. Tornberg, A. B. Wollmer, P. Eriksson, K. F. Groop, L. Hansson, O. TI Less pronounced response to exercise in healthy relatives to type 2 diabetic subjects compared with controls SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE type 2 diabetes; exercise intervention; expression analysis; genetic predisposition; muscle ID HUMAN SKELETAL-MUSCLE; 1ST-DEGREE RELATIVES; PHYSICAL-ACTIVITY; FOLLOW-UP; OXIDATIVE-PHOSPHORYLATION; INSULIN-RESISTANCE; AEROBIC CAPACITY; FAMILY-HISTORY; LIPID-CONTENT; WEIGHT-LOSS AB Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility compared with subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared with FH-. Sixteen FH+ and 19 FH- insulin-sensitive men similar in age, peak oxygen consumption ((V) over dot(O2 peak)), and body mass index completed an exercise intervention with heart rate monitored during exercise for 7 mo. Before and after the exercise intervention, the participants underwent a physical examination and tests for glucose tolerance and exercise capacity, and muscle biopsies were taken for expression analysis. The participants attended, on average, 39 training sessions during the intervention and spent 18.8 MJ on exercise. (V) over dot(O2 peak)/kg increased by 14%, and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH- group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on (V) over dot(O2 peak), weight, and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation, and cellular respiration increased more in the FH- compared with the FH+ group. This suggests that healthy, insulin-sensitive FH+ and FH- participants with similar age, (V) over dot(O2 peak), and body mass index may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals. C1 [Ekman, C.; Elgzyri, T.; Strom, K.; Almgren, P.; Parikh, H.; Nitert, Marloes Dekker; Ronn, T.; Ling, C.; Eriksson, K. F.; Groop, L.; Hansson, O.] Lund Univ, Malmo Univ Hosp, Clin Res Ctr, Dept Clin Sci, Malmo, Sweden. [Strom, K.] Mid Sweden Univ, Dept Hlth Sci, Swedish Winter Sports Res Ctr, Ostersund, Sweden. [Parikh, H.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Koivula, Fiona Manderson; Tornberg, A. B.; Wollmer, P.] Lund Univ, Div Physiotherapy, Dept Hlth Sci, Lund, Sweden. [Tornberg, A. B.] Lund Univ, Genet Mol Epidemiol Unit, Ctr Diabet, Clin Res Ctr, Malmo, Sweden. [Wollmer, P.] Lund Univ, Dept Clin Sci, Clin Physiol & Nucl Med Unit, Malmo, Sweden. RP Hansson, O (reprint author), CRC, SUS, Diabet & Endocrinol, Entrance 72,Bldg 91,Level 12, S-20502 Malmo, Sweden. EM Ola.Hansson@med.lu.se RI Ling, Charlotte/Q-2432-2015; Hansson, Ola/F-1793-2011; Dekker Nitert, Marloes/A-8822-2011 OI Ling, Charlotte/0000-0003-0587-7154; Hansson, Ola/0000-0002-7394-7639; Dekker Nitert, Marloes/0000-0002-1909-8920 FU Swedish Research Council Linnaeus grant: Lund University Diabetes Centre [Dnr 349-2006-237]; SFO Exodiab [Dnr 2009-1039]; European Research Council Advanced Researcher Grant [GA 269045]; NuGo; ALF; Crafoord Foundation; SV Skanes Diabetes Forening; Wallenberg Foundation; Novo Nordisk Foundation; EXGENESIS; UMAS Fonder, Magn. Bergvalls Stiftelse; Syskonen Svenssons Fond; Swedish Diabetes Research Foundation [2009-060]; European Community FX This study was supported by the Swedish Research Council Linnaeus grant: Lund University Diabetes Centre (Dnr 349-2006-237) and SFO Exodiab (Dnr 2009-1039); European Research Council Advanced Researcher Grant (GA 269045); NuGo; ALF; the Crafoord Foundation; SV Skanes Diabetes Forening; the Wallenberg Foundation; the Novo Nordisk Foundation; EXGENESIS; UMAS Fonder, Magn. Bergvalls Stiftelse; Syskonen Svenssons Fond; the Swedish Diabetes Research Foundation (2009-060); and the European Community's Seventh Framework Programme (FP7/2007-2013). NR 42 TC 2 Z9 2 U1 3 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD NOV 1 PY 2015 VL 119 IS 9 BP 953 EP 960 DI 10.1152/japplphysiol.01067.2014 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA CV7TO UT WOS:000364478200001 PM 26338460 ER PT J AU Zheng, WW Borgia, A Borgia, MB Schuler, B Best, RB AF Zheng, Wenwei Borgia, Alessandro Borgia, Madeleine B. Schuler, Benjamin Best, Robert B. TI Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID POLARIZABLE FORCE-FIELD; AQUEOUS UREA SOLUTIONS; DER-WAALS INTERACTIONS; HELIX-COIL TRANSITION; TRP-CAGE MINIPROTEIN; DISORDERED PROTEINS; FREE-ENERGY; HYDROPHOBIC INTERACTIONS; DISPERSION INTERACTIONS; GUANIDINIUM CHLORIDE AB Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea and guanidinium chloride, to develop a combined force field that is able to capture the strength of interactions between proteins and denaturants. We use solubility data for a model tetraglycine peptide in each denaturant to tune the protein-denaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule Forster resonance energy transfer data for a 34-residue fragment of the globular protein CspTm and photoinduced electron transfer quenching data for the disordered peptides C(AGQ)(n)W in denaturant solution as well as the chemical denaturation of the mini-protein Trp cage. The combined force field model should aid our understanding of denaturation mechanisms and the interpretation of experiment. C1 [Zheng, Wenwei; Best, Robert B.] NIH, Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, Bethesda, MD 20892 USA. [Borgia, Alessandro; Borgia, Madeleine B.; Schuler, Benjamin] Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland. RP Best, RB (reprint author), NIH, Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI Best, Robert/H-7588-2016; Schuler, Benjamin/E-7342-2011 OI Best, Robert/0000-0002-7893-3543; Schuler, Benjamin/0000-0002-5970-4251 FU Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health; Swiss National Science Foundation FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (W.Z. and R.B.B.) and by the Swiss National Science Foundation (A.B., M.B.B., and B.S.). NR 70 TC 3 Z9 3 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD NOV PY 2015 VL 11 IS 11 BP 5543 EP 5553 DI 10.1021/acs.jctc.5b00778 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CV9NN UT WOS:000364614000045 PM 26574341 ER PT J AU Wang, WX Corrigan-Cummins, M Barber, EA Saleh, LM Zingone, A Ghafoor, A Costello, R Zhang, Y Kurlander, RJ Korde, N Roccaro, AM Ghobrial, IM Landgren, O Calvo, KR AF Wang, Weixin Corrigan-Cummins, Meghan Barber, Emily A. Saleh, Layla M. Zingone, Adriana Ghafoor, Azam Costello, Rene Zhang, Yong Kurlander, Roger J. Korde, Neha Roccaro, Aldo M. Ghobrial, Irene M. Landgren, Ola Calvo, Katherine R. TI Aberrant Levels of miRNAs in Bone Marrow Microenvironment and Peripheral Blood of Myeloma Patients and Disease Progression SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID UNDETERMINED SIGNIFICANCE MGUS; SMOLDERING MULTIPLE-MYELOMA; MONOCLONAL GAMMOPATHY; MICRORNA EXPRESSION; GENE-EXPRESSION; CIRCULATING MICRORNAS; 14Q32 TRANSLOCATIONS; DOWN-REGULATION; HUMAN LEUKEMIA; PLASMA-CELLS AB The bone marrow (BM) microenvironment of multiple myeloma (MM) is reported to play a role in the biology of disease. In this study, we found that the extracellular BM microenvironment in MM contains a unique miRNA signature detectable by miRNA microarray and quantitative real-time PCR, which is partially represented in the peripheral blood. Eleven miRNAs were significantly decreased in both BM and serum of MM patients in comparison with controls. Evaluation of these miRNAs in plasma of a separate cohort of MM patients and controls confirmed significantly aberrant Levels of let-7a, let-7b, let-7i, miR-15b, miR-16, and miR-20a in both serum and plasma. We then studied the myeLoma precursor diseases and found that a subset of the MM miRNAs exhibited aberrant expression in monoclonal gammopathy of undetermined significance and smoldering myeLoma. miRNA analysis of enriched CD138(+) plasma cells from MM and monoclonal gammopathy of undetermined significance found that most of the validated MM BM signature miRNAs were significantly decreased in MM plasma cells. Gene expression profiling indicated that multiple targets of the decreased miRNAs found increased expression in MM plasma cells, including ATF2, HRAS, HDAC4, TGFB1, TGFBR1, and mitogen-activated protein kinases. The findings suggest that these miRNAs are detectable in aberrant levels in the peripheral blood of patients with plasma cell proliferation and may play a role in aberrant plasma cell proliferation and disease progression. C1 [Wang, Weixin; Corrigan-Cummins, Meghan; Barber, Emily A.; Saleh, Layla M.; Ghafoor, Azam; Kurlander, Roger J.; Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Zingone, Adriana; Costello, Rene; Zhang, Yong; Korde, Neha; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Calvo, KR (reprint author), NIH, Hematol Sect, Dept Lab Med, Ctr Clin, 10 Ctr Dr,Bldg 10-2C306, Bethesda, MD 20892 USA. EM calvok@cc.nih.gov OI Roccaro, Aldo/0000-0002-1872-5128 FU Intramural NIH HHS NR 56 TC 3 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 BP 669 EP 678 DI 10.1016/j.jmoldx.2015.06.006 PG 10 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000006 PM 26433312 ER PT J AU Andersen, M Cullen, M Boland, J Schiffman, M Zhang, X Wentzensen, N Yang, Q Chen, Z Yu, K Mitchell, J Roberson, D Bass, S Burdette, L Machado, M Ravichandran, S Luke, B Machiele, M Osentoski, M AF Andersen, M. Cullen, M. Boland, J. Schiffman, M. Zhang, X. Wentzensen, N. Yang, Q. Chen, Z. Yu, K. Mitchell, J. Roberson, D. Bass, S. Burdette, L. Machado, M. Ravichandran, S. Luke, B. Machiele, M. Osentoski, M. TI A New High-Throughput Tool for Exploring the Carcinogenicity and Natural History of HPV16 Infections in Research Samples SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 05-07, 2015 CL Austin, TX SP Assoc Mol Pathol C1 [Andersen, M.; Osentoski, M.] Thermo Fisher Sci, Carlsbad, CA USA. [Cullen, M.; Boland, J.; Schiffman, M.; Zhang, X.; Wentzensen, N.; Yang, Q.; Yu, K.; Mitchell, J.; Roberson, D.; Bass, S.; Burdette, L.; Machiele, M.] NCI, Rockville, MD USA. [Chen, Z.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Machado, M.] Univ Fed Minas Gerais, Inst Ciencias Biol, Belo Horizonte, MG, Brazil. [Ravichandran, S.; Luke, B.] Frederick Natl Lab Canc Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 MA ID07 BP 780 EP 780 PG 1 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000129 ER PT J AU Jour, G Wang, L Midha, S Zehir, AA Chen, W Sadowska, J Healey, J Choi, LL Agaram, N Nafa, K Hameed, M AF Jour, G. Wang, L. Midha, S. Zehir, A. Ahmet Chen, W. Sadowska, J. Healey, J. Choi, L. Lisa Agaram, N. Nafa, K. Hameed, M. TI The Molecular Landscape of Extraskeletal Osteosarcoma SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 05-07, 2015 CL Austin, TX SP Assoc Mol Pathol C1 [Jour, G.; Wang, L.; Midha, S.; Zehir, A. Ahmet; Sadowska, J.; Healey, J.; Choi, L. Lisa; Agaram, N.; Nafa, K.; Hameed, M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chen, W.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 MA ST45 BP 823 EP 823 PG 1 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000305 ER PT J AU Huang, CE Dickens, J Konigshofer, Y Vemula, R Lih, J Sims, D Williams, M Garlick, R Anekella, B AF Huang, C. E. Dickens, J. Konigshofer, Y. Vemula, R. Lih, J. Sims, D. Williams, M. Garlick, R. Anekella, B. TI Development of Highly Multiplexed, Semi-Quantitative Reference Materials for Somatic Tumor Mutation Profiling SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 05-07, 2015 CL Austin, TX SP Assoc Mol Pathol C1 [Huang, C. E.; Dickens, J.; Konigshofer, Y.; Vemula, R.; Anekella, B.] SeraCare Life Sci, Gaithersburg, MD USA. [Lih, J.; Sims, D.; Williams, M.] NCI, Frederick Lab Canc Res, Frederick, MD 21701 USA. [Garlick, R.] SeraCare Life Sci, Milford, MA USA. RI Dickens, James/H-5993-2016 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 MA TT59 BP 857 EP 858 PG 2 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000447 ER PT J AU Barcus, M Rao, A Golubeva, Y Ardlie, K Branton, P Roche, N Sobin, L Valentino, K Warner, A Moore, H AF Barcus, M. Rao, A. Golubeva, Y. Ardlie, K. Branton, P. Roche, N. Sobin, L. Valentino, K. Warner, A. Moore, H. TI Laser Capture Microdissection (LCM) of PAXgene-Fixed Paraffin-Embedded (PFPE) Specimens, a Genotype Tissue-Expression (GTEx) Pilot Project SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 05-07, 2015 CL Austin, TX SP Assoc Mol Pathol C1 [Barcus, M.; Golubeva, Y.; Roche, N.; Sobin, L.; Valentino, K.; Warner, A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Rao, A.; Branton, P.; Moore, H.] NCI, Rockville, MD USA. [Ardlie, K.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2015 VL 17 IS 6 MA TT61 BP 858 EP 858 PG 1 WC Pathology SC Pathology GA CU8YM UT WOS:000363830000449 ER PT J AU Tam, J Merino, D AF Tam, Johnny Merino, David TI Stochastic optical reconstruction microscopy (STORM) in comparison with stimulated emission depletion (STED) and other imaging methods SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE confocal; fluorescence microscopy; stimulated emission depletion; stochastic optical reconstruction microscopy; super resolution; total internal reflectance fluorescence ID PHOTOACTIVATED LOCALIZATION MICROSCOPY; STRUCTURED-ILLUMINATION MICROSCOPY; DIFFRACTION RESOLUTION BARRIER; FIELD FLUORESCENCE MICROSCOPY; GROUND-STATE-DEPLETION; SUPERRESOLUTION MICROSCOPY; NANOSCALE RESOLUTION; SUBDIFFRACTION-RESOLUTION; LATERAL RESOLUTION; SCALE RESOLUTION AB Stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion (STED) microscopy are two super-resolution optical microscopy approaches that have rapidly gained popularity in recent years. Both modalities offer super-resolution imaging capabilities with the potential for imaging in multiple colors, three-dimensions, and the possibility to image in live cells. In this review, we focus on the specific advantages and disadvantages of each technique in the context of each other. STORM has been reported to achieve higher spatial resolution when compared to STED, but a lengthy acquisition may be required. STED utilizes relatively higher laser intensities, but is able to generate a super-resolution image immediately after acquisition without the need for any additional data processing. Ultimately, the choice between STORM and STED will depend not only on the specific application, but also on the users' ability to understand and optimize the various parameters ranging from sample preparation to image acquisition, which determine the quality of the final image. C1 [Tam, Johnny] NEI, NIH, Bethesda, MD 20892 USA. [Merino, David] ICFO Inst Ciencies Foton, Barcelona, Spain. RP Tam, J (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM johnny@nih.gov RI Merino, David/G-5179-2015 OI Merino, David/0000-0002-0119-9459 NR 103 TC 5 Z9 6 U1 19 U2 85 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2015 VL 135 IS 4 BP 643 EP 658 DI 10.1111/jnc.13257 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CV9ZV UT WOS:000364649300002 PM 26222552 ER PT J AU Jacobson, O Weiss, ID Wang, L Wang, Z Yang, XY Dewhurst, A Ma, Y Zhu, GZ Niu, G Kiesewetter, DO Vasdev, N Liang, SH Chen, XY AF Jacobson, Orit Weiss, Ido D. Wang, Lu Wang, Zhe Yang, Xiangyu Dewhurst, Andrew Ma, Ying Zhu, Guizhi Niu, Gang Kiesewetter, Dale O. Vasdev, Neil Liang, Steven H. Chen, Xiaoyuan TI F-18-Labeled Single-Stranded DNA Aptamer for PET Imaging of Protein Tyrosine Kinase-7 Expression SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PTK7; PET imaging; F-18; click chemistry; ssDNA aptamer ID CELL POLARITY; PTK7; CANCER; REGULATOR; CARCINOMA; LEUKEMIA; FAMILY; PROBES; GENES; ROLES AB Protein tyrosine kinase-7 (PTK7), a member of receptor tyrosine kinase superfamily initially identified as colon carcinoma kinase-4, is highly expressed in various human malignancies. Its expression was found to correlate with aggressive biologic behaviors such as increased cell proliferation, invasiveness, and migration. Despite the importance and unmet need of imaging PTK7 in vivo, there is currently no clinically relevant method to visualize tumoral PTK7 expression noninvasively such as PET or SPEC. This study aimed to develop a specific, selective, and high-affinity PET radioligand based on single-stranded DNA aptamer to address this challenge. Methods: Sgc8, a 41-oligonucleotide that targets to PTK7, was labeled with F-18 using a 2-step radiochemical synthesis, which featured a direct 1-step radio-fluorination on the distinctive spirocyclic hypervalent iodine(III) precursor to give F-18-fluorobenzyl azide followed by copper-mediated click conjugation with Sgc8-allcyne. F-18-Sgc8 was evaluated in vitro and in vivo in 2 cell lines, HCT116 and U87MG, which express high and low amounts of PTK7, respectively. Results: Sgc8 was labeled efficiently with F-18 in an isolated radiochemical yield of 62% 2%, non decay-corrected based on F-18-fluorobenzyl azide. F-18-Tr-Sgc8 was found to possess high-affinity binding to both cell lines, with binding affinity values of 2.7 +/- 0.6 nM for HCT116 and 16.9 +/- 2.1 nM for U87MG. In vivo PET imaging clearly visualized PTK7 expression in HCT116 xenografted mice, with tumor uptake of 0.76 +/- 0.09 percentage injected dose per gram (%ID/g) at 30 min after injection for the subcutaneous tumor model and greater than 1.5 %ID/g for the liver metastasis model. U87MG xenograft tumors had much lower tracer accumulation (0.13 +/- 0.06 %ID/g at 30 min after injection), which was consistent with the lower expression of PTK7 in this tumor model. The labeled aptamer was rapidly cleared from the blood through the kidneys and bladder to give high tumor-to-blood and tumor-to-muscle ratios of 7.29 +/- 1.51 and 10.25 +/- 2.08, respectively. Conclusion: The F-18-radiolabeling methodology shown here is a robust procedure for labeling aptamers and similar chemical moieties and can be applied to many different targets. Quantification of PTK7 using F-18-Tr-Sgc8 may be suitable for clinical translation and might help in the future to select and monitor appropriate therapies. C1 [Jacobson, Orit; Wang, Zhe; Yang, Xiangyu; Dewhurst, Andrew; Ma, Ying; Zhu, Guizhi; Niu, Gang; Kiesewetter, Dale O.; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. [Weiss, Ido D.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wang, Lu; Vasdev, Neil; Liang, Steven H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Wang, Lu; Vasdev, Neil; Liang, Steven H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Chen, XY (reprint author), NIH, 35A Convent Dr,GD937, Bethesda, MD 20892 USA. EM Liang.Steven@mgh.harvard.edu; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). No other potential conflict of interest relevant to this article was reported. NR 26 TC 6 Z9 6 U1 16 U2 33 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD NOV PY 2015 VL 56 IS 11 BP 1780 EP 1785 DI 10.2967/jnumed.115.160960 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV6BQ UT WOS:000364356100027 PM 26315836 ER PT J AU Koenig, J Windham, BG Ferrucci, L Sonntag, D Fischer, JE Thayer, JF Jarczok, MN AF Koenig, J. Windham, B. G. Ferrucci, L. Sonntag, D. Fischer, J. E. Thayer, J. F. Jarczok, M. N. TI Association strength of three adiposity measures with autonomic nervous system function in apparently healthy employees SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Adiposity; autonomic nervous system; heart rate variability; body mass index; waist circumference; waist-to-height ratio ID HEART-RATE-VARIABILITY; BODY-MASS INDEX; RISK-FACTORS; OBESITY; DISEASE AB To investigate the association of different measures of central (abdominal) and overall adiposity with autonomic nervous system (ANS) function, indexed by heart rate variability (HRV), in apparently healthy human adults. Cross-sectional data of 8,538 participants (20% female, age: 41 +/- 11 years, body mass index (BMI): 24 +/- 4 kg/m2, waist circumference (WC): 91 +/- 12 cm, waist-to-height ratio (WHtR): 0.45 +/- 0.08) were available for analysis. All measures of adiposity were inversely correlated with vagally-mediated HRV indexed by RMSSD (all p < 0.001). Strongest associations were found with WC and RMSSD (r = -0.29). Associations were stronger in males (WC r = -0.32) than in females (WC r = -0.23). Partial correlations revealed the same pattern for RMSSD (WC all pcc = -0.12 p < 0.001; WC male pcc = -0.14 p < 0.001; WC female pcc = -0.06 p < 0.05). Correlation strength of BMI and WHtR with RMSSD were similar and significantly weaker compared to WC (p <.001) in unadjusted analysis. Overall, nonparametric Kendall's tb led to the same conclusions. The present data supports previous findings, that HRV is related to measures of adiposity in healthy individuals. In line with previous research, we found that WC is more strongly related to measures of HRV, indicating that WC best captures adiposity related risk. C1 [Koenig, J.; Thayer, J. F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Windham, B. G.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Sonntag, D.; Fischer, J. E.; Jarczok, M. N.] Heidelberg Univ, Mannheim Med Fac, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. RP Koenig, J (reprint author), Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. EM koenig.393@osu.edu RI Jarczok, Marc/A-2383-2014; OI Jarczok, Marc/0000-0002-6055-385X; Koenig, Julian/0000-0003-1009-9625 NR 21 TC 2 Z9 2 U1 2 U2 3 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD NOV PY 2015 VL 19 IS 9 BP 879 EP 882 DI 10.1007/s12603-015-0508-x PG 4 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA CV8ZP UT WOS:000364577300002 PM 26482688 ER PT J AU Darbari, DS Hampson, JP Ichesco, E Kadom, N Vezina, G Evangelou, I Clauw, DJ Taylor, JG Harris, RE AF Darbari, Deepika S. Hampson, Johnson P. Ichesco, Eric Kadom, Nadja Vezina, Gilbert Evangelou, Iordanis Clauw, Daniel J. Taylor, James G. Harris, Richard E. TI Frequency of Hospitalizations for Pain and Association With Altered Brain Network Connectivity in Sickle Cell Disease SO JOURNAL OF PAIN LA English DT Article DE Sickle cell disease; pain; brain network connectivity; functional neuroimaging ID INDEPENDENT COMPONENT ANALYSIS; RESTING-STATE CONNECTIVITY; HEALTH-CARE UTILIZATION; HYDROXYUREA TREATMENT; FIBROMYALGIA; MECHANISMS; INSULA; ANEMIA; ADULTS; MODULATION AB Sickle cell disease (SCD) is a hemoglobinopathy that affects more than 100,000 individuals in the United States. The disease is characterized by the presence of sickle hemoglobin and recurrent episodes of pain. Some individuals with SCD experience frequent hospitalizations and a high burden of pain. The role of central mechanisms in SCD pain has not been explored. Twenty-five adolescents and young adults with SCD underwent functional magnetic resonance imaging. Participants were stratified into groups with high pain or low pain based on the number of hospitalizations for pain in the preceding 12 months. Resting state functional connectivity was analyzed using seed-based and dual regression independent component analysis. Intrinsic brain connectivity was compared between the high pain and low pain groups, and association with fetal hemoglobin, a known modifier of SCD, was explored. Patients in the high pain group displayed an excess of pronociceptive connectivity such as between anterior cingulate and default mode network structures, such as the precuneus, whereas patients in the low pain group showed more connectivity to antinociceptive structures such as the perigenual and subgenual cingulate. Although a similar proportion of patients in both groups reported that they were on hydroxyurea, the fetal hemoglobin levels were significantly higher in the low pain group and were associated with greater connectivity to antinociceptive structures. These findings support the role of central mechanisms in SCD pain. Intrinsic brain connectivity should be explored as a complementary and objective outcome measure in SCD pain research. Perspective: Altered connectivity patterns associated with high pain experience in patients with sickle cell disease suggest a possible role of central mechanisms in sickle cell pain. Resting state brain connectivity studies should be explored as an effective methodology to investigate pain in SCD. (C) 2015 by the American Pain Society C1 [Darbari, Deepika S.] Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Div Hematol, Washington, DC USA. [Vezina, Gilbert; Evangelou, Iordanis] Childrens Natl Hlth Syst, Dept Diagnost Imaging & Radiol, Washington, DC USA. [Darbari, Deepika S.; Vezina, Gilbert] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20010 USA. [Darbari, Deepika S.; Evangelou, Iordanis; Taylor, James G.] NHLBI, Genom Med Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hampson, Johnson P.; Ichesco, Eric; Clauw, Daniel J.; Harris, Richard E.] Univ Michigan, Dept Anesthesiol, Chron Pain & Fatigue Res Ctr, Ann Arbor, MI 48109 USA. [Kadom, Nadja] Boston Univ, Med Ctr, Dept Radiol, Boston, MA 02118 USA. RP Darbari, DS (reprint author), George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Hlth Syst,Dept Pediat, Div Hematol,Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM ddarbari@childrensnational.org OI Taylor, James/0000-0002-4421-1809 FU intramural research programs of National Heart, Lung and Blood Institute [1 ZIA HL006012, 1 ZIA HL006160] FX This work was supported by the intramural research programs of the National Heart, Lung and Blood Institute; contract grant numbers: 1 ZIA HL006012; 1 ZIA HL006160 (J.G.T.). The authors declare no competing conflicts of interest. NR 44 TC 4 Z9 4 U1 0 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD NOV PY 2015 VL 16 IS 11 BP 1077 EP 1086 DI 10.1016/j.jpain.2015.07.005 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CV9MX UT WOS:000364612400002 PM 26291276 ER PT J AU Nahin, RL Stussman, BJ Herman, PM AF Nahin, Richard L. Stussman, Barbara J. Herman, Patricia M. TI Out-Of-Pocket Expenditures on Complementary Health Approaches Associated With Painful Health Conditions in a Nationally Representative Adult Sample SO JOURNAL OF PAIN LA English DT Article DE Complementary and alternative medicine; out-of-pocket costs; expenditures; back pain; chronic pain ID ALTERNATIVE MEDICINE PROVIDERS; UNITED-STATES; INTERVIEW SURVEY; INSURANCE-COVERAGE; CARE EXPENDITURES; BACK-PAIN; COST DATA; PATTERNS; OSTEOARTHRITIS; INDIVIDUALS AB National surveys suggest that millions of adults in the United States use complementary health approaches such as acupuncture, chiropractic manipulation, and herbal medicines to manage painful conditions such as arthritis, back pain, and fibromyalgia. Yet, national and per person out-of-pocket (OOP) costs attributable to this condition-specific use are unknown. In the 2007 National Health Interview Survey, the use of complementary health approaches, the reasons for this use, and the associated OOP costs were captured in a nationally representative sample of 5,467 adults. Ordinary least square regression models that controlled for comorbid conditions were used to estimate aggregate and per person OOP costs associated with 14 painful health conditions. Individuals using complementary approaches spent a total of $14.9 billion (standard error [SE] = $.9 billion) on these approaches to manage these painful conditions. Total OOP expenditures by those using complementary approaches for their back pain ($8.7 billion, SE = $.8 billion) far outstripped OOP expenditures for any other condition; the majority of these costs ($4.7 billion, SE = $.4 billion) were for visits to complementary providers. Annual condition-specific per person OOP costs varied from a low of $568 (SE = $144) for regular headaches to a high of $895 (SE = $163) for fibromyalgia. Perspective: Adults in the United States spent $14.9 billion on complementary health approaches (eg, acupuncture, chiropractic manipulation, and herbal medicines) to manage painful conditions including back pain ($8.7 billion). This back pain estimate is almost one-third of the total conventional health care expenditure for back pain ($30.4 billion) and two-thirds higher than conventional OOP expenditures ($5.1 billion). Published by Elsevier Inc. on behalf of the American Pain Society C1 [Nahin, Richard L.; Stussman, Barbara J.] NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA. [Herman, Patricia M.] RAND Corp, RAND Hlth, Santa Monica, CA USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 FU Intramural NIH HHS [Z99 AT999999] NR 47 TC 2 Z9 2 U1 2 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD NOV PY 2015 VL 16 IS 11 BP 1147 EP 1162 DI 10.1016/j.jpain.2015.07.013 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CV9MX UT WOS:000364612400009 PM 26320946 ER PT J AU Hernandez-Andrade, E Garcia, M Ahn, H Korzeniewski, SJ Saker, H Yeo, L Chaiworapongsa, T Hassan, SS Romero, R AF Hernandez-Andrade, Edgar Garcia, Maynor Ahn, Hyunyoung Korzeniewski, Steven J. Saker, Homam Yeo, Lami Chaiworapongsa, Tinnakorn Hassan, Sonia S. Romero, Roberto TI Strain at the internal cervical os assessed with quasi-static elastography is associated with the risk of spontaneous preterm delivery at <= 34 weeks of gestation SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Cervical elasticity; cervical stiffness; prematurity; preterm labor; short cervix ID HUMAN UTERINE CERVIX; SONOGRAPHIC SHORT CERVIX; EARLY TERM INFANTS; SHEAR-WAVE SPEED; IN-VIVO; QUANTITATIVE ELASTOGRAPHY; BIOMECHANICAL PROPERTIES; MECHANICAL-PROPERTIES; EXTRACELLULAR-MATRIX; ASYMPTOMATIC WOMEN AB Aim: To evaluate the association between cervical strain assessed with quasi-static elastography and spontaneous preterm delivery. Methods: Quasi-static elastography was used to estimate cervical strain in 545 pregnant women with singleton pregnancies from 11 weeks to 28 weeks of gestation. Cervical strain was evaluated in one sagittal plane and in the cross-sectional planes of the internal cervical os and external cervical os. The distribution of strain values was categorized into quartiles for each studied region and their association with spontaneous preterm delivery at <= 34 weeks and at < 37 weeks of gestation was evaluated using logistic regression. Results: The prevalence of spontaneous preterm delivery at < 37 weeks of gestation was 8.2% (n=45), and that at <= 34 weeks of gestation was 3.8% (n=21). Strain in the internal cervical os was the only elastography value associated with spontaneous preterm delivery. Women with strain values in the 3rd and 4th quartiles had a significantly higher risk of spontaneous preterm delivery at <= 34 weeks and at < 37 weeks of gestation when compared to women with strain values in the lowest quartile. When adjusting for a short cervix (< 25 mm) and gestational age at examination, women with strain values in the 3rd quartile maintained a significant association with spontaneous preterm delivery at <= 34 weeks (OR 9.0; 95% CI, 1.1-74.0; P=0.02), whereas women with strain values in the highest quartile were marginally more likely than women with lowest quartile strain values to deliver spontaneously at < 37 weeks of gestation (OR 95% CI: 2.8; [0.9-9.0]; P=0.08). Conclusion: Increased strain in the internal cervical os is associated with higher risk of spontaneous preterm delivery both at <= 34 and < 37 weeks of gestation. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Korzeniewski, Steven J.; Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Hernandez-Andrade, Edgar; Garcia, Maynor; Ahn, Hyunyoung; Korzeniewski, Steven J.; Saker, Homam; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Hernandez-Andrade, Edgar; Garcia, Maynor; Ahn, Hyunyoung; Korzeniewski, Steven J.; Saker, Homam; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Hernandez-Andrade, Edgar; Garcia, Maynor; Ahn, Hyunyoung; Korzeniewski, Steven J.; Saker, Homam; Yeo, Lami; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Perinatol Res Branch, NICHD,NIH,DHHS, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM ehernand@med.wayne.edu; romeror@mail.nih.gov FU Federal funds from the NICHD/NIH/DHHS [HHSN275201300006C]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS) FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from the NICHD/NIH/DHHS under Contract No. HHSN275201300006C. The ultrasound experience and technical support of senior Registered Diagnostic Medical Sonographers (RDMS) Catherine Ducharme and Denise Haggerty are gratefully acknowledged. NR 92 TC 1 Z9 2 U1 2 U2 3 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD NOV PY 2015 VL 43 IS 6 BP 657 EP 666 DI 10.1515/jpm-2014-0382 PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CV9AM UT WOS:000364579700003 PM 25781664 ER PT J AU Kumar, A Baycin-Hizal, D Wolozny, D Pedersen, LE Lewis, NE Heffner, K Chaerkady, R Cole, RN Shiloach, J Zhang, H Bowen, MA Betenbaugh, MJ AF Kumar, Amit Baycin-Hizal, Deniz Wolozny, Daniel Pedersen, Lasse Ebdrup Lewis, Nathan E. Heffner, Kelley Chaerkady, Raghothama Cole, Robert N. Shiloach, Joseph Zhang, Hui Bowen, Michael A. Betenbaugh, Michael J. TI Elucidation of the CHO Super-Ome (CHO-SO) by Proteoinformatics SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE proteomics; secretome; CHO; signal peptides; ontology; host cell proteins; immunogenicity ID HAMSTER OVARY CELLS; INTEGRIN-LINKED KINASE; SECRETED PROTEIN PREDICTION; GROWTH-FACTOR-BETA; TIME-OF-FLIGHT; PROTEOMIC ANALYSIS; INTRAVENOUS IMMUNOGLOBULINS; RAPID CHARACTERIZATION; EXTRACELLULAR-MATRIX; REGULATED EXOCYTOSIS AB Chinese hamster ovary (CHO) cells are the preferred host cell line for manufacturing a variety of complex biotherapeutic drugs including monoclonal antibodies. We performed a proteomics and bioinformatics analysis on the spent medium from adherent CHO cells. Supernatant from CHO-K1 culture was collected and subjected to in-solution digestion followed by LC/LC-MS/MS analysis, which allowed the identification of 3281 different host cell proteins (HCPs). To functionally categorize them, we applied multiple bioinformatics tools to the proteins identified in our study including SignalP, TargetP, SecretomeP, TMHMM, WoLF PSORT, and Phobius. This analysis provided information on the presence of signal peptides, transmembrane domains, and cellular localization and showed that both secreted and intracellular proteins were constituents of the supernatant. Identified proteins were shown to be localized to the secretory pathway including ones playing roles in cell growth, proliferation, and folding as well as those involved in protein degradation and removal. After combining proteins predicted to be secreted or having a signal peptide, we identified 1015 proteins, which we termed as CHO supernatant-ome (CHO-SO), or superome. As a part of this effort, we created a publically accessible web-based tool called GO-CHO to functionally categorize proteins found in CHO-SO and identify enriched molecular functions, biological processes, and cellular components. We also used a tool to evaluate the immunogenicity potential of high-abundance HCPs. Among enriched functions were catalytic activity and structural constituents of the cytoskeleton. Various transport related biological processes, such as vesicle mediated transport, were found to be highly enriched. Extracellular space and vesicular exosome associated proteins were found to be the most enriched cellular components. The superome also contained proteins secreted from both classical and nonclassical secretory pathways. The work and database described in our study will enable the CHO community to rapidly identify high-abundance HCPs in their cultures and therefore help assess process and purification methods used in the production of biologic drugs. C1 [Kumar, Amit; Wolozny, Daniel; Heffner, Kelley; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Kumar, Amit; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Pedersen, Lasse Ebdrup] Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, DK-2970 Horsholm, Denmark. [Lewis, Nathan E.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Lewis, Nathan E.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Chaerkady, Raghothama; Cole, Robert N.] Johns Hopkins Univ, Sch Med, Mass Spectrometry & Prote Facil, Inst Basic Biomed Sci, Baltimore, MD 21205 USA. [Zhang, Hui] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Baycin-Hizal, Deniz; Bowen, Michael A.] MedImmune LLC, Antibody Discovery & Prot Engn, Gaithersburg, MD 20878 USA. RP Betenbaugh, MJ (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. EM beten@jhu.edu OI Pedersen, Lasse Ebdrup/0000-0002-6064-919X; Lewis, Nathan/0000-0001-7700-3654 FU MedImmune LLC; Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding for the study was provided by MedImmune LLC and the Intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, or preparation of the manuscript. NR 121 TC 2 Z9 2 U1 5 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2015 VL 14 IS 11 BP 4687 EP 4703 DI 10.1021/acs.jproteome.5b00588 PG 17 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CV7EL UT WOS:000364435100022 PM 26418914 ER PT J AU Brooks-Russell, A Conway, KP Liu, DP Xie, YL Vullo, GC Li, KG Iannotti, RJ Compton, W Simons-Morton, B AF Brooks-Russell, Ashley Conway, Kevin P. Liu, Danping Xie, Yunlong Vullo, Genevieve C. Li, Kaigang Iannotti, Ronald J. Compton, Wilson Simons-Morton, Bruce TI Dynamic Patterns of Adolescent Substance Use: Results From a Nationally Representative Sample of High School Students SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID LATENT CLASS ANALYSIS; ALCOHOL-USE; PARENTING PRACTICES; PROTECTIVE FACTORS; YOUNG ADULTHOOD; RISK BEHAVIORS; COOCCURRENCE; CONSEQUENCES; TRAJECTORIES; PREVALENCE AB Objective: Use of tobacco, alcohol, marijuana, and other drugs increases during the high school years, yet little is known about individual patterns over time, particularly patterns of contemporaneous multiple-substance use. This study examined trajectories of contemporaneous substance use and how individual and social factors differentially predict patterns of substance use. Method: Longitudinal trajectories of substance use were examined in a nationally representative sample of students (N = 2,512) over a 3-year period (10th through 12th grades) using latent class analysis. Individual, parental, and peer risk factors in 10th grade were examined in relation to membership in trajectory classes. Result: A five-class model was identified: nonusers (45.5%); tobacco, alcohol, and other drug users (9.2%); alcohol and other drug users (9.2%); increasing multiple-substance users (16.7%); and decreasing multiple-substance users (19.4%). Depressive symptoms at baseline were associated with a higher likelihood of membership in all classes except the increasing multiple-substance-user class, but the association becomes insignificant when social influence factors were adjusted. Parental-monitoring knowledge was associated with a lower likelihood of membership in all classes except increasing multiple-substance-user class, whereas perceived parental disapproval was associated with a lower likelihood of membership in the tobacco, alcohol, and other drug user class. Peer substance use was associated with a higher likelihood of membership in each of the substance use classes. Conclusions: The identified longitudinal profiles highlight the pervasiveness and dynamic patterns of contemporaneous multiple-substance use during 10th through 12th grades. Negative peer influence increased risk, whereas positive parenting behaviors decreased risk. The findings are consistent with the need to foster social influences and protective factors against adolescent substance use. C1 [Brooks-Russell, Ashley] Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Aurora, CO 80045 USA. [Conway, Kevin P.; Vullo, Genevieve C.; Compton, Wilson] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Liu, Danping; Xie, Yunlong; Li, Kaigang; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Xie, Yunlong] Glotech Inc, Bethesda, MD USA. [Vullo, Genevieve C.] Kelly Govt Solut, Bethesda, MD USA. [Iannotti, Ronald J.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Brooks-Russell, A (reprint author), Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Anschutz Med Campus,13001 E 17th Pl B119,Bldg 500, Aurora, CO 80045 USA. EM Ashley.brooks-russell@ucdenver.edu OI Conway, Kevin/0000-0002-7638-339X; Simons-Morton, Bruce/0000-0003-1099-6617 FU intramural research program of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN267200800009C]; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of Health Resources and Services Administration (HRSA) FX This research (contract number HHSN267200800009C) was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). The views and opinions expressed in this article are those of the authors and do not necessarily represent the views of NIDA, the NICHD, the National Institutes of Health, or any other governmental agency. NR 41 TC 1 Z9 1 U1 2 U2 6 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD NOV PY 2015 VL 76 IS 6 BP 962 EP 970 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA CW2DQ UT WOS:000364801700017 PM 26562606 ER PT J AU Baird, DD Harmon, QE Upson, K Moore, KR Barker-Cummings, C Baker, S Cooper, T Wegienka, G AF Baird, Donna D. Harmon, Quaker E. Upson, Kristen Moore, Kristen R. Barker-Cummings, Christie Baker, Susan Cooper, Tracy Wegienka, Ganesa TI A Prospective, Ultrasound-Based Study to Evaluate Risk Factors for Uterine Fibroid Incidence and Growth: Methods and Results of Recruitment SO JOURNAL OF WOMENS HEALTH LA English DT Article ID UNITED-STATES; WOMENS HEALTH; WHITE WOMEN; VITAMIN-D; LEIOMYOMA; AGE; PREVALENCE; EXPRESSION; QUESTIONNAIRE; HYPOTHESIS AB Background: Uterine fibroids are common, benign, smooth-muscle tumors that can cause major morbidity for reproductive-age women, often requiring invasive treatment. Despite this personal and public health burden, no prior study has attempted to periodically screen fibroid-free women with ultrasound to detect incident disease and identify risk factors. Methods: We designed a study to prospectively investigate development of fibroids by enrolling women without a clinical diagnosis of fibroids and screening for fibroids with ultrasound at baseline. Enrollment procedures included extensive questionnaires and specimen collection (blood, urine, vaginal swabs). The cohort is followed at approximately 20-month intervals. At each follow-up there are updates to the questionnaire data, further specimen collection, and an ultrasound examination. We identify incident disease and measure tumor growth. The two exposures of primary interest are vitamin D insufficiency and reproductive tract infections. This manuscript provides a detailed description of the study methods, recruitment results, and participant characteristics. Results: The Study of Environment, Lifestyle and Fibroids enrolled 1,696 African American women aged 23-34 years. Family and friends was a leading recruitment source. More than 95% of participants contributed all the requested biological specimens at baseline. Study ultrasound examinations revealed undiagnosed fibroids in 378 women (22% of participants). The retention rate for the first follow-up was 87%. Conclusions: Study design aspects likely to be important for long-term studies in young African Americans include personalized recruitment, multiple steps to the enrollment process that rely on the initiative of the participant, and methods for tracing highly mobile study subjects. C1 [Baird, Donna D.; Upson, Kristen; Moore, Kristen R.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Harmon, Quaker E.; Barker-Cummings, Christie; Baker, Susan] Social & Sci Syst Inc, Durham, NC USA. [Cooper, Tracy] Henry Ford Hlth Syst, Dept Radiol, Div Ultrasound, Detroit, MI USA. [Wegienka, Ganesa] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, Bldg 101,Room A308,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Moore, Kristen/C-2303-2017; Upson, Kristen/D-4504-2017; Baird, Donna/D-5214-2017; OI Moore, Kristen/0000-0001-9993-3270; Upson, Kristen/0000-0001-9598-8776; Baird, Donna/0000-0002-5544-2653; Harmon, Quaker/0000-0002-5866-848X FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; American Recovery and Reinvestment Act FX We thank the participants for sharing their valuable information and taking time to complete the numerous study activities. Drs. Gordon Flake and Anne Marie Jukic reviewed an earlier version of the manuscript. We also thank the following study team members without whom the recruitment and retention of study participants, day-to-day operations, and data and specimen collection would not be possible: at Social and Scientific Systems, Inc., Taylor Abernathy, Jackie Allison, Thomasina Austin, Ans Bilhorn, Deborah Cousins, Carrissa Dixon, Suzie Dollar, Judith Fontanelle, Elizabeth Ganze, Irina Khodush, Jason Langfahl, Christina Makarushka, Carol Messler, Naomi Piserchia, Ellen Revak, Tina Richmond, Diana Smith, Nick Verna, Terri Young (Westat), Fikri Yucel, and the Telephone Research Center staff; and at HFHS, Kyra Jones, Karen Bourgeois, Louise Brennan, Tangi Dargin, Vickie Gaines, Wanda Greene, Yolanda Harris, Cynthia Hill, Melissa Houston, Darine Joumaa, LaSalle McKenzie, Dojna Mototolea, Rita Norman, Debbie Williams, Evangeline Griesemer, and LaToya Allen. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, and, in part, by funds allocated for health research by the American Recovery and Reinvestment Act. NR 42 TC 9 Z9 9 U1 3 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD NOV 1 PY 2015 VL 24 IS 11 BP 907 EP 915 DI 10.1089/jwh.2015.5277 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA CV6SI UT WOS:000364400300009 PM 26334691 ER PT J AU Kopp, JB AF Kopp, Jeffrey B. TI Replenishment of the podocyte compartment by parietal epithelial cells SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RENAL PROGENITORS; DISEASE AB While progressive podocytopenia is a characteristic feature of chronic glomerular disease, the visceral epithelial niche can be replenished from the parietal epithelium. Two new reports demonstrate this process in genetically engineered mice, using fate mapping, and in human renal biopsies manifesting segmental glomerulosclerosis in diverse settings, using cellular and extracellular matrix markers. C1 [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDKD, NIH, 10 Ctr Dr,3N116, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU Intramural NIH HHS NR 9 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2015 VL 88 IS 5 BP 934 EP 935 DI 10.1038/ki.2015.256 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CW2CR UT WOS:000364799200002 PM 26579676 ER PT J AU Bouhrara, M Spencer, RG AF Bouhrara, Mustapha Spencer, Richard G. TI Incorporation of nonzero echo times in the SPGR and bSSFP signal models used in mcDESPOT SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE mcDESPOT; SPGR; bSSFP; quantitative MRI ID MYELIN WATER FRACTION; WHITE-MATTER DEVELOPMENT; STOCHASTIC REGION CONTRACTION; STATE FREE PRECESSION; STEADY-STATE; MAGNETIC-RESONANCE; GRADIENT-ECHO; MULTICOMPONENT T-1; RELAXATION-TIME; RADIOFREQUENCY AB PurposeTo analyze the effect of neglecting nonzero echo times (TEs) in the conventional model of multicomponent driven equilibrium single pulse observation of T-1 and T-2 (mcDESPOT). Theory and MethodsFormulations of the two-component spoiled gradient recalled echo (SPGR) and balanced steady state free precession (bSSFP) models that incorporate nonzero TE effects are presented in the context of mcDESPOT and compared with the conventionally used SPGR and bSSFP models which ignore nonzero TEs. Relative errors in derived parameter estimates from conventional mcDESPOT, omitting TE effects, are assessed using simulations over a wide range of experimental and sample parameters. ResultsThe neglect of nonzero TE leads to an overestimate of the SPGR signal and an underestimate of the bSSFP signal. These effects can introduce large errors in parameter estimates derived from conventional mcDESPOT under realistic imaging conditions. ConclusionSPGR and bSSFP signal models accounting for nonzero TE effects should be incorporated into quantitative mcDESPOT analyses. Magn Reson Med 74:1227-1235, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA C1 [Bouhrara, Mustapha; Spencer, Richard G.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. RP Spencer, RG (reprint author), NIA, NIH, Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov FU NIH, National Institute on Aging FX We gratefully acknowledge the comments of an anonymous reviewer of a previous publication, which led to this analysis. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 39 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2015 VL 74 IS 5 BP 1227 EP 1235 DI 10.1002/mrm.25984 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV4DK UT WOS:000364215900005 PM 26407635 ER PT J AU Ahmad, R Xue, H Giri, S Ding, Y Craft, J Simonetti, OP AF Ahmad, Rizwan Xue, Hui Giri, Shivraman Ding, Yu Craft, Jason Simonetti, Orlando P. TI Variable density incoherent spatiotemporal acquisition (VISTA) for highly accelerated cardiac MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Fekete points; Riesz energy; pseudo-random; cardiac; cine; MRI; compressive sensing; sampling ID T SPARSE-SENSE; CINE MRI; FEKETE POINTS; K-SPACE; RECONSTRUCTION; RESOLUTION; RECOVERY; ERRORS AB PurposeFor the application of compressive sensing to parallel MRI, Poisson disk sampling (PDS) has been shown to generate superior results compared with random sampling methods. However, due to its limited flexibility to incorporate additional constraints, PDS is not readily extendible to dynamic applications. Here, we propose and validate a pseudo-random sampling technique that allows incorporating constraints specific to dynamic imaging. MethodsThe proposed sampling scheme, called variable density incoherent spatiotemporal acquisition (VISTA), is based on constrained minimization of Riesz energy on a spatiotemporal grid. Data from both a digital phantom and real-time cine were used to compare VISTA with uniform interleaved sampling (UIS) and variable density random sampling (VRS). The image quality was assessed qualitatively and quantitatively. ResultsVISTA improved the trade-off between noise and sharpness. Also, VISTA produced diagnostic quality images at an acceleration rate of 15, whereas UIS and VRS images degraded below the diagnostic threshold at lower acceleration rates. ConclusionsVISTA generates spatiotemporal sampling patterns with high levels of uniformity and incoherence, while maintaining a constant temporal resolution. Using a small pilot study, VISTA was shown to produce diagnostic quality images at acceleration rates up to 15. Magn Reson Med 74:1266-1278, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Ahmad, Rizwan] Ohio State Univ, Dept Elect & Comp Engn, Columbus, OH 43210 USA. [Xue, Hui] NIH, Bethesda, MD USA. [Giri, Shivraman] Siemens Healthcare, Chicago, IL USA. [Ding, Yu; Simonetti, Orlando P.] Ohio State Univ, Dorothy M Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. [Craft, Jason; Simonetti, Orlando P.] Ohio State Univ, Dept Internal Med, Div Cardiovasc Med, Columbus, OH 43210 USA. [Simonetti, Orlando P.] Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. RP Ahmad, R (reprint author), Ohio State Univ, 420 West 12th Ave,Room 126A, Columbus, OH 43210 USA. EM ahmad.46@osumc.edu FU National Heart, Lung, and Blood Institute [R01HL102450] FX Grant sponsor: National Heart, Lung, and Blood Institute; Grant number: R01HL102450. NR 39 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2015 VL 74 IS 5 BP 1266 EP 1278 DI 10.1002/mrm.25507 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV4DK UT WOS:000364215900009 PM 25385540 ER PT J AU van Gelderen, P Mandelkow, H de Zwart, JA Duyn, JH AF van Gelderen, Peter Mandelkow, Hendrik de Zwart, Jacco A. Duyn, Jeff H. TI A torque balance measurement of anisotropy of the magnetic susceptibility in white matter SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE white matter; magnetic susceptibility; magnetic anisotropy ID NERVOUS-SYSTEM MYELIN; GRADIENT-ECHO MRI; HUMAN-BRAIN; MEMBRANE-LIPIDS; DIAMAGNETIC ANISOTROPY; BIOPHYSICAL MECHANISMS; LECITHIN MEMBRANES; ORIENTATION; CONTRAST; FIELD AB PurposeRecent MRI studies have suggested that the magnetic susceptibility of white matter (WM) in the human brain is anisotropic, providing a new contrast mechanism for the visualization of fiber bundles and allowing the extraction of cellular compartment-specific information. This study provides an independent confirmation and quantification of this anisotropy. MethodsAnisotropic magnetic susceptibility results in a torque exerted on WM when placed in a uniform magnetic field, tending to align the WM fibers with the field. To quantify the effect, excised spinal cord samples were placed in a torque balance inside the magnet of a 7 T MRI system and the magnetic torque was measured as function of orientation. ResultsAll tissue samples (n=5) showed orienting effects, confirming the presence of anisotropic susceptibility. Analysis of the magnetic torque resulted in reproducible values for the WM volume anisotropy that ranged from 13.6 to 19.2 ppb. ConclusionThe independently determined anisotropy values confirm estimates inferred from MRI experiments and validate the use of anisotropy to extract novel information about brain fiber structure and myelination. Magn Reson Med 74:1388-1396, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [van Gelderen, Peter; Mandelkow, Hendrik; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP van Gelderen, P (reprint author), NINDS, AMRI, LFMI, NIH, 10 Ctr Dr,Bldg 10,Room B1D-725, Bethesda, MD 20892 USA. EM gelderen@nih.gov FU National Institute of Neurological Disorders and Stroke FX We acknowledge the Intramural Research Program of the National Institute of Neurological Disorders and Stroke for support. NR 38 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2015 VL 74 IS 5 BP 1388 EP 1396 DI 10.1002/mrm.25524 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CV4DK UT WOS:000364215900020 PM 25399830 ER PT J AU Lang, M Vocke, CD Merino, MJ Schmidt, LS Linehan, WM AF Lang, Martin Vocke, Cathy D. Merino, Maria J. Schmidt, Laura S. Linehan, W. Marston TI Mitochondrial DNA mutations distinguish bilateral multifocal renal oncocytomas from familial Birt-Hogg-Dube tumors SO MODERN PATHOLOGY LA English DT Article ID COMPLEX-I; CELL CARCINOMAS; METABOLISM; TUMORIGENESIS; DEFECTS; BIOPSY; GENOME; CANCER; NEEDLE AB Oncocytomas are mostly benign tumors characterized by accumulation of defective mitochondria, and in sporadic cases, are associated with disruptive mitochondrial DNA (mtDNA) mutations. However, the role mtDNA mutations have in renal tumors of Birt-Hogg-Dube (BHD) patients and other renal oncocytomas with an apparent genetic component has not been investigated to date. Here we characterize the mitochondrial genome in different renal tumors and investigate the possibility of employing mtDNA sequencing analyses of biopsy specimens to aid in the differential diagnosis of oncocytomas. The entire mitochondrial genome was sequenced in 25 samples of bilateral and multifocal (BMF) renal oncocytomas, 30 renal tumors from BHD patients and 36 non-oncocytic renal tumors of different histologies as well as in biopsy samples of kidney tumors. mtDNA sequencing in BMF oncocytomas revealed that all tumors carry disruptive mutations, which impair the assembly of the NADH-ubiquinone oxidoreductase. Multiple tumors from a given BMF oncocytoma patient mainly harbor the same somatic mutation and the kidneys of these patients display diffuse oncocytosis. In contrast, renal oncocytomas of patients with BHD syndrome and renal tumors with different histologies do not show disruptive mtDNA mutations. Moreover, we demonstrate that it is feasible to amplify and sequence the entire mtDNA in biopsy specimens, and that these sequences are representative of the tumor DNA. These results show that pathogenic mtDNA mutations affecting complex I of the respiratory chain are strongly correlated with the oncocytoma phenotype in non-BHD-related renal tumors and that mtDNA sequences from biopsies are predictive of the tumor genotype. This work supports a role for mtDNA mutations in respiratory chain complexes as diagnostic markers for renal oncocytomas. C1 [Lang, Martin; Vocke, Cathy D.; Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res, Frederick, MD USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike CRC Room 1-5940W, Bethesda, MD 20892 USA. EM WML@nih.gov OI Lang, Martin/0000-0002-0242-6713 FU Fondazione Italiana Ricerca sul Cancro (FIRC) 'Fellowship; Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research; Frederick National Laboratory for Cancer Research, NTH [HHSN261200800001E]; Associazione Italiana per la Ricerca sul Cancro FX The present work was funded in part by Fondazione Italiana Ricerca sul Cancro (FIRC) 'Fellowship for abroad-2011' to ML and was supported by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NTH, under the contract HHSN261200800001E (LSS). 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. We thank Hisashi Hasumi, Yukiko Hasumi, Masaya Baba, and Christopher Ricketts for helpful discussions and advice. NR 43 TC 2 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2015 VL 28 IS 11 BP 1458 EP 1469 DI 10.1038/modpathol.2015.101 PG 12 WC Pathology SC Pathology GA CV4YZ UT WOS:000364273700006 PM 26428318 ER PT J AU Teicher, BA Polley, E Kunkel, M Evans, D Silvers, T Delosh, R Laudeman, J Ogle, C Reinhart, R Selby, M Connelly, J Harris, E Monks, A Morris, J AF Teicher, Beverly A. Polley, Eric Kunkel, Mark Evans, David Silvers, Thomas Delosh, Rene Laudeman, Julie Ogle, Chad Reinhart, Russell Selby, Michael Connelly, John Harris, Erik Monks, Anne Morris, Joel TI Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PRECLINICAL TESTING PROGRAM; SOFT-TISSUE SARCOMA; STAGE 1; KINASE INHIBITOR; AURORA KINASES; EWINGS-SARCOMA; OVARIAN-CANCER; PART SARCOMA; SENSITIVITY; APOPTOSIS AB The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA-approved oncology agents and 345 investigational agents. The investigational agents' library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at nine concentrations in triplicate with an exposure time of 96 hours using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression, and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community. (C) 2015 AACR. C1 [Teicher, Beverly A.; Kunkel, Mark; Morris, Joel] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD USA. [Polley, Eric] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD USA. [Evans, David; Silvers, Thomas; Delosh, Rene; Laudeman, Julie; Ogle, Chad; Reinhart, Russell; Selby, Michael; Connelly, John; Harris, Erik; Monks, Anne] Leidos Biomed Res Inc, Mol Pharmacol Grp, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Teicher, BA (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM teicherba@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 69 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2015 VL 14 IS 11 BP 2452 EP 2462 DI 10.1158/1535-7163.MCT-15-0074 PG 11 WC Oncology SC Oncology GA CV9FE UT WOS:000364592000005 PM 26351324 ER PT J AU Seol, Y Zhang, HL Agama, K Lorence, N Pommier, Y Neuman, KC AF Seol, Yeonee Zhang, Hongliang Agama, Keli Lorence, Nicholas Pommier, Yves Neuman, Keir C. TI Single-Molecule Supercoil Relaxation Assay as a Screening Tool to Determine the Mechanism and Efficacy of Human Topoisomerase IB Inhibitors SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DNA TOPOISOMERASES; ANTICANCER DRUGS; ANTITUMOR DRUGS; LAMELLARIN-D; CAMPTOTHECIN; CLEAVAGE; COMPLEXES; TOPOLOGY; BINDING; SENSITIVITY AB Human nuclear type IB topoisomerase (Top1) inhibitors are widely used and powerful anticancer agents. In this study, we introduce and validate a single-molecule supercoil relaxation assay as a molecular pharmacology tool for characterizing therapeutically relevant Top1 inhibitors. Using this assay, we determined the effects on Top1 supercoil relaxation activity of four Top1 inhibitors; three clinically relevant: camptothecin, LMP-400, LMP-776 (both indenoisoquinoline derivatives), and one natural product in preclinical development, lamellarin-D. Our results demonstrate that Top1 inhibitors have two distinct effects on Top1 activity: a decrease in supercoil relaxation rate and an increase in religation inhibition. The type and magnitude of the inhibition mode depend both on the specific inhibitor and on the topology of the DNA substrate. In general, the efficacy of inhibition is significantly higher with supercoiled than with relaxed DNA substrates. Comparing single-molecule inhibition with cell growth inhibition (IC50) measurements showed a correlation between the binding time of the Top1 inhibitors and their cytotoxic efficacy, independent of the mode of inhibition. This study demonstrates that the single-molecule supercoil relaxation assay is a sensitive method to elucidate the detailed mechanisms of Top1 inhibitors and is relevant for the cellular efficacy of Top1 inhibitors. (C) 2015 AACR. C1 [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Single Mol Biophys, NIH, Bethesda, MD 20892 USA. [Zhang, Hongliang; Agama, Keli; Lorence, Nicholas; Pommier, Yves] NCI, Lab Mol Pharmacol, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NIH, Room 3517,Bldg 50,50 South Dr, Bethesda, MD 20817 USA. EM pommier@nih.gov; neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural NIH HHS [Z01 BC006161-24, ZIA HL001056-03]; NCI NIH HHS [Z01 BC006161]; NHLBI NIH HHS [Z01 HL001056] NR 42 TC 0 Z9 0 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2015 VL 14 IS 11 BP 2552 EP 2559 DI 10.1158/1535-7163.MCT-15-0454 PG 8 WC Oncology SC Oncology GA CV9FE UT WOS:000364592000014 PM 26351326 ER PT J AU Adachi, T Kobayashi, T Sugihara, E Yamada, T Ikuta, K Pittaluga, S Saya, H Amagai, M Nagao, K AF Adachi, Takeya Kobayashi, Tetsuro Sugihara, Eiji Yamada, Taketo Ikuta, Koichi Pittaluga, Stefania Saya, Hideyuki Amagai, Masayuki Nagao, Keisuke TI Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma SO NATURE MEDICINE LA English DT Article ID MYCOSIS-FUNGOIDES; SEZARY-SYNDROME; STEM-CELLS; INFECTION; TISSUE; TUMOR; EXPRESSION; IMMUNITY; SUBSETS; CD4(+) AB The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (T-RM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. T-RM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) T-RM cells, and IL-7 for CD8(+) and CD4(+) T-RM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) T-RM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant T-RM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma. C1 [Adachi, Takeya; Kobayashi, Tetsuro; Amagai, Masayuki; Nagao, Keisuke] Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan. [Kobayashi, Tetsuro; Nagao, Keisuke] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sugihara, Eiji; Saya, Hideyuki] Keio Univ, Sch Med, Inst Adv Med Res, Div Gene Regulat, Tokyo, Japan. [Yamada, Taketo] Keio Univ, Sch Med, Dept Pathol, Tokyo 160, Japan. [Ikuta, Koichi] Kyoto Univ, Inst Virus Res, Dept Biol Responses, Lab Biol Protect, Kyoto 606, Japan. [Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nagao, K (reprint author), Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan. EM keisuke.nagao@nih.gov RI Amagai, Masayuki/K-5325-2013; Nagao, Keisuke/J-5116-2013 OI Amagai, Masayuki/0000-0003-3314-7052; Nagao, Keisuke/0000-0002-7005-3138 FU Japan Society for the Promotion of Science; Kanae Foundation for the Promotion of Medical Science; Japanese Society for Investigative Dermatology's (JSID's) Fellowship Shiseido Award; NIH NCI Intramural Research Programs FX We thank M. Ohyama for helpful discussion on human hair follicles; N. Sakai, K. Eguchi and S. Sato (Keio University School of Medicine) for their technical assistance; H. Kong (National Institutes of Health) for their discussions on human CTCL; Y. Madokoro (Keio University School of Medicine) for human CTCL immunohistochemical staining; T. Kitamura (University of Tokyo) for providing the retroviral vector pMXs-IG and Plat-E cells; J. Takeda (Osaka University) for providing K5-Cre mice; D.H. Kaplan (University of Minnesota) for providing Langerin-DTA mice; and B.E. Clausen (Johannes Gutenberg University of Mainz) for providing Langerin-DTR mice. This work was supported by the Japan Society for the Promotion of Science, The Kanae Foundation for the Promotion of Medical Science, the Japanese Society for Investigative Dermatology's (JSID's) Fellowship Shiseido Award and the NIH NCI Intramural Research Programs. NR 33 TC 13 Z9 13 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2015 VL 21 IS 11 BP 1272 EP 1279 DI 10.1038/nm.3962 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CV9QH UT WOS:000364621200011 PM 26479922 ER PT J AU Goedeke, L Rotllan, N Canfran-Duque, A Aranda, JF Ramirez, CM Araldi, E Lin, CS Anderson, NN Wagschal, A de Cabo, R Horton, JD Lasuncion, MA Naar, AM Suarez, Y Fernandez-Hernando, C AF Goedeke, Leigh Rotllan, Noemi Canfran-Duque, Alberto Aranda, Juan. F. Ramirez, Cristina M. Araldi, Elisa Lin, Chin-Sheng Anderson, Norma N. Wagschal, Alexandre de Cabo, Rafael Horton, Jay D. Lasuncion, Miguel A. Naeaer, Anders M. Suarez, Yajaira Fernandez-Hernando, Carlos TI MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels SO NATURE MEDICINE LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; LEUCINE ZIPPER PROTEIN; CHOLESTEROL HOMEOSTASIS; LIPID-METABOLISM; TRANSCRIPTION FACTOR; NONHUMAN-PRIMATES; MESSENGER-RNAS; TARGET GENES; HUMAN GENOME; MICE AB The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease. C1 [Goedeke, Leigh; Rotllan, Noemi; Canfran-Duque, Alberto; Aranda, Juan. F.; Ramirez, Cristina M.; Araldi, Elisa; Suarez, Yajaira; Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA. [Goedeke, Leigh; Rotllan, Noemi; Canfran-Duque, Alberto; Aranda, Juan. F.; Ramirez, Cristina M.; Araldi, Elisa; Suarez, Yajaira; Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Comparat Med Sect, Integrat Cell Signaling & Neurobiol Metab Program, New Haven, CT 06510 USA. [Goedeke, Leigh; Aranda, Juan. F.; Araldi, Elisa; Lin, Chin-Sheng; Suarez, Yajaira; Fernandez-Hernando, Carlos] NYU, Sch Med, Dept Med, Leon H Charney Div Cardiol, New York, NY USA. [Goedeke, Leigh; Araldi, Elisa; Lin, Chin-Sheng; Suarez, Yajaira; Fernandez-Hernando, Carlos] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Anderson, Norma N.; Horton, Jay D.] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. [Anderson, Norma N.; Horton, Jay D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Wagschal, Alexandre; Naeaer, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Wagschal, Alexandre; Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Lasuncion, Miguel A.] Hosp Univ Ramon y Cajal, Serv Bioquim Invest, Inst Ramon y Cajal Invest Sanitaria, Madrid, Spain. [Lasuncion, Miguel A.] Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Madrid, Spain. RP Fernandez-Hernando, C (reprint author), Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA. EM carlos.fernandez@yale.edu RI Lasuncion, Miguel A./K-6167-2014; de Cabo, Rafael/J-5230-2016; OI Lasuncion, Miguel A./0000-0003-0299-9391; de Cabo, Rafael/0000-0002-3354-2442; Ramirez, Cristina M/0000-0003-2589-0786; , rafael/0000-0003-2830-5693 FU US National Institutes of Health (NIH) [R01HL107953, R01HL107953-04S1, R01HL106063, R01HL105945, 1F31AG043318, P30KD034989]; American Heart Association [15SDG23000025]; Howard Hughes Medical Institute International Student Research Fellowship; Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research; Ministerio de Industria y Comercio, Spain [SAF2011-29951]; NIH, National Institute of Aging; NIH [R01DK 094184, U24 DK059635]; Laura and Isaac Perlmutter Cancer Center (NIH, National Cancer Institute grant) [P30CA16087]; New York State Stem Cell Science (NYSTEM) [C026719] FX We thank C. Yun, J. Recio, S. Katz and R. DasGupta at the New York University (NYU) RNAi Core for their advice and assistance with the miRNA screen, K. Harry and members of the Yale University Liver Center for primary mouse hepatocyte isolation, members of the Iwakiri laboratory for reagents and advice on primary hepatocyte culture, the Yale University School of Medicine Mouse Metabolic Phenotyping Center (MMPC) for liver toxicity measurements, P. Tontonoz (UCLA) for generously providing the LDLR-GFP plasmid, the Nonhuman Primate Core of the National Institute on Aging for providing liver samples and E. Fisher (NYU School of Medicine) for kindly providing the human hepatocellular carcinoma cell line (Huh7) and mouse hepatic cell line (Hepal-6). This work was supported through grants by the US National Institutes of Health (NIH; grants R01HL107953, R01HL107953-04S1 and R01HL106063 (C.F.-H.); grant R01HL105945 (Y.S.); grant 1F31AG043318 (L.G.); grant P30KD034989 (Yale University Liver Center), the American Heart Association (grant 15SDG23000025 (C.M.R.)), the Howard Hughes Medical Institute International Student Research Fellowship (E.A.), the Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research (C.F.-H.) and the Ministerio de Industria y Comercio, Spain (grant SAF2011-29951 (M.A.L.)). Centro de Investigacion Biomedica en Red Fisiopatologia de Obesidad y Nutricion (CIBERobn) is an initiative of Instituto de Salud Carlos III (ISCIII), Spain. R.d.C. is supported by the Intramural Research Program of the NIH, National Institute of Aging. A.M.N. and A.W. are supported by NIH grant R01DK 094184. The NYU RNAi core is supported by the Laura and Isaac Perlmutter Cancer Center (NIH, National Cancer Institute grant P30CA16087) and the New York State Stem Cell Science (NYSTEM) contract C026719. The Yale University School of Medicine MMPC is supported by NIH grant U24 DK059635. NR 60 TC 25 Z9 25 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2015 VL 21 IS 11 BP 1280 EP 1289 DI 10.1038/nm.3949 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CV9QH UT WOS:000364621200012 PM 26437365 ER PT J AU Wagschal, A Najafi-Shoushtari, SH Wang, L Goedeke, L Sinha, S deLemos, AS Black, JC Ramirez, CM Li, YX Tewhey, R Hatoum, I Shah, N Lu, Y Kristo, F Psychogios, N Vrbanac, V Lu, YC Hla, T de Cabo, R Tsang, JS Schadt, E Sabeti, PC Kathiresan, S Cohen, DE Whetstine, J Chung, RT Fernandez-Hernando, C Kaplan, LM Bernards, A Gerszten, RE Naar, AM AF Wagschal, Alexandre Najafi-Shoushtari, S. Hani Wang, Lifeng Goedeke, Leigh Sinha, Sumita deLemos, Andrew S. Black, Josh C. Ramirez, Cristina M. Li, Yingxia Tewhey, Ryan Hatoum, Ida Shah, Naisha Lu, Yong Kristo, Fjoralba Psychogios, Nikolaos Vrbanac, Vladimir Lu, Yi-Chien Hla, Timothy de Cabo, Rafael Tsang, John S. Schadt, Eric Sabeti, Pardis C. Kathiresan, Sekar Cohen, David E. Whetstine, Johnathan Chung, Raymond T. Fernandez-Hernando, Carlos Kaplan, Lee M. Bernards, Andre Gerszten, Robert E. Naeaer, Anders M. TI Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis SO NATURE MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS; HDL; MICE; HYPERCHOLESTEROLEMIA; TRANSPORTERS; METABOLISM; MECHANISMS; RECEPTOR; BINDING AB Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders. C1 [Wagschal, Alexandre; Najafi-Shoushtari, S. Hani; Wang, Lifeng; Black, Josh C.; Kristo, Fjoralba; Whetstine, Johnathan; Bernards, Andre; Naeaer, Anders M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Wagschal, Alexandre; Najafi-Shoushtari, S. Hani; Wang, Lifeng; Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Goedeke, Leigh; Ramirez, Cristina M.; Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Dept Pathol, Comparat Med Sect, New Haven, CT 06510 USA. [Sinha, Sumita; Psychogios, Nikolaos; Kathiresan, Sekar; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [deLemos, Andrew S.; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Liver, Boston, MA USA. [deLemos, Andrew S.; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Div, Boston, MA USA. [Black, Josh C.; Kathiresan, Sekar; Whetstine, Johnathan; Chung, Raymond T.; Kaplan, Lee M.; Bernards, Andre; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Charlestown, MA USA. [Li, Yingxia; Cohen, David E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Gastroenterol, Boston, MA 02115 USA. [Tewhey, Ryan; Sabeti, Pardis C.; Kathiresan, Sekar] MIT, Broad Inst, Cambridge, MA 02139 USA. [Tewhey, Ryan; Sabeti, Pardis C.; Kathiresan, Sekar] Harvard, Cambridge, MA USA. [Tewhey, Ryan; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Hatoum, Ida; Kaplan, Lee M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Obes Metab & Nutr Inst, Boston, MA USA. [Hatoum, Ida; Kaplan, Lee M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Shah, Naisha; Lu, Yong; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Vrbanac, Vladimir] Harvard Univ, Ctr AIDS Res, Cambridge, MA 02138 USA. [Lu, Yi-Chien; Hla, Timothy] Cornell Univ, Weill Cornell Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10021 USA. [de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Schadt, Eric] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kathiresan, Sekar; Bernards, Andre] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu RI Black, Joshua/Q-2484-2015; de Cabo, Rafael/J-5230-2016; Hla, Timothy/G-5873-2012; OI de Cabo, Rafael/0000-0002-3354-2442; Kristo, Fjoralba/0000-0002-8045-9756; Hla, Timothy/0000-0001-8355-4065; Ramirez, Cristina M/0000-0003-2589-0786; , rafael/0000-0003-2830-5693 FU US National Institutes of Health (NIH) [R21DK084459, R01DK094184, R37DK048873, R01DK056626, K24DK078772, R01HL107953, R01HL106063]; Massachusetts General Hospital (MGH); American Heart Association; Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research Award; NIH [R01HL49094]; US National Institute of Allergy and Infectious Diseases; American Heart Association SDG Grant [15SDG23000025]; MGH Executive Committee on Research; Neural Imaging Center as part of a National Institutes on Neurological Disorders and Stroke P30 Core Center grant [NS072030]; Harvard Digestive Diseases Center [P30 DK034854] FX This work was supported by the following grants: US National Institutes of Health (NIH) grants R21DK084459 and R01DK094184 (A.M.N); R37DK048873 and R01DK056626 to D.E.C.; K24DK078772 to R.T.C.; and R01HL107953 and R01HL106063 to C.F.-H. A.M.N. was supported by a scholar award from the Massachusetts General Hospital (MGH). R.E.G. was supported by an Established Investigator Award from the American Heart Association. C.F.-H. was supported by a Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research Award. T.H. acknowledges the support of NIH grant R01HL49094 and a Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research Award. N.S. and J.S.T. were supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases. C.M.R. was supported by the American Heart Association SDG Grant 15SD G23000025. A.W. was supported bye fellowship from the MGH Executive Committee on Research. We thank C. Molony of Merck Research Laboratories for help with genotyping data quality assessment. We thank the Harvard Medical School Neurobiology Department and the Neurobiology Imaging Facility for consultation and instrument availability that supported this work. This facility is supported in part by the Neural Imaging Center as part of a National Institutes on Neurological Disorders and Stroke P30 Core Center grant no. NS072030, and by the Harvard Digestive Diseases Center (P30 DK034854). NR 31 TC 30 Z9 30 U1 5 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2015 VL 21 IS 11 BP 1290 EP 1297 DI 10.1038/nm.3980 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CV9QH UT WOS:000364621200013 PM 26501192 ER PT J AU Bhiman, JN Anthony, C Doria-Rose, NA Karimanzira, O Schramm, CA Khoza, T Kitchin, D Botha, G Gorman, J Garrett, NJ Karim, SSA Shapiro, L Williamson, C Kwong, PD Mascola, JR Morris, L Moore, PL AF Bhiman, Jinal N. Anthony, Colin Doria-Rose, Nicole A. Karimanzira, Owen Schramm, Chaim A. Khoza, Thandeka Kitchin, Dale Botha, Gordon Gorman, Jason Garrett, Nigel J. Karim, Salim S. Abdool Shapiro, Lawrence Williamson, Carolyn Kwong, Peter D. Mascola, John R. Morris, Lynn Moore, Penny L. TI Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies SO NATURE MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; B-CELL RECEPTORS; INFECTION; VACCINE; PATHWAYS; ESCAPE; TARGET AB The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast, some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation may be required for neutralization breadth(1-6). Recent studies have shown that viral diversification precedes the emergence of bNAbs, but the significance of this observation is unknown(7,8). Here we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants, termed bNAb-initiating envelopes, that were distinct from both of the transmitted/founder (T/F) viruses and that efficiently engaged the bNAb precursor. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a 'dead-end' antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for antibody sublineages 'that Can tolerate these changes, thereby providing a mechanism for the generation of neutralization breadth within a developing antibody lineage. C1 [Bhiman, Jinal N.; Karimanzira, Owen; Khoza, Thandeka; Kitchin, Dale; Morris, Lynn; Moore, Penny L.] NICD, Ctr HIV & STIs, NHLS, Johannesburg, South Africa. [Bhiman, Jinal N.; Morris, Lynn; Moore, Penny L.] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa. [Anthony, Colin; Botha, Gordon; Williamson, Carolyn] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Doria-Rose, Nicole A.; Gorman, Jason; Shapiro, Lawrence; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Schramm, Chaim A.; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Syst Biol, New York, NY USA. [Garrett, Nigel J.; Karim, Salim S. Abdool; Williamson, Carolyn; Morris, Lynn; Moore, Penny L.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. [Williamson, Carolyn] Natl Hlth Lab Serv, Johannesburg, South Africa. RP Moore, PL (reprint author), NICD, Ctr HIV & STIs, NHLS, Johannesburg, South Africa. EM pennym@nicd.ac.za OI Bhiman, Jinal/0000-0001-6354-4003; Moore, Penny/0000-0001-8719-4028; , Carolyn/0000-0003-0125-1226; , Lynn/0000-0003-3961-7828; Abdool Karim, Salim/0000-0002-4986-2133 FU Centre for the AIDS Programme of Research (CAPRISA); South African Medical Research Council (MRC) SHIP program; NIH [AI116086-01]; Vaccine Research Center; National Institute of Allergy and Infectious Diseases (NIAID); South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology; US NIAID, NIH, US Department of Health and Human Services grant [U19 AI51794]; Columbia University-Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH [5 D43 TW000231]; University of the Witwatersrand Postgraduate Merit Award; Poliomyelitis Research Foundation PhD Bursary; National Research Foundation of South Africa Innovation PhD Bursary; National Research Foundation of South Africa; Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine [089933/Z/09/Z] FX We thank the participants in the CAPRISA 002 cohort for their commitment to attending the CAPRISA clinics in South Africa. Thanks to the CAPRISA 002 study team (including N. Naicker, V. Asari, N. Majola, T. Cekwane, N. Samsunder, Z. Mchunu, D. Nkosi, H. Shozi, S. Ndlovu, P. Radebe, K. Leask and M. Upfold) for managing the cohort and providing specimens. We are grateful to C. K. Wibmer for useful discussions. We thank P. Labuschagne, D. Matten and T. York for assistance with viral next-generation sequence analysis, R. Bailer and M. Louder for the CAP256-VRC26 UCA neutralization data against the large virus panel and J. Mulllikin and the US National Institutes of Health (NIH) Intramural Sequencing Center (NISC) Comparative Sequencing Program for antibody NGS data at 34 weeks. We are grateful to J. Baalwa, D. Ellenberger, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra and L. Zhang for contributing the HIV-1 envelope plasmids used in our neutralization panel. The JC53bl-13 (TZM-bl) and 293T cell lines were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH from J.C. Kappes, X. Wu and Tranzyme, Inc., and A. Rice, respectively. We acknowledge research funding from the Centre for the AIDS Programme of Research (CAPRISA) (S.S.A.K.), the South African Medical Research Council (MRC) SHIP program (P.L.M.), the NIH through a U01 grant (AI116086-01) (P.L.M.), the intramural research programs of the Vaccine Research Center and the National Institute of Allergy and Infectious Diseases (NIAID) (J.R.M.). CAPRISA is funded by the South African HIV/AIDS Research and Innovation Platform of the South African Department of Science and Technology, and was initially supported by the US NIAID, NIH, US Department of Health and Human Services grant U19 AI51794 (S.S.A.K.). Funding was received by J.N.B. and CA. from the Columbia University-Southern African Fogarty AIDS International Training and Research Program through the Fogarty International Center, NIH grant 5 D43 TW000231 (to Quarraisha Abdool Karim). Additional fellowships included a University of the Witwatersrand Postgraduate Merit Award (J.N.B.), a Poliomyelitis Research Foundation PhD Bursary (J.N.B.), a National Research Foundation of South Africa Innovation PhD Bursary (J.N.B.), a National Research Foundation of South Africa Postdoctoral Fellowship (CA.), and a Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine, grant 089933/Z/09/Z (P.L.M.). NR 26 TC 40 Z9 40 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2015 VL 21 IS 11 BP 1332 EP 1336 DI 10.1038/nm.3963 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CV9QH UT WOS:000364621200018 PM 26457756 ER PT J AU Alam, MS Gaida, MM Bergmann, F Lasitschka, F Giese, T Giese, NA Hackert, T Hinz, U Hussain, SP Kozlov, SV Ashwell, JD AF Alam, Muhammad S. Gaida, Matthias M. Bergmann, Frank Lasitschka, Felix Giese, Thomas Giese, Nathalia A. Hackert, Thilo Hinz, Ulf Hussain, S. Perwez Kozlov, Serguei V. Ashwell, Jonathan D. TI Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression SO NATURE MEDICINE LA English DT Article ID DUCTAL ADENOCARCINOMA; PROTEIN-KINASE; TUMOR-GROWTH; INFLAMMATION; MICE; THERAPY; METASTASIS; PROGNOSIS; NEOPLASIA; CARCINOMA AB Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment(1), the presence of which can promote both cancer induction and growth(2-4). Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production(5,6). Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-alpha- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-alpha, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of INF-alpha, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit. C1 [Alam, Muhammad S.; Gaida, Matthias M.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gaida, Matthias M.; Bergmann, Frank; Lasitschka, Felix] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Giese, Thomas] Heidelberg Univ, Inst Immunol, Heidelberg, Germany. [Giese, Nathalia A.; Hackert, Thilo; Hinz, Ulf] Univ Heidelberg Hosp, Dept Surg, Heidelberg, Germany. [Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kozlov, Serguei V.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; German Research Foundation (DFG) [Ga-1818/1-1]; German Research Foundation [SFB 938/TP Z2] FX We thank J. Scheuerer, M. Clauter, B. Walter and E. Castro for expert technical assistance, J. Greiner for Panc02 cells, the Center for Advanced Preclinical Research (CAPR) program at the Frederick National Laboratory for Cancer Research for providing KPC mice for some studies, T. Longerich and B. Lahrmann for technical advice in computer-based tissue analysis and P. Schirmacher for critical review of the manuscript. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. M.M.G. was supported by a fellowship from the German Research Foundation (DFG; Ga-1818/1-1). The work of F.L. was in part funded by the German Research Foundation (grant no. SFB 938/TP Z2). NR 34 TC 6 Z9 6 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2015 VL 21 IS 11 BP 1337 EP 1343 DI 10.1038/nm.3957 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CV9QH UT WOS:000364621200019 PM 26479921 ER PT J AU Narayan, K Subramaniam, S AF Narayan, Kedar Subramaniam, Sriram TI Focused ion beams in biology SO NATURE METHODS LA English DT Review ID SCANNING-ELECTRON-MICROSCOPY; ATOM-PROBE TOMOGRAPHY; CRYOELECTRON TOMOGRAPHY; CORRELATED LIGHT; IN-SITU; MAMMALIAN-CELLS; CELLULAR ULTRASTRUCTURE; SPECIMEN PREPARATION; DENDRITIC CELLS; NEURAL CIRCUITS AB A quiet revolution is under way in technologies used for nanoscale cellular imaging. Focused ion beams, previously restricted to the materials sciences and semiconductor fields, are rapidly becoming powerful tools for ultrastructural imaging of biological samples. Cell and tissue architecture, as preserved in plastic-embedded resin or in plunge-frozen form, can be investigated in three dimensions by scanning electron microscopy imaging of freshly created surfaces that result from the progressive removal of material using a focused ion beam. The focused ion beam can also be used as a sculpting tool to create specific specimen shapes such as lamellae or needles that can be analyzed further by transmission electron microscopy or by methods that probe chemical composition. Here we provide an in-depth primer to the application of focused ion beams in biology, including a guide to the practical aspects of using the technology, as well as selected examples of its contribution to the generation of new insights into subcellular architecture and mechanisms underlying host-pathogen interactions. C1 [Narayan, Kedar; Subramaniam, Sriram] NCI, Ctr Mol Microscopy, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Narayan, Kedar] Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Ctr Mol Microscopy, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA FX This work was supported by funds from the intramural program of the National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. The authors thank E. Tyler for artistic rendering of the figures; E. He, A. Brust and D. Bliss for help creating Supplementary Video 1 describing the FIB-SEM imaging process; and L. Earl and other members of their laboratory for many fruitful discussions. The authors apologize to those colleagues whose work has not been cited owing to space constraints. NR 109 TC 6 Z9 6 U1 10 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD NOV PY 2015 VL 12 IS 11 BP 1021 EP 1031 DI 10.1038/NMETH.3623 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CV8BG UT WOS:000364500900015 PM 26513553 ER PT J AU Makarova, KS Wolf, YI Alkhnbashi, OS Costa, F Shah, SA Saunders, SJ Barrangou, R Brouns, SJJ Charpentier, E Haft, DH Horvath, P Moineau, S Mojica, FJM Terns, RM Terns, MP White, MF Yakunin, AF Garrett, RA van der Oost, J Backofen, R Koonin, EV AF Makarova, Kira S. Wolf, Yuri I. Alkhnbashi, Omer S. Costa, Fabrizio Shah, Shiraz A. Saunders, Sita J. Barrangou, Rodolphe Brouns, Stan J. J. Charpentier, Emmanuelle Haft, Daniel H. Horvath, Philippe Moineau, Sylvain Mojica, Francisco J. M. Terns, Rebecca M. Terns, Michael P. White, Malcolm F. Yakunin, Alexander F. Garrett, Roger A. van der Oost, John Backofen, Rolf Koonin, Eugene V. TI An updated evolutionary classification of CRISPR-Cas systems SO NATURE REVIEWS MICROBIOLOGY LA English DT Article ID SHORT PALINDROMIC REPEATS; RNA-SILENCING COMPLEX; GUIDED SURVEILLANCE COMPLEX; BACTERIAL IMMUNE-SYSTEM; DNA-REPAIR SYSTEM; ADAPTIVE IMMUNITY; CRYSTAL-STRUCTURE; STREPTOCOCCUS-THERMOPHILUS; ESCHERICHIA-COLI; DEFENSE SYSTEMS AB The evolution of CRISPR-cas loci, which encode adaptive immune systems in archaea and bacteria, involves rapid changes, in particular numerous rearrangements of the locus architecture and horizontal transfer of complete loci or individual modules. These dynamics complicate straightforward phylogenetic classification, but here we present an approach combining the analysis of signature protein families and features of the architecture of cas loci that unambiguously partitions most CRISPR-cas loci into distinct classes, types and subtypes. The new classification retains the overall structure of the previous version but is expanded to now encompass two classes, five types and 16 subtypes. The relative stability of the classification suggests that the most prevalent variants of CRISPR-Cas systems are already known. However, the existence of rare, currently unclassifiable variants implies that additional types and subtypes remain to be characterized. C1 [Makarova, Kira S.; Wolf, Yuri I.; Haft, Daniel H.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Alkhnbashi, Omer S.; Costa, Fabrizio; Saunders, Sita J.; Backofen, Rolf] Univ Freiburg, Bioinformat Grp, Dept Comp Sci, D-79110 Freiburg, Germany. [Shah, Shiraz A.; Garrett, Roger A.] Univ Copenhagen, Archaea Ctr, Dept Biol, DK-2200 Copenhagen N, Denmark. [Barrangou, Rodolphe] N Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27606 USA. [Brouns, Stan J. J.; van der Oost, John] Wageningen Univ, Microbiol Lab, NL-6703 HB Wageningen, Netherlands. [Charpentier, Emmanuelle] Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, D-38124 Braunschweig, Germany. [Horvath, Philippe] DuPont Nutr & Hlth, F-86220 Dange St Romain, France. [Moineau, Sylvain] Univ Laval, Dept Biochim Microbiol & Bioinformat, Felix Herelle Reference Ctr Bacterial Viruses, Fac Sci & Genie,Grp Rech Ecol Buccale,Fac Med Den, Quebec City, PQ, Canada. [Mojica, Francisco J. M.] Univ Alicante, Dept Fisiol Genet & Microbiol, E-03080 Alicante, Spain. [Terns, Rebecca M.; Terns, Michael P.] Univ Georgia, Biochem & Mol Biol, Genet & Microbiol, Athens, GA 30602 USA. [White, Malcolm F.] Univ St Andrews, St Andrews KY16 9TZ, Fife, Scotland. [Yakunin, Alexander F.] Univ Toronto, Dept Chem Engn & Appl Chem, Toronto, ON M5S 3E5, Canada. [Backofen, Rolf] Univ Freiburg, BIOSS Ctr Biol Signaling Studies, Cluster Excellence, Freiburg, Germany. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbl.nlm.nih.gov RI Barrangou, Rodolphe/I-2878-2014; Mojica, Francisco/K-2414-2014; Shah, Shiraz/M-5132-2016; Terns, Michael/N-6435-2016; Garrett, Roger/M-2450-2014; HORVATH, Philippe/K-5266-2015; OI Barrangou, Rodolphe/0000-0002-0648-3504; Mojica, Francisco/0000-0002-6660-4996; Shah, Shiraz/0000-0002-4665-577X; HORVATH, Philippe/0000-0003-2015-8123; White, Malcolm/0000-0003-1543-9342; Yakunin, Alexander/0000-0003-0813-6490; Costa, Fabrizio/0000-0002-4900-995X FU National Institutes of Health (NIH) Intramural Research Program at the National Library of Medicine, US Department of Health and Human Services; NIH [RO1 GM54682, RO1 GM99876]; SIAM Gravitation Grant from the Netherlands Organization for Scientific Research [024.002.002]; NWO Vidi grant [864.11.005]; European Research Council (ERC) Stg [639707]; Natural Sciences and Engineering Research Council (NSERC) Strategic Network Grant IBN; NSERC Discovery grant; Natural Sciences and Engineering Research Council of Canada (Discovery program); Ministerio de Economia y Competitividad [B102014-53029]; Deutsche Forschungsgemeinschaft (DFG) [BA 2168/5-2]; Danish Natural Science Research Council FX K.S.M., Y.I.W., D.H. and E.V.K. are supported by the National Institutes of Health (NIH) Intramural Research Program at the National Library of Medicine, US Department of Health and Human Services. R.M.T. and M.P.T. are supported by NIH grants RO1 GM54682 and RO1 GM99876. J.v.d.O. was partly supported by SIAM Gravitation Grant 024.002.002 from the Netherlands Organization for Scientific Research (N.W.O.). S.J.J.B. was financially supported by an NWO Vidi grant (864.11.005) and European Research Council (ERC) Stg (639707). A.F.Y. is supported by the Natural Sciences and Engineering Research Council (NSERC) Strategic Network Grant IBN and NSERC Discovery grant. S.M. acknowledges funding from Natural Sciences and Engineering Research Council of Canada (Discovery program) and holds a Tier 1 Canada Research Chair in Bacteriophages. F.J.M.M. is supported by the Ministerio de Economia y Competitividad (B102014-53029). R.B. is supported by the Deutsche Forschungsgemeinschaft (DFG) grant (BA 2168/5-2). S.A.S. and R.A.G. were funded primarily by the Danish Natural Science Research Council. O.S.A., F C., S.J.S., R.B., S.A.S and R A.G. are grateful to all members of the FOR1680 for helpful discussions. NR 117 TC 190 Z9 195 U1 49 U2 155 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD NOV PY 2015 VL 13 IS 11 BP 722 EP 736 DI 10.1038/nrmicro3569 PG 15 WC Microbiology SC Microbiology GA CV9QE UT WOS:000364620900009 PM 26411297 ER PT J AU Kiage, JN Sampson, UKA Lipworth, L Fazio, S Mensah, GA Yu, Q Munro, H Akwo, EA Dai, Q Blot, WJ Kabagambe, EK AF Kiage, J. N. Sampson, U. K. A. Lipworth, L. Fazio, S. Mensah, G. A. Yu, Q. Munro, H. Akwo, E. A. Dai, Q. Blot, W. J. Kabagambe, E. K. TI Intake of polyunsaturated fat in relation to mortality among statin users and non-users in the Southern Community Cohort Study SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE PUFA; Fish; Hypertension; Mortality; Cardiovascular disease; Prospective ID REDUCE BLOOD-PRESSURE; STROKE REGARDS COHORT; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; RACIAL-DIFFERENCES; RISK-FACTORS; TRANS FAT; FISH-OIL; ACIDS; HYPERTENSION AB Background and aims: Consumption of polyunsaturated fatty acids (PUFA), especially the n3-series, may protect against cardiovascular disease (CVD), but recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that PUFA intake may not confer benefits beyond those provided by statins, but studies comparing statin users to non-users with regard to effects of PUFA are lacking. Methods and results: Black and white men and women (n = 69,559) in the Southern Community Cohort Study were studied. Cox regression models adjusting for age, sex, race, BMI, recruitment site, education, income, smoking, diabetes, and dietary variables were used. Results: At baseline the mean +/- SD age was 52 +/- 9 years, 60% of participants were women, 54% had hypertension and 16% used statins. We observed modest inverse associations between n3-PUFA and n6-PUFA intake with mortality among non-statin users but not among statin users. In adjusted analyses, the HRs (95% CIs) for all-cause mortality (6,396 deaths over a median of 6.4 years) comparing the highest to the lowest quintile were 0.90 (0.82-1.00) for n3-PUFA and 0.80 (0.70-0.92) for n6-PUFA among non-statin users, whereas they were 1.06 (0.87-1.28) and 0.96 (0.78-1.19) for n3-PUFA and n6-PUFA, respectively, among statin users. Conclusions: Our results suggest potential benefits of PUFA consumption on mortality which are only apparent in the absence of statin therapy. It seems prudent to consider the potential benefit of PUFA consumption in the primary prevention of CVD among patients who are not candidates for statin therapy but are at increased risk for CVD and mortality. (C) 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. C1 [Kiage, J. N.; Lipworth, L.; Akwo, E. A.; Dai, Q.; Blot, W. J.; Kabagambe, E. K.] Vanderbilt Univ, Div Epidemiol, Dept Med, Med Ctr, Nashville, TN 37203 USA. [Sampson, U. K. A.; Mensah, G. A.] NHLBI, CTRIS, Bethesda, MD USA. [Lipworth, L.; Akwo, E. A.; Kabagambe, E. K.] Vanderbilt Univ, Vanderbilt Ctr Translat & Clin Cardiovasc Res, Med Ctr, Nashville, TN 37203 USA. [Fazio, S.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Ctr Prevent Cardiol, Portland, OR 97239 USA. [Yu, Q.] Westat Corp, Rockville, MD 20850 USA. [Munro, H.; Blot, W. J.] Int Epidemiol Inst, Rockville, MD 20850 USA. RP Kabagambe, EK (reprint author), Vanderbilt Univ, Div Epidemiol, Dept Med, Nashville, TN 37203 USA. EM kiagejn@gmail.com; uchechukwu.sampson@nih.gov; lipworth@vanderbilt.edu; fazio@ohsu.edu; george.mensah@nih.gov; qiluyu@westat.com; heather@iei.us; elvis.a.akwo@vanderbilt.edu; qi.dai@vanderbilt.edu; william.j.blot@vanderbilt.edu; edmond.kabagambe@vanderbilt.edu FU National Cancer Institute [R01 CA092447]; American Recovery and Reinvestment Act [3R01 CA092447-08S1]; PepsiCo Global Research and Development FX This study was primarily supported by a grant from the National Cancer Institute (R01 CA092447) and funds from the American Recovery and Reinvestment Act (3R01 CA092447-08S1). Additional funding for this study was provided by PepsiCo Global Research and Development. NR 42 TC 3 Z9 3 U1 2 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 EI 1590-3729 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD NOV PY 2015 VL 25 IS 11 BP 1016 EP 1024 DI 10.1016/j.numecd.2015.07.006 PG 9 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA CV7EA UT WOS:000364434000005 PM 26298428 ER PT J AU Reynolds, CP Kang, MH Maris, JM Kolb, EA Gorlick, R Wu, JR Kurmasheva, RT Houghton, PJ Smith, MA AF Reynolds, C. Patrick Kang, Min H. Maris, John M. Kolb, E. Anders Gorlick, Richard Wu, Jianrong Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial Testing (Stage 1) of the Anti-Microtubule Agents Cabazitaxel and Docetaxel, by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; taxane derivatives ID CHILDRENS-ONCOLOGY-GROUP; SOLID TUMORS; PHASE-II; PROSTATE-CANCER; BONE SARCOMA; BRAIN-TUMORS; PACLITAXEL; TAXANES; MODELS; GEMCITABINE AB Background. Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. Procedures. Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01nM to 0.1 mu M and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5 mg/kg on an every 4 days x 3 I. V. schedule. Results. In vitro, both cabazitaxel and docetaxel had similar potency (median rIC(50) 0.47nM and 0.88 nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. Conclusions. Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting. Pediatr Blood Cancer (C) 2015 Wiley Periodicals, Inc. 2015; 62:1897-1905. (C) 2015 Wiley Periodicals, Inc. C1 [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Reynolds, CP (reprint author), Texas Tech Univ, Hlth Sci Ctr, 3601 4th St STOP 9445, Lubbock, TX 79430 USA. EM Patrick.Reynolds@TTUHSC.edu OI Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [CA21765, N01-CM-42216, N01CM42216, P01 CA023099, P30 CA013330, P30 CA021765, P50 CA108786, CA108786] NR 25 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 IS 11 BP 1897 EP 1905 DI 10.1002/pbc.25611 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CV9BA UT WOS:000364581100006 PM 26154614 ER PT J AU Gu, QP Dillon, CF Eberhardt, MS Wright, JD Burt, VL AF Gu, Qiuping Dillon, Charles F. Eberhardt, Mark S. Wright, Jacqueline D. Burt, Vicki L. TI Preventive Aspirin and Other Antiplatelet Medication Use Among US Adults Aged >= 40 Years: Data from the National Health and Nutrition Examination Survey, 2011-2012 SO PUBLIC HEALTH REPORTS LA English DT Article ID AMERICAN-HEART-ASSOCIATION; OF-CARDIOLOGY FOUNDATION; EXPERT CONSENSUS DOCUMENT; LOW-DOSE ASPIRIN; CARDIOVASCULAR-DISEASE; TASK-FORCE; MYOCARDIAL-INFARCTION; DIABETES-ASSOCIATION; SECONDARY PREVENTION; SCIENTIFIC STATEMENT AB Objective. We estimated the prevalence of preventive aspirin and/or other antiplatelet medication use and the dosage of aspirin use in the U.S. adult population. Methods. We conducted cross-sectional analyses of a representative sample (n=3,599) of U.S. adults aged >= 40 years from the National Health and Nutrition Examination Survey, 2011-2012. Results. In 2011-2012, one-third of U.S. adults aged >= 40 years reported taking preventive aspirin and/or other antiplatelet medications, 97% of whom indicated preventive aspirin use. Preventive aspirin use increased with age (from 11% of those aged 40-49 years to 54% of those >= 80 years of age, p<0.001). Non-Hispanic white (35%) and black (30%) adults were more likely to take preventive aspirin than non-Hispanic Asian (20%, p<0.001) and Hispanic (22%, p=0.013) adults. Adults with, compared with those without health insurance, and adults with >= 2 doctor visits in the past year, diagnosed diabetes, hypertension, or high cholesterol were twice as likely to take preventive aspirin. Among those with cardiovascular disease, 76% reported taking preventive aspirin and/or other antiplatelet medications, of whom 91% were taking preventive aspirin. Among adults without cardiovascular disease, 28% reported taking preventive aspirin. Adherence rates to medically recommended aspirin use were 82% overall, 91% for secondary prevention, and 79% for primary prevention. Among current preventive aspirin users, 70% were taking 81 milligrams (mg) of aspirin daily and 13% were taking 325 mg of aspirin daily. Conclusion. The vast majority of antiplatelet therapy is preventive aspirin use. A health-care provider's recommendation to take preventive aspirin is an important determinant of current preventive aspirin use. C1 [Gu, Qiuping; Dillon, Charles F.; Eberhardt, Mark S.; Burt, Vicki L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth & Nutr Examinat Surveys, Hyattsville, MD 20782 USA. [Wright, Jacqueline D.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Gu, QP (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth & Nutr Examinat Surveys, 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM qag3@cdc.gov NR 39 TC 0 Z9 0 U1 2 U2 6 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1900 M ST NW, STE 710, WASHINGTON, DC 20036 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD NOV-DEC PY 2015 VL 130 IS 6 BP 643 EP 654 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CV8CI UT WOS:000364503700013 PM 26556936 ER PT J AU Culty, M Liu, Y Manku, G Chan, WY Papadopoulos, V AF Culty, Martine Liu, Ying Manku, Gurpreet Chan, Wai-Yee Papadopoulos, Vassilios TI Expression of steroidogenesis-related genes in murine male germ cells SO STEROIDS LA English DT Article DE Testis; Germ cells; Steroidogenesis; Spermatogenesis ID 18 KDA TSPO; TRANSLOCATOR PROTEIN; LEYDIG-CELLS; SEMINIFEROUS EPITHELIUM; ESTROGEN-RECEPTORS; STEROID-HORMONES; GROWTH-FACTOR; START DOMAIN; RAT TESTIS; IN-VITRO AB For decades, only few tissues and cell types were defined as steroidogenic, capable of de novo steroid synthesis from cholesterol. However, with the refinement of detection methods, several tissues have now been added to the list of steroidogenic tissues. Besides their critical role as long-range acting hormones, steroids are also playing more discreet roles as local mediators and signaling molecules within the tissues they are produced. In testis, steroidogenesis is carried out by the Leydig cells through a broad network of proteins, mediating cholesterol delivery to CYP11A1, the first cytochrome of the steroidogenic cascade, and the sequential action of enzymes insuring the production of active steroids, the main one being testosterone. The knowledge that male germ cells can be directly regulated by steroids and that they express several steroidogenesis-related proteins led us to hypothesize that germ cells could produce steroids, acting as autocrine, intracrine and juxtacrine modulators, as a way to insure synchronized progression within spermatogenic cycles, and preventing inappropriate cell behaviors between neighboring cells. Gene expression and protein analyses of mouse and rat germ cells from neonatal gonocytes to spermatozoa showed that most steroidogenesis-associated genes are expressed in germ cells, showing cell type-, spermatogenic cycle-, and age-specific expression profiles. Highly expressed genes included genes involved in steroidogenesis and other cell functions, such as Acbd1 and 3, Tspo and Vdac1-3, and genes involved in fatty acids metabolism or synthesis, including Hsb17b4 10 and 12, implying broader roles than steroid synthesis in germ cells. These results support the possibility of an additional level of regulation of spermatogenesis exerted between adjacent germ cells. (C) 2015 Elsevier Inc. All rights reserved. C1 [Culty, Martine; Manku, Gurpreet; Papadopoulos, Vassilios] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ H4A 3J1, Canada. [Culty, Martine; Manku, Gurpreet; Papadopoulos, Vassilios] McGill Univ, Dept Med, Montreal, PQ H4A 3J1, Canada. [Culty, Martine; Manku, Gurpreet; Papadopoulos, Vassilios] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H4A 3J1, Canada. [Liu, Ying] NHLBI, Sect Expt Atherosclerosis, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Chan, Wai-Yee] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. RP Culty, M (reprint author), McGill Univ, Res Inst, Ctr Hlth, 1001 Decarie Blvd,Bloc E,Room EM1-3218, Montreal, PQ H4A 3J1, Canada. EM martine.culty@mcgill.ca OI Papadopoulos, Vassilios/0000-0002-1183-8568 FU Natural Sciences and Engineering Research Council of Canada (NSERC) [386038-2013]; Canadian Institutes of Health Research (CIHR) Operating Grant [MOP-102647]; Canada Research Chair; Division of Endocrinology and Metabolism of the MUHC; Reseau Quebecois en Reproduction (RQR); Center Grant from Le Fonds de la Recherche en Sante du Quebec (FRSQ) FX We are thankful to Dr. Jaroslav Novak for his assistance with the statistical analysis of the gene expression arrays. This work was supported in part by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) (No. 386038-2013) to M.C.; a Canadian Institutes of Health Research (CIHR) Operating Grant (No. MOP-102647) and a Canada Research Chair to V.P.; and scholarship awards from the Division of Endocrinology and Metabolism of the MUHC and the Reseau Quebecois en Reproduction (RQR) to G.M. The Research Institute of the MUHC is supported in part by a Center Grant from Le Fonds de la Recherche en Sante du Quebec (FRSQ). NR 59 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD NOV PY 2015 VL 103 SI SI BP 105 EP 114 DI 10.1016/j.steroids.2015.08.011 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CV9LB UT WOS:000364607600011 PM 26302977 ER PT J AU Insel, T AF Insel, Thomas TI The Treatment Gap SO TECHNOLOGY REVIEW LA English DT Editorial Material C1 NIMH, Washington, DC 20892 USA. RP Insel, T (reprint author), NIMH, Washington, DC 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TECHNOL REV PI CAMBRIDGE PA 1 MAIN ST, 13 FLR, CAMBRIDGE, MA 02142 USA SN 1099-274X J9 TECHNOL REV JI Technol. Rev. PD NOV-DEC PY 2015 VL 118 IS 6 BP 13 EP 13 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV9QL UT WOS:000364621600015 ER PT J AU Taraska, JW AF Taraska, Justin W. TI SIMply Better Resolution in Live Cells SO TRENDS IN CELL BIOLOGY LA English DT Editorial Material ID STRUCTURED-ILLUMINATION MICROSCOPY; FLUORESCENCE MICROSCOPY; EXCITATION MICROSCOPY; IMPROVEMENT C1 NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20824 USA. RP Taraska, JW (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, 50 South Dr,Bldg 50, Bethesda, MD 20824 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural NIH HHS [ZIA HL006098-05, Z99 HL999999] NR 10 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD NOV PY 2015 VL 25 IS 11 BP 636 EP 638 DI 10.1016/j.tcb.2015.09.007 PG 3 WC Cell Biology SC Cell Biology GA CV9LI UT WOS:000364608300003 PM 26458328 ER PT J AU Petrie, RJ Yamada, KM AF Petrie, Ryan J. Yamada, Kenneth M. TI Fibroblasts Lead the Way: A Unified View of 3D Cell Motility SO TRENDS IN CELL BIOLOGY LA English DT Review ID INTERMEDIATE-FILAMENTS; MIGRATING CELLS; FORCE TRANSMISSION; ADHESION DYNAMICS; STRESS FIBERS; LIVING CELLS; MYOSIN IIB; MATRIX; CONTRACTILITY; ACTIVATION AB Primary human fibroblasts are remarkably adaptable, able to migrate in differing types of physiological 3D tissue and on rigid 2D tissue culture surfaces. The crawling behavior of these and other vertebrate cells has been studied intensively, which has helped generate the concept of the cell motility cycle as a comprehensive model of 2D cell migration. However, this model fails to explain how cells force their large nuclei through the confines of a 3D matrix environment and why primary fibroblasts can use more than one mechanism to move in 3D. Recent work shows that the intracellular localization of myosin II activity is governed by cell-matrix interactions to both force the nucleus through the extracellular matrix (ECM) and dictate the type of protrusions used to migrate in 3D. C1 [Petrie, Ryan J.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Petrie, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM petrier@mail.nih.gov; kyamada@mail.nlh.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (NIH, NIDCR) FX We thank C. Parent, A. Doyle, W. Daley, and M. Hague for their critical comments and suggestions on the manuscript. Work in the authors' laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (NIH, NIDCR). NR 69 TC 8 Z9 8 U1 5 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD NOV PY 2015 VL 25 IS 11 BP 666 EP 674 DI 10.1016/j.tcb.2015.07.013 PG 9 WC Cell Biology SC Cell Biology GA CV9LI UT WOS:000364608300006 PM 26437597 ER PT J AU Traslavina, RP Reilly, CM Vasireddy, R Samitz, EM Stepnik, CT Outerbridge, C Affolter, VK Byrne, BA Lowenstine, LJ White, SD Murphy, B AF Traslavina, R. P. Reilly, C. M. Vasireddy, R. Samitz, E. M. Stepnik, C. T. Outerbridge, C. Affolter, V. K. Byrne, B. A. Lowenstine, L. J. White, S. D. Murphy, B. TI Laser Capture Microdissection of Feline Streptomyces spp Pyogranulomatous Dermatitis and Cellulitis SO VETERINARY PATHOLOGY LA English DT Article DE cats; Streptomyces; Actinomycetales; dermatitis; cellulitis; laser capture microdissection; mycetoma ID ACTINOMYCOTIC MYCETOMA AB Suspected Streptomyces spp infections were identified in 4 cats at UC Davis Veterinary Medical Teaching Hospital between 1982 and 2011. Three had ulcerated, dark red mycetomas involving the dermis, subcutis, and fascia with fistulous tracts and/or regional lymphadenopathy. One cat had pyogranulomatous mesenteric lymphadenitis. Granulomatous inflammation in all cats contained colonies of Gram-positive, non-acid-fast organisms. All 4 cats failed to respond to aggressive medical and surgical treatment and were euthanized. Laser capture microdissection (LCM) was used to selectively harvest DNA from the affected formalin-fixed, paraffin-embedded (FFPE) tissues. Cloned amplicons from LCM-derived tissue confirmed the presence of Streptomyces spp in the dermatitis cases. Amplicons from the remaining cat with peritoneal involvement aligned with the 16S ribosomal RNA gene for Actinomycetales. Usually considered a contaminant, Streptomyces spp can be associated with refractory pyogranulomatous dermatitis and cellulitis in cats with outdoor access. LCM is useful in the diagnosis of bacterial diseases where contamination may be an issue. C1 [Traslavina, R. P.; Reilly, C. M.; Samitz, E. M.; Stepnik, C. T.; Outerbridge, C.; Affolter, V. K.; Byrne, B. A.; Lowenstine, L. J.; White, S. D.; Murphy, B.] Univ Calif Davis, Sch Vet Med, Davis, CA 95616 USA. [Traslavina, R. P.] NINDS, NIH, Sect Infect Nervous Syst, Bethesda, MD 20892 USA. [Vasireddy, R.] Univ Texas Tyler, Hlth Sci Ctr, Tyler, TX 75799 USA. RP Traslavina, RP (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 7C120, Bethesda, MD 20892 USA. EM ryan.traslavina@nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD NOV PY 2015 VL 52 IS 6 BP 1172 EP 1175 DI 10.1177/0300985814561094 PG 4 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA CW1FF UT WOS:000364734300025 PM 25516065 ER PT J AU Zablotska, LB Nadyrov, EA Polyanskaya, ON McConnell, RJ O'Kane, P Lubin, J Hatch, M Little, MP Brenner, AV Veyalkin, IV Yauseyenka, VV Bouville, A Drozdovitch, VV Minenko, VF Demidchik, YE Mabuchi, K Rozhko, AV AF Zablotska, Lydia B. Nadyrov, Eldar A. Polyanskaya, Olga N. McConnell, Robert J. O'Kane, Patrick Lubin, Jay Hatch, Maureen Little, Mark P. Brenner, Alina V. Veyalkin, Ilya V. Yauseyenka, Vasilina V. Bouville, Andre Drozdovitch, Vladimir V. Minenko, Viktor F. Demidchik, Yuri E. Mabuchi, Kiyohiko Rozhko, Alexander V. TI Risk of Thyroid Follicular Adenoma Among Children and Adolescents in Belarus Exposed to Iodine-131 After the Chornobyl Accident SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenoma; Chornobyl nuclear accident; dose-response relationship; interaction; iodine deficiency; iodine radioisotopes; radiation; thyroid neoplasms ID DOSE-RESPONSE RELATIONSHIPS; POOLED ANALYSIS; CANCER; RADIATION; CHILDHOOD; DISEASES; NODULES; COHORT; GUIDELINES; NEOPLASIA AB Several studies reported an increased risk of thyroid cancer in children and adolescents exposed to radioactive iodines, chiefly iodine-131 (I-131), after the 1986 Chornobyl (Ukrainian spelling) nuclear power plant accident. The risk of benign thyroid tumors following such radiation exposure is much less well known. We have previously reported a novel finding of significantly increased risk of thyroid follicular adenoma in a screening study of children and adolescents exposed to the Chornobyl fallout in Ukraine. To verify this finding, we analyzed baseline screening data from a cohort of 11,613 individuals aged <= 18 years at the time of the accident in Belarus (mean age at screening = 21 years). All participants had individual I-131 doses estimated from thyroid radioactivity measurements and were screened according to a standardized protocol. We found a significant linear dose response for 38 pathologically confirmed follicular adenoma cases. The excess odds ratio per gray of 2.22 (95% confidence interval: 0.41, 13.1) was similar in males and females but decreased significantly with increasing age at exposure (P < 0.01), with the highest radiation risks estimated for those exposed at < 2 years of age. Follicular adenoma radiation risks were not significantly modified by most indicators of past and current iodine deficiency. The present study confirms the I-131-associated increases in risk of follicular adenoma in the Ukrainian population and adds new evidence on the risk increasing with decreasing age at exposure. C1 [Zablotska, Lydia B.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Nadyrov, Eldar A.; Polyanskaya, Olga N.; Veyalkin, Ilya V.; Yauseyenka, Vasilina V.; Rozhko, Alexander V.] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [McConnell, Robert J.] Columbia Univ, Thyroid Ctr, New York, NY USA. [O'Kane, Patrick] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Lubin, Jay; Hatch, Maureen; Little, Mark P.; Brenner, Alina V.; Bouville, Andre; Drozdovitch, Vladimir V.; Mabuchi, Kiyohiko] NCI, Radiat Oncol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Minenko, Viktor F.] Res Inst Nucl Problems, Minsk, Byelarus. [Demidchik, Yuri E.] NN Alexandrov Natl Canc Ctr, Minsk, Byelarus. RP Zablotska, LB (reprint author), Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, 3333 Calif St,Suite 280, San Francisco, CA 94118 USA. EM Lydia.Zablotska@ucsf.edu OI Little, Mark/0000-0003-0980-7567 FU National Cancer Institute [CA132918]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; US Department of Energy; Nuclear Regulatory Commission; [NO1-CP-21178] FX Funding for this study was provided by the National Cancer Institute (grant CA132918 to L.B.Z.; contract NO1-CP-21178 with L.B.Z., R.J.M., and P.O.; and funds from the Intramural Research Program of the Division of Cancer Epidemiology and Genetics to J.L., M.H., M.P.L., A.V.B., A.B., V.V.D., and K.M.). The US Department of Energy provided funding at the earlier stages of the study, and the Nuclear Regulatory Commission provided the initial funds for purchase of equipment. NR 38 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 1 PY 2015 VL 182 IS 9 BP 781 EP 790 DI 10.1093/aje/kwv127 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CV0IX UT WOS:000363935500010 PM 26443421 ER PT J AU Schinzari, F Iantorno, M Campia, U Mores, N Rovella, V Tesauro, M Di Daniele, N Cardillo, C AF Schinzari, Francesca Iantorno, Micaela Campia, Umberto Mores, Nadia Rovella, Valentina Tesauro, Manfredi Di Daniele, Nicola Cardillo, Carmine TI Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE obesity; endothelium; endothelin-1; metabolic syndrome; vasodilation ID CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; DIABETES-MELLITUS; SYSTEM ACTIVITY; RISK; DYSFUNCTION; HYPERINSULINEMIA; ATHEROSCLEROSIS; METAANALYSIS; OVERWEIGHT AB Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS. C1 [Schinzari, Francesca; Cardillo, Carmine] Univ Cattolica Sacro Cuore, Sch Med, Dept Internal Med, Rome, Italy. [Iantorno, Micaela] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Iantorno, Micaela] Johns Hopkins Univ Hosp, Dept Med, Baltimore, MD 21287 USA. [Campia, Umberto] MedStar Cardiovasc Res Network, Washington, DC USA. [Mores, Nadia] Univ Cattolica Sacro Cuore, Sch Med, Dept Pharmacol, Rome, Italy. [Rovella, Valentina; Tesauro, Manfredi; Di Daniele, Nicola] Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy. RP Cardillo, C (reprint author), Univ Cattolica Sacro Cuore, Ist Patol Speciale Med & Semeiot Med, Largo Gemelli 8, I-00168 Rome, Italy. EM carmine.cardillo@rm.unicatt.it OI Cardillo, Carmine/0000-0001-5182-3005 FU Fondi d'Ateneo grants from Catholic University; Italian Ministry of Health (Ministero della Salute) grant [RF-2010-2313809] FX This work was partially supported by Fondi d'Ateneo grants from Catholic University and from an Italian Ministry of Health (Ministero della Salute) grant (RF-2010-2313809) to C. Cardillo. NR 33 TC 7 Z9 7 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD NOV 1 PY 2015 VL 309 IS 9 BP E787 EP E792 DI 10.1152/ajpendo.00278.2015 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA CV2CU UT WOS:000364065300003 PM 26374766 ER PT J AU Varga, ZV Ferdinandy, P Liaudet, L Pacher, P AF Varga, Zoltan V. Ferdinandy, Peter Liaudet, Lucas Pacher, Pal TI Drug-induced mitochondrial dysfunction and cardiotoxicity SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Review DE heart; heart failure; cardiomyopathy; toxicology; drug development; reactive oxygen species ID DOXORUBICIN-INDUCED CARDIOTOXICITY; INDUCED CARDIAC DYSFUNCTION; MANGANESE SUPEROXIDE-DISMUTASE; MYOFIBRILLAR CREATINE-KINASE; LEFT-VENTRICULAR DYSFUNCTION; PROTEIN-TYROSINE NITRATION; METASTATIC BREAST-CANCER; HEART-FAILURE; OXIDATIVE STRESS; CELL-DEATH AB Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Gyorgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities. C1 [Varga, Zoltan V.; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA. [Varga, Zoltan V.; Ferdinandy, Peter] Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, Cardiometab Res Grp, H-1085 Budapest, Hungary. [Ferdinandy, Peter] Pharmahungary Grp, Szeged, Hungary. [Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. RP Pacher, P (reprint author), Lab Cardiovasc Physiol & Tissue Injury, 5625 Fishers Lane,Rm 2N-17, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Liaudet, Lucas/E-1322-2017 OI Liaudet, Lucas/0000-0003-2670-4930 FU Intramural Research Program of the of National Institutes of Health/NIAAA; Rosztoczy Foundation FX This study was supported by the Intramural Research Program of the of National Institutes of Health/NIAAA (to P. Pacher). Z. V. Varga was supported by the Rosztoczy Foundation. NR 177 TC 24 Z9 26 U1 5 U2 42 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD NOV 1 PY 2015 VL 309 IS 9 BP H1453 EP H1467 DI 10.1152/ajpheart.00554.2015 PG 15 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA CV2NH UT WOS:000364092900007 PM 26386112 ER PT J AU Rauhauser, AA Ren, CY Lu, DM Li, BH Zhu, JL McEnery, K Vadnagara, K Zepeda-Orozco, D Zhou, XJ Lin, FM Jetten, AM Attanasio, M AF Rauhauser, Alysha A. Ren, Chongyu Lu, Dongmei Li, Binghua Zhu, Jili McEnery, Kayla Vadnagara, Komal Zepeda-Orozco, Diana Zhou, Xin J. Lin, Fangming Jetten, Anton M. Attanasio, Massimo TI Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE hedgehog signaling; kidney injury; UUO ID NG2 PROTEOGLYCAN; SONIC HEDGEHOG; GROWTH-FACTOR; FIBROSIS; MACROPHAGES; ACTIVATION; REPAIR; PROLIFERATION; FIBROBLASTS; PERICYTES AB Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular beta-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes. C1 [Rauhauser, Alysha A.; Ren, Chongyu; Lu, Dongmei; Li, Binghua; Zhu, Jili; McEnery, Kayla; Vadnagara, Komal; Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Zhu, Jili] Wuhan Univ, Dept Nephrol, Wuhan 430072, Hubei, Peoples R China. [Zepeda-Orozco, Diana] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Zhou, Xin J.] Baylor Univ, Med Ctr, Pathologist BioMed Labs, Renal Path Diagnost, Dallas, TX USA. [Zhou, Xin J.] Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX USA. [Lin, Fangming] Columbia Univ, Dept Pediat Pathol & Cell Biol, New York, NY USA. [Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Growth & Dev, Dallas, TX 75390 USA. RP Attanasio, M (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM massimo.attanasio@utsouthwestern.edu OI Jetten, Anton/0000-0003-0954-4445 FU National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK090326-01A1]; Satellite Healthcare Norman Coplon Extramural Research Award; American Society of Nephrology Norman Siegel Research Scholar Grant FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant 1R01DK090326-01A1, a Satellite Healthcare Norman Coplon Extramural Research Award, and an American Society of Nephrology Norman Siegel Research Scholar Grant. NR 27 TC 4 Z9 4 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD NOV 1 PY 2015 VL 309 IS 9 BP F770 EP F778 DI 10.1152/ajprenal.00232.2015 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA CV2QO UT WOS:000364101600003 PM 26290370 ER PT J AU Stein, MB Kessler, RC Heeringa, SG Jain, S Campbell-Sills, L Colpe, LJ Fullerton, CS Nock, MK Sampson, NA Schoenbaum, M Sun, XY Thomas, ML Ursano, RJ AF Stein, Murray B. Kessler, Ronald C. Heeringa, Steven G. Jain, Sonia Campbell-Sills, Laura Colpe, Lisa J. Fullerton, Carol S. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Sun, Xiaoying Thomas, Michael L. Ursano, Robert J. CA Army STARRS Collaborators TI Prospective Longitudinal Evaluation of the Effect of Deployment-Acquired Traumatic Brain Injury on Posttraumatic Stress and Related Disorders: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MILITARY PERSONNEL; CLINICAL PRESENTATION; MENTAL-HEALTH; SUICIDE RISK; SYMPTOMS; PTSD; DEPRESSION; ASSOCIATION; IRAQ; TBI AB Objective: Traumatic brain injury (TBI) is increasingly recognized as a risk factor for deleterious mental health and functional outcomes. The purpose of this study was to examine the strength and specificity of the association between deployment-acquired TBI and subsequent posttraumatic stress and related disorders among U.S. Army personnel. Method: A prospective, longitudinal survey of soldiers in three Brigade CombatTeams was conducted 1-2 months prior to an average 10-month deployment to Afghanistan (T0), upon redeployment to the United States (T1), approximately 3 months later (T2), and approximately 9 months later (T3). Outcomes of interest were 30-day prevalence. postdeployment of posttraumatic stress disorder (PTSD), major depressive episode, generalized anxiety disorder, and suicidality, as well as presence and severity of postdeployment PTSD symptoms. Results: Complete information was available for 4,645 soldiers. Approximately one in five soldiers reported exposure to mild (18.0%) or more-than-mild (1.2%) TBI(s) during the index deployment. Even after adjusting for other risk factors (e g., predeployment mental health status, severity of deployment stress, prior TBI history), deployment-acquired TBI was associated with elevated adjusted odds of PTSD and generalized anxiety disorder at T2 and T3 and of major depressive episode at T2. Suicidality risk at T2 appeared similarly elevated, but this association did not reach statistical significance. Conclusions: The findings highlight the importance of surveillance efforts to identify soldiers who have sustained TBIs and are therefore at risk for an array of postdeployment adverse mental health outcomes, including but not limited to PTSD. The mechanism(s) accounting for these associations need to be elucidated to inform development of effective preventive and early intervention programs. C1 [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. VA San Diego Healthcare Syst, San Diego, CA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Univ Michigan, Inst Social Res, Ann Arbor, MI USA. NIMH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. Harvard Univ, Dept Psychol, Cambridge, MA USA. RP Stein, MB (reprint author), Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. EM mstein@ucsd.edu FU Department of the Army [U01MH087981]; U S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). NR 40 TC 10 Z9 10 U1 4 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2015 VL 172 IS 11 BP 1101 EP 1111 DI 10.1176/appi.ajp.2015.14121572 PG 11 WC Psychiatry SC Psychiatry GA CV0CJ UT WOS:000363914700013 PM 26337036 ER PT J AU Kunii, Y Zhang, WY Xu, Q Hyde, TM McFadden, W Shin, JH Deep-Soboslay, A Ye, TZ Li, C Kleinman, JE Wang, KH Lipska, BK AF Kunii, Yasuto Zhang, Wenyu Xu, Qing Hyde, Thomas M. McFadden, Whitney Shin, Joo Heon Deep-Soboslay, Amy Ye, Tianzhang Li, Chao Kleinman, Joel E. Wang, Kuan Hong Lipska, Barbara K. TI CHRNA7 and CHRFAM7A mRNAs: Co-Localized and Their Expression Levels Altered in the Postmortem Dorsolateral Prefrontal Cortex in Major Psychiatric Disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RECEPTOR SUBUNIT GENE; NICOTINIC ACETYLCHOLINE-RECEPTORS; BIPOLAR DISORDER; BINDING-SITES; DEPRESSIVE DISORDER; PARTIAL DUPLICATION; ALPHA-BUNGAROTOXIN; FRONTAL-CORTEX; MOUSE-BRAIN; RAT-BRAIN AB Objective: CHRNA7, coding alpha-7 nicotinic acetylcholine receptor (alpha 7 nAChR), is involved in cognition through interneuron modulation of dopamine and glutamate signaling. CHRNA7 and its partially duplicated chimeric gene CHRFAM7A have been implicated in schizophrenia through linkage and association studies. Method: Expression of CHRNA7 and CHRFAM7A mRNA was measured in the postmortem prefrontal cortex in more than 700 subjects, including patients with schizophrenia, bipolar disorder, major depression, and normal comparison subjects. The effects of antipsychotics and nicotine, as well as associations of CHRNA7 SNPs with gene expression, were explored. Fluorescent in-situ hybridization was used to examine coexpression of both transcripts in the human cortex. Results: CHRFAM7A expression and CHRFAM7A/CHRNA7 ratios were higher in fetal compared with postnatal life, whereas CHRNA7 expression was relatively stable. CHRFAM7A expression was significantly elevated in all diagnostic groups, while CHRNA7 expression was reduced in the schizophrenia group and increased in the major depression group compared with the comparison group. CHRFAM7A/CHRNA7 ratios were significantly increased in the schizophrenia and bipolar disorder groups compared with the comparison group There was no effect of nicotine or antipsychotics and no association of SNPs in CHRNA7 with expression. CHRNA7 and CHRFAM7A mRNAs were expressed in the same neuronal nuclei of the human neocortex. Conclusions: These data show preferential fetal CHRFAM7A expression in the human prefrontal cortex and suggest abnormalities in the CHRFAM7A/CHRNA7 ratios in schizophrenia and bipolar disorder, due mainly to overexpression of CHRFAM7A. Given that these transcripts are coexpressed in a subset of human cortical neurons and can interact to alter function of nAChRs, these results support the concept of aberrant function of nAChRs in mental illness. C1 [Lipska, Barbara K.] NIMH, Human Brain Collect Core, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. Fukushima Med Univ, Sch Med, Dept Neuropsychiat, Fukushima, Fukushima, Japan. NIMH, Unit Neural Circuits & Adapt Behav, NIH, Bethesda, MD 20892 USA. Lieber Inst Brain Dev, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Lipska, BK (reprint author), NIMH, Human Brain Collect Core, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM lipskab@mail.nih.gov RI Wang, Kuan Hong/J-1150-2016; Lipska, Barbara/E-4569-2017 OI Wang, Kuan Hong/0000-0002-2249-5417; FU Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health FX Supported by the Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health. NR 45 TC 3 Z9 3 U1 1 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2015 VL 172 IS 11 BP 1122 EP 1130 DI 10.1176/appi.ajp.2015.14080978 PG 9 WC Psychiatry SC Psychiatry GA CV0CJ UT WOS:000363914700015 PM 26206074 ER PT J AU Schaffer, A Isometsa, ET Azorin, JM Cassidy, F Goldstein, T Rihmer, Z Sinyor, M Tondo, L Moreno, DH Turecki, G Reis, C Kessing, LV Ha, K Weizman, A Beautrais, A Chou, YH Diazgranados, N Levitt, AJ Zarate, CA Yatham, L AF Schaffer, Ayal Isometsa, Erkki T. Azorin, Jean-Michel Cassidy, Frederick Goldstein, Tina Rihmer, Zoltan Sinyor, Mark Tondo, Leonardo Moreno, Doris H. Turecki, Gustavo Reis, Catherine Kessing, Lars Vedel Ha, Kyooseob Weizman, Abraham Beautrais, Annette Chou, Yuan-Hwa Diazgranados, Nancy Levitt, Anthony J. Zarate, Carlos A., Jr. Yatham, Lakshmi TI A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Review DE Bipolar disorder; suicide; suicide attempts ID MAJOR AFFECTIVE-DISORDER; NATIONAL EPIDEMIOLOGIC SURVEY; COMORBID ANXIETY DISORDERS; SUBSTANCE USE DISORDERS; ALCOHOL-USE DISORDERS; AGE-OF-ONSET; RISK-FACTORS; FAMILY-HISTORY; CLINICAL CHARACTERISTICS; PREDOMINANT POLARITY AB Objectives: Many factors influence the likelihood of suicide attempts or deaths in persons with bipolar disorder. One key aim of the International Society for Bipolar Disorders Task Force on Suicide was to summarize the available literature on the presence and magnitude of effect of these factors. Methods: A systematic review of studies published from 1 January 1980 to 30 May 2014 identified using keywords bipolar disorder' and suicide attempts or suicide'. This specific paper examined all reports on factors putatively associated with suicide attempts or suicide deaths in bipolar disorder samples. Factors were subcategorized into: (1) sociodemographics, (2) clinical characteristics of bipolar disorder, (3) comorbidities, and (4) other clinical variables. Results: We identified 141 studies that examined how 20 specific factors influenced the likelihood of suicide attempts or deaths. While the level of evidence and degree of confluence varied across factors, there was at least one study that found an effect for each of the following factors: sex, age, race, marital status, religious affiliation, age of illness onset, duration of illness, bipolar disorder subtype, polarity of first episode, polarity of current/recent episode, predominant polarity, mood episode characteristics, psychosis, psychiatric comorbidity, personality characteristics, sexual dysfunction, first-degree family history of suicide or mood disorders, past suicide attempts, early life trauma, and psychosocial precipitants. Conclusion: There is a wealth of data on factors that influence the likelihood of suicide attempts and suicide deaths in people with bipolar disorder. Given the heterogeneity of study samples and designs, further research is needed to replicate and determine the magnitude of effect of most of these factors. This approach can ultimately lead to enhanced risk stratification for patients with bipolar disorder. C1 [Schaffer, Ayal] ISBD, Task Force Suicide, Pittsburgh, PA USA. [Schaffer, Ayal; Reis, Catherine] Sunnybrook Hlth Sci Ctr, Dept Psychiat, Mood & Anxiety Disorders Program, Toronto, ON M4N 3M5, Canada. [Schaffer, Ayal; Sinyor, Mark; Levitt, Anthony J.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Isometsa, Erkki T.] Univ Helsinki, Inst Clin Med, Dept Psychiat, Helsinki, Finland. [Azorin, Jean-Michel] St Marguerite Hosp, Dept Adult Psychiat, Marseille, France. [Azorin, Jean-Michel] Univ Aix Marseille 2, F-13284 Marseille 07, France. [Cassidy, Frederick] Duke Univ, Dept Psychiat & Behav Sci, Div Brain Stimulat & Neurophysiol, Durham, NC USA. [Goldstein, Tina] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Child & Adolescent Psychiat, Pittsburgh, PA USA. [Rihmer, Zoltan] Semmelweis Univ, Dept Clin & Theoret Mental Hlth, Budapest, Hungary. [Rihmer, Zoltan] Semmelweis Univ, Dept Psychiat & Psychotherapy, Budapest, Hungary. [Sinyor, Mark; Levitt, Anthony J.] Sunnybrook Hlth Sci Ctr, Dept Psychiat, Toronto, ON M4N 3M5, Canada. [Tondo, Leonardo] Lucio Bini Ctr, Cagliari, Italy. [Tondo, Leonardo] Harvard Univ, Sch Med, Boston, MA USA. [Tondo, Leonardo] McLean Hosp, Belmont, MA 02178 USA. [Moreno, Doris H.] Univ Sao Paulo, Dept & Inst Psychiat, Sect Psychiat Epidemiol, Sao Paulo, Brazil. [Moreno, Doris H.] Univ Sao Paulo, Dept & Inst Psychiat, Mood Disorders Unit, Sao Paulo, Brazil. [Turecki, Gustavo] McGill Univ, Dept Psychiat, Res & Acad Affairs, Montreal, PQ, Canada. [Turecki, Gustavo] McGill Grp Suicide Studies, Montreal, PQ, Canada. [Turecki, Gustavo] Douglas Inst, Depress Disorders Program, Montreal, PQ, Canada. [Turecki, Gustavo] McGill Univ, Dept Psychiat, Dept Human Genet, Montreal, PQ, Canada. [Turecki, Gustavo] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Kessing, Lars Vedel] Univ Copenhagen, Fac Hlth Sci, Psychiat Ctr Copenhagen, Copenhagen, Denmark. [Ha, Kyooseob] Seoul Natl Univ, Bundang Hosp, Mood Disorders Clin & Affect Neurosci Lab, Songnam, South Korea. [Ha, Kyooseob] Korea Assoc Suicide Prevent, Seoul, South Korea. [Weizman, Abraham] Felsenstein Med Res Ctr, Lab Biol Psychiat, Petah Tiqwa, Israel. [Weizman, Abraham] Geha Mental Hlth Ctr, Res Unit, Petah Tiqwa, Israel. [Weizman, Abraham] Tel Aviv Univ, Sackler Fac Med, Dept Psychiat, IL-69978 Tel Aviv, Israel. [Beautrais, Annette] Yale Univ, Yale Sch Med, Dept Emergency Med, New Haven, CT USA. [Chou, Yuan-Hwa] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Dept Psychiat, Sect Psychosomat Med, Taipei 112, Taiwan. [Diazgranados, Nancy] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Yatham, Lakshmi] Univ British Columbia, Dept Psychiat, Vancouver, BC V5Z 1M9, Canada. RP Schaffer, A (reprint author), Sunnybrook Hlth Sci Ctr, Dept Psychiat, Mood & Anxiety Disorders Program, 2075 Bayview Ave,Room FG 52, Toronto, ON M4N 3M5, Canada. EM ayal.schaffer@sunnybrook.ca FU Brenda Smith Bipolar Disorder Research Fund, Sunnybrook Health Sciences Centre, University of Toronto FX Partial support for this project was provided by the Brenda Smith Bipolar Disorder Research Fund, Sunnybrook Health Sciences Centre, University of Toronto. NR 156 TC 6 Z9 6 U1 7 U2 21 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0004-8674 EI 1440-1614 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD NOV PY 2015 VL 49 IS 11 SI SI BP 1006 EP 1020 DI 10.1177/0004867415594428 PG 15 WC Psychiatry SC Psychiatry GA CV0UV UT WOS:000363970000010 PM 26175498 ER PT J AU Pfefferkorn, CM Walker, RL He, Y Gruschus, JM Lee, JC AF Pfefferkorn, Candace M. Walker, Robert L., III He, Yi Gruschus, James M. Lee, Jennifer C. TI Tryptophan probes reveal residue-specific phospholipid interactions of apolipoprotein C-III SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Fluorescence; Circular dichroism; Penetration depth; Protein-lipid interaction ID LIPOPROTEIN-LIPASE ACTIVITY; LIPID-PROTEIN INTERACTIONS; CARDIOVASCULAR RISK-FACTOR; MEMBRANE-PROTEIN; PLASMA-LIPOPROTEINS; AMPHIPATHIC HELIX; PARTICLE-SIZE; FLUORESCENCE; DEPTH; DISPLACEMENT AB Apolipoproteins are essential human proteins for lipid metabolism. Together with phospholipids, they constitute lipoproteins, nm to pm sized particles responsible for transporting cholesterol and triglycerides throughout the body. To investigate specific protein-lipid interactions, we produced and characterized three single-Trp containing apolipoprotein (ApoCIII) variants (W42 (W54F/W65F), W54 (W42F/W65F), W65 (W42F/W54F)). Upon binding to phospholipid vesicles, wild-type ApoCIII adopts an a-helical conformation (50% helicity) as determined by circular dichroism spectroscopy with an approximate apparent partition constant of 3 x 10(4) M-1 Steady-state and time-resolved fluorescence measurements reveal distinct residue-specific behaviors with W54 experiencing the most hydrophobic environment followed by W42 and W65. Interestingly, time-resolved anisotropy measurements show a converse trend for relative Trp mobility with position 54 being the least immobile. To determine the relative insertion depths of W42, W54, and W65 in the bilayer, fluorescence quenching experiments were performed using three different brominated lipids. W65 had a clear preference for residing near the headgroup while W54 and W42 sample the range of depths similar to 8-11 angstrom from the bilayer center. On average, W54 is slightly more embedded than W42. Based on Trp spectral differences between ApoCIII binding to phospholipid vesicles and sodium dodecyl sulfate micelles, we suggest that ApoCIII adopts an alternate helical conformation on the bilayer which could have functional implications. Published by Elsevier B.V. C1 [Pfefferkorn, Candace M.; Walker, Robert L., III; Gruschus, James M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [He, Yi] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program at the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) FX This work is supported by the Intramural Research Program at the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). DLS and CD measurements were performed using instruments in the NHLBI Biophysics Core Facility. We thank Duck-Yeon Lee (Biochemistry Core Facility, NHLBI) for the technical assistance with mass spectrometry. NR 47 TC 1 Z9 1 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD NOV PY 2015 VL 1848 IS 11 BP 2821 EP 2828 DI 10.1016/j.bbamem.2015.08.018 PN A PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CV4XW UT WOS:000364270800007 PM 26301570 ER PT J AU Joo, HS Otto, M AF Joo, Hwang-Soo Otto, Michael TI Mechanisms of resistance to antimicrobial peptides in staphylococci SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Staphylococcus aureus; Staphylococcus epidermidis; Antimicrobial peptides; Bacterial resistance ID WALL TEICHOIC-ACID; GRAM-POSITIVE BACTERIA; PHENOL-SOLUBLE MODULINS; POLYSACCHARIDE INTERCELLULAR ADHESIN; VANCOMYCIN-INTERMEDIATE RESISTANCE; 2-COMPONENT REGULATORY SYSTEM; ALANYL-LIPOTEICHOIC ACID; VRAFG ABC TRANSPORTER; PSEUDOMONAS-AERUGINOSA; BIOFILM FORMATION AB Staphylococci are commensal bacteria living on the epithelial surfaces of humans and other mammals. Many staphylococci, including the dangerous pathogen Staphylococcus aureus, can cause severe disease when they breach the epithelial barrier. Both during their commensal life and during infection, staphylococci need to evade mechanisms of innate host defense, of which antimicrobial peptides (AMPs) play a key role in particular on the skin. Mechanisms that staphylococci have developed to evade the bactericidal activity of AMPs are manifold, comprising repulsion of AMPs via alteration of cell wall and membrane surface charges, proteolytic inactivation, sequestration, and secretion. Furthermore, many staphylococci form biofilms, which represents an additional way of protection from antimicrobial agents, including AMPs. Finally, staphylococci can sense the presence of AMPs by sensor/regulator systems that control many of those resistance mechanisms. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. Published by Elsevier B.V. C1 [Joo, Hwang-Soo; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, US Natl Inst Hlth,NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), 9000 Rockville Pike,Bldg 33 1W10A, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115; JOO, HWANG-SOO/0000-0003-4668-3225 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) [ZIA AI000904-14] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), grant ZIA AI000904-14. NR 104 TC 10 Z9 10 U1 6 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 EI 0006-3002 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD NOV PY 2015 VL 1848 IS 11 SI SI BP 3055 EP 3061 DI 10.1016/j.bbamem.2015.02.009 PN B PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CV4XX UT WOS:000364270900006 PM 25701233 ER PT J AU Saunders, EFH Reider, A Singh, G Gelenberg, AJ Rapoport, SI AF Saunders, Erika F. H. Reider, Aubrey Singh, Gagan Gelenberg, Alan J. Rapoport, Stanley I. TI Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; eicosapentaenoic acid; inflammation; omega-3 ID POLYUNSATURATED FATTY-ACIDS; PLACEBO-CONTROLLED TRIAL; TASK-FORCE REPORT; OPEN-LABEL TRIAL; DOUBLE-BLIND; N-3 PUFA; DOCOSAHEXAENOIC ACID; CLINICAL-TRIAL; INTERNATIONAL-SOCIETY; BRAIN PHOSPHOLIPIDS AB ObjectivesOmega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. MethodsThis observational, parallel group study compared biomarkers between HCs (n=31) and symptomatic subjects with BD (n=27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. ResultsUE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d=0.86, p<0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p<0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p<0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p<0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. ConclusionsA large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake. C1 [Saunders, Erika F. H.; Reider, Aubrey; Singh, Gagan; Gelenberg, Alan J.] Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Dept Psychiat, Hershey, PA 17033 USA. [Saunders, Erika F. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Saunders, Erika F. H.] Univ Michigan, Depress Ctr, Ann Arbor, MI 48109 USA. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. RP Saunders, EFH (reprint author), Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Dept Psychiat, 500 Univ Dr,POB 850 Mail Code HO73, Hershey, PA 17033 USA. EM esaunders@hmc.psu.edu FU National Center for Research Resources [KL2 RR033180]; National Center for Advancing Translational Sciences [KL2 TR000126]; Intramural Program of the National Institute on Aging, NIH FX The authors wish to acknowledge the participants in the study who donated time and effort to research. The project described was supported by the National Center for Research Resources, Grant KL2 RR033180 (EFHS), now the National Center for Advancing Translational Sciences, Grant KL2 TR000126. We thank Mr. Kaizong Ma at the Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health (NIH) for performing the plasma fatty acid analyses. The contributions of Kaizong Ma and SIR were supported entirely by the Intramural Program of the National Institute on Aging, NIH. SIR has no conflict of interest with regard to this paper. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The sponsors of this research did not have direct influence over the collection, analysis or interpretation of data. NR 103 TC 6 Z9 6 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD NOV PY 2015 VL 17 IS 7 BP 729 EP 742 DI 10.1111/bdi.12337 PG 14 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CU9UD UT WOS:000363890100004 PM 26424416 ER PT J AU Morken, NH Skjaerven, R Wilcox, AJ AF Morken, N-H Skjaerven, R. Wilcox, A. J. TI Ultrasound prediction of perinatal outcome: the unrecognised value of sibling data SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Fetal size; perinatal mortality; prediction; small for gestational age; ultrasound ID LAST MENSTRUAL PERIOD; LOW-BIRTH-WEIGHT; GESTATIONAL-AGE; BIPARIETAL DIAMETER; EARLY-PREGNANCY; INCREASED RISK; NORWAY; DELIVERY; BIOMETRY; GROWTH AB ObjectiveTo identify high-risk fetuses at the first routinely performed ultrasound examination by making use of information from the mother's previous pregnancy. DesignA population-based cohort study. SettingNorway, 1999-2009. PopulationAll singleton first live births and their second-born siblings registered in the Medical Birth Registry of Norway (166786 eligible sibling pairs). MethodsOdds ratios were calculated by logistic regression. Main outcome measuresVery small for gestational age (vSGA; birthweight -1.96 standard deviations) and perinatal death (stillbirth at 22weeks of gestation or death within 28days of life). ResultsSmall fetal size at ultrasound (i.e. a fetus smaller than expected by last menstrual period, LMP) is only weakly predictive of vSGA or perinatal death; however, if the firstborn sibling was vSGA at birth, ultrasound measures in the next pregnancy become strongly informative of risk. The smaller the fetal size on ultrasound, the higher its risk of vSGA (3-18%; P-trend<0.0001) and perinatal death (4-19 per thousand, P-trend=0.012). In contrast, if the first baby was not vSGA, small fetal size on ultrasound is uninformative. ConclusionsWhen the firstborn baby is vSGA, discrepancies between fetal size on ultrasound and LMP become highly predictive of risk of vSGA and perinatal mortality in the second-born infant. The value of combining these routinelycollected clinical data has not previously been recognised. C1 [Morken, N-H; Skjaerven, R.] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5018 Bergen, Norway. [Morken, N-H] Univ Bergen, Dept Clin Sci, N-5018 Bergen, Norway. [Skjaerven, R.] Norwegian Inst Publ Hlth, Bergen, Norway. [Wilcox, A. J.] NIEHS, Epidemiol Branch, NIH, Durham, NC USA. RP Morken, NH (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Kalfarveien 31, N-5018 Bergen, Norway. EM nils-halvdan.morken@kk.uib.no OI Wilcox, Allen/0000-0002-3376-1311 FU University of Bergen; Unger-Vetlesen Medical Foundation FX NHM was funded with grants from the University of Bergen and the Unger-Vetlesen Medical Foundation. The funding organisation had no influence on planning or performing the project, interpretation of data, or preparation of the article. NR 23 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD NOV PY 2015 VL 122 IS 12 BP 1674 EP 1681 DI 10.1111/1471-0528.13022 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CU7NY UT WOS:000363729300048 PM 25135694 ER PT J AU Pillai, VC Han, KL Beigi, RH Hankins, GD Clark, S Hebert, MF Easterling, TR Zajicek, A Ren, ZX Caritis, SN Venkataramanan, R AF Pillai, Venkateswaran C. Han, Kelong Beigi, Richard H. Hankins, Gary D. Clark, Shannon Hebert, Mary F. Easterling, Thomas R. Zajicek, Anne Ren, Zhaoxia Caritis, Steve N. Venkataramanan, Raman TI Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE oseltamivir; population pharmacokinetics; pregnancy ID VIRUS-INFECTION; RO 64-0802; INFLUENZA; H1N1; INFANTS; DEATHS; DRUG AB AimsPhysiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. MethodsA multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. ResultsThe systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P<0.001) in pregnant women. Pregnancy significantly (P<0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. ConclusionBased on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women. C1 [Pillai, Venkateswaran C.; Venkataramanan, Raman] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Han, Kelong] Genentech Inc, Clin Pharmacol, San Francisco, CA USA. [Beigi, Richard H.; Caritis, Steve N.] Univ Pittsburgh, Med Ctr, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. [Hankins, Gary D.; Clark, Shannon] Univ Texas Med Branch, Dept Obstet & Gynecol, Austin, TX USA. [Hebert, Mary F.; Easterling, Thomas R.] Univ Washington, Dept Pharm & Obstet & Gynecol, Seattle, WA 98195 USA. [Zajicek, Anne; Ren, Zhaoxia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Obstet & Pediat Pharmacol & Therapeut Branch, Bethesda, MD USA. RP Venkataramanan, R (reprint author), Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, 718 Salk Hall,3501 Terrace St, Pittsburgh, PA 15261 USA. EM rv@pitt.edu FU Obstetric Pharmacology Research Unit Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [5U10 HD 047905, U10 HD047892, 3U10 HD047891-05S2] FX This work is funded by grants (5U10 HD 047905, U10 HD047892 and 3U10 HD047891-05S2) from Obstetric Pharmacology Research Unit Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). We acknowledge the clinical staff (Donna Deangetlis and Dawn Fisher from University of Pittsburgh Medical Center, Holly West from University of Texas Medical Branch, Claudine Hernandez and Karen Hays from University of Washington) who helped for study conduct/data collection for this research. The study team also acknowledges Roche Pharmaceuticals for the logistic support for bio-analysis of oseltamivir and oseltamivir carboxylate. NR 27 TC 1 Z9 1 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0306-5251 EI 1365-2125 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD NOV PY 2015 VL 80 IS 5 BP 1042 EP 1050 DI 10.1111/bcp.12691 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU9UF UT WOS:000363890400013 PM 26040405 ER PT J AU Ayanwuyi, LO Stopponi, S Ubaldi, M Cippitelli, A Nasuti, C Damadzic, R Heilig, M Schank, J Cheng, KJ Rice, KC Ciccocioppo, R AF Ayanwuyi, Lydia O. Stopponi, Serena Ubaldi, Massimo Cippitelli, Andrea Nasuti, Cinzia Damadzic, Ruslan Heilig, Markus Schank, Jesse Cheng, Kejun Rice, Kenner C. Ciccocioppo, Roberto TI Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; CENTRAL-NERVOUS-SYSTEM; SUBSTANCE-P RECEPTOR; PREFERRING MSP RATS; NORADRENERGIC MECHANISMS; VOLUNTARY CONSUMPTION; SEEKING BEHAVIOR; ADDICTION FOCUS; NK-1 RECEPTOR; NK1 RECEPTOR AB Background and PurposeSubstance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse. Experimental ApproachThe effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. Key ResultsSystemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism. C1 [Ayanwuyi, Lydia O.; Stopponi, Serena; Ubaldi, Massimo; Cippitelli, Andrea; Nasuti, Cinzia; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, MC, Italy. [Damadzic, Ruslan; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Schank, Jesse] Univ Georgia, Coll Vet Med, Dept Physiol & Pharmacol, Athens, GA 30602 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Ciccocioppo, R (reprint author), Univ Camerino, Sch Pharm, Pharmacol Unit, Via Madonna Carceri 9, I-62032 Camerino, MC, Italy. EM roberto.ciccocioppo@unicam.it RI nasuti, cinzia/F-5212-2011; OI nasuti, cinzia/0000-0002-4470-7345; Ubaldi, Massimo/0000-0002-4089-2483 FU NIH [AA014351, AA017447]; NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute of Alcohol Abuse and Alcoholism FX This study was supported by NIH grants nos. AA014351 and AA017447. A portion of this work was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism. We are thankful to Alfredo Fiorelli for technical support as well as Rina Righi and Mariangela Fiorelli for animal care. NR 62 TC 1 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD NOV PY 2015 VL 172 IS 21 BP 5136 EP 5146 DI 10.1111/bph.13280 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU9XS UT WOS:000363900900009 PM 26275374 ER PT J AU Wei, GS Coady, SA Reis, JP Carnethon, MR Coresh, J D'Agostino, RB Goff, DC Jacobs, DR Selvin, E Fox, CS AF Wei, Gina S. Coady, Sean A. Reis, Jared P. Carnethon, Mercedes R. Coresh, Josef D'Agostino, Ralph B., Sr. Goff, David C., Jr. Jacobs, David R., Jr. Selvin, Elizabeth Fox, Caroline S. TI Duration and Degree of Weight Gain and Incident Diabetes in Younger Versus Middle-Aged Black and White Adults: ARIC, CARDIA, and the Framingham Heart Study SO DIABETES CARE LA English DT Article ID BODY-MASS INDEX; IMPAIRED GLUCOSE-TOLERANCE; ATHEROSCLEROSIS RISK; UNITED-STATES; INSULIN-RESISTANCE; AFRICAN-AMERICANS; OBESITY; MELLITUS; DISEASE; COMMUNITIES AB OBJECTIVE To determine whether duration and degree of weight gain are differentially associated with diabetes risk in younger versus middle-aged black and white adults. RESEARCH DESIGN AND METHODS We combined data from three cohort studies: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study. A total of 17,404 participants (56% women; 21% black) were stratified by baseline age (younger: >= 30 and <45 years; middle-aged: >= 45 and <60 years) and examined for incident diabetes (median follow-up 9 years). Duration and degree of gain in BMI were calculated as "BMI-years" above one's baseline BMI. RESULTS Diabetes incidence per 1,000 person-years in the younger and middle-aged groups was 7.2 (95% CI 5.7, 8.7) and 24.4 (22.0, 26.8) in blacks, respectively, and 3.4 (2.8, 4.0) and 10.5 (9.9, 11.2) in whites, respectively. After adjusting for sex, baseline BM I and other cardiometabolic factors, and age and race interaction terms, gains in BMI-years were associated with higher risk of diabetes in the younger compared with middle-aged groups: hazard ratios for 1-unit increase in log BMI-years in younger versus middle-aged blacks were 1.18 (P = 0.02) and 1.02 (P = 0.39), respectively (P for interaction by age-group = 0.047), and in whites were 1.35 (P < 0.001) and 1.11 (P < 0.001), respectively (P for interaction by age-group = 0.008). CONCLUSIONS Although middle-aged adults have higher rates of diabetes, younger adults are at greater relative risk of developing diabetes for a given level of duration and degree of weight gain. C1 [Wei, Gina S.; Coady, Sean A.; Reis, Jared P.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Coresh, Josef; Selvin, Elizabeth] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, Baltimore, MD USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Off Dean, Aurora, CO USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Wei, GS (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM weig@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NHLBI [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C, AG0005]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; Boston University [N01-HC-25195] FX The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). CARDIA is supported by NHLBI contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C; the Intramural Research Program of the National Institute on Aging (NIA); and an intra-agency agreement between the NIA and NHLBI (AG0005). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (contract N01-HC-25195). NR 34 TC 3 Z9 3 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2015 VL 38 IS 11 BP 2042 EP 2049 DI 10.2337/dc14-2770 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CV5WQ UT WOS:000364342500022 PM 26358286 ER PT J AU Esparza-Romero, J Valencia, ME Urquidez-Romero, R Chaudhari, LS Hanson, RL Knowler, WC Ravussin, E Bennett, PH Schulz, LO AF Esparza-Romero, Julian Valencia, Mauro E. Urquidez-Romero, Rene Chaudhari, Lisa S. Hanson, Robert L. Knowler, William C. Ravussin, Eric Bennett, Peter H. Schulz, Leslie O. TI Environmentally Driven Increases in Type 2 Diabetes and Obesity in Pima Indians and Non-Pimas in Mexico Over a 15-Year Period: The Maycoba Project SO DIABETES CARE LA English DT Article ID RISK-FACTORS; PHYSICAL-ACTIVITY; PREVALENCE; GLUCOSE AB OBJECTIVE The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle. RESEARCH DESIGN AND METHODS Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995. RESULTS During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women). CONCLUSIONS Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle. C1 [Esparza-Romero, Julian; Valencia, Mauro E.; Urquidez-Romero, Rene] Ctr Invest Alimentac & Desarrollo AC, Dept Nutr Publ & Salud, Coordinac Nutr, Hermosillo, Sonora, Mexico. [Chaudhari, Lisa S.; Schulz, Leslie O.] No Arizona Univ, Coll Hlth & Human Serv, Flagstaff, AZ 86011 USA. [Hanson, Robert L.; Knowler, William C.; Bennett, Peter H.] Natl Inst Diabet & Digest & Kidney Dis, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Schulz, LO (reprint author), No Arizona Univ, Coll Hlth & Human Serv, Flagstaff, AZ 86011 USA. EM rhanson@phx.niddk.nih.gov; leslie.schulz@nau.edu FU U.S. National Institutes of Health [1R01DK082568-01A1]; U.S. National Institute of Diabetes and Digestive and Kidney Diseases FX The Maycoba Project was funded by the U.S. National Institutes of Health (grant 1R01DK082568-01A1 to L.O.S.). The study was also supported in part by the intramural research program of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases. NR 21 TC 3 Z9 3 U1 2 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2015 VL 38 IS 11 BP 2075 EP 2082 DI 10.2337/dc15-0089 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CV5WQ UT WOS:000364342500026 PM 26246457 ER PT J AU Sharma, V Khurana, S Kubben, N Abdelmohsen, K Oberdoerffer, P Gorospe, M Misteli, T AF Sharma, Vivek Khurana, Simran Kubben, Nard Abdelmohsen, Kotb Oberdoerffer, Philipp Gorospe, Myriam Misteli, Tom TI A BRCA1-interacting lncRNA regulates homologous recombination SO EMBO REPORTS LA English DT Article DE BRCA1; hnRNPUL1; p53; RAP80; repair ID DNA-DAMAGE RESPONSE; LONG NONCODING RNA; DOUBLE-STRAND BREAKS; GENE-EXPRESSION; END RESECTION; CELL-CYCLE; REPAIR; P53; CHROMATIN; COMPLEX AB Long non-coding RNAs (lncRNAs) are important players in diverse biological processes. Upon DNA damage, cells activate a complex signaling cascade referred to as the DNA damage response (DDR). Using a microarray screen, we identify here a novel lncRNA, DDSR1 (DNA damage-sensitive RNA1), which is induced upon DNA damage. DDSR1 induction is triggered in an ATM-NF-B pathway-dependent manner by several DNA double-strand break (DSB) agents. Loss of DDSR1 impairs cell proliferation and DDR signaling and reduces DNA repair capacity by homologous recombination (HR). The HR defect in the absence of DDSR1 is marked by aberrant accumulation of BRCA1 and RAP80 at DSB sites. In line with a role in regulating HR, DDSR1 interacts with BRCA1 and hnRNPUL1, an RNA-binding protein involved in DNA end resection. Our results suggest a role for the lncRNA DDSR1 in modulating DNA repair by HR. C1 [Sharma, Vivek; Khurana, Simran; Kubben, Nard; Oberdoerffer, Philipp; Misteli, Tom] Natl Canc Inst, NIH, Bethesda, MD 20892 USA. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. RP Sharma, V (reprint author), Natl Canc Inst, NIH, Bethesda, MD 20892 USA. EM viveksharmabt@gmail.com; mistelit@mail.nih.gov FU Khorana Nirenberg Fellowship; Intramural Research Program of the National Institutes of Health (NIH); NIA; NCI Center for Cancer Research FX We thank David Sun, Xiaolin Wu, Li Jia, and Anand Merchant for Microarray experiments and analysis; Katherine McKinnon for help with FACS experiments; Tatiana Karpova (NCI Fluorescence Imaging Microscopy Facility) for help with microscopy; Murali Palangat for FISH imaging; Andy Tran for ssBrDU/cyclin A staining analysis; and Sudipto Das and Thorkell Anderson for help with mass spectrometry experiments. The authors would like to thank Misteli Lab members for helpful feedback and discussions. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NIA, NCI Center for Cancer Research, and by a Khorana Nirenberg Fellowship to VS. NR 57 TC 7 Z9 8 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD NOV PY 2015 VL 16 IS 11 BP 1520 EP 1534 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CV5NX UT WOS:000364318900016 PM 26412854 ER PT J AU Lhatoo, S Noebels, J Whittemore, V AF Lhatoo, Samden Noebels, Jeffrey Whittemore, Vicky CA NINDS Ctr SUDEP Res TI Sudden unexpected death in epilepsy: Identifying risk and preventing mortality SO EPILEPSIA LA English DT Article DE Cardiorespiratory; Autonomic dysfunction; Imaging; Genetics; Induced pluripotent stem cell; Neuropathology ID POSTICTAL EEG SUPPRESSION; TEMPORAL-LOBE EPILEPSY; UNEXPLAINED DEATH; RESPIRATORY DYSFUNCTION; CONVULSIVE SEIZURES; SUDEP; MECHANISMS; PATIENT; NEURONS; PATHWAY AB Premature death among individuals with epilepsy is higher than in the general population, and sudden unexpected death is the most common cause of this mortality. A new multisite collaborative research consortium, the Center for sudden unexpected death in epilepsy (SUDEP) Research (CSR), has received major funding from the National Institutes of Health (NIH) to examine the possible biologic mechanisms underlying this potentially preventable comorbidity and develop predictive biomarkers for interventions that could lower SUDEP incidence. This inaugural report describes the structure of the CSR, its priorities for human and experimental research, and the strategic collaborations and advanced tools under development to reduce this catastrophic outcome of epilepsy. The CSR Partners Program will work closely with committed volunteer agencies, industry, and academic institutions to accelerate and communicate these advances to the professional and lay community. C1 [Lhatoo, Samden] Case Western Reserve Univ, Neurol, Cleveland, OH 44106 USA. [Noebels, Jeffrey] Baylor Coll Med, Neurol, Houston, TX 77030 USA. [Whittemore, Vicky] NINDS, Epilepsy Channels, Synapses & Circuits, NIH, Rockville, MD USA. RP Noebels, J (reprint author), Baylor Coll Med, Neurol, Houston, TX 77030 USA. EM jnoebels@bcm.edu OI Noebels, Jeffrey /0000-0002-2887-0839 FU NINDS [U01-NS090407, U01-NS090408, U01-NS090415, U01-NS090364, U01-NS090340, U01-NS090406, U01-NS090362, U01-NS090414, U01-NS090405] FX The Center for SUDEP Research is supported by NINDS grants U01-NS090407, U01-NS090408, U01-NS090415, U01-NS090364, U01-NS090340, U01-NS090406, U01-NS090362, U01-NS090414, and U01-NS090405. NR 45 TC 7 Z9 7 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD NOV PY 2015 VL 56 IS 11 BP 1700 EP 1706 DI 10.1111/epi.13134 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CU9RZ UT WOS:000363884100011 PM 26494436 ER PT J AU Lemire, M Qu, CH Loo, LWM Zaidi, SHE Wang, H Berndt, SI Bezieau, S Brenner, H Campbell, PT Chan, AT Chang-Claude, J Du, MM Edlund, CK Gallinger, S Haile, RW Harrison, TA Hoffmeister, M Hopper, JL Hou, LF Hsu, L Jacobs, EJ Jenkins, MA Jeon, J Kury, S Li, L Lindor, NM Newcomb, PA Potter, JD Rennert, G Rudolph, A Schoen, RE Schumacher, FR Seminara, D Severi, G Slattery, ML White, E Woods, MO Cotterchio, M Le Marchand, L Casey, G Gruber, SB Peters, U Hudson, TJ AF Lemire, Mathieu Qu, Conghui Loo, Lenora W. M. Zaidi, Syed H. E. Wang, Hansong Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Campbell, Peter T. Chan, Andrew T. Chang-Claude, Jenny Du, Mengmeng Edlund, Christopher K. Gallinger, Steven Haile, Robert W. Harrison, Tabitha A. Hoffmeister, Michael Hopper, John L. Hou, Lifang Hsu, Li Jacobs, Eric J. Jenkins, Mark A. Jeon, Jihyoun Kuery, Sebastien Li, Li Lindor, Noralane M. Newcomb, Polly A. Potter, John D. Rennert, Gad Rudolph, Anja Schoen, Robert E. Schumacher, Fredrick R. Seminara, Daniela Severi, Gianluca Slattery, Martha L. White, Emily Woods, Michael O. Cotterchio, Michelle Le Marchand, Loic Casey, Graham Gruber, Stephen B. Peters, Ulrike Hudson, Thomas J. TI A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1 SO HUMAN GENETICS LA English DT Article ID SOCIETY-TASK-FORCE; SUSCEPTIBILITY LOCI; ER STRESS; METAANALYSIS; TUMORS; CELLS; SCAN; SURVEILLANCE; VARIANTS; 8Q24 AB Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 x 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 x 10(-8)). C1 [Lemire, Mathieu; Zaidi, Syed H. E.; Hudson, Thomas J.] Ontario Inst Canc Res, MaRS Ctr, Toronto, ON M5G 0A3, Canada. [Qu, Conghui; Harrison, Tabitha A.; Hsu, Li; Jeon, Jihyoun; Newcomb, Polly A.; Potter, John D.; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Loo, Lenora W. M.; Wang, Hansong; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Berndt, Sonja I.] NCI, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Bezieau, Stephane; Kuery, Sebastien] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France. [Bezieau, Stephane] Univ Nantes, Fac Med, EA 4273, Nantes, France. [Brenner, Hermann; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Campbell, Peter T.; Jacobs, Eric J.] Amer Canc Soc, Atlanta, GA 30329 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Unit Genet Epidemiol, Heidelberg, Germany. [Edlund, Christopher K.; Schumacher, Fredrick R.; Casey, Graham; Gruber, Stephen B.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Gallinger, Steven] Samuel Lunenfeld Res Inst, Toronto, ON M5S 1X5, Canada. [Gallinger, Steven] Toronto Gen Hosp, Div Gen Surg, Toronto, ON M5G 2C4, Canada. Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA. Univ Melbourne, Ctr Biostat & Epidemiol, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Evanston, IL USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Evanston, IL USA. [Hsu, Li] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, Li] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Li, Li] Case Western Reserve Univ, Swetland Ctr Environm Hlth, Cleveland, OH 44106 USA. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Newcomb, Polly A.; Potter, John D.; White, Emily] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] Natl Canc Control Ctr, Clalit Hlth Serv, Haifa, Israel. [Rennert, Gad] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Severi, Gianluca] Human Genet Fdn HuGeF, Turin, Italy. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Woods, Michael O.] Mem Univ Newfoundland, Discipline Genet, St John, NF A1B 3V6, Canada. [Cotterchio, Michelle] Univ Toronto, Canc Care Ontario, Toronto, ON, Canada. [Gruber, Stephen B.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Med, Los Angeles, CA USA. [Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. RP Lemire, M (reprint author), Ontario Inst Canc Res, MaRS Ctr, 661 Univ Ave,Suite 510, Toronto, ON M5G 0A3, Canada. EM mathieu.lemire@oicr.on.ca; cqu@fredhutch.org; lloo@cc.hawaii.edu; hassan.zaidi@oicr.on.ca; hwang@cc.hawaii.edu; berndts@mail.nih.gov; stephane.bezieau@univ-nantes.fr; h.brenner@dkfz.de; Peter.Campbell@cancer.org; achan@mgh.harvard.edu; j.chang-claude@dkfz.de; mdu@fredhutch.org; cedlund@usc.edu; Steven.Gallinger@uhn.on.ca; rhaile@stanford.edu; tharriso@fredhutch.org; m.hoffmeister@dkfz.de; j.hopper@unimelb.edu.au; l-hou@northwestern.edu; lih@fredhutch.org; Eric.Jacobs@cancer.org; m.jenkins@unimelb.edu.au; jhjeon@fredhutch.org; sebastien.kury@chu-nantes.fr; lxl62@cwru.edu; nlindor@mayo.edu; pnewcomb@fredhutch.org; jpotter@fredhutch.org; rennert@tx.technion.ac.il; a.rudolph@dkfz.de; rschoen@pitt.edu; fschumac@usc.edu; seminard@mail.nih.gov; Gianluca.Severi@cancervic.org.au; marty.slattery@hsc.utah.edu; ewhite@fredhutch.org; mwoods@mun.ca; michelle.cotterchio@cancercare.on.ca; loic@cc.hawaii.edu; gcasey@usc.edu; sgruber@usc.edu; upeters@fredhutch.org; tom.hudson@oicr.on.ca RI Jenkins, Mark/P-7803-2015; KURY, Sebastien/G-5971-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; OI Jenkins, Mark/0000-0002-8964-6160; KURY, Sebastien/0000-0001-5497-0465; Brenner, Hermann/0000-0002-6129-1572; Potter, John/0000-0001-5439-1500; Hoffmeister, Michael/0000-0002-8307-3197 FU American Cancer Society (ACS); Centers for Disease Control and Prevention National Program of Cancer Registries; National Cancer Institute Surveillance Epidemiology and End Results program FX CANCER PREVENTION STUDY II: CPS-II is supported by the American Cancer Society (ACS). We would like to thank the CPS-II participants and the CPS-II Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. NR 37 TC 5 Z9 5 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD NOV PY 2015 VL 134 IS 11-12 BP 1249 EP 1262 DI 10.1007/s00439-015-1598-6 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CV0VZ UT WOS:000363973000008 PM 26404086 ER PT J AU Lu, JH Sun, PD AF Lu, Jinghua Sun, Peter D. TI Structural mechanism of high affinity FcRI recognition of immunoglobulin G SO IMMUNOLOGICAL REVIEWS LA English DT Review DE CD64; antibody recognition; high affinity Fc gamma receptor; FcgammaRI-Fc complex structure; glycan recognition by Fc receptor ID GAMMA RECEPTOR; HUMAN IGG1; CRYSTAL-STRUCTURE; THERAPEUTIC ANTIBODIES; EFFECTOR FUNCTIONS; BINDING; COMPLEX; FRAGMENT; CANCER; FUCOSE AB Antibody-based immunotherapies are becoming powerful means of modern medicine for treating cancers and autoimmune diseases. The increasing popularity of antibody-based treatment demands a better understanding of antibody functions and in particular, their interaction with Fc receptors as effectiveness of antibodies often depends on their ability to activate or avoid effector cell functions through Fc receptors. Until recently, our understanding of antibody recognition by Fc receptors is based on the structures of low affinity Fc receptor in complex with Fc. These structural studies provided significant insights to our understanding of how an IgG antibody generally docks on Fc receptor and the requirement of immune complex formation for effector cell activations. They are less informative, however, to the molecular forces underlying the vast different affinities between antibodies and their Fc receptors. Recently, the structure of the high affinity FcRI in complex with IgG-Fc has been determined. This review will focus on the knowledge learned from the high affinity complex structural work and a potential receptor-glycan interaction as an important contribution to the receptor affinity. C1 [Lu, Jinghua; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov FU Intramural Research program of National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors acknowledge no potential conflict of interest involved in this review article. The work was supported by the Intramural Research program of National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 41 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2015 VL 268 IS 1 SI SI BP 192 EP 200 DI 10.1111/imr.12346 PG 9 WC Immunology SC Immunology GA CU9TJ UT WOS:000363887900013 PM 26497521 ER PT J AU Leung, JM Olivier, KN Prevots, DR McDonnell, NB AF Leung, Janice M. Olivier, Kenneth N. Prevots, D. Rebecca McDonnell, Nazli B. TI Beyond Marfan: the clinical impact of bronchiectasis and non-tuberculous mycobacteria in connective tissue diseases SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Letter C1 [Leung, Janice M.] Univ British Columbia, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Olivier, Kenneth N.] NHLBI, Bethesda, MD 20892 USA. [Prevots, D. Rebecca] NIAID, Bethesda, MD 20892 USA. [McDonnell, Nazli B.] Eastern Colorado Hlth Syst, Vet Adm, Denver, CO 80220 USA. RP McDonnell, NB (reprint author), Eastern Colorado Hlth Syst, Vet Adm, Denver, CO 80220 USA. EM nazli.mcdonnell@va.gov FU Intramural NIH HHS NR 3 TC 1 Z9 1 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD NOV PY 2015 VL 19 IS 11 BP 1409 EP 1409 DI 10.5588/ijtld.15.0597 PG 1 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA CV4XQ UT WOS:000364270200025 PM 26467599 ER PT J AU Arango, CA Arias, AA Franco, JL Orrego, JC Rojas, JL Lopez, JA Patino, PJ Moncada-Velez, M Velez, GJ Grimbacher, B Woellner, C Danielian, S Rosenzweig, S Walter, JE Candotti, F Picard, C Bustamante, J Casanova, JL Germeshausen, M Hershfield, M Eraso, RM Sanchez, IP Trujillo-Vargas, CM Builes, LN Alvarez, JA AF Andres Arango, Carlos Augusto Arias, Andres Luis Franco, Jose Cesar Orrego, Julio Lineth Rojas, Jessica Alvaro Lopez, Juan Javier Patino, Pablo Moncada-Velez, Marcela Jaime Velez, Gabriel Grimbacher, Bodo Woellner, Cristina Danielian, Silvia Rosenzweig, Sergio Walter, Jolan E. Candotti, Fabio Picard, Capucine Bustamante, Jacinta Casanova, Jean Laurent Germeshausen, Manuela Hershfield, Michael Maria Eraso, Ruth Pilar Sanchez, Isaura Milena Trujillo-Vargas, Claudia Natalia Builes, Luz Armando Alvarez, Jesus TI Molecular Characterization of Genes Mutated in Patients with Primary Immunodeficiency Diseases (PIDS) at the Group of Primary Immunodeficiencies in Colombia 2015: An Update SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 4th Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY NOV 18-21, 2015 CL Buenos Aires, ARGENTINA SP Latin Amer Soc Immunodeficiencies C1 [Andres Arango, Carlos; Augusto Arias, Andres; Luis Franco, Jose; Cesar Orrego, Julio; Lineth Rojas, Jessica; Alvaro Lopez, Juan; Javier Patino, Pablo; Moncada-Velez, Marcela; Jaime Velez, Gabriel; Pilar Sanchez, Isaura; Milena Trujillo-Vargas, Claudia; Armando Alvarez, Jesus] Univ Antioquia, Fac Med, Grp Inmunodeficiencias Primarias, Medellin, Colombia. [Andres Arango, Carlos; Augusto Arias, Andres; Luis Franco, Jose; Cesar Orrego, Julio; Lineth Rojas, Jessica; Alvaro Lopez, Juan; Javier Patino, Pablo; Moncada-Velez, Marcela; Jaime Velez, Gabriel; Pilar Sanchez, Isaura; Milena Trujillo-Vargas, Claudia; Armando Alvarez, Jesus] Univ Antioquia, Fac Med, Jeffrey Modell Diagnost JMC & Res Ctr, Medellin, Colombia. [Andres Arango, Carlos; Augusto Arias, Andres; Alvaro Lopez, Juan] Univ Antioquia, Escuela Microbiol, Grp Invest Microbiol Basica & Aplicada MICROBA, Medellin, Colombia. [Grimbacher, Bodo; Woellner, Cristina] Univ Med Ctr, Ctr Chron Immunodeficiency, Freiburg, Germany. [Danielian, Silvia] Hosp Pediat Pr Juan P Garrahan, Mol Biol Lab, Buenos Aires, DF, Argentina. [Rosenzweig, Sergio] NIH, Serv Immunol, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Rosenzweig, Sergio] NIAID, Primary Immunodeficiency Clin, NIH, Bethesda, MD 20892 USA. [Walter, Jolan E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Allergy, Pediat Immunodeficiency Program, Boston, MA 02114 USA. [Candotti, Fabio] NHGRI, NIH, Bethesda, MD 20892 USA. [Candotti, Fabio] Univ Lausanne Hosp, Div Immunol & Allergy, CH-1011 Lausanne, Switzerland. [Picard, Capucine; Bustamante, Jacinta; Casanova, Jean Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Picard, Capucine; Bustamante, Jacinta; Casanova, Jean Laurent] Howard Hughes Med Inst, New York, NY 10065 USA. [Picard, Capucine; Bustamante, Jacinta; Casanova, Jean Laurent] Necker Hosp Sick Children, Lab Human Genet Infect Dis, INSERM, Necker Branch,U980, F-75015 Paris, France. [Picard, Capucine; Bustamante, Jacinta; Casanova, Jean Laurent] Paris Descartes Univ, Imagine Inst, F-75015 Paris, France. [Germeshausen, Manuela] Hannover Med Sch, Dept Pediat Hematol & Oncol, Hannover, Germany. [Hershfield, Michael] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27706 USA. [Maria Eraso, Ruth] Hosp Pablo Tobon Uribe, Serv Reumatol Pediat, Medellin, Colombia. [Natalia Builes, Luz] Hosp Pablo Tobon Uribe, Dept Pediat, Medellin, Colombia. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 SU 1 MA PL052 BP S23 EP S23 PG 1 WC Immunology SC Immunology GA CV0XR UT WOS:000363977700049 ER PT J AU Cabanillas, D Ninomiya, M Garcia, M Sosa, F Blanco, J Perez, L Marciano, BE Rosenzweig, S Regairaz, L AF Cabanillas, Diana Ninomiya, Mariel Garcia, Mariel Sosa, Fernanda Blanco, Jorgelina Perez, Laura Marciano, Beatriz E. Rosenzweig, Sergio Regairaz, Lorena TI Granulocytes Transfusions as Salvage Therapy in 2 Patients with Congenital Defects of Phagocyte and Invasive Fungal Infection SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 4th Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY NOV 18-21, 2015 CL Buenos Aires, ARGENTINA SP Latin Amer Soc Immunodeficiencies C1 [Cabanillas, Diana; Regairaz, Lorena] Hosp Ninos Sor Maria Ludovica, Unidad Inmunol, La Plata, Buenos Aires, Argentina. [Ninomiya, Mariel] Hosp Ninos Sor Maria Ludovica, Serv Hemoterapia, La Plata, Buenos Aires, Argentina. [Garcia, Mariel; Sosa, Fernanda] Hosp Ninos Sor Maria Ludovica, Serv Infectol, La Plata, Buenos Aires, Argentina. [Blanco, Jorgelina] Hosp Ninos Sor Maria Ludovica, Serv Neumonol, La Plata, Buenos Aires, Argentina. [Perez, Laura] Hosp Pediat Juan P Garrahan, Lab Inmunol Humoral, Buenos Aires, DF, Argentina. [Marciano, Beatriz E.] NIAID, Lab Clin Infect Dis, NIH, College Pk, MD USA. [Rosenzweig, Sergio] NIH, Serv Immunol, Ctr Clin, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 SU 1 MA PL122 BP S54 EP S55 PG 2 WC Immunology SC Immunology GA CV0XR UT WOS:000363977700116 ER PT J AU Nievas, E Rosenzweig, S Bernasconi, A Mannino, L Dominguez, N Ranea, G Fernandez, MM Stoddard, J Niemela, J AF Nievas, Elma Rosenzweig, Sergio Bernasconi, Andrea Mannino, Leonardo Dominguez, Nancy Ranea, Gabriela Marta Fernandez, Maria Stoddard, Jennifer Niemela, Julie TI Recurrent and Severe Herpes Simplex Virus (HSV) Infection as the Only Manifestation in a Patient with Tyk2 Deficiency (Tyk2D) SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 4th Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY NOV 18-21, 2015 CL Buenos Aires, ARGENTINA SP Latin Amer Soc Immunodeficiencies C1 [Nievas, Elma] Pediat Hosp A Fleming OSEP, Immunoligy Unit, Mendoza, Argentina. [Rosenzweig, Sergio] NIAID, Primary Immunodeficiency Clin, NIH, Bethesda, MD 20892 USA. [Bernasconi, Andrea] Garrahan Hosp, Immunol & Reumatol Serv, Buenos Aires, DF, Argentina. [Mannino, Leonardo] Pediat Hosp A Fleming OSEP, Infectol Unit, Mendoza, Argentina. [Dominguez, Nancy; Ranea, Gabriela; Marta Fernandez, Maria] Pediat Hosp A Fleming OSEP, Pediat Unit, Mendoza, Argentina. [Stoddard, Jennifer; Niemela, Julie] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 SU 1 MA PL037 BP S15 EP S16 PG 2 WC Immunology SC Immunology GA CV0XR UT WOS:000363977700034 ER PT J AU Vargas-Hernandez, A Mace, EM Freemabn, AF Rosenzweig, S Chinn, IK Holland, SM Orange, JS Forbes, LR AF Vargas-Hernandez, Alexander Mace, Emily M. Freemabn, Alexandra F. Rosenzweig, Sergio Chinn, Ivan K. Holland, Steve M. Orange, Jordan S. Forbes, Lisa R. TI Immature NK Cells with Impaired IL-15 Response in Patients with STAT1-GOF Mutations SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 4th Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY NOV 18-21, 2015 CL Buenos Aires, ARGENTINA SP Latin Amer Soc Immunodeficiencies C1 [Vargas-Hernandez, Alexander; Mace, Emily M.; Chinn, Ivan K.; Orange, Jordan S.; Forbes, Lisa R.] Baylor Coll Med, Houston, TX 77030 USA. [Vargas-Hernandez, Alexander; Mace, Emily M.; Chinn, Ivan K.; Orange, Jordan S.; Forbes, Lisa R.] Texas Childrens Hosp, Ctr Human Immunobiol, Dept Allergy Immunol & Rheumatol, Houston, TX 77030 USA. [Freemabn, Alexandra F.] NIAID, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio; Holland, Steve M.] NIH, Clin Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 SU 1 MA PL038 BP S16 EP S16 PG 1 WC Immunology SC Immunology GA CV0XR UT WOS:000363977700035 ER PT J AU Villa, M Rossi, J Bernasconi, A Rosenzweig, S Stoddard, J Niemela, J Galeano, A Daniela, F Merhar, C Lampugnani, A Oleastro, M AF Villa, Mariana Rossi, Jorge Bernasconi, Andrea Rosenzweig, Sergio Stoddard, Jennifer Niemela, Julie Galeano, Adriana Daniela, Fortunati Merhar, Claudia Lampugnani, Alejandra Oleastro, Matias TI Central Nervous System (CNS) HHV-6 Infection in an Unusual Severe Combined Immunodeficiency (SCID): ZAP 70 Deficiency SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 4th Meeting of the Latin-American-Society-for-Immunodeficiencies (LASID) CY NOV 18-21, 2015 CL Buenos Aires, ARGENTINA SP Latin Amer Soc Immunodeficiencies C1 [Villa, Mariana; Rossi, Jorge; Bernasconi, Andrea; Daniela, Fortunati; Merhar, Claudia; Oleastro, Matias] Hosp Pediat Prof Dr Juan P Garrahan, Immunol & Rheumatol Unit, Bethesda, MD USA. [Rosenzweig, Sergio] NIH Clin Ctr, Serv Immunol, Bethesda, MD USA. [Stoddard, Jennifer; Niemela, Julie] NIH Clin Ctr, DNA Sequencing Lab, Dept Lab Med, Bethesda, MD USA. [Galeano, Adriana] FUNDALEU, Buenos Aires, DF, Argentina. [Lampugnani, Alejandra] Hosp Rawson, San Juan, Provincia De Sa, Argentina. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD NOV PY 2015 VL 35 SU 1 MA PL099 BP S44 EP S45 PG 2 WC Immunology SC Immunology GA CV0XR UT WOS:000363977700095 ER PT J AU Walter, JE Rosen, LB Csomos, K Rosenberg, JM Mathew, D Keszei, M Ujhazi, B Chen, K Lee, YN Tirosh, I Dobbs, K Al-Herz, W Cowan, MJ Puck, J Bleesing, JJ Grimley, MS Malech, H De Ravin, SS Gennery, AR Abraham, RS Joshi, AY Boyce, TG Butte, MJ Nadeau, KC Balboni, I Sullivan, KE Akhter, J Adeli, M El-Feky, RA El-Ghoneimy, DH Dbaibo, G Wakim, R Azzari, C Palma, P Cancrini, C Capuder, K Condino-Neto, A Costa-Carvalho, BT Oliveira, JB Roifman, C Buchbinder, D Kumanovics, A Franco, JL Niehues, T Schuetz, C Kuijpers, T Yee, C Chou, J Masaad, MJ Geha, R Uze, G Gelman, R Holland, SM Recher, M Utz, PJ Browne, SK Notarangelo, LD AF Walter, Jolan E. Rosen, Lindsey B. Csomos, Krisztian Rosenberg, Jacob M. Mathew, Divij Keszei, Marton Ujhazi, Boglarka Chen, Karin Lee, Yu Nee Tirosh, Irit Dobbs, Kerry Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer Bleesing, Jack J. Grimley, Michael S. Malech, Harry De Ravin, Suk See Gennery, Andrew R. Abraham, Roshini S. Joshi, Avni Y. Boyce, Thomas G. Butte, Manish J. Nadeau, Kari C. Balboni, Imelda Sullivan, Kathleen E. Akhter, Javeed Adeli, Mehdi El-Feky, Reem A. El-Ghoneimy, Dalia H. Dbaibo, Ghassan Wakim, Rima Azzari, Chiara Palma, Paolo Cancrini, Caterina Capuder, Kelly Condino-Neto, Antonio Costa-Carvalho, Beatriz T. Oliveira, Joao Bosco Roifman, Chaim Buchbinder, David Kumanovics, Attila Luis Franco, Jose Niehues, Tim Schuetz, Catharina Kuijpers, Taco Yee, Christina Chou, Janet Masaad, Michel J. Geha, Raif Uze, Gulbu Gelman, Rebecca Holland, Steven M. Recher, Mike Utz, Paul J. Browne, Sarah K. Notarangelo, Luigi D. TI Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC MUCOCUTANEOUS CANDIDIASIS; IMMUNOGLOBULIN-SECRETING CELLS; ACTIVATING GENE-1 DEFICIENCY; MYASTHENIA-GRAVIS PATIENTS; SYNDROME TYPE-I; OMENN-SYNDROME; AUTOIMMUNE-DISEASE; GRANULOMATOUS-DISEASE AB Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/ autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-alpha or anti-IFN-omega antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1(5723C/5723C) mice, Le which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations. C1 [Walter, Jolan E.; Csomos, Krisztian; Ujhazi, Boglarka] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA USA. [Walter, Jolan E.; Csomos, Krisztian; Ujhazi, Boglarka] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Walter, Jolan E.; Lee, Yu Nee; Dobbs, Kerry; Capuder, Kelly; Yee, Christina; Chou, Janet; Masaad, Michel J.; Geha, Raif; Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Rosen, Lindsey B.; Uze, Gulbu; Holland, Steven M.; Browne, Sarah K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rosenberg, Jacob M.; Utz, Paul J.] Stanford Univ, Dept Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA. [Mathew, Divij] Univ Colorado, Integrated Dept Immunol, Natl Jewish Hlth, Denver, CO 80202 USA. [Keszei, Marton] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Ujhazi, Boglarka] Univ Debrecen, Dept Biochem & Mol Biol, Debrecen, Hungary. [Chen, Karin] Univ Utah, Div Allergy Immunol & Rheumatol, Dept Pediat, Salt Lake City, UT USA. [Tirosh, Irit] Boston Childrens Hosp, Pediat Rheumatol, Boston, MA 02115 USA. [Al-Herz, Waleed] Kuwait Univ, Dept Pediat, Fac Med, Kuwait, Kuwait. [Cowan, Morton J.; Puck, Jennifer] UCSF Benioff Childrens Hosp, Pediat Allergy Immunol & Blood & MarrowTransplant, San Francisco, CA USA. [Bleesing, Jack J.; Grimley, Michael S.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immunodeficiency, Cincinnati, OH 45229 USA. [Malech, Harry; De Ravin, Suk See] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Gennery, Andrew R.] Newcastle Upon Tyne Hosp, Dept Pediat Immunol, Newcastle Upon Tyne, Tyne & Wear, England. [Gennery, Andrew R.] Newcastle Upon Tyne Hosp, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Abraham, Roshini S.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Joshi, Avni Y.] Mayo Clin, Div Pediat Allergy Immunol, Dept Pediat & Adolescent Med, Rochester, MN USA. [Boyce, Thomas G.] Mayo Clin, Div Pediat Infect Dis, Dept Pediat, Rochester, MN USA. [Butte, Manish J.; Nadeau, Kari C.; Balboni, Imelda] Stanford Univ, Dept Pediat, Div Allergy, Immunol,Rheumatol, Stanford, CA 94305 USA. [Sullivan, Kathleen E.] Childrens Hosp Philadelphia, Allergy & Immunol, Philadelphia, PA 19104 USA. [Akhter, Javeed] Advocate Childrens Hosp, Jeffrey Modell Fdn Immunol Referral Ctr, Oak Lawn, IL USA. [Adeli, Mehdi] Hamad Med Corp, Dept Pediat, Weill Cornell Med Coll, Doha, Qatar. [El-Feky, Reem A.; El-Ghoneimy, Dalia H.] Ain Shams Univ, Dept Pediat Allergy & Immunol, Childrens Hosp, Fac Med, Cairo, Egypt. [Dbaibo, Ghassan; Wakim, Rima] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut, Lebanon. [Azzari, Chiara] Anna Meyer Childrens Univ Hosp, Florence, Italy. [Palma, Paolo; Cancrini, Caterina] IRCCS Bambino Gasu Childrens Hosp, Univ Dept Paediat, Rome, Italy. [Condino-Neto, Antonio] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, Sao Paulo, Brazil. [Costa-Carvalho, Beatriz T.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Oliveira, Joao Bosco] Inst Med Integral, Recife, PE, Brazil. [Roifman, Chaim] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Buchbinder, David] UC Irvine, Pediat Hematol, CHOC Childrens Hosp, Orange, CA USA. [Kumanovics, Attila] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Luis Franco, Jose] Univ Antioquia, Grp Primary Immunodeficiencies, Dept Microbiol & Parasitol, Sch Med, Medellin, Colombia. [Niehues, Tim] Univ Dusseldorf, Ctr Child Hlth & Adolescence, Helios Klinikum Krefeld Acad Hosp, Dusseldorf, Germany. [Schuetz, Catharina] Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. [Kuijpers, Taco] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, NL-1105 AZ Amsterdam, Netherlands. [Gelman, Rebecca] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Recher, Mike] Univ Basel Hosp, Immunodeficiency Clin, Med Outpatient Unit, CH-4031 Basel, Switzerland. [Recher, Mike] Univ Basel Hosp, Immunodeficiency Lab, Dept Biomed, CH-4031 Basel, Switzerland. [Utz, Paul J.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Notarangelo, Luigi D.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Notarangelo, LD (reprint author), Boston Childrens Hosp, Div Immunol, Karp Res Bldg,Room 10217,One Blackfan Circle, Boston, MA 02115 USA. EM jewalter@mgh.harvard.edu; Luigi.Notarangelo@childrens.harvard.edu RI Notarangelo, Luigi/F-9718-2016; Keszei, Marton/F-3295-2014; OI Notarangelo, Luigi/0000-0002-8335-0262; Keszei, Marton/0000-0002-1158-2179; Adeli, Mehdi/0000-0002-3051-3080; Malech, Harry/0000-0001-5874-5775; Palma, Paolo/0000-0002-3066-4719; cancrini, caterina/0000-0001-8410-9617; Butte, Manish/0000-0002-4490-5595 FU NIAID, NIH [5R01AI100887, U54AI082973, 5K08AI103035, T32GM007365]; Manton Foundation; Jeffrey Modell Foundation; Intramural Research Program of the NIAID, NIH FX This work was partly supported by grants from the NIAID, NIH (5R01AI100887 and U54AI082973, to L.D. Notarangelo; 5K08AI103035, to J.E. Walter; and T32GM007365, to P.J. Utz); the Manton Foundation (to L.D. Notarangelo); and the Jeffrey Modell Foundation (to L.D. Notarangelo). This research was also supported in part by the Intramural Research Program of the NIAID, NIH (to L.B. Rosen, S.M. Holland, and S.K. Browne). We acknowledge Quan-Zhen Li and Jinchun Zhou of the Genomics and Microarray Core Facility at the University of Texas Southwestern Medical Center for autoantibody profiling using autoantigen microarrays. NR 68 TC 16 Z9 16 U1 3 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2015 VL 125 IS 11 BP 4135 EP 4148 DI 10.1172/JCI80477 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CV2TL UT WOS:000364110000017 PM 26457731 ER PT J AU Gao, QQ Wyatt, E Goldstein, JA LoPresti, P Castillo, LM Gazda, A Petrossian, N Earley, JU Hadhazy, M Barefield, DY Demonbreun, AR Bonnemann, C Wolf, M McNally, EM AF Gao, Quan Q. Wyatt, Eugene Goldstein, Jeff A. LoPresti, Peter Castillo, Lisa M. Gazda, Alec Petrossian, Natalie Earley, Judy U. Hadhazy, Michele Barefield, David Y. Demonbreun, Alexis R. Boennemann, Carsten Wolf, Matthew McNally, Elizabeth M. TI Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MURINE SKELETAL-MUSCLE; SARCOGLYCAN COMPLEX; GAMMA-SARCOGLYCAN; GLYCOPROTEIN COMPLEX; BETA-SARCOGLYCAN; DELTA-SARCOGLYCAN; GENE-EXPRESSION; DROSOPHILA; MUTATIONS; HEART AB Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein gamma-sarcoglycan is functional. We generated an internally truncated gamma-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of gamma-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking gamma-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human gamma-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in gamma-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with gamma-sarcoglycan gene mutations. C1 [Gao, Quan Q.] Univ Chicago, Comm Dev Regenerat & Stem Cell Biol, Chicago, IL 60637 USA. [Wyatt, Eugene; Castillo, Lisa M.; Earley, Judy U.; Hadhazy, Michele; Barefield, David Y.; Demonbreun, Alexis R.; McNally, Elizabeth M.] Northwestern Univ, Ctr Genet Med, Evanston, IL USA. [Goldstein, Jeff A.; LoPresti, Peter; Gazda, Alec; Petrossian, Natalie] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Boennemann, Carsten] NINDS, NIH, Bethesda, MD 20892 USA. [Wolf, Matthew] Duke Univ, Dept Med, Durham, NC USA. RP McNally, EM (reprint author), Northwestern Univ, Ctr Genet Med, 303 E Super St, Chicago, IL 60302 USA. EM elizabeth.mcnally@northwestern.edu FU NIH [R01HL61322, U54AR052646, R01HL116581] FX We thank the Kurt + Peter Foundation for facilitating these studies, and the patient and families for participation. We thank Jeff Chamberlain for providing the inducible MyoD construct. This work was supported by NIH R01HL61322 and U54AR052646 (to E.M. McNally), and NIH R01HL116581 (to M.J. Wolf). NR 57 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2015 VL 125 IS 11 BP 4186 EP 4195 DI 10.1172/JCI82768 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CV2TL UT WOS:000364110000021 PM 26457733 ER PT J AU Brehm, A Liu, Y Sheikh, A Marrero, B Omoyinmi, E Zhou, Q Montealegre, G Biancotto, A Reinhardt, A de Jesus, AA Pelletier, M Tsai, WXL Remmers, EF Kardava, L Hill, S Kim, H Lachmann, HJ Megarbane, A Chae, JJ Brady, J Castillo, RD Brown, D Casano, AV Gao, L Chapelle, D Huang, Y Stone, D Chen, YQ Sotzny, F Lee, CCR Kastner, DL Torrelo, A Zlotogorski, A Moir, S Gadina, M McCoy, P Wesley, R Rother, K Hildebrand, PW Brogan, P Kruger, E Aksentijevich, I Goldbach-Mansky, R AF Brehm, Anja Liu, Yin Sheikh, Afzal Marrero, Bernadette Omoyinmi, Ebun Zhou, Qing Montealegre, Gina Biancotto, Angelique Reinhardt, Adam de Jesus, Adriana Almeida Pelletier, Martin Tsai, Wanxia L. Remmers, Elaine F. Kardava, Lela Hill, Suvimol Kim, Hanna Lachmann, Helen J. Megarbane, Andre Chae, Jae Jin Brady, Jilian Castillo, Rhina D. Brown, Diane Vera Casano, Angel Gao, Ling Chapelle, Dawn Huang, Yan Stone, Deborah Chen, Yongqing Sotzny, Franziska Lee, Chyi-Chia Richard Kastner, Daniel L. Torrelo, Antonio Zlotogorski, Abraham Moir, Susan Gadina, Massimo McCoy, Phil Wesley, Robert Rother, Kristina Hildebrand, Peter W. Brogan, Paul Krueger, Elke Aksentijevich, Ivona Goldbach-Mansky, Raphaela TI Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID AUTOINFLAMMATORY DISEASES; DIGENIC INHERITANCE; IMMUNE-RESPONSES; 20S PROTEASOME; LINKED LMP; GENE; IMMUNOPROTEASOMES; LIPODYSTROPHY; MHC; EXPRESSION AB Autosomal recessive mutations in proteasome subunit beta 8 (PSMB8), which encodes the inducible proteasome subunit beta Si, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes alpha 7), PSMB4 (encodes beta 7) PSMB9 (encodes beta 1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. C1 [Brehm, Anja; Sotzny, Franziska; Krueger, Elke] Charite, Inst Biochem, D-13353 Berlin, Germany. [Liu, Yin; Sheikh, Afzal; Marrero, Bernadette; Montealegre, Gina; de Jesus, Adriana Almeida; Kim, Hanna; Chapelle, Dawn; Huang, Yan; Chen, Yongqing; Goldbach-Mansky, Raphaela] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Sheikh, Afzal; Zhou, Qing; Remmers, Elaine F.; Chae, Jae Jin; Brady, Jilian; Stone, Deborah; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Omoyinmi, Ebun; Brogan, Paul] UCL, Inst Child Hlth, London, England. [Omoyinmi, Ebun; Brogan, Paul] NHS Fdn Trust, Great Ormond St Hosp, London, England. [Biancotto, Angelique; McCoy, Phil] NHLBI, Ctr Human Immunol, NIH, Bethesda, MD 20892 USA. [Reinhardt, Adam] Childrens Hosp & Med Ctr, Omaha, NE USA. [Reinhardt, Adam] Univ Nebraska Med Ctr, Omaha, NE USA. [Pelletier, Martin] NIAMS, Autoimmun Branch, Bethesda, MD USA. [Tsai, Wanxia L.; Gadina, Massimo] NIAMS, Off Sci & Technol, Bethesda, MD USA. [Kardava, Lela; Moir, Susan] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Hill, Suvimol] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lachmann, Helen J.] UCL, Sch Med, Natl Amyloidosis Ctr, London W1N 8AA, England. [Megarbane, Andre] St Joseph Univ, Med Genet Unit, Beirut, Lebanon. [Megarbane, Andre] Inst Jerome Lejeune, Paris, France. [Castillo, Rhina D.; Brown, Diane] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Castillo, Rhina D.; Brown, Diane] Univ So Calif, Los Angeles, CA USA. [Vera Casano, Angel] Hosp Carlos Haya, Malaga, Andalusia, Spain. [Gao, Ling] Univ Arkansas Med Sci, Coll Med, Little Rock, AR 72205 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Torrelo, Antonio] Hosp Nino Jesus, Pediat Dermatol, Madrid, Spain. [Zlotogorski, Abraham] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Wesley, Robert] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, Bethesda, MD USA. [Rother, Kristina] NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Hildebrand, Peter W.] Charite, Inst Med Phys & Biophys, D-10117 Berlin, Germany. RP Goldbach-Mansky, R (reprint author), NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bldg 10,Room 6D47B,10 Ctr Dr, Bethesda, MD 20892 USA. EM elke.krueger@charite.de; goldbacr@mail.nih.gov RI Yu, Xiaomin/I-6407-2016; Kruger, Elke/B-1462-2012; OI Kruger, Elke/0000-0002-2551-242X; Kim, Hanna/0000-0002-0595-6533 FU Intramural Research Program of NIAMS at the NIH; Berlin Institute of Health; Deutsche Forschungsgemeinschaft [SFB TR 43, SFB740] FX The authors would like to thank the following colleagues for their help: Christina Zaal and Evelyn Ralston for microscopy images, Hong-Wei Sun and Stephen Brooks for gene-expression analysis, Nigel Klein for proteolytic functional work on patients 4 and 5, Clarissa Pilkington for clinical recruitment of patients 6 and 7, Mirna Hashem Medly, Elon Pras for the Palestinian control samples, Nicole Plass and Michelle O'Brien for patient care, and Daniela Ludwig for technical help on siRNA experiments. This research was supported by the Intramural Research Program of NIAMS at the NIH, by the Berlin Institute of Health, and by the Deutsche Forschungsgemeinschaft (SFB TR 43 to E. Kruger, SFB740 to E. Kruger and P.W. Hildebrand). NR 46 TC 22 Z9 25 U1 3 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2015 VL 125 IS 11 BP 4196 EP 4211 DI 10.1172/JCI81260 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CV2TL UT WOS:000364110000022 PM 26524591 ER PT J AU Grady, PA Gough, LL AF Grady, Patricia A. Gough, Lisa Lucio TI Nursing Science: Claiming the Future SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE History/trends; other ID SELF-MANAGEMENT INTERVENTION; IRRITABLE-BOWEL-SYNDROME; NATIONAL INSTITUTE; AFRICAN-AMERICAN; EMERGING AREAS; LATINO PARENTS; IDEA FESTIVAL; PROGRAM; PREVENTION; EDUCATION AB PurposeThe National Institute of Nursing Research (NINR) is dedicated to improving health and health care through the funding of nursing science and research training. With a focus on guiding the nation's nursing science research agenda and improving quality of life, the NINR is ideally positioned to meet current healthcare challenges and anticipate future challenges and priorities. In this article, coinciding with the NINR's 30th anniversary, examples of NINR-supported research are described, along with its training activities designed to develop a strong cadre of 21st century nurse scientists. In addition, we discuss priorities and future directions for advancing cutting-edge nursing science to claim the future and improve the health of the nation over the next 30 years and beyond. C1 [Grady, Patricia A.; Gough, Lisa Lucio] NINR, NIH, Bethesda, MD 20817 USA. RP Gough, LL (reprint author), NINR, Div Sci Policy & Publ Liaison, Sci Implementat Branch, 6701 Democracy Blvd,Suite 710, Bethesda, MD 20817 USA. EM goughll@mail.nih.gov NR 49 TC 3 Z9 3 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 EI 1547-5069 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD NOV PY 2015 VL 47 IS 6 BP 512 EP 521 DI 10.1111/jnu.12170 PG 10 WC Nursing SC Nursing GA CV0NY UT WOS:000363948700005 PM 26448502 ER PT J AU Mumford, SL Kim, S Chen, Z Barr, DB Louis, GMB AF Mumford, Sunni L. Kim, Sungduk Chen, Zhen Barr, Dana Boyd Louis, Germaine M. Buck TI Urinary Phytoestrogens Are Associated with Subtle Indicators of Semen Quality among Male Partners of Couples Desiring Pregnancy SO JOURNAL OF NUTRITION LA English DT Article DE isoflavones; lignans; phytoestrogens; semen quality; male fertility ID SERUM ENTEROLACTONE CONCENTRATION; CHROMATIN STRUCTURE ASSAY; SPERM DNA INTEGRITY; REPRODUCTIVE HEALTH; LIPID CONCENTRATIONS; MALE-INFERTILITY; MALE RATS; SOY FOOD; MEN; EXPOSURE AB Background: Phytoestrogens have been associated with subtle hormonal changes, although effects on male fecundity are largely unknown. Objective: We evaluated associations between male urinary phytoestrogen (isoflavone and lignan) concentrations and semen quality. Methods: This study was a prospective cohort study of 501 male partners of couples desiring pregnancy and discontinuing contraception. Each participant provided up to 2 semen samples that were analyzed for 35 semen quality endpoints the following day. Linear mixed-effects models were used to estimate associations between baseline urinary phytoestrogen concentrations and semen,quality parameters, adjusted for age, body mass index (BM!), research site, and serum lipid and cotinine concentrations. Results: Most associations between urinary phytoestrogens and semen quality parameters were null. However, select individual phytoestrogens were associated with semen quality parameters, with associations dependent on the class of phytoestrogens and modified by BMI. Specifically, genistein and daidzein were associated with a lower percentage of normal sperm and increased abnormalities in semen morphology, with reduced associations observed as BMI increased (P < 0.05) [percentages (95% CIs) of normal morphology by WHO traditional criteria: genistein, main effect: -5.61% (-9.42%, -1.79%); interaction: 0.19% (0.06%, 0.31%) per log unit increase; daidzein, main effect: -5.35% (-9.36%, -1.34%); interaction: 0.18% (0.05%, 0.32%) per log unit increase]. Enterolactone was associated with fewer abnormalities in semen morphometry and morphology and decreased DNA fragmentation, with reduced associations observed as BMI increased (P < 0.05) [percentages (95% CIs) of abnormalities in the neck and midpiece: enterolactone, main effect: -3.35% (-6.51%, -0.19%); interaction: 0.11% (0.01%, 0.21%) per log unit increase]. Conclusions: These results suggest that male urinary phytoestrogen concentrations characteristic of the US population may be associated with subtle indicators of male fecundity and semen quality but were not associated with couple fecundity. C1 [Mumford, Sunni L.; Kim, Sungduk; Chen, Zhen; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355, N01-HD-3-3356, and N01-HD-3-3358). NR 65 TC 3 Z9 3 U1 4 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD NOV PY 2015 VL 145 IS 11 BP 2535 EP 2541 DI 10.3945/jn.115.214973 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CV4VP UT WOS:000364264900014 PM 26423741 ER PT J AU Littmann, T Gottle, M Reinartz, MT Kalble, S Wainer, IW Ozawa, T Seifert, R AF Littmann, Timo Goettle, Martin Reinartz, Michael T. Kaelble, Solveig Wainer, Irving W. Ozawa, Takeaki Seifert, Roland TI Recruitment of beta-Arrestin 1 and 2 to the beta(2)-Adrenoceptor: Analysis of 65 Ligands SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; AIRWAY SMOOTH-MUSCLE; 7-TRANSMEMBRANE RECEPTORS; FENOTEROL STEREOISOMERS; RACEMIC ALBUTEROL; CELLS; ADRENOCEPTOR; MICE; DESENSITIZATION; ACTIVATION AB Beyond canonical signaling via G(alpha)s and cAMP, the concept of functional selectivity at beta(2)-adrenoceptors (beta(2)ARs) describes the ability of adrenergic drugs to stabilize ligand-specific receptor conformations to initiate further signaling cascades comprising additional G-protein classes or beta-arrestins (beta arr). A set of 65 adrenergic ligands including 40 agonists and 25 antagonists in either racemic or enantiopure forms was used for barr recruitment experiments based on a split-luciferase assay in a cellular system expressing beta(2)AR. Many agonists showed only (weak) partial agonism regarding barr recruitment. Potencies and/or efficacies increased depending on the number of chirality centers in (R) configuration; no (S)-configured distomer was more effective at inducing beta arr recruitment other than the eutomer. beta arr2 was recruited more effectively than beta arr1. The analysis of antagonists revealed no significant effects on barr recruitment. Several agonists showed preference for activation of G(alpha)s GTPase relative to beta arr recruitment, and no beta arr-biased ligand was identified. In conclusion: 1) agonists show strong bias for G(alpha)s activation relative to barr recruitment; 2) agonists recruit beta arr1 and beta arr2 with subtle differences; and 3) there is no evidence for beta arr recruitment by antagonists. C1 [Littmann, Timo; Goettle, Martin; Reinartz, Michael T.; Kaelble, Solveig; Seifert, Roland] Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany. [Wainer, Irving W.] NIA, Lab Clin Invest, Baltimore, MD 21224 USA. [Ozawa, Takeaki] Univ Tokyo, Dept Chem, Sch Sci, Tokyo 113, Japan. RP Seifert, R (reprint author), Hannover Med Sch, Inst Pharmacol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM seifert.roland@mh-hannover.de FU internal funds of the Hannover Medical School FX This work was supported by internal funds of the Hannover Medical School. The authors declare no conflict of interest. NR 53 TC 0 Z9 0 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD NOV PY 2015 VL 355 IS 2 BP 183 EP + DI 10.1124/jpet.115.227959 PG 30 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CV3MT UT WOS:000364164000007 PM 26306764 ER PT J AU Lee, JW Chou, CL Knepper, MA AF Lee, Jae Wook Chou, Chung-Lin Knepper, Mark A. TI Deep Sequencing in Microdissected Renal Tubules Identifies Nephron Segment-Specific Transcriptomes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID COLLECTING DUCT CELLS; RNA-SEQ; GENE-EXPRESSION; MESSENGER-RNA; SINGLE-CELL; RAT-KIDNEY; NA,K-ATPASE; SUSPENSION; PROTEIN; VIEW AB The function of each renal tubule segment depends on the genes expressed therein. High-throughput methods used for global profiling of gene expression in unique cell types have shown low sensitivity and high false positivity, thereby limiting the usefulness of these methods in transcriptomic research. However, deep sequencing of RNA species (RNA-seq) achieves highly sensitive and quantitative transcriptomic profiling by sequencing RNAs in a massive, parallel manner. Here, we used RNA-seq coupled with classic renal tubule microdissection to comprehensively profile gene expression in each of 14 renal tubule segments from the proximal tubule through the inner medullary collecting duct of rat kidneys. Polyadenylated mRNAs were captured by oligo-dT primers and processed into adapter-ligated cDNA libraries that were sequenced using an Illumina platform. Transcriptomes were identified to a median depth of 8261 genes in microdissected renal tubule samples (105 replicates in total) and glomeruli (5 replicates). Manual nnicrodissection allowed a high degree of sample purity, which was evidenced by the observed distributions of well established cell specific markers. The main product of this work is an extensive database of gene expression along the nephron provided as a publicly accessible webpage (https://helixweb.nih.gov/ESBUDatabase/NephronRNAseq/index.html). The data also provide genome-wide maps of alternative exon usage and polyadenylation sites in the kidney. We illustrate the use of the data by profiling transcription factor expression along the renal tubule and mapping metabolic pathways. C1 [Lee, Jae Wook; Chou, Chung-Lin; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Room 6N307,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Division of Intramural Research, NHLBI [ZIA-HL001285, ZIA-HL006129] FX The work was funded by Division of Intramural Research, NHLBI Projects ZIA-HL001285 and ZIA-HL006129 (to M.A.K.). NR 41 TC 44 Z9 44 U1 2 U2 7 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2015 VL 26 IS 11 BP 2669 EP 2677 DI 10.1681/ASN.2014111067 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CV0CR UT WOS:000363915500012 PM 25817355 ER PT J AU Kasembeli, AN Duarte, R Ramsay, M Mosiane, P Dickens, C Dix-Peek, T Limou, S Sezgin, E Nelson, GW Fogo, AB Goetsch, S Kopp, JB Winkler, CA Naicker, S AF Kasembeli, Alex N. Duarte, Raquel Ramsay, Michele Mosiane, Pulane Dickens, Caroline Dix-Peek, Therese Limou, Sophie Sezgin, Efe Nelson, George W. Fogo, Agnes B. Goetsch, Stewart Kopp, Jeffrey B. Winkler, Cheryl A. Naicker, Saraladevi TI APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GENOME-WIDE ASSOCIATION; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; POPULATION; AMERICANS; PROGRESSION; INITIATION; INFECTION; SPECTRUM AB APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a SouthAfrican black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polynnorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naive South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa. C1 [Kasembeli, Alex N.; Duarte, Raquel; Dickens, Caroline; Dix-Peek, Therese; Naicker, Saraladevi] Univ Witwatersrand, Fac Hlth Sci, Dept Internal Med, ZA-2193 Johannesburg, South Africa. [Ramsay, Michele] Univ Witwatersrand, Sydney Brenner Inst Mol Biosci, Fac Hlth Sci, Div Human Genet,Natl Hlth Lab Serv,Sch Pathol, ZA-2193 Johannesburg, South Africa. [Mosiane, Pulane] Univ Witwatersrand, Natl Hlth Lab Serv, Dept Anat Pathol, ZA-2193 Johannesburg, South Africa. [Limou, Sophie; Sezgin, Efe; Nelson, George W.; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Frederick Natl Lab,Leidos Biomed Inc, Frederick, MD 20878 USA. [Sezgin, Efe] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Fogo, Agnes B.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Div Renal Pathol Electron Microscopy, Nashville, TN USA. [Goetsch, Stewart] Lancet Pathol Lab, Johannesburg, South Africa. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Naicker, Saraladevi] Univ Witwatersrand, Div Nephrol, ZA-2193 Johannesburg, South Africa. RP Naicker, S (reprint author), Univ Witwatersrand, Fac Hlth Sci, Sch Clin Med, 7 York Rd,Room 4B41, ZA-2193 Johannesburg, South Africa. EM winklerc@mail.nih.gov; Saraladevi.Naicker@wits.ac.za RI Sezgin, Efe/B-8418-2012 OI Sezgin, Efe/0000-0002-8000-7485 FU National Institutes of Health (NIH) Fogarty International Center [1D43TW008330-01A1]; National Institute of Diabetes and Digestive and Kidney Diseases; Non-communicable Chronic Diseases Leadership Training Program; Medical Research Council of South Africa; National Research Foundation of South Africa; National Health Laboratory Service Research Trust; Columbia University-South Africa Training Program for Research on AIDS-Related Malignancies; NIH National Cancer Institute [1D43CA153715-03, HHSN26120080001E]; Division of Nephrology of University of the Witwatersrand; Faculty Research Committee individual grant, University of the Witwatersrand; NIH National Cancer Institute Center for Cancer Research FX This project was funded by the National Institutes of Health (NIH) Fogarty International Center (Grant 1D43TW008330-01A1 [July 1, 2010- June 30, 2015] Millennium Promise Award), the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Programs, the Non-communicable Chronic Diseases Leadership Training Program, the Medical Research Council of South Africa, the National Research Foundation of South Africa, the National Health Laboratory Service Research Trust, the Columbia University-South Africa Training Program for Research on AIDS-Related Malignancies, the NIH National Cancer Institute (Grant 1D43CA153715-03), the Division of Nephrology of University of the Witwatersrand and the Faculty Research Committee individual grant, University of the Witwatersrand. This project was also funded in part with federal funds from the NIH National Cancer Institute (Contract HHSN26120080001E), and was supported in part by the Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research. NR 41 TC 24 Z9 25 U1 1 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2015 VL 26 IS 11 BP 2882 EP 2890 DI 10.1681/ASN.2014050469 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CV0CR UT WOS:000363915500031 PM 25788523 ER PT J AU Taylor, J Hampshire, V AF Taylor, Joni Hampshire, Victoria TI Basic research support for shared magnetic resonance imaging resources SO LAB ANIMAL LA English DT Editorial Material ID CARE AB Procedures that enable the collection of longitudinal physiologic and anatomic information can contribute to the reduction and refinement of animal. use. Scientists are increasingly turning to noninvasive magnetic resonance imaging (MRI) to obtain such information from animal research subjects. As they make this important investment, research support veterinarians are often tasked with ensuring the proper care and use of laboratory animal research subjects. A basic understanding of MRI equipment, personnel practices, safety, and monitoring of animals and their recoveries is key to implementing a centralized animal MRI facility. C1 [Taylor, Joni] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Hampshire, Victoria] Capital Preclin Sci Res Consultants LLC, Bethesda, MD 20817 USA. RP Hampshire, V (reprint author), Capital Preclin Sci Res Consultants LLC, Bethesda, MD 20817 USA. EM vahampshire@gmail.com NR 8 TC 1 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 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD NOV PY 2015 VL 44 IS 11 BP 435 EP 437 PG 3 WC Veterinary Sciences SC Veterinary Sciences GA CV2UL UT WOS:000364112600016 PM 26484818 ER PT J AU Reich, DS White, R Cortese, ICM Vuolo, L Shea, CD Collins, TL Petkau, J AF Reich, Daniel S. White, Richard Cortese, Irene C. M. Vuolo, Luisa Shea, Colin D. Collins, Tassie L. Petkau, John TI Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in multiple sclerosis lesions via conventional clinical imaging SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE MRI; T2 lesions; clinical trial design; repair ID MAGNETIZATION-TRANSFER RATIO; BLOOD-BRAIN-BARRIER; HIGH-FIELD MRI; SPINAL-CORD; TRIALS; REMYELINATION; EVOLUTION; SERIAL; NEUROPROTECTION; POSTMORTEM AB Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions 15 mm(3), as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset. C1 [Reich, Daniel S.; Cortese, Irene C. M.; Vuolo, Luisa; Shea, Colin D.] NINDS, Div Neuroimmunol & Neurovirol, NIH, Bethesda, MD 20892 USA. [White, Richard; Petkau, John] Univ British Columbia, Dept Stat, Vancouver, BC V5Z 1M9, Canada. [Collins, Tassie L.] Myelin Repair Fdn, Saratoga Springs, NY USA. RP Reich, DS (reprint author), NINDS, Div Neuroimmunol & Neurovirol, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; Myelin Repair Foundation FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke and the Myelin Repair Foundation. NR 34 TC 5 Z9 5 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD NOV PY 2015 VL 21 IS 13 BP 1693 EP 1704 DI 10.1177/1352458515569098 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CV3LP UT WOS:000364161000010 PM 25662351 ER PT J AU Kumari, D Hayward, B Nakamura, AJ Bonner, WM Usdin, K AF Kumari, Daman Hayward, Bruce Nakamura, Asako J. Bonner, William M. Usdin, Karen TI Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Friedreich ataxia; FXN; Frataxin; Repeat expansion; GAA/TTC-triplet repeat; Chromosome fragility ID X-SYNDROME; REPEAT EXPANSION; SITE STABILITY; GENOME-WIDE; TRANSCRIPTION ELONGATION; DELAYED REPLICATION; PARTIAL TETRASOMY-9; EPIGENETIC CHANGES; CGG REPEATS; DNA AB Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site. Published by Elsevier B.V. C1 [Kumari, Daman; Hayward, Bruce; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Nakamura, Asako J.; Bonner, William M.] NCI, Lab Mol Pharmacol, CCR, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU Intramural program of the National Institute of Diabetes, Digestive and Kidney Diseases [DK057808 08] FX This work was supported by a grant from the Intramural program of the National Institute of Diabetes, Digestive and Kidney Diseases to KU (DK057808 08). NR 60 TC 1 Z9 1 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD NOV PY 2015 VL 781 BP 14 EP 21 DI 10.1016/j.mrfmmm.2015.08.007 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CV3LH UT WOS:000364160200003 PM 26379101 ER PT J AU Danjou, F Zoledziewska, M Sidore, C Steri, M Busonero, F Maschio, A Mulas, A Perseu, L Barella, S Porcu, E Pistis, G Pitzalis, M Pala, M Menzel, S Metrustry, S Spector, TD Leoni, L Angius, A Uda, M Moi, P Thein, SL Galanello, R Abecasis, GR Schlessinger, D Sanna, S Cucca, F AF Danjou, Fabrice Zoledziewska, Magdalena Sidore, Carlo Steri, Maristella Busonero, Fabio Maschio, Andrea Mulas, Antonella Perseu, Lucia Barella, Susanna Porcu, Eleonora Pistis, Giorgio Pitzalis, Maristella Pala, Mauro Menzel, Stephan Metrustry, Sarah Spector, Timothy D. Leoni, Lidia Angius, Andrea Uda, Manuela Moi, Paolo Thein, Swee Lay Galanello, Renzo Abecasis, Gonaalo R. Schlessinger, David Sanna, Serena Cucca, Francesco TI Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels SO NATURE GENETICS LA English DT Article ID HUMAN GENE-EXPRESSION; RED-BLOOD-CELL; FETAL-HEMOGLOBIN; DEFINITIVE ERYTHROPOIESIS; TRANSCRIPTION FACTOR; GENOTYPE IMPUTATION; HEMATOPOIETIC STEM; BETA-THALASSEMIA; GLOBIN GENE; DNASE-II AB We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production. C1 [Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo; Steri, Maristella; Busonero, Fabio; Maschio, Andrea; Mulas, Antonella; Perseu, Lucia; Porcu, Eleonora; Pistis, Giorgio; Pitzalis, Maristella; Pala, Mauro; Angius, Andrea; Uda, Manuela; Sanna, Serena; Cucca, Francesco] CNR, Isti Ric Genet & Biomed, Cagliari, Italy. [Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Pistis, Giorgio; Abecasis, Gonaalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sidore, Carlo; Mulas, Antonella; Porcu, Eleonora; Pistis, Giorgio; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Busonero, Fabio; Maschio, Andrea] Univ Michigan, DNA Sequencing Core, Ann Arbor, MI 48109 USA. [Barella, Susanna; Moi, Paolo; Galanello, Renzo] Osped Reg Microcitemie, ASL8, Cagliari, Italy. [Menzel, Stephan; Thein, Swee Lay] Kings Coll London, Dept Mol Hematol, London, England. [Metrustry, Sarah; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Leoni, Lidia; Angius, Andrea] Parco Sci & Tecnol Sardegna, Res & Dev Sardinia CRS4, Ctr Adv Studies, Pula, Italy. [Moi, Paolo; Galanello, Renzo] Univ Cagliari, Dept Publ Hlth & Clin & Mol Med, Cagliari, Italy. [Thein, Swee Lay] Kings Coll Hosp Natl Hlth Serv NHS Fdn Trust, Dept Hematol Med, London, England. [Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Danjou, F (reprint author), CNR, Isti Ric Genet & Biomed, Cagliari, Italy. EM fabrice.danjou@irgb.cnr.it; fcucca@uniss.it RI Angius, Andrea/P-9549-2015; Danjou, Fabrice/D-1563-2014; OI Angius, Andrea/0000-0003-2596-6461; Danjou, Fabrice/0000-0002-4976-2327; Mulas, Antonella/0000-0002-6856-1483; MOI, Paolo/0000-0001-7879-8057; sanna, serena/0000-0002-3768-1749; Pitzalis, Maristella/0000-0003-4975-6987; Steri, Anna Maristella/0000-0001-5869-3872 FU US National Institutes of Health (National Institute on Aging); National Human Genome Research Institute [HG005581, HG005552, HG006513, HG007022]; National Heart, Lung, and Blood Institute [HL117626]; US National Institutes of Health, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]; Sardinian Autonomous Region [cRP3-154, 7/2009]; grant FaReBio "Farmaci e Reti Biotecnologiche di Qualita"; PB05 InterOmics MIUR Flagship Project; Wellcome Trust; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust; Medical Research Council, UK [G0000111, ID51640]; British Society for Haematology; US National Institutes of Health (National Heart, Lung, and Blood Institute); US National Institutes of Health (National Human Genome Research Institute); King's College London FX This work is dedicated to Antonio Cao, Renzo Galanello and Maurizio Longinotti, who devoted their scientific lives to understanding, preventing and treating hematological diseases in Sardinia. We are also grateful to M.S. Ristaldi and M.G. Marini for knowledge and insight that they freely shared with us. Finally, we thank all the volunteers who generously participated in this study and made this research possible. The SardiNIA study was funded in part by the US National Institutes of Health (National Institute on Aging, National Heart, Lung, and Blood Institute, and). This research was supported by National Human Genome Research Institute grants HG005581, HG005552, HG006513 and HG007022; by National Heart, Lung, and Blood Institute grant HL117626; by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging, contracts N01-AG-1-2109 and HHSN271201100005C; by Sardinian Autonomous Region (L.R. number 7/2009) grant cRP3-154; by grant FaReBio2011 "Farmaci e Reti Biotecnologiche di Qualita"; and by the PB05 InterOmics MIUR Flagship Project. The TwinsUK study was funded by the Wellcome Trust; the European Community's Seventh Framework Programme (FP7/2007-2013); and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. Genotyping in the replication cohorts was performed by the Wellcome Trust Sanger Institute and National Eye Institute via the US National Institutes of Health/Center for Inherited Disease Research (CIDR). S.L.T. was supported by the Medical Research Council, UK (grant G0000111, ID51640), and S. Menzel received funding from the British Society for Haematology (start-up grant). NR 82 TC 8 Z9 8 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2015 VL 47 IS 11 BP 1264 EP + DI 10.1038/ng.3307 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CV1BN UT WOS:000363988200010 PM 26366553 ER PT J AU Sidore, C Busonero, F Maschio, A Porcu, E Naitza, S Zoledziewska, M Mulas, A Pistis, G Steri, M Danjou, F Kwong, A del Vecchyo, VDO Chiang, CWK Bragg-Gresham, J Pitzalis, M Nagaraja, R Tarrier, B Brennan, C Uzzau, S Fuchsberger, C Atzeni, R Reinier, F Berutti, R Huang, J Timpson, NJ Toniolo, D Gasparini, P Malerba, G Dedoussis, G Zeggini, E Soranzo, N Jones, C Lyons, R Angius, A Kang, HM Novembre, J Sanna, S Schlessinger, D Cucca, F Abecasis, GR AF Sidore, Carlo Busonero, Fabio Maschio, Andrea Porcu, Eleonora Naitza, Silvia Zoledziewska, Magdalena Mulas, Antonella Pistis, Giorgio Steri, Maristella Danjou, Fabrice Kwong, Alan del Vecchyo, Vicente Diego Ortega Chiang, Charleston W. K. Bragg-Gresham, Jennifer Pitzalis, Maristella Nagaraja, Ramaiah Tarrier, Brendan Brennan, Christine Uzzau, Sergio Fuchsberger, Christian Atzeni, Rossano Reinier, Frederic Berutti, Riccardo Huang, Jie Timpson, Nicholas J. Toniolo, Daniela Gasparini, Paolo Malerba, Giovanni Dedoussis, George Zeggini, Eleftheria Soranzo, Nicole Jones, Chris Lyons, Robert Angius, Andrea Kang, Hyun M. Novembre, John Sanna, Serena Schlessinger, David Cucca, Francesco Abecasis, Goncalo R. TI Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers SO NATURE GENETICS LA English DT Article ID RARE VARIANT ASSOCIATION; MAPPING COMPLEX TRAITS; C-REACTIVE PROTEIN; WIDE ASSOCIATION; GENOTYPE IMPUTATION; BETA-THALASSEMIA; DEMOGRAPHIC HISTORY; MULTIPLE-SCLEROSIS; HEART-DISEASE; POPULATION AB We report similar to 17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, similar to 76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population. C1 [Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Naitza, Silvia; Zoledziewska, Magdalena; Mulas, Antonella; Pistis, Giorgio; Steri, Maristella; Danjou, Fabrice; Pitzalis, Maristella; Angius, Andrea; Sanna, Serena; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Sidore, Carlo; Busonero, Fabio; Maschio, Andrea; Porcu, Eleonora; Pistis, Giorgio; Kwong, Alan; Bragg-Gresham, Jennifer; Fuchsberger, Christian; Kang, Hyun M.; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Sidore, Carlo; Porcu, Eleonora; Mulas, Antonella; Pistis, Giorgio; Berutti, Riccardo; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Busonero, Fabio; Maschio, Andrea; Tarrier, Brendan; Brennan, Christine; Lyons, Robert] Univ Michigan, DNA Sequencing Core, Ann Arbor, MI 48109 USA. [del Vecchyo, Vicente Diego Ortega] Univ Calif Los Angeles, Interdept Program Bioinformat, Los Angeles, CA USA. [Chiang, Charleston W. K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Uzzau, Sergio] Porto Conte Ric, Tramariglio, Alghero, Italy. [Atzeni, Rossano; Reinier, Frederic; Berutti, Riccardo; Jones, Chris; Angius, Andrea] Parco Sci & Tecnol Sardegna, Res & Dev Sardinia CRS4, Ctr Adv Studies, Pula, Italy. [Huang, Jie; Zeggini, Eleftheria; Soranzo, Nicole] Wellcome Trust Sanger Inst, Human Genet, Hinxton, England. [Timpson, Nicholas J.] Univ Bristol, Integrat Epidemiol Unit, MRC, Bristol, Avon, England. [Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Gasparini, Paolo] Univ Trieste, Dipartimento Salute Mentale, Trieste, Italy. [Gasparini, Paolo] Burlo Garofolo Children Hosp, Ist Ricovero & Cura Carattere Sci, Trieste, Italy. [Gasparini, Paolo] Sidra, Expt Genet Div, Doha, Qatar. [Malerba, Giovanni] Univ Verona, Dept Life & Reprod Sci, I-37100 Verona, Italy. [Dedoussis, George] Harokopio Univ Athens, Dept Nutr & Dietet, Athens, Greece. [Soranzo, Nicole] Univ Cambridge, Dept Haematol, Cambridge, England. [Novembre, John] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Cucca, F (reprint author), CNR, Ist Ric Genet & Biomed, Cagliari, Italy. EM fcucca@uniss.it; goncalo@umich.edu RI Angius, Andrea/P-9549-2015; Fox, Laura /C-6249-2016; Danjou, Fabrice/D-1563-2014; Naitza, Silvia/D-5620-2017; OI Steri, Anna Maristella/0000-0001-5869-3872; Soranzo, Nicole/0000-0003-1095-3852; Angius, Andrea/0000-0003-2596-6461; Danjou, Fabrice/0000-0002-4976-2327; Fuchsberger, Christian/0000-0002-5918-8947; Sidore, Carlo/0000-0001-7504-7477; Malerba, Giovanni/0000-0001-8705-8560; sanna, serena/0000-0002-3768-1749; Mulas, Antonella/0000-0002-6856-1483; Pitzalis, Maristella/0000-0003-4975-6987; Chiang, Charleston/0000-0002-0668-7865; Timpson, Nicholas/0000-0002-7141-9189 FU National Human Genome Research Institute [HG005581, HG005552, HG006513, HG007022, HG007089]; National Heart, Lung, and Blood Institute [HL117626]; US National Institutes of Health, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]; Sardinian Autonomous Region [cRP3-154]; InterOmics MIUR Flagship Project [PB05]; FaReBio 'Farmaci e Reti Biotecnologiche di Qualita'; US National Institutes of Health National Research Service Award (NRSA) [F32GM106656]; UC MEXUS/CONOCYT fellowship; Wellcome Trust [WT091310, WT098051, 098051, WT091310/C/10/Z]; European Union [257082, HEALTH-F5-2011-282510]; National Institute for Health Research (NIHR) British Research Council (BRC); Ministero della Salute-Ricerca Finalizzata [PE-2011-02347500]; Fondazione Cariplo (Italy); Ministry of Health; Public Health Genomics Project; European Research Council [ERC-2011-StG 280559-SEPI]; Ricerca Finalizzata (Italy) FX We thank all the volunteers who generously participated in this study and made this research possible. This research was supported by National Human Genome Research Institute grants HG005581, HG005552, HG006513, HG007022 and HG007089; by National Heart, Lung, and Blood Institute grant HL117626; by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging, contracts N01-AG-1-2109 and HHSN271201100005C; by Sardinian Autonomous Region (L.R. 7/2009) grant cRP3-154; by the PB05 InterOmics MIUR Flagship Project; by grant FaReBio2011 'Farmaci e Reti Biotecnologiche di Qualita'; by a US National Institutes of Health National Research Service Award (NRSA) postdoctoral fellowship (F32GM106656) to C.W.K.C.; and by the UC MEXUS/CONOCYT fellowship to V.D.O.d.V. The replication cohorts acknowledge the use of data generated by the UK10K Consortium, supported by Wellcome Trust award WT091310. The UK10K research was specifically funded by a Wellcome Trust award, '10,000 UK Genome Sequences: Accessing the Role of Rare Genetic Variants in Health and Disease' (WT091310/C/10/Z). The research of N.S. is supported by the Wellcome Trust (grants WT098051 and WT091310), the European Union's Seventh Framework Programme (EPIGENESYS grant 257082 and BLUEPRINT grant HEALTH-F5-2011-282510) and the National Institute for Health Research (NIHR) British Research Council (BRC). The ING-FVG cohort was supported by grant Ministero della Salute-Ricerca Finalizzata PE-2011-02347500 (to P.G.); the ING-VB study thanks the inhabitants of Val Borbera for participating in the study, M. Traglia, C. Sala and C. Masciullo for data management, and the funding sources Fondazione Cariplo (Italy), the Ministry of Health, Ricerca Finalizzata (Italy) 2008, 2011-2012, and the Public Health Genomics Project 2010. The HELIC cohorts are thankful to the residents of the Pomak villages and the Mylopotamos villages for participating and to their funding sources, including the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). NR 76 TC 20 Z9 20 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2015 VL 47 IS 11 BP 1272 EP + DI 10.1038/ng.3368 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA CV1BN UT WOS:000363988200011 PM 26366554 ER PT J AU Day, FR Ruth, KS Thompson, DJ Lunetta, KL Pervjakova, N Chasman, DI Stolk, L Finucane, HK Sulem, P Bulik-Sullivan, B Esko, T Johnson, AD Elks, CE Franceschini, N He, CY Altmaier, E Brody, JA Franke, LL Huffman, JE Keller, MF McArdle, PF Nutile, T Porcu, E Robino, A Rose, LM Schick, UM Smith, JA Teumer, A Traglia, M Vuckovic, D Yao, J Zhao, W Albrecht, E Amin, N Corre, T Hottenga, JJ Mangino, M Smith, AV Tanaka, T Abecasis, GR Andrulis, IL Anton-Culver, H Antoniou, AC Arndt, V Arnold, AM Barbieri, C Beckmann, MW Beeghly-Fadiel, A Benitez, J Bernstein, L Bielinski, SJ Blomqvist, C Boerwinkle, E Bogdanova, NV Bojesen, SE Bolla, MK Borresen-Dale, AL Boutin, TS Brauch, H Brenner, H Bruning, T Burwinkel, B Campbell, A Campbell, H Chanock, SJ Chapman, JR Chen, YDI Chenevix-Trench, G Couch, FJ Coviello, AD Cox, A Czene, K Darabi, H De Vivo, I Demerath, EW Dennis, J Devilee, P Dork, T Dos-Santos-Silva, I Dunning, AM Eicher, JD Fasching, PA Faul, JD Figueroa, J Flesch-Janys, D Gandin, I Garcia, ME Garcia-Closas, M Giles, GG Girotto, GG Goldberg, MS Gonzalez-Neira, A Goodarzi, MO Grove, ML Gudbjartsson, DF Guenel, P Guo, XQ Haiman, CA Hall, P Hamann, U Henderson, BE Hocking, LJ Hofman, A Homuth, G Hooning, MJ Hopper, JL Hu, FB Huang, JY Humphreys, K Hunter, DJ Jakubowska, A Jones, SE Kabisch, M Karasik, D Knight, JA Kolcic, I Kooperberg, C Kosma, VM Kriebel, J Kristensen, V Lambrechts, D Langenberg, C Li, JM Li, X Lindstrom, S Liu, YM Luan, JN Lubinski, J Magi, R Mannermaa, A Manz, J Margolin, S Marten, J Martin, NG Masciullo, C Meindl, A Michailidou, K Mihailov, E Milani, L Milne, RL Muller-Nurasyid, M Nalls, M Neale, BM Nevanlinna, H Neven, P Newman, AB Nordestgaard, BG Olson, JE Padmanabhan, S Peterlongo, P Peters, U Petersmann, A Peto, J Pharoah, PDP Pirastu, NN Pirie, A Pistis, G Polasek, O Porteous, D Psaty, BM Pylkas, K Radice, P Raffel, LJ Rivadeneira, F Rudan, I Rudolph, A Ruggiero, D Sala, CF Sanna, S Sawyer, EJ Schlessinger, D Schmidt, MK Schmidt, F Schmutzler, RK Schoemaker, MJ Scott, RA Seynaeve, CM Simard, J Sorice, R Southey, MC Stockl, D Strauch, K Swerdlow, A Taylor, KD Thorsteinsdottir, U Toland, AE Tomlinson, I Truong, T Tryggvadottir, L Turner, ST Vozzi, D Wang, Q Wellons, M Willemsen, G Wilson, JF Winqvist, R Wolffenbuttel, BBHR Wright, AF Yannoukakos, D Zemunik, T Zheng, W Zygmunt, M Bergmann, S Boomsma, DI Buring, JE Ferrucci, L Montgomery, GW Gudnason, V Spector, TD van Duijn, CM Alizadeh, BZ Ciullo, M Crisponi, L Easton, DF Gasparini, PP Gieger, C Harris, TB Hayward, C Kardia, SLR Kraft, P McKnight, B Metspalu, A Morrison, AC Reiner, AP Ridker, PM Rotter, JI Toniolo, D Uitterlinden, AG Ulivi, S Volzke, H Wareham, NJ Weir, DR Yerges-Armstrong, LM Price, AL Stefansson, K Visser, JA Ong, KK Chang-Claude, J Murabito, JM Perry, JRB Murray, A AF Day, Felix R. Ruth, Katherine S. Thompson, Deborah J. Lunetta, Kathryn L. Pervjakova, Natalia Chasman, Daniel I. Stolk, Lisette Finucane, Hilary K. Sulem, Patrick Bulik-Sullivan, Brendan Esko, Tonu Johnson, Andrew D. Elks, Cathy E. Franceschini, Nora He, Chunyan Altmaier, Elisabeth Brody, Jennifer A. Franke, Lude L. Huffman, Jennifer E. Keller, Margaux F. McArdle, Patrick F. Nutile, Teresa Porcu, Eleonora Robino, Antonietta Rose, Lynda M. Schick, Ursula M. Smith, Jennifer A. Teumer, Alexander Traglia, Michela Vuckovic, Dragana Yao, Jie Zhao, Wei Albrecht, Eva Amin, Najaf Corre, Tanguy Hottenga, Jouke-Jan Mangino, Massimo Smith, Albert V. Tanaka, Toshiko Abecasis, Goncalo R. Andrulis, Irene L. Anton-Culver, Hoda Antoniou, Antonis C. Arndt, Volker Arnold, Alice M. Barbieri, Caterina Beckmann, Matthias W. Beeghly-Fadiel, Alicia Benitez, Javier Bernstein, Leslie Bielinski, Suzette J. Blomqvist, Carl Boerwinkle, Eric Bogdanova, Natalia V. Bojesen, Stig E. Bolla, Manjeet K. Borresen-Dale, Anne-Lise Boutin, Thibaud S. Brauch, Hiltrud Brenner, Hermann Bruening, Thomas Burwinkel, Barbara Campbell, Archie Campbell, Harry Chanock, Stephen J. Chapman, J. Ross Chen, Yii-Der Ida Chenevix-Trench, Georgia Couch, Fergus J. Coviello, Andrea D. Cox, Angela Czene, Kamila Darabi, Hatef De Vivo, Immaculata Demerath, Ellen W. Dennis, Joe Devilee, Peter Doerk, Thilo dos-Santos-Silva, Isabel Dunning, Alison M. Eicher, John D. Fasching, Peter A. Faul, Jessica D. Figueroa, Jonine Flesch-Janys, Dieter Gandin, Ilaria Garcia, Melissa E. Garcia-Closas, Montserrat Giles, Graham G. Girotto, Giorgia G. Goldberg, Mark S. Gonzalez-Neira, Anna Goodarzi, Mark O. Grove, Megan L. Gudbjartsson, Daniel F. Guenel, Pascal Guo, Xiuqing Haiman, Christopher A. Hall, Per Hamann, Ute Henderson, Brian E. Hocking, Lynne J. Hofman, Albert Homuth, Georg Hooning, Maartje J. Hopper, John L. Hu, Frank B. Huang, Jinyan Humphreys, Keith Hunter, David J. Jakubowska, Anna Jones, Samuel E. Kabisch, Maria Karasik, David Knight, Julia A. Kolcic, Ivana Kooperberg, Charles Kosma, Veli-Matti Kriebel, Jennifer Kristensen, Vessela Lambrechts, Diether Langenberg, Claudia Li, Jingmei Li, Xin Lindstroem, Sara Liu, Yongmei Luan, Jian'an Lubinski, Jan Maegi, Reedik Mannermaa, Arto Manz, Judith Margolin, Sara Marten, Jonathan Martin, Nicholas G. Masciullo, Corrado Meindl, Alfons Michailidou, Kyriaki Mihailov, Evelin Milani, Lili Milne, Roger L. Mueller-Nurasyid, Martina Nalls, Michael Neale, Benjamin M. Nevanlinna, Heli Neven, Patrick Newman, Anne B. Nordestgaard, Borge G. Olson, Janet E. Padmanabhan, Sandosh Peterlongo, Paolo Peters, Ulrike Petersmann, Astrid Peto, Julian Pharoah, Paul D. P. Pirastu, Nicola N. Pirie, Ailith Pistis, Giorgio Polasek, Ozren Porteous, David Psaty, Bruce M. Pylkas, Katri Radice, Paolo Raffel, Leslie J. Rivadeneira, Fernando Rudan, Igor Rudolph, Anja Ruggiero, Daniela Sala, Cinzia F. Sanna, Serena Sawyer, Elinor J. Schlessinger, David Schmidt, Marjanka K. Schmidt, Frank Schmutzler, Rita K. Schoemaker, Minouk J. Scott, Robert A. Seynaeve, Caroline M. Simard, Jacques Sorice, Rossella Southey, Melissa C. Stoeckl, Doris Strauch, Konstantin Swerdlow, Anthony Taylor, Kent D. Thorsteinsdottir, Unnur Toland, Amanda E. Tomlinson, Ian Truong, Therese Tryggvadottir, Laufey Turner, Stephen T. Vozzi, Diego Wang, Qin Wellons, Melissa Willemsen, Gonneke Wilson, James F. Winqvist, Robert Wolffenbuttel, Bruce B. H. R. Wright, Alan F. Yannoukakos, Drakoulis Zemunik, Tatijana Zheng, Wei Zygmunt, Marek Bergmann, Sven Boomsma, Dorret I. Buring, Julie E. Ferrucci, Luigi Montgomery, Grant W. Gudnason, Vilmundur Spector, Tim D. van Duijn, Cornelia M. Alizadeh, Behrooz Z. Ciullo, Marina Crisponi, Laura Easton, Douglas F. Gasparini, Paolo P. Gieger, Christian Harris, Tamara B. Hayward, Caroline Kardia, Sharon L. R. Kraft, Peter McKnight, Barbara Metspalu, Andres Morrison, Alanna C. Reiner, Alex P. Ridker, Paul M. Rotter, Jerome I. Toniolo, Daniela Uitterlinden, Andre G. Ulivi, Sheila Voelzke, Henry Wareham, Nicholas J. Weir, David R. Yerges-Armstrong, Laura M. Price, Alkes L. Stefansson, Kari Visser, Jenny A. Ong, Ken K. Chang-Claude, Jenny Murabito, Joanne M. Perry, John R. B. Murray, Anna CA EPIC-InterAct Consortium LifeLines Cohort Study TI Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair SO NATURE GENETICS LA English DT Article ID PREMATURE OVARIAN FAILURE; BRCA2 MUTATION CARRIERS; BODY-MASS INDEX; NATURAL MENOPAUSE; HOMOLOGOUS RECOMBINATION; CHROMOSOMAL INSTABILITY; WIDE ASSOCIATION; BLOOD-PRESSURE; CELL-TYPES; LOCI AB Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms. C1 [Day, Felix R.; Elks, Cathy E.; Langenberg, Claudia; Luan, Jian'an; Scott, Robert A.; Wareham, Nicholas J.; Ong, Ken K.; Perry, John R. B.] Univ Cambridge, MRC, Epidemiol Unit, Sch Clin Med,Inst Metab Sci, Cambridge, England. [Ruth, Katherine S.; Jones, Samuel E.; Murray, Anna] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. [Thompson, Deborah J.; Antoniou, Antonis C.; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Pharoah, Paul D. P.; Pirie, Ailith; Wang, Qin; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lunetta, Kathryn L.; Johnson, Andrew D.; Huffman, Jennifer E.; Eicher, John D.; Murabito, Joanne M.] NHLBI, Framingham, MA USA. [Lunetta, Kathryn L.; Johnson, Andrew D.; Huffman, Jennifer E.; Eicher, John D.; Murabito, Joanne M.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Pervjakova, Natalia; Esko, Tonu; Maegi, Reedik; Mihailov, Evelin; Milani, Lili; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Pervjakova, Natalia] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Chasman, Daniel I.; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel I.; Karasik, David; Buring, Julie E.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.; Visser, Jenny A.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.] Natl Genom Initiat, Leiden, Netherlands. [Finucane, Hilary K.; De Vivo, Immaculata; Hu, Frank B.; Hunter, David J.; Li, Xin; Lindstroem, Sara; Kraft, Peter; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Finucane, Hilary K.] MIT, Dept Math, Cambridge, MA 02139 USA. [Sulem, Patrick; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet Amgen Inc, Reykjavik, Iceland. [Bulik-Sullivan, Brendan; Neale, Benjamin M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Bulik-Sullivan, Brendan; Neale, Benjamin M.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Bulik-Sullivan, Brendan; Neale, Benjamin M.] Broad Inst, Med & Populat Genet, Cambridge, MA USA. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Esko, Tonu; Hunter, David J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [He, Chunyan] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [He, Chunyan] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Altmaier, Elisabeth; Kriebel, Jennifer; Manz, Judith] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Altmaier, Elisabeth; Albrecht, Eva; Mueller-Nurasyid, Martina; Strauch, Konstantin] Helmholtz Zenntrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Brody, Jennifer A.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Franke, Lude L.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Huffman, Jennifer E.; Boutin, Thibaud S.; Marten, Jonathan; Wilson, James F.; Wright, Alan F.; Hayward, Caroline] Univ Edinburgh, Human Genet Unit, MRC, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Keller, Margaux F.] Merck Pharmaceut, Boston, MA USA. [McArdle, Patrick F.; Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Program Personalized Med, Baltimore, MD 21201 USA. [Nutile, Teresa; Ruggiero, Daniela; Sorice, Rossella; Ciullo, Marina] CNR, Inst Genet & Biophys, Naples, Italy. [Porcu, Eleonora; Pistis, Giorgio; Sanna, Serena; Crisponi, Laura] CNR, Inst Genet & Biomed Res, Cagliari, Italy. [Porcu, Eleonora; Pistis, Giorgio] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. [Porcu, Eleonora; Abecasis, Goncalo R.; Pistis, Giorgio] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Robino, Antonietta; Vuckovic, Dragana; Barbieri, Caterina; Gandin, Ilaria; Pirastu, Nicola N.; Vozzi, Diego; Gasparini, Paolo P.; Ulivi, Sheila] Sci Inst Res Hospitalisat & Hlth Care Burlo Garof, Inst Maternal & Child Hlth, Trieste, Italy. [Schick, Ursula M.; Kooperberg, Charles; Peters, Ulrike; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Teumer, Alexander; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Traglia, Michela; Barbieri, Caterina; Masciullo, Corrado; Sala, Cinzia F.; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Vuckovic, Dragana; Gandin, Ilaria; Girotto, Giorgia G.; Pirastu, Nicola N.; Gasparini, Paolo P.] Univ Trieste, Dept Clin Med Sci Surg & Hlth, Trieste, Italy. [Yao, Jie; Chen, Yii-Der Ida; Guo, Xiuqing; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, LABioMed, Torrance, CA 90509 USA. [Amin, Najaf; Hofman, Albert; Rivadeneira, Fernando; van Duijn, Cornelia M.; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Corre, Tanguy; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Corre, Tanguy; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Mangino, Massimo] Guys & St Thomas Fdn Trust, Biomed Res Ctr, Natl Inst Hlth Res, London, England. [Smith, Albert V.; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Thorsteinsdottir, Unnur; Gudnason, Vilmundur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Arnold, Alice M.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Obstet & Gynaecol, D-91054 Erlangen, Germany. [Beeghly-Fadiel, Alicia; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Bielinski, Suzette J.; Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Boerwinkle, Eric; Grove, Megan L.; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Med & Hlth Sci, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Borresen-Dale, Anne-Lise; Kristensen, Vessela] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Borresen-Dale, Anne-Lise; Kristensen, Vessela] Univ Oslo, Fac Med, Dept Clin Med, Oslo, Norway. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Inst Clin Pharmacol, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Bruening, Thomas] Univ Bochum IPA, Inst Ruhr, German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, Mol Biol Breast Canc, Heidelberg, Germany. [Campbell, Archie; Porteous, David] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland. [Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chapman, J. Ross; Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MI USA. [Coviello, Andrea D.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Coviello, Andrea D.] Boston Univ, Sch Med, Dept Med, Endocrinol Sect, Boston, MA 02118 USA. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Czene, Kamila; Darabi, Hatef; Hall, Per; Humphreys, Keith; Li, Jingmei] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [De Vivo, Immaculata; Hu, Frank B.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [De Vivo, Immaculata; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Demerath, Ellen W.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Non Communicable Dis Epidemiol Dept, London WC1, England. [Dunning, Alison M.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat; Schoemaker, Minouk J.; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Dept Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Gudbjartsson, Daniel F.] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris Sud, UMRS 1018, Villejuif, France. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hamann, Ute; Kabisch, Maria] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen, Scotland. [Homuth, Georg; Schmidt, Frank] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany. [Hooning, Maartje J.; Seynaeve, Caroline M.] Erasmus Univ, Med Ctr, Dept Med Oncol, Rotterdam, Netherlands. [Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Med, Dept Nutr, Boston, MA USA. [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom,Shanghai Inst Hematol, Shanghai 200030, Peoples R China. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Karasik, David] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Kolcic, Ivana; Polasek, Ozren; Zemunik, Tatijana] Univ Split, Fac Med, Split, Croatia. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Pathol & Forens Med, Inst Clin Med, Sch Med, Kuopio, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kriebel, Jennifer] German Ctr Diabet Res, Neuherberg, Germany. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC USA. [Margolin, Sara] Karolinska Inst, Dept Oncology Pathol, Stockholm, Sweden. [Martin, Nicholas G.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Meindl, Alfons] Tech Univ Munich, Div Obstet & Gynecol, D-80290 Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina] German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany. [Nalls, Michael] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Neven, Patrick] Univ Hosp Leuven, Dept Oncol, Leuven, Belgium. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA USA. [Padmanabhan, Sandosh] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci,Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol IFOM, Milan, Italy. [Petersmann, Astrid] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Psaty, Bruce M.; Reiner, Alex P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Pylkas, Katri; Winqvist, Robert] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Pylkas, Katri; Winqvist, Robert] Ctr NordLab, Northern Finland Lab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Radice, Paolo] Fdn IRCCS, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Med Genet Res Ctr, Los Angeles, CA 90048 USA. [Raffel, Leslie J.] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Clin & Translat Sci Inst, Los Angeles, CA 90048 USA. [Rudolph, Anja; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London WC2R 2LS, England. [Schlessinger, David] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Gynecol & Obstet, 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. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Toland, Amanda E.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Strauch, Konstantin] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Tomlinson, Ian] Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LJ, England. [Tryggvadottir, Laufey] Icelandic Canc Registry, Reykjavik, Iceland. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Wellons, Melissa] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Wolffenbuttel, Bruce B. H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Wolffenbuttel, Bruce B. H. R.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study & Biobank, Groningen, Netherlands. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Inst Radioisotopes & Radiodiagnost Prod, Mol Diagnost Lab, Athens, Greece. [Zygmunt, Marek] Univ Med Greifswald, Dept Gynecol & Obstet, Greifswald, Germany. [Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Kraft, Peter; Ong, Ken K.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ong, Ken K.] Univ Cambridge, Dept Paediat, Cambridge, England. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Perry, JRB (reprint author), Univ Cambridge, MRC, Epidemiol Unit, Sch Clin Med,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England. EM john.perry@mrc-epid.cam.ac.uk RI Padmanabhan, Sandosh/S-3963-2016; Brenner, Hermann/B-4627-2017; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Gudnason, Vilmundur/K-6885-2015; Smith, Albert Vernon/K-5150-2015; ruggiero, daniela/K-5638-2016; mangino, massimo/F-5134-2011; Dork, Thilo/J-8620-2012; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Schmidt, Frank, ZIK FunGene/B-6075-2009; Knight, Julia/A-6843-2012; Montgomery, Grant/B-7148-2008; Li, Jingmei/I-2904-2012; Bielinski, Suzette/A-2238-2009; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013 OI Smith, Jennifer/0000-0002-3575-5468; Ewing, Ailith/0000-0002-2272-1277; Arndt, Volker/0000-0001-9320-8684; Bergmann, Sven/0000-0002-6785-9034; Tryggvadottir, Laufey/0000-0001-8067-9030; NUTILE, TERESA/0000-0001-7062-8352; Dunning, Alison Margaret/0000-0001-6651-7166; Karasik, David/0000-0002-8826-0530; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; dos Santos Silva, Isabel/0000-0002-6596-8798; vozzi, diego/0000-0002-2902-8184; Cox, Angela/0000-0002-5138-1099; Girotto, Giorgia/0000-0003-4507-6589; Chapman, Ross/0000-0002-6477-4254; Yannoukakos, Drakoulis/0000-0001-7509-3510; Brenner, Hermann/0000-0002-6129-1572; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Day, Felix/0000-0003-3789-7651; Vuckovic, Dragana/0000-0001-9343-6142; Magi, Reedik/0000-0002-2964-6011; Schoemaker, Minouk/0000-0001-8403-2234; Murray, Anna/0000-0002-2351-2522; Hocking, Lynne J/0000-0002-2414-2826; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert Vernon/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; mangino, massimo/0000-0002-2167-7470; Franke, Lude/0000-0002-5159-8802; Montgomery, Grant/0000-0002-4140-8139; Li, Jingmei/0000-0001-8587-7511; Bielinski, Suzette/0000-0002-2905-5430; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; FU Cancer Research UK [C5047/A15007, 10124, 11174, C12292/A11174, C1281/A12014, C1287/A 10710, C1287/A10118, C5047/A10692, C5047/A8384, C8197/A16565]; Chief Scientist Office [CZD/16/6/4]; Medical Research Council [MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UU_12015/1, MC_UU_12015/2]; NCATS NIH HHS [UL1 TR000124, UL1 TR001108, UL1TR000124]; NCI NIH HHS [1U19 CA148065, 1U19 CA148112, 1U19 CA148537, CA128978, CA164920, P30 CA015704, UM1 CA182910, UM1 CA182913]; NCRR NIH HHS [UL1RR025005]; NHGRI NIH HHS [HG005552, HG005581, HG006513, HG007022, HG007089, U01HG004402]; NHLBI NIH HHS [5RC2HL102419, HL043851, HL054457, HL054464, HL054481, HL080295, HL080467, HL087652, HL087660, HL105756, K01-HL116770, N01-HC-25195, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N02-HL-6-4278, R01 HL087660, R01 HL119443, R01HL087641, R01HL59367, U01-HL72515, U01-HL84756]; NIA NIH HHS [1R01AG032098-01A1, AG009740, AG023629, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-1-2109, N01-AG-5-0002, N01AG62101, N01AG62103, N01AG62106, R01AG29451, R21AG032598, RC2 AG036495, RC4 AG039029, U01AG009740]; NIDDK NIH HHS [DK063491, P30 DK063491, P30 DK072488, P30-DK072488, R01DK075787]; PHS HHS [HHSN268200625226C, HHSN268200782096C, HHSN268200800007C, HHSN268200960009C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201100046C, HHSN268201200036C, HHSN271201100004C, HHSN271201100005C, R01-088119]; Wellcome Trust [090532] NR 60 TC 22 Z9 23 U1 4 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2015 VL 47 IS 11 BP 1294 EP + DI 10.1038/ng.3412 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CV1BN UT WOS:000363988200013 PM 26414677 ER PT J AU Zoledziewska, M Sidore, C Chiang, CWK Sanna, S Mulas, A Steri, M Busonero, F Marcus, JH Marongiu, M Maschio, A Del Vecchyo, DO Floris, M Meloni, A Delitala, A Concas, MP Murgia, F Biino, G Vaccargiu, S Nagaraja, R Lohmueller, KE Timpson, NJ Soranzo, N Tachmazidou, I Dedoussis, G Zeggini, E Uzzau, S Jones, C Lyons, R Angius, A Abecasis, GR Novembre, J Schlessinger, D Cucca, F AF Zoledziewska, Magdalena Sidore, Carlo Chiang, Charleston W. K. Sanna, Serena Mulas, Antonella Steri, Maristella Busonero, Fabio Marcus, Joseph H. Marongiu, Michele Maschio, Andrea Del Vecchyo, Diego Ortega Floris, Matteo Meloni, Antonella Delitala, Alessandro Concas, Maria Pina Murgia, Federico Biino, Ginevra Vaccargiu, Simona Nagaraja, Ramaiah Lohmueller, Kirk E. Timpson, Nicholas J. Soranzo, Nicole Tachmazidou, Ioanna Dedoussis, George Zeggini, Eleftheria Uzzau, Sergio Jones, Chris Lyons, Robert Angius, Andrea Abecasis, Goncalo R. Novembre, John Schlessinger, David Cucca, Francesco CA UK10K Consortium Understanding Soc Sci Grp TI Height-reducing variants and selection for short stature in Sardinia SO NATURE GENETICS LA English DT Article ID HORMONE RECEPTOR DEFICIENCY; BECKWITH-WIEDEMANN-SYNDROME; LOCI; ASSOCIATION; ECUADOR; EUROPE; WOMEN AB We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals. C1 [Zoledziewska, Magdalena; Sidore, Carlo; Sanna, Serena; Mulas, Antonella; Steri, Maristella; Busonero, Fabio; Marongiu, Michele; Maschio, Andrea; Floris, Matteo; Concas, Maria Pina; Murgia, Federico; Vaccargiu, Simona; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Sidore, Carlo; Maschio, Andrea; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Chiang, Charleston W. K.; Lohmueller, Kirk E.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Mulas, Antonella; Floris, Matteo; Uzzau, Sergio; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Marcus, Joseph H.; Novembre, John] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Maschio, Andrea; Lyons, Robert] Univ Michigan, DNA Sequencing Core, Ann Arbor, MI 48109 USA. [Del Vecchyo, Diego Ortega] Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA USA. [Floris, Matteo; Jones, Chris; Angius, Andrea] Parco Sci & Tecnol Sardegna, Adv Genom Comp Technol, Ctr Adv Studies Res & Dev Sardinia CRS4, Pula, Italy. [Meloni, Antonella] Osped Microcitemico, Clin Pediat 2, Cagliari, Italy. [Delitala, Alessandro] Azienda Osped Univ Sassari, Dept Clin & Expt Med, Sassari, Italy. [Biino, Ginevra] CNR, Ist Genet Mol, I-27100 Pavia, Italy. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Timpson, Nicholas J.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Soranzo, Nicole; Tachmazidou, Ioanna; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Human Genet, Hinxton, England. [Soranzo, Nicole] Univ Cambridge, Dept Haematol, Cambridge, England. [Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Uzzau, Sergio] Porto Conte Ric, Tramariglio, Alghero, Italy. RP Zoledziewska, M (reprint author), CNR, Ist Ric Genet & Biomed, Cagliari, Italy. EM magdalena.zoledziewska@irgb.cnr.it; schlessingerd@mail.nih.gov; fcucca@uniss.it RI Biino, Ginevra/B-5334-2013; Angius, Andrea/P-9549-2015; Fox, Laura /C-6249-2016; Delitala, Alessandro/L-3194-2016; OI Biino, Ginevra/0000-0002-9936-946X; Angius, Andrea/0000-0003-2596-6461; Delitala, Alessandro/0000-0003-1729-8969; McKechanie, Andrew/0000-0003-4273-9906; Timpson, Nicholas/0000-0002-7141-9189; Mulas, Antonella/0000-0002-6856-1483; Marongiu, Michele/0000-0002-7289-9815; Steri, Anna Maristella/0000-0001-5869-3872; Soranzo, Nicole/0000-0003-1095-3852; Chiang, Charleston/0000-0002-0668-7865 FU US National Institutes of Health (National Institute on Aging, National Heart, Lung, and Blood Institute); US National Institutes of Health (National Human Genome Research Institute); National Human Genome Research Institute [HG005581, HG005552, HG006513, HG007089, HG007022]; National Heart, Lung, and Blood Institute [HL117626]; Intramural Research Program of the US National Institutes of Health, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]; Sardinian Autonomous Region [cRP3-154, L.R.7/2009]; grant FaReBio 'Farmaci e Reti Biotecnologiche di Qualita'; InterOmics MIUR Flagship Project [PB05]; US National Institutes of Health National Research Service Award (NRSA) [F32GM106656]; UC MEXUS-CONACYT [213627]; Italian Ministry of Education, University and Research (MIUR) grant [5571/DSPAR/2002]; Wellcome Trust [098051, WT091310]; European Research Council [ERC-2011-StG 280559-SEPI]; European Union (European Social Fund (ESF)); Greek national funds through the Operational Programme 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) research funding programme Heracleitus II, Investing in Knowledge Society Through the European Social Fund; Economic and Social Research Council; UK10K FX We thank all the volunteers who generously participated in this study and made this research possible. All participants provided informed consent, and the studies were approved by local research ethic committees: Comitato Etico di Azienda Sanitaria Locale 8, Lanusei (2009/0016600) and Comitato Etico di Azienda Sanitaria Locale 1, Sassari (2171/CE). This study was funded in part by the US National Institutes of Health (National Institute on Aging, National Heart, Lung, and Blood Institute, and National Human Genome Research Institute). This research was supported by National Human Genome Research Institute grants HG005581, HG005552, HG006513, HG007089, HG007022 and HG007089; by National Heart, Lung, and Blood Institute grant HL117626; by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging, contracts N01-AG-1-2109 and HHSN271201100005C; by Sardinian Autonomous Region (L.R.7/2009) grant cRP3-154; by grant FaReBio2011 'Farmaci e Reti Biotecnologiche di Qualita'; by the PB05 InterOmics MIUR Flagship Project; by a US National Institutes of Health National Research Service Award (NRSA) postdoctoral fellowship (F32GM106656) to C.W.K.C.; by UC MEXUS-CONACYT doctoral fellowship 213627 to D.O.D.V.; and by Italian Ministry of Education, University and Research (MIUR) grant 5571/DSPAR/2002. The HELIC study was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). The TEENAGE study has been supported by the Wellcome Trust (098051), European Union (European Social Fund (ESF)) and Greek national funds through the Operational Programme 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF) research funding programme Heracleitus II, Investing in Knowledge Society Through the European Social Fund. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. Information on how to access the data can be found on the Understanding Society website (https://www.understandingsociety.ac.uk/). This study makes use of data generated by the UK10K Consortium, derived from samples from UK10K_COHORTS_TWINSUK (the TwinsUK cohort) and UK10K_COHORT_ALSPAC (the Avon Longitudinal Study of Parents and Children cohort). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We thank J. Berg for scripts and suggestions on the polygenic score analysis. NR 35 TC 8 Z9 8 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2015 VL 47 IS 11 BP 1352 EP + DI 10.1038/ng.3403 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CV1BN UT WOS:000363988200020 PM 26366551 ER PT J AU Robinson, MR Hemani, G Medina-Gomez, C Mezzavilla, M Esko-, T Shakhbazov, K Powell, JE Vinkhuyzen, A Berndt, SI Gustafsson, S Justice, AE Kahali, B Locke, AE Pers, TH Vedantam, S Wood, AR van Rheenen, W Andreassen, OA Gasparini, P Metspalu, A van den Berg, LH Veldink, JH Rivadeneira, F Werge, TM Abecasis, GR Boomsma, DI Chasman, DI de Geus, EJC Frayling, TM Hirschhorn, JN Hottenga, JJ Ingelsson, E Loos, RJF Magnusson, PKE Martin, NG Montgomery, GW North, KE Pedersen, NL Spector, TD Speliotes, EK Goddard, ME Yang, J Visscher, PM AF Robinson, Matthew R. Hemani, Gibran Medina-Gomez, Carolina Mezzavilla, Massimo Esko-, Tonu Shakhbazov, Konstantin Powell, Joseph E. Vinkhuyzen, Anna Berndt, Sonja I. Gustafsson, Stefan Justice, Anne E. Kahali, Bratati Locke, Adam E. Pers, Tune H. Vedantam, Sailaja Wood, Andrew R. van Rheenen, Wouter Andreassen, Ole A. Gasparini, Paolo Metspalu, Andres van den Berg, Leonard H. Veldink, Jan H. Rivadeneira, Fernando Werge, Thomas M. Abecasis, Goncalo R. Boomsma, Dorret I. Chasman, Daniel I. de Geus, Eco J. C. Frayling, Timothy M. Hirschhorn, Joel N. Hottenga, Jouke Jan Ingelsson, Erik Loos, Ruth J. F. Magnusson, Patrik K. E. Martin, Nicholas G. Montgomery, Grant W. North, Kari E. Pedersen, Nancy L. Spector, Timothy D. Speliotes, Elizabeth K. Goddard, Michael E. Yang, Jian Visscher, Peter M. TI Population genetic differentiation of height and body mass index across Europe SO NATURE GENETICS LA English DT Article ID ESTIMATING F-STATISTICS; NATURAL-SELECTION; NONCOMMUNICABLE DISEASES; SYSTEMATIC ANALYSIS; GLOBAL VARIATION; COMPLEX TRAITS; HUMAN GENOME; COMMON SNPS; BURDEN; MORTALITY AB Across-nation differences in the mean values for complex traits are common(1-8), but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 x 10(-8); BMI, P < 5.95 x 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58). C1 [Robinson, Matthew R.; Hemani, Gibran; Shakhbazov, Konstantin; Powell, Joseph E.; Vinkhuyzen, Anna; Yang, Jian; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Medina-Gomez, Carolina; Rivadeneira, Fernando] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands. [Mezzavilla, Massimo; Gasparini, Paolo] Ist Ricovero & Cura Carattere Sci IRCCS, Inst Maternal & Child Hlth, Trieste, Italy. [Mezzavilla, Massimo] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Esko-, Tonu; Metspalu, Andres; Hirschhorn, Joel N.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko-, Tonu; Pers, Tune H.; Vedantam, Sailaja; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Esko-, Tonu; Pers, Tune H.; Vedantam, Sailaja; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Esko-, Tonu; Pers, Tune H.; Chasman, Daniel I.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Powell, Joseph E.; Yang, Jian; Visscher, Peter M.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gustafsson, Stefan] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Justice, Anne E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Kahali, Bratati; North, Kari E.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Kahali, Bratati; North, Kari E.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Locke, Adam E.; Abecasis, Goncalo R.; Speliotes, Elizabeth K.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Frayling, Timothy M.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. [van Rheenen, Wouter; van den Berg, Leonard H.; Veldink, Jan H.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands. [Andreassen, Ole A.] Univ Oslo, Oslo Univ Hosp, Norwegian Ctr Mental Disorders Res NORMENT, KG Jebsen Ctr Psychosis Res,Div Mental Hlth & Add, Oslo, Norway. [Andreassen, Ole A.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Werge, Thomas M.] Mental Hlth Devices Copenhagen, MHC Sct Hans, Inst Biol Psychiat, Roskilde, Denmark. [Werge, Thomas M.] Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark. [Werge, Thomas M.] Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark. [Boomsma, Dorret I.; de Geus, Eco J. C.; Hottenga, Jouke Jan] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Boomsma, Dorret I.; de Geus, Eco J. C.; Hottenga, Jouke Jan] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Boomsma, Dorret I.; de Geus, Eco J. C.; Hottenga, Jouke Jan] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Loos, Ruth J. F.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC,Epidemiol Unit, Cambridge CB2 2QQ, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Martin, Nicholas G.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Spector, Timothy D.] Kings Coll London, St Thomas Hosp, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Melbourne, Vic, Australia. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic, Australia. RP Robinson, MR (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. EM m.robinson11@uq.edu.au; peter.visscher@uq.edu.au RI Montgomery, Grant/B-7148-2008; Yang, Jian/A-5852-2010; Magnusson, Patrik/C-4458-2017; OI Vinkhuyzen, Anna/0000-0003-3352-0603; Visscher, Peter/0000-0002-2143-8760; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Yang, Jian/0000-0003-2001-2474; Mezzavilla, Massimo/0000-0002-9000-4595; Goddard, Michael/0000-0001-9917-7946; Locke, Adam/0000-0001-6227-198X; Rivadeneira, Fernando/0000-0001-9435-9441 FU Australian National Health and Medical Research Council (NHMRC) [1078037, 1048853, 1050218]; Australian Research Council [DE130100691]; Charles and Sylvia Viertel Senior Medical Research Fellowship; NHMRC [1052684]; Swedish Research Council [M-2005-1112]; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; US National Institutes of Health (NIH) [DK U01-066134]; Swedish Foundation for Strategic Research (SSF); Heart and Lung Foundation [20070481]; Netherlands Organization for Scientific Research (NWO; MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-11-09-032, Spinozapremie 56-464-14192]; Center for Medical Systems Biology (CSMB; NWO Genomics); NBIC/BioAssist/RK [2008.024]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) [184.021.007]; VU University's Institute for Health and Care Research (EMGO+); Neuroscience Campus Amsterdam (NCA); European Science Foundation (ESF) [EU/QLRT-2001-01254]; European Community [HEALTH-F4-2007-201413]; European Research Council (ERC) [230374]; Rutgers University Cell and DNA Repository (National Institute for Mental Health (NIMH)) [U24-MH068457-06]; Avera Institute (Sioux Falls, South Dakota, USA); US NIH [R01-D0042157-01A, 1RC2-MH089951-01, 1RC2-MH089995-01, AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; Wellcome Trust; UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; King's College London; National Eye Institute via a US NIH/Center for Inherited Disease Research (CIDR); National Heart, Lung, and Blood Institute (NHLBI); Boston University [N01-HC-25195]; NHLBI [N02-HL-64278]; Illumina; Australian NHMRC [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485]; Health Research Board, Ireland; National Institute on Aging (NIA) [U01-AG09740]; ALS Foundation Netherlands FX We thank the reviewers for their very helpful and insightful comments that greatly improved the manuscript. We also thank B. Hill and O. Ovaskainen for useful discussions. The University of Queensland group is supported by the Australian National Health and Medical Research Council (NHMRC; grants 1078037, 1048853 and 1050218). J.E.P. is supported by Australian Research Council grant DE130100691. J.Y. is supported by a Charles and Sylvia Viertel Senior Medical Research Fellowship and by NHMRC grant 1052684. We thank our colleagues at the Centre for Neurogenetics and Statistical Genomics for comments and suggestions. We are grateful to the twins and their families for their generous participation in the full-sibling family data set, which includes data from many cohorts and received support from many funding bodies. TWINGENE was supported by the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254 and QLG2-CT-2002-01254), US National Institutes of Health (NIH) grant DK U01-066134, the Swedish Foundation for Strategic Research (SSF), and the Heart and Lung Foundation (20070481). For the Netherlands Twin Register (NTR), funding was obtained from the Netherlands Organization for Scientific Research (NWO; MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-11-09-032 and Spinozapremie 56-464-14192), the Center for Medical Systems Biology (CSMB; NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL; 184.021.007), the VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), the European Science Foundation (ESF; EU/QLRT-2001-01254), the European Community's Seventh Framework Programme (FP7/2007-2013) under the ENGAGE project grant agreement (HEALTH-F4-2007-201413), the European Research Council (ERC Advanced; 230374), the Rutgers University Cell and DNA Repository (National Institute for Mental Health (NIMH), U24-MH068457-06), the Avera Institute (Sioux Falls, South Dakota, USA) and the US NIH (R01-D0042157-01A, Grand Opportunity grants 1RC2-MH089951-01 and 1RC2-MH089995-01). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The TwinsUK study was funded by the Wellcome Trust and the European Community's Seventh Framework Programme (FP7/2007-2013) under the ENGAGE project grant agreement (HEALTH-F4-2007-201413). TwinsUK also receives support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. T.D.S. is the holder of an ERC Advanced Principal Investigator award. Genotyping for the TwinsUK study was performed by the Wellcome Trust Sanger Institute, with the support of the National Eye Institute via a US NIH/Center for Inherited Disease Research (CIDR) genotyping project. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI contract N02-HL-64278.; Funding for SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. The QIMR researchers acknowledge funding from the Australian NHMRC (grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688 and 552485) and the US NIH (grants AA07535, AA10248, AA014041, AA13320, AA13321, AA13326 and DA12854). We are grateful to M. Gill (Trinity College Dublin) and K. Nicodemus (University of Edinburgh) for access to the ISC-Trinity College Dublin cohort, which was supported by the Wellcome Trust and the Health Research Board, Ireland. Access to the Bulgarian cohort data was kindly facilitated by G. Kirov and V. Excott-Price. For the Danish cohort, the Danish Scientific Committees and the Danish Data Protection Agency approved the study and all the patients gave written informed consent before inclusion in the project. The National Institute on Aging (NIA) provided funding for the Health and Retirement Study (HRS; U01-AG09740). The HRS is performed at the Institute for Social Research at the University of Michigan. This manuscript was not prepared in collaboration with investigators of the HRS and does not necessarily reflect the opinions or views of the HRS, University of Michigan or NIA. The Netherlands genotype samples were part of Project MinE, which was supported by the ALS Foundation Netherlands. Research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). NR 58 TC 13 Z9 13 U1 8 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2015 VL 47 IS 11 BP 1357 EP + DI 10.1038/ng.3401 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CV1BN UT WOS:000363988200021 PM 26366552 ER PT J AU Yang, W Lee, YS AF Yang, Wei Lee, Young-Sam TI A DNA-hairpin model for repeat-addition processivity in telomere synthesis SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID CATALYTIC SUBUNIT TERT; TETRAHYMENA TELOMERASE; REVERSE-TRANSCRIPTASE; STRUCTURAL BASIS; RNA; TEMPLATE; FIDELITY; SEQUENCE; BINDING AB We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis. C1 [Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Young-Sam] Samsung Adv Inst Technol, Well Aging Res Ctr, Suwon, South Korea. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [DK036146-08] NR 35 TC 2 Z9 2 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2015 VL 22 IS 11 BP 844 EP 847 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CV4ZA UT WOS:000364273800005 PM 26581517 ER PT J AU Freudenthal, BD Beard, WA Cuneo, MJ Dyrkheeva, NS Wilson, SH AF Freudenthal, Bret D. Beard, William A. Cuneo, Matthew J. Dyrkheeva, Nadezhda S. Wilson, Samuel H. TI Capturing snapshots of APE1 processing DNA damage SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; BASE EXCISION-REPAIR; HUMAN ABASIC ENDONUCLEASE; DOUBLE-STRANDED DNA; METAL-BINDING SITE; INCISION ACTIVITY; CATALYTIC MECHANISM; PHOSPHODIESTER-BOND; POLYMERASE-BETA; CPG ISLANDS AB DNA apurinic-apyrimidinic (AP) sites are prevalent noncoding threats to genomic stability and are processed by AP endonuclease 1 (APE1). APE1 incises the AP-site phosphodiester backbone, generating a DNA-repair intermediate that is potentially cytotoxic. The molecular events of the incision reaction remain elusive, owing in part to limited structural information. We report multiple high-resolution human APE1-DNA structures that divulge new features of the APE1 reaction, including the metal-binding site, the nucleophile and the arginine clamps that mediate product release. We also report APE1-DNA structures with a T-G mismatch 5' to the AP site, representing a clustered lesion occurring in methylated CpG dinucleotides. These structures reveal that APE1 molds the T-G mismatch into a unique Watson-Crick-like geometry that distorts the active site, thus reducing incision. These snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage. C1 [Freudenthal, Bret D.; Beard, William A.; Dyrkheeva, Nadezhda S.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Cuneo, Matthew J.] Oak Ridge Natl Lab, Neutron Sci Directorate, Oak Ridge, TN USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov OI Cuneo, Matthew/0000-0002-1475-6656 FU US National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050161]; United States Department of Energy, Office of Basic Energy Sciences; Eli Lilly and Co.; United States Department of State, as part of the United States-Russia Collaboration in the Biomedical Sciences US National Institutes of Health Visiting Fellows Program FX We thank the Collaborative Crystallography group at NIEHS for help with data collection and analysis. We thank L. Pedersen and L. Perera for valuable discussions. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (project numbers Z01-ES050158 and Z01-ES050161 (S.H.W.)). A part of this research was performed at Oak Ridge National Laboratory's Spallation Neutron Source and the Joint Institute for Neutron Sciences Biophysical Characterization Laboratory, sponsored by the United States Department of Energy, Office of Basic Energy Sciences (M.J.C.). N.S.D is supported in part by Eli Lilly and Co. and the United States Department of State, as part of the United States-Russia Collaboration in the Biomedical Sciences US National Institutes of Health Visiting Fellows Program. NR 57 TC 12 Z9 13 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2015 VL 22 IS 11 BP 924 EP 931 DI 10.1038/nsmb.3105 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CV4ZA UT WOS:000364273800017 PM 26458045 ER PT J AU Miyabe, I Mizuno, K Keszthelyi, A Daigaku, Y Skouteri, M Mohebi, S Kunkel, TA Murray, JM Carr, AM AF Miyabe, Izumi Mizuno, Ken'Ichi Keszthelyi, Andrea Daigaku, Yasukazu Skouteri, Meliti Mohebi, Saed Kunkel, Thomas A. Murray, Johanne M. Carr, Antony M. TI Polymerase delta replicates both strands after homologous recombination-dependent fork restart SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BREAK-INDUCED REPLICATION; GROSS CHROMOSOMAL REARRANGEMENTS; ONCOGENE-INDUCED SENESCENCE; CONSERVATIVE DNA-SYNTHESIS; GENOME INSTABILITY; TEMPLATE EXCHANGE; INVERTED REPEATS; DAMAGE RESPONSE; CNV FORMATION; HUMAN-CELLS AB To maintain genetic stability, DNA must be replicated only once per cell cycle, and replication must be completed even when individual replication forks are inactivated. Because fork inactivation is common, passive convergence of an adjacent fork is insufficient to rescue all inactive forks. Thus, eukaryotic cells have evolved homologous recombination-dependent mechanisms to restart persistent inactive forks. Completing DNA synthesis via homologous recombination-restarted replication (HoRReR) ensures cell survival, but at a cost. One such cost is increased mutagenesis because HoRReR is more error prone than canonical replication. This increased error rate implies the HoRReR mechanism is distinct from that of a canonical fork. Here we demonstrate, in Schizosaccharomyces pombe, that a DNA sequence duplicated by HoRReR during S phase is replicated semiconservatively, but both the leading and lagging strands are synthesized by DNA polymerase delta. C1 [Miyabe, Izumi; Mizuno, Ken'Ichi; Keszthelyi, Andrea; Skouteri, Meliti; Mohebi, Saed; Murray, Johanne M.; Carr, Antony M.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. [Daigaku, Yasukazu] Tohoku Univ, Frontier Res Inst Interdisciplinary Sci, Sendai, Miyagi 980, Japan. [Kunkel, Thomas A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Carr, AM (reprint author), Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. EM a.m.carr@sussex.ac.uk RI Mizuno, Ken'Ichi/P-7350-2015 OI Mizuno, Ken'Ichi/0000-0001-8115-7808 FU Division of Intramural Research of the US National Institutes of Health [Z01 ES065070]; Medical Research Council (UK) [G0801078, G1100074]; European Research Council [268788-SMI-DDR] FX This work was supported by Project Z01 ES065070 (T.A.K.) from the Division of Intramural Research of the US National Institutes of Health, by Medical Research Council (UK) grants G0801078 and G1100074 (A.M.C.) and by European Research Council grant 268788-SMI-DDR (A.M.C.). We thank H. Masukata (Osaka University) for the cdc20::hphMX6-Pnmtl-cdc2OCTD strain. NR 53 TC 7 Z9 7 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD NOV PY 2015 VL 22 IS 11 BP 932 EP 938 DI 10.1038/nsmb.3100 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CV4ZA UT WOS:000364273800018 PM 26436826 ER PT J AU Findling, RL Robb, A McNamara, NK Pavuluri, MN Kafantaris, V Scheffer, R Frazier, JA Rynn, M DelBello, M Kowatch, RA Rowles, BM Lingler, J Martz, K Anand, R Clemons, TE Taylor-Zapata, P AF Findling, Robert L. Robb, Adelaide McNamara, Nora K. Pavuluri, Mani N. Kafantaris, Vivian Scheffer, Russell Frazier, Jean A. Rynn, Moira DelBello, Melissa Kowatch, Robert A. Rowles, Brieana M. Lingler, Jacqui Martz, Karen Anand, Ravinder Clemons, Traci E. Taylor-Zapata, Perdita TI Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study SO PEDIATRICS LA English DT Article ID DEPRESSION RATING-SCALE; SUICIDE ATTEMPTS; CONTROLLED-TRIAL; ADOLESCENTS; CHILDREN; MANIA; RELIABILITY; VALIDITY; YOUTH; METAANALYSIS AB BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 +/- 3.1 mIU/L) compared with placebo (-0.1 +/- 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder. C1 [Findling, Robert L.] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD 21287 USA. [Robb, Adelaide] George Washington Univ, Childrens Natl Med Ctr, Washington, DC USA. [McNamara, Nora K.; Lingler, Jacqui] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. [Pavuluri, Mani N.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Kafantaris, Vivian] Zucker Hillside Hosp, Manhasset, NY USA. [Kafantaris, Vivian] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Scheffer, Russell] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Frazier, Jean A.] Univ Massachusetts, Sch Med, UMASS Mem Med Ctr, Dept Psychiat, Worcester, MA USA. [Rynn, Moira] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [DelBello, Melissa] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Kowatch, Robert A.] Ohio State Univ, Nationwide Childrens Hosp, Wexner Med Ctr, Columbus, OH 43210 USA. [Rowles, Brieana M.] UPMC CancerCtr, Pittsburgh, PA USA. [Martz, Karen; Anand, Ravinder; Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Taylor-Zapata, Perdita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Findling, RL (reprint author), Johns Hopkins Univ, 1800 Orleans St,Suite 12344A, Baltimore, MD 21287 USA. EM rfindli1@jhmi.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200503406C]; National Institutes of Health (NIH) FX This work was sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, "Best Pharmaceuticals for Children Act Pediatric Off-Patent Drug Study (PODS): Lithium in the Treatment of Pediatric Mania" (contract HHSN275200503406C). Funded by the National Institutes of Health (NIH). NR 33 TC 7 Z9 7 U1 8 U2 13 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2015 VL 136 IS 5 BP 885 EP 894 DI 10.1542/peds.2015-0743 PG 10 WC Pediatrics SC Pediatrics GA CV0US UT WOS:000363969600053 PM 26459650 ER PT J AU Nesin, M Sparer, O AF Nesin, Mirjana Sparer, Olivia TI Vaccine monitoring systems: A potential model for medications in pregnancy SO SEMINARS IN PERINATOLOGY LA English DT Review DE Vaccine safety monitoring; Maternal immunizations; Medications in pregnancy ID SAFETY; IMMUNIZATION; PROGRAM; MOTHERS AB Multiple vaccine safety systems contribute to monitor and assess the safety of vaccines given to pregnant women and their offspring. This article presents a review of the strengths and limitations of several national vaccine safety systems. The review concludes that the present framework of vaccine safety systems offers lessons to be learned toward the design of a system for monitoring and assessing the safety of medications administered to pregnant women in clinical practice and research. Published by Elsevier Inc. C1 [Nesin, Mirjana; Sparer, Olivia] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Nesin, M (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 5601 Fishers Lane,MSC 9806, Bethesda, MD 20892 USA. EM nesinm@niaid.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD NOV PY 2015 VL 39 IS 7 BP 524 EP 529 DI 10.1053/j.semperi.2015.08.005 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CV4VY UT WOS:000364265800005 PM 26433628 ER PT J AU Ren, ZX Zajicek, A AF Ren, Zhaoxia Zajicek, Anne TI Review of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act: What can the obstetric community learn from the pediatric experience? SO SEMINARS IN PERINATOLOGY LA English DT Review DE Pediatrics; Medications; Pharmacology; Clinical trials; Obstetrics; Labeling; FDA; Safety; Efficacy; Pharmacokinetics; Outcome measures AB Children have been called therapeutic orphans as they have been excluded from drug research and new drug development resulting in the lack of proper labels for majority of the drugs for pediatric use. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are two legislative mandates to improve pediatric drug labeling. The BPCA legislation authorizes the National Institutes of Health (NIH) to implement research programs through funding clinical trials to study off-patent drugs in pediatric population. Obstetric pharmacology research gaps are in many ways similar to those in pediatrics, including off-label use of common medications, and lack of knowledge of appropriate dosing, safety, and efficacy of drugs. Much research is needed to define mechanisms of disease and drug actions in pregnant women to fill the knowledge gaps. Published by Elsevier Inc. C1 [Ren, Zhaoxia; Zajicek, Anne] NICHHD, Obstet & Pediat Pharmacol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Zajicek, A (reprint author), NICHHD, Obstet & Pediat Pharmacol & Therapeut Branch, NIH, 6100 Execut Blvd,Suite 4A01,MSC 7510, Bethesda, MD 20892 USA. EM zajiceka@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 4 TC 2 Z9 2 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD NOV PY 2015 VL 39 IS 7 BP 530 EP 531 DI 10.1053/j.semperi.2015.08.006 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CV4VY UT WOS:000364265800006 PM 26455383 ER PT J AU White, A AF White, Amina TI Accelerating the paradigm shift toward inclusion of pregnant women in drug research: Ethical and regulatory considerations SO SEMINARS IN PERINATOLOGY LA English DT Review ID CLINICAL-RESEARCH; TRIALS; RISK AB Although there has been long-standing reluctance to include pregnant women as clinical trial participants, increasing recognition of profound gaps in research on the safety and efficacy of drugs often prescribed to pregnant women calls into question the practice of routinely excluding them. This article presents compelling reasons for including pregnant women in clinical research, highlights certain regulatory barriers to the inclusion of pregnant women, and proposes that professional societies with expertise in obstetrics and maternal-fetal medicine can be instrumental in hastening the paradigm shift from the systematic exclusion of pregnant women in research to a one of responsible and fair inclusion. Published by Elsevier Inc. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP White, A (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM Amina.white@nih.gov NR 23 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD NOV PY 2015 VL 39 IS 7 BP 537 EP 540 DI 10.1053/j.semperi.2015.08.008 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CV4VY UT WOS:000364265800008 PM 26385413 ER PT J AU Nguyen, NL Powers, KA Hughes, JP MacPhail, CL Piwowar-Manning, E Patel, EU Gomez-Olive, FX Kahn, K Pettifor, AE AF Nguyen, Nadia L. Powers, Kimberly A. Hughes, James P. MacPhail, Catherine L. Piwowar-Manning, Estelle Patel, Eshan U. Gomez-Olive, F. Xavier Kahn, Kathleen Pettifor, Audrey E. TI Sexual Partnership Patterns Among South African Adolescent Girls Enrolled in STI Preventions Trial Network 068: Measurement Challenges and Implications for HIV/STI Transmission SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SUB-SAHARAN AFRICA; CONCURRENT PARTNERSHIPS; HIV EPIDEMICS; ROSENTHAL; LURIE; GAPS; DYNAMICS; LENGTHS; DISEASE; HEALTH AB Background Estimates of sexual partnership durations, gaps between partnerships, and overlaps across partnerships are important for understanding sexual partnership patterns and developing interventions to prevent transmission of HIV/sexually transmitted infections (STIs). However, a validated, optimal approach for estimating these parameters, particularly when partnerships are ongoing, has not been established. Methods We assessed 4 approaches for estimating partnership parameters using cross-sectional reports on dates of first and most recent sex and partnership status (ongoing or not) from 654 adolescent girls in rural South Africa. The first, commonly used, approach assumes all partnerships have ended, resulting in underestimated durations for ongoing partnerships. The second approach treats reportedly ongoing partnerships as right-censored, resulting in bias if partnership status is reported with error. We propose 2 hybrid approaches, which assign partnership status to reportedly ongoing partnerships based on how recently girls last had sex with their partner. We estimate partnership duration, gap length, and overlap length under each approach using Kaplan-Meier methods with a robust variance estimator. Results Median partnership duration and overlap length varied considerably across approaches (from 368 to 1024 days and 168 to 409 days, respectively), but gap length was stable. Lifetime prevalence of concurrency ranged from 28% to 33%, and at least half of gap lengths were shorter than 6 months, suggesting considerable potential for HIV/STI transmission. Conclusions Estimates of partnership duration and overlap lengths are highly dependent on measurement approach. Understanding the effect of different approaches on estimates is critical for interpreting partnership data and using estimates to predict HIV/STI transmission rates. C1 [Nguyen, Nadia L.; Powers, Kimberly A.; Pettifor, Audrey E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [MacPhail, Catherine L.] Univ New England, Armidale, NSW, Australia. [Piwowar-Manning, Estelle] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Patel, Eshan U.] NIH, Bethesda, MD 20892 USA. [Gomez-Olive, F. Xavier; Kahn, Kathleen] Agincourt, MRC Wits Rural Publ Hlth & Hlth Transit Res Unit, Johannesburg, South Africa. RP Nguyen, NL (reprint author), 135 Dauer Dr,2101 McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM nadia.nguyen@unc.edu OI Patel, Eshan/0000-0003-2174-5004 FU National Institutes of Health [T32 AI007001, KL2 TR001109]; National Institute of Mental Health [R01 MH087118, UM1 AI068619, UM1 AI068617, UM1 AI068613]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse FX Financial support: This work was supported by the National Institutes of Health (T32 AI007001, KL2 TR001109), the National Institute of Mental Health (R01 MH087118), and the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases. Additional support was provided, in part, by the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, and the National Institute of Mental Health through Cooperative Agreements (UM1 AI068619, UM1 AI068617, and UM1 AI068613). NR 31 TC 1 Z9 1 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD NOV PY 2015 VL 42 IS 11 BP 612 EP 618 DI 10.1097/OLQ.0000000000000357 PG 7 WC Infectious Diseases SC Infectious Diseases GA CV2LY UT WOS:000364089400003 PM 26462185 ER PT J AU Hofer, E Cavalieri, M Bis, JC DeCarli, C Fornage, M Sigurdsson, S Srikanth, V Trompet, S Verhaaren, BFJ Wolf, C Yang, Q Adams, HHH Amouyel, P Beiser, A Buckley, BM Callisaya, M Chauhan, G de Craen, AJM Dufouil, C van Duijn, CM Ford, I Freudenberger, P Gottesman, RF Gudnason, V Heiss, G Hofman, A Lumley, T Martinez, O Mazoyer, B Moran, C Niessen, WJ Phan, T Psaty, BM Satizabal, CL Sattar, N Schilling, S Shibata, DK Slagboom, PE Smith, A Stott, DJ Taylor, KD Thomson, R Toglhofer, AM Tzourio, C van Buchem, M Wang, J Westendorp, RGJ Windham, BG Vernooij, MW Zijdenbos, A Beare, R Debette, S Ikram, MA Jukema, JW Launer, LJ Longstreth, WT Mosley, TH Seshadri, S Schmidt, H Schmidt, R AF Hofer, Edith Cavalieri, Margherita Bis, Joshua C. DeCarli, Charles Fornage, Myriam Sigurdsson, Sigurdur Srikanth, Velandai Trompet, Stella Verhaaren, Benjamin F. J. Wolf, Christiane Yang, Qiong Adams, Hieab H. H. Amouyel, Philippe Beiser, Alexa Buckley, Brendan M. Callisaya, Michele Chauhan, Ganesh de Craen, Anton J. M. Dufouil, Carole van Duijn, Cornelia M. Ford, Ian Freudenberger, Paul Gottesman, Rebecca F. Gudnason, Vilmundur Heiss, Gerardo Hofman, Albert Lumley, Thomas Martinez, Oliver Mazoyer, Bernard Moran, Chris Niessen, Wiro J. Thanh Phan Psaty, Bruce M. Satizabal, Claudia L. Sattar, Naveed Schilling, Sabrina Shibata, Dean K. Slagboom, P. Eline Smith, Albert Stott, David J. Taylor, Kent D. Thomson, Russell Toeglhofer, Anna M. Tzourio, Christophe van Buchem, Mark Wang, Jing Westendorp, Rudi G. J. Windham, B. Gwen Vernooij, Meike W. Zijdenbos, Alex Beare, Richard Debette, Stephanie Ikram, M. Arfan Jukema, J. Wouter Launer, Lenore J. Longstreth, W. T., Jr. Mosley, Thomas H. Seshadri, Sudha Schmidt, Helena Schmidt, Reinhold CA Cohorts Heart Aging Res Genomic Ep TI White Matter Lesion Progression Genome-Wide Search for Genetic Influences SO STROKE LA English DT Article ID SMALL-VESSEL DISEASE; RENIN-ANGIOTENSIN SYSTEM; CEREBROVASCULAR RISK-FACTORS; AUSTRIAN STROKE PREVENTION; ANALYSIS IDENTIFIES 13; ELDERLY MALE TWINS; BLOOD-PRESSURE; HYPERINTENSITY VOLUME; CAROTID ATHEROSCLEROSIS; FUNCTIONAL ANNOTATION C1 [Hofer, Edith; Schmidt, Helena] Med Univ Graz, Dept Neurol, A-8036 Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Shibata, Dean K.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol & Epidemiol, Seattle, WA 98195 USA. [DeCarli, Charles; Martinez, Oliver] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles; Martinez, Oliver] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Gudnason, Vilmundur; Smith, Albert] Iceland Heart Assoc, Kopavogur, Iceland. [Srikanth, Velandai; Moran, Chris; Thanh Phan; Beare, Richard] Monash Univ, Southern Clin Sch, Dept Med, Stroke & Ageing Res Grp, Melbourne, Vic 3004, Australia. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.; Westendorp, Rudi G. J.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [van Buchem, Mark] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Verhaaren, Benjamin F. J.; Adams, Hieab H. H.; van Duijn, Cornelia M.; Hofman, Albert; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Verhaaren, Benjamin F. J.; Adams, Hieab H. H.; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Niessen, Wiro J.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Wolf, Christiane; Chauhan, Ganesh; Dufouil, Carole; Debette, Stephanie] Univ Bordeaux Segalen, INSERM U897, Bordeaux, France. [Mazoyer, Bernard] Univ Bordeaux Segalen, CNRS CEA UMR5296, Bordeaux, France. [Tzourio, Christophe] Univ Bordeaux Segalen, INSERM U708, Bordeaux, France. [Wolf, Christiane] Max Planck Inst Psychiat, Dept Stat Genet, D-80804 Munich, Germany. [Yang, Qiong; Beiser, Alexa; Wang, Jing] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Amouyel, Philippe] Inst Pasteur, INSERM U744, F-59019 Lille, France. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Chauhan, Ganesh; Debette, Stephanie] Univ Paris 07, INSERM U1161, Paris, France. [Chauhan, Ganesh; Debette, Stephanie] Univ Paris 07, Lariboisiere Hosp, Paris, France. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Freudenberger, Paul; Toeglhofer, Anna M.; Schmidt, Helena] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Res Unit Genet Epidemiol, Graz, Austria. [Gottesman, Rebecca F.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Gudnason, Vilmundur; Smith, Albert] Univ Iceland, Reykjavik, Iceland. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Satizabal, Claudia L.; Debette, Stephanie] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Sattar, Naveed; Stott, David J.] Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Taylor, Kent D.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Los Angeles, CA USA. [Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Thomson, Russell] Menzies Res Inst, Hobart, Tas, Australia. [Westendorp, Rudi G. J.] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Windham, B. Gwen; Mosley, Thomas H.] Univ Mississippi, Dept Med, Jackson, MS 39216 USA. [Zijdenbos, Alex] Biospective Inc, Montreal, PQ, Canada. [Beare, Richard] Royal Childrens Hosp, Murdoch Childrens Res Inst, Dev Imaging, Parkville, Vic 3052, Australia. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. RP Schmidt, R (reprint author), Med Univ Graz, Dept Neurol, Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria. EM reinhold.schmidt@medunigraz.at RI Vernooij, Meike/E-4061-2016; Tzourio, christophe/B-4015-2009; Callisaya, Michele/I-2333-2013 OI Tzourio, christophe/0000-0002-6517-2984; Callisaya, Michele/0000-0003-2122-1622 FU National Institute on Aging (NIA) [N01-AG-12100]; National Heart, Lung, and Blood Institute (NHLBI); NIA Intramural Research Program, Hjartavernd; Icelandic Heart Association; Althingi (the Icelandic Parliament); NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH; Austrian Science Fond (Fonds zur Forderung der wissenschaftlichen Forschung) [P20545-P05, P13180]; Medical University of Graz; NIA [R01AG023629]; National Center for Advancing Translational Sciences, University of California Los Angeles Clinical and Translational Science Institute [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]; NHLBI's FHS [N01-HC-25195]; Affymetrix, Inc for genotyping services [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of NINDS [R01 NS17950]; National Institute of Aging [R01s AG08122, AG16495, AG033193, U0149505]; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (NGI; Netherlands Consortium for Healthy Aging grant) [050-060-810]; Netherlands Organization of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) [175.010.2005.011]; NGI/Netherlands Organization for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization of Scientific Research (NWO) [918-46-615, 904-61-096, 904-61-133, 948-00-010]; Dutch Heart Foundation (Nederlandse Hartstichting) [2009B102]; Dutch Technology Foundation Stichting Technische Wetenschappen Perspectief programme ImaGene; EU; National Health and Medical Research Council (NHMRC) [403000, 491109, 606543]; Wicking Dementia Education and Research Centre; NHMRC/National Heart Foundation; Heart Foundation; NHMRC; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France; Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques; Eisai; National Foundation for Alzheimer Disease and Related Disorders; Institut Pasteur de Lille; Centre National de Genotypage; French National Research Agency; Fondation Leducq; [UL1RR025005]; [HL093029]; [HHSN268201200036C]; [HHSN268200800007C]; [N01HC55222]; [N01HC85079]; [N01HC85080]; [N01HC85081]; [N01HC85082]; [N01HC85083]; [N01HC85086]; [N01HC15103]; [U01HL080295]; [R01HL087652]; [R01HL105756]; [R01HL103612]; [R01HL120393]; [U01 HL096917]; [R01 HL093029] FX Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by the National Institute on Aging (NIA) contract N01-AG-12100 with contributions from the National Eye Institute, the National Institute on Deafness and Other Communication Disorders and the National Heart, Lung, and Blood Institute (NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Atherosclerosis Risk in Communities Study: The research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Funds for this project were also supported by grant HL093029 to Dr Fornage. Austrian Stroke Prevention Study (ASPS): The research reported in this article was funded by the Austrian Science Fond (Fonds zur Forderung der wissenschaftlichen Forschung) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. Cardiovascular Health Study (CHS): This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and N01HC15103; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, University of California Los Angeles Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Framingham Heart Study (FHS): From the FHS of the NHLBI of the NIH and Boston University School of Medicine. This work was supported by the NHLBI's FHS (contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of NINDS (R01 NS17950), the National Institute of Aging (R01s AG08122, AG16495, AG033193, and U0149505) and the NHLBI (U01 HL096917 and R01 HL093029). Prospective Study of Pravastatin in the Elderly at Risk: This study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Dr. Jukema is an established clinical investigator of the Netherlands Heart Foundation (grant 2001 D 032).; Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (NGI; Netherlands Consortium for Healthy Aging grant 050-060-810). Rotterdam Study (RS): The GWA database of the RS was funded through the Netherlands Organization of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; no. 175.010.2005.011). This study was further supported by the NGI/Netherlands Organization for Scientific Research (NWO) project no. 050-060-810. The RS is supported by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Rotterdam Scan Study was supported by the Netherlands Organization of Scientific Research (NWO) project nos. 918-46-615, 904-61-096, 904-61-133, and 948-00-010. Dr Verhaaren was supported by the Dutch Heart Foundation (Nederlandse Hartstichting), grant number 2009B102. Erasmus Medical Center was further supported by the Dutch Technology Foundation Stichting Technische Wetenschappen Perspectief programme ImaGene and the EU Seventh Framework Programme for Research (FP7) grant VPH-Dare@IT (Virtual Physiological Human: DementiA Research Enabled By IT). Tasmanian Study of Cognition and Gait: This study is supported by Project Grants from the National Health and Medical Research Council (NHMRC IDs 403000, 491109, and 606543), and a grant from the Wicking Dementia Education and Research Centre, Hobart. Dr Srikanth is supported by an NHMRC/National Heart Foundation Career Development Fellowship and a Heart Foundation Future Fellowship. Dr Thomson is supported by an NHMRC Project Grant. Three City Study (3C): The 3C Study is conducted under a partnership agreement between the Institut National de la Sante et de la Recherche Medicale (INSERM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques. Lille Genopole received an unconditional grant from Eisai. This work was supported by the National Foundation for Alzheimer Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. Dr Debette is recipient of a Chair of Excellence grant from the French National Research Agency. Drs Tzourio and Debette are supported by a grant from the Fondation Leducq. NR 67 TC 3 Z9 3 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2015 VL 46 IS 11 BP 3048 EP 3057 PG 10 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CV0WN UT WOS:000363974500004 PM 26451028 ER PT J AU Lutsep, HL Lynn, MJ Cotsonis, GA Derdeyn, CP Turan, TN Fiorella, D Janis, LS Lane, BF Montgomery, J Chimowitz, MI AF Lutsep, Helmi L. Lynn, Michael J. Cotsonis, George A. Derdeyn, Colin P. Turan, Tanya N. Fiorella, David Janis, L. Scott Lane, Bethany F. Montgomery, Jean Chimowitz, Marc I. CA SAMMPRIS Investigators TI Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis? SO STROKE LA English DT Article ID ARTERIAL-STENOSIS; SAMMPRIS; STROKE C1 [Lutsep, Helmi L.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Lynn, Michael J.; Cotsonis, George A.; Lane, Bethany F.; Montgomery, Jean] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Turan, Tanya N.; Chimowitz, Marc I.] Med Univ S Carolina, Dept Neurol, Charleston, SC USA. [Fiorella, David] SUNY Coll Old Westbury, Dept Neurol Surg, Old Westbury, NY USA. [Janis, L. Scott] NIH, Bethesda, MD 20892 USA. RP Lutsep, HL (reprint author), Oregon Hlth & Sci Univ, Oregon Stroke Ctr, 3181 SW Sam Jackson Pk Rd,CR131, Portland, OR 97239 USA. EM lutseph@ohsu.edu OI Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728]; Stryker Neurovascular FX Stenting Versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) U01 NS058728. Stryker Neurovascular provided study devices and supplemental funding for third party device distribution, site monitoring, and study auditing and AstraZeneca donated rosuvastatin (Crestor) to study patients in the SAMMPRIS trial. NR 5 TC 7 Z9 7 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2015 VL 46 IS 11 BP 3282 EP 3284 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CV0WN UT WOS:000363974500041 PM 26382173 ER PT J AU Iordanskiy, S Van Duyne, R Sampey, GC Woodson, CM Fry, K Saifuddin, M Guo, J Wu, YT Romerio, F Kashanchi, F AF Iordanskiy, Sergey Van Duyne, Rachel Sampey, Gavin C. Woodson, Caitlin M. Fry, Kelsi Saifuddin, Mohammed Guo, Jia Wu, Yuntao Romerio, Fabio Kashanchi, Fatah TI Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells SO VIROLOGY LA English DT Article DE HIV-1 latency; CD4+T cells; Monocytes; X-ray; Irradiation; Transcription; Apoptosis; HIV-1 reactivation; Humanized mice ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; HUMANIZED MOUSE MODELS; LONG TERMINAL REPEAT; NF-KAPPA-B; HISTONE DEACETYLASE INHIBITORS; HEMATOPOIETIC STEM-CELLS; HIV-1 TAR ELEMENT; DNA-DAMAGE; LATENT HIV AB The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4(+) T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the "Shock and Kill" strategy for latently HIV-1 infected cells. (C) 2015 Elsevier Inc. All rights reserved. C1 [Iordanskiy, Sergey; Van Duyne, Rachel; Sampey, Gavin C.; Woodson, Caitlin M.; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao; Kashanchi, Fatah] George Mason Univ, Mol Virol Lab, Sch Syst Biol, Manassas, VA 20110 USA. [Van Duyne, Rachel] NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Romerio, Fabio] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Kashanchi, F (reprint author), George Mason Univ, Mol Virol Lab, Discovery Hall,Room 182,10900 Univ Blvd MS 1H8, Manassas, VA 20110 USA. EM fkashanc@gmu.edu FU NIH [AI043894, AI114490, AI113140] FX The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: U1 and ACH-2 cells from Dr. Thomas Folks; HIV-1 89.6 dual-tropic viral strain from Dr. Ronald Collman; anti-HIV-1 p24 mouse monoclonal antibody from Dr. Michael Malim. The antiretrovirals lamivudine/emtricitabine, tenofovir, indinavir, raltegravir, and maraviroc as well as LRA bryostatin 1 were also from AIDS Research and Reference Reagent Program. The HIV-1 proviral clone NL was kindly provided by Dr. Lee Ratner. Authors are grateful to Dr. Shabana Shabbeer Meyering for reading of the manuscript This work was supported by NIH grants AI043894, AI114490, and AI113140 to FK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 119 TC 8 Z9 8 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2015 VL 485 BP 1 EP 15 DI 10.1016/j.virol.2015.06.021 PG 15 WC Virology SC Virology GA CV1DH UT WOS:000363993100001 PM 26184775 ER PT J AU Johnson, RF Via, LE Kumar, MR Cornish, JP Yellayi, S Huzella, L Postnikova, E Oberlander, N Bartos, C Ork, BL Mazur, S Allan, C Holbrook, MR Solomon, J Johnson, JC Pickel, J Hensley, LE Jahrling, PB AF Johnson, Reed F. Via, Laura E. Kumar, Mia R. Cornish, Joseph P. Yellayi, Srikanth Huzella, Louis Postnikova, Elena Oberlander, Nicholas Bartos, Christopher Ork, Britini L. Mazur, Steven Allan, Cindy Holbrook, Michael R. Solomon, Jeffrey Johnson, Joshua C. Pickel, James Hensley, Lisa E. Jahrling, Peter B. TI Intratracheal exposure of common marmosets to MERS-CoV Jordan-n3/2012 or MERS-CoV EMC/2012 isolates does not result in lethal disease SO VIROLOGY LA English DT Article DE MERS; Middle East Respiratory Syndrome; MERS-CoV; Nonhuman primate; Animal model; Coronavirus ID RESPIRATORY SYNDROME CORONAVIRUS; RHESUS MACAQUES; COMPUTED-TOMOGRAPHY; SAUDI-ARABIA; EMBL-EBI; INFECTION; QUANTIFICATION; PROGRESSION; GENERATION; MODEL AB Middle East Respiratory Syndrome Coronavirus (MERS-CoV) continues to be a threat to human health in the Middle East. Development of countermeasures is ongoing; however, an animal model that faithfully recapitulates human disease has yet to be defined. A recent study indicated that inoculation of common marmosets resulted in inconsistent lethality. Based on these data we sought to compare two isolates of MERS-CoV. We followed disease progression in common marmosets after intratracheal exposure with: MERS-C0V-EMC/2012, MERS-CoV-Jordan-n3/202, media, or inactivated virus. Our data suggest that common marmosets developed a mild to moderate non-lethal respiratory disease, which was quantifiable by computed tomography (CT), with limited other clinical signs. Based on CT data, clinical data, and virological data, MERS-CoV inoculation of common marmosets results in mild to moderate clinical signs of disease that are likely due to manipulations of the marmoset rather than as a result of robust viral replication. Published by Elsevier Inc. C1 [Johnson, Reed F.; Kumar, Mia R.; Cornish, Joseph P.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. [Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Yellayi, Srikanth; Huzella, Louis; Postnikova, Elena; Oberlander, Nicholas; Bartos, Christopher; Ork, Britini L.; Mazur, Steven; Allan, Cindy; Holbrook, Michael R.; Johnson, Joshua C.; Hensley, Lisa E.; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Solomon, Jeffrey] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. RP Johnson, RF (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. EM johnsonreed@mail.nih.gov FU National Institute of Allergy and Infectious Disease, Division of Intramural Research; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX This work was supported by the National Institute of Allergy and Infectious Disease, Division of Intramural Research. We are grateful to Marisa St. Claire, Russell Byrum, Dan Ragland, and the entire EVPS and IRF team for their contributions to these studies. We thank Jiro Wada for his contribution to the preparation of figures and Laura Bollinger for providing technical writing services for preparation of this manuscript. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract no. HHSN272200700016I. B.L.O., M.R.H., J.C.J. performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are E.P. an employee of Tunnell Government Services, Inc.; N. O., S.Y. and L.H. are employees of Charles River Laboratories, S.M. an employee of MRI Global, CB an employee of MedRelief. NR 23 TC 14 Z9 14 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2015 VL 485 BP 422 EP 430 DI 10.1016/j.virol.2015.07.013 PG 9 WC Virology SC Virology GA CV1DH UT WOS:000363993100044 PM 26342468 ER PT J AU Silberman, Y Fetterly, TL Awad, EK Milano, EJ Usdin, TB Winder, DG AF Silberman, Yuval Fetterly, Tracy L. Awad, Elias K. Milano, Elana J. Usdin, Ted B. Winder, Danny G. TI Ethanol Produces Corticotropin-Releasing Factor Receptor-Dependent Enhancement of Spontaneous Glutamatergic Transmission in the Mouse Central Amygdala SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Central Nucleus of the Amygdala; CRF Reporter Mice; Whole-Cell Patch-Clamp Electrophysiology; Diphtheria Toxin; Selective Deletion ID ALCOHOL DEPENDENCE; EXPRESSION; DRINKING; MODULATION; BEHAVIOR; NUCLEUS; PATHWAY; MEDIATE; RATS; MICE AB BackgroundEthanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOHxCRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling. MethodsThe effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRFCeAhDTR) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRFDTA mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA. ResultsAcute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRFCeAhDTR mice despite a similar to 78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRFDTA mice despite a 3-fold reduction in CRF mRNA levels. ConclusionsThese findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR-dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF. C1 [Silberman, Yuval; Fetterly, Tracy L.; Awad, Elias K.; Milano, Elana J.; Winder, Danny G.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Fetterly, Tracy L.; Winder, Danny G.] Vanderbilt Univ, Sch Med, Vanderbilt Brain Inst, Nashville, TN 37232 USA. [Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. RP Winder, DG (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, 750 Robinson Res Bldg,2200 Pierce Ave, Nashville, TN 37232 USA. EM danny.winder@vanderbilt.edu FU Intramural NIH HHS; NIAAA NIH HHS [AA 22937, AA 20140, AA 19455, F32 AA020140, R01 AA019455, K99 AA022937]; NIDA NIH HHS [DA 19112, R01 DA019112]; NIMH NIH HHS [ZIA-MH002685] NR 27 TC 0 Z9 0 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD NOV PY 2015 VL 39 IS 11 BP 2154 EP 2162 DI 10.1111/acer.12881 PG 9 WC Substance Abuse SC Substance Abuse GA CU6ZR UT WOS:000363684700012 PM 26503065 ER PT J AU Kessler, J Ruggles, K Patel, A Nucifora, K Li, LF Roberts, MS Bryant, K Braithwaite, RS AF Kessler, Jason Ruggles, Kelly Patel, Anik Nucifora, Kimberly Li, Lifeng Roberts, Mark S. Bryant, Kendall Braithwaite, R. Scott TI Targeting an Alcohol Intervention Cost-Effectively to Persons Living with HIV/AIDS in East Africa SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE HIV Prevention; Alcohol; Cost-Effectiveness; Mathematical Modeling ID SUB-SAHARAN AFRICA; FEMALE SEX WORKERS; SEXUALLY-TRANSMITTED INFECTIONS; ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; COLLABORATIVE PROJECT; NORTHERN TANZANIA; WESTERN KENYA; RISK-FACTORS; VIRAL LOAD AB BackgroundIn the current report, we ask if targeting a cognitive behavioral therapy (CBT)-based intervention aimed at reducing hazardous alcohol consumption to HIV-infected persons in East Africa would have a favorable value at costs that are feasible for scale-up. MethodsUsing a computer simulation to inform HIV prevention decisions in East Africa, we compared 4 different strategies for targeting a CBT intervention(i) all HIV-infected persons attending clinic; (ii) only those patients in the pre-antiretroviral therapy (ART) stages of care; (iii) only those patients receiving ART; and (iv) only those patients with detectable viral loads (VLs) regardless of disease stage. We define targeting as screening for hazardous alcohol consumption (e.g., using the Alcohol Use Disorders Identification Test and offering the CBT intervention to those who screen positive). We compared these targeting strategies to a null strategy (no intervention) or a hypothetical scenario where an alcohol intervention was delivered to all adults regardless of HIV status. ResultsAn intervention targeted to HIV-infected patients could prevent 18,000 new infections, add 46,000 quality-adjusted life years (QALYs), and yield an incremental cost-effectiveness ratio of $600/QALY compared to the null scenario. Narrowing the prioritized population to only HIV-infected patients in pre-ART phases of care results in 15,000 infections averted, the addition of 21,000 QALYs and would be cost-saving, while prioritizing based on an unsuppressed HIV-1 VL test results in 8,300 new infections averted, adds 6,000 additional QALYs, and would be cost-saving as well. ConclusionsOur results suggest that targeting a cognitive-based treatment aimed at reducing hazardous alcohol consumption to subgroups of HIV-infected patients provides favorable value in comparison with other beneficial strategies for HIV prevention and control in this region. It may even be cost-saving under certain circumstances. C1 [Kessler, Jason; Ruggles, Kelly; Patel, Anik; Nucifora, Kimberly; Li, Lifeng; Braithwaite, R. Scott] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Patel, Anik] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Roberts, Mark S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA USA. [Bryant, Kendall] NIAAA, NIH, Bethesda, MD USA. RP Kessler, J (reprint author), 227 E 30th St,Room 650, New York, NY 10016 USA. EM jason.kessler@nyumc.org RI Erita, Dewi/N-4649-2016; OI Ruggles, Kelly/0000-0002-0152-0863 FU NIAAA NIH HHS [R01 AA017385] NR 56 TC 2 Z9 2 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD NOV PY 2015 VL 39 IS 11 BP 2179 EP 2188 DI 10.1111/acer.12890 PG 10 WC Substance Abuse SC Substance Abuse GA CU6ZR UT WOS:000363684700015 PM 26463727 ER PT J AU Lee, IH Miller, NR Zan, E Tavares, F Blitz, AM Sung, H Yousem, DM Boland, MV AF Lee, In Ho Miller, Neil R. Zan, Elcin Tavares, Fabiana Blitz, Ari M. Sung, Heejong Yousem, David M. Boland, Michael V. TI Visual Defects in Patients With Pituitary Adenomas: The Myth of Bitemporal Hemianopsia SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE optic chiasm; pituitary adenoma; visual deficits ID MANAGEMENT; PATTERN AB OBJECTIVE. The objective of this study was to test the hypothesis that bitemporal hemianopsia (BHA) is the most common visual field (VF) defect in patients with pituitary macroadenoma and to assess the degree of optic pathway compression necessary to produce visual defects. MATERIALS AND METHODS. We reviewed the MRI findings and medical records of 119 patients with pituitary macroadenoma who had undergone formal assessment of VFs. We then evaluated the degree of optic pathway displacement caused by the pituitary macroadenoma, as observed on MR images. The classifications of optic pathway displacement included no contact, abutment but no displacement, mild displacement (< 3 mm), and moderate displacement (>= 3 mm). Qualitative analysis classified VFs as normal or as having defects that were monocular, bitemporal, mixed (bitemporal with additional defects), homonymous, or nonspecific. RESULTS. A total of 89 of 115 patients had an abnormal VF. Only one patient had true BHA. The most common defects were bitemporal or mixed defects (in 49 of 115 patients [42.6%]), likely because more than just the chiasm is often compressed by the pituitary macroadenoma. Classification of optic pathway displacement by the pituitary macroadenoma was as follows: 23 patients had no contact, eight had abutment but no displacement, 27 had mild displacement, and 57 had moderate displacement. In 78 of the 92 patients (84.8%) with pituitary macroadenoma that had contact with the optic pathway, contact was with the optic chiasm and the prechiasmal optic nerve. Of the 49 patients with bitemporal or mixed defects, 42 had moderate displacement of the optic pathway caused by their tumors. CONCLUSION. BHA is exceedingly uncommon in patients with pituitary macroadenoma. However, although bitemporal and mixed defects are the most common abnormal VF findings, they were found in only 42.6% of patients. Such defects rarely occur if the tumor displaces the optic pathway less than 3 mm from baseline. C1 [Lee, In Ho; Zan, Elcin; Tavares, Fabiana; Blitz, Ari M.; Yousem, David M.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Lee, In Ho] Chungnam Natl Univ Hosp, Dept Radiol, Daejeon, South Korea. [Miller, Neil R.; Boland, Michael V.] Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Sung, Heejong] NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. RP Yousem, DM (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St,Phipps B100F, Baltimore, MD 21287 USA. EM dyousem1@jhu.edu NR 17 TC 1 Z9 1 U1 1 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD NOV PY 2015 VL 205 IS 5 BP W512 EP W518 DI 10.2214/AJR.15.14527 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CU8SV UT WOS:000363814900007 PM 26496573 ER PT J AU Schinasi, LH De Roos, AJ Ray, RM Edlefsen, KL Parks, CG Howard, BV Meliker, JR Bonner, MR Wallace, RB LaCroix, AZ AF Schinasi, Leah H. De Roos, Anneclaire J. Ray, Roberta M. Edlefsen, Kerstin L. Parks, Christine G. Howard, Barbara V. Meliker, Jaymie R. Bonner, Matthew R. Wallace, Robert B. LaCroix, Andrea Z. TI Insecticide exposure and farm history in relation to risk of lymphomas and leukemias in the Women's Health Initiative observational study cohort SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Pesticides; Insecticides; Women; Lymphoma; Leukemia ID NON-HODGKINS-LYMPHOMA; OCCUPATIONAL-EXPOSURE; PESTICIDE EXPOSURE; MULTIPLE-MYELOMA; UNITED-STATES; CANCER; MEN; METAANALYSES; MINNESOTA; NEOPLASMS AB Purpose: Relationships of farm history and insecticide exposure at home or work with lymphohematopoietic (LH) neoplasm risk were investigated in a large prospective cohort of US women. Methods: In questionnaires, women self-reported history living or working on a farm, personally mixing or applying insecticides, insecticide application in the home or workplace by a commercial service, and treating pets with insecticides. Relationships with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLIKL), follicular lymphoma, plasma cell neoplasms, and myeloid leukemia were investigated using Cox proportional hazard models. Age and farming history were explored as effect modifiers. Results: The analysis included 76,493 women and 822 NHL cases. Women who ever lived or worked on a farm had 1.12 times the risk of NHL (95% confidence interval [Cl] = 0.95-1.32) compared to those who did not. Women who reported that a commercial service ever applied insecticides in their immediate surroundings had 65% higher risk of CLL/SLL (95% Cl = 1.15-2.38). Women aged less than 65 years who ever applied insecticides had 87% higher risk of DLBCL (95% Cl = 1.13-3.09). Conclusions: Insecticide exposures may contribute to risk of CLL/SLL and DLBCL Future studies should examine relationships of LH subtypes with specific types of household insecticides. (C) 2015 Elsevier Inc. All rights reserved. C1 [Schinasi, Leah H.; De Roos, Anneclaire J.] Drexel Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Ray, Roberta M.; LaCroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Edlefsen, Kerstin L.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Parks, Christine G.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Howard, Barbara V.] MedStar Res Inst, Dept Field Studies, Hyattsville, MD USA. [Howard, Barbara V.] Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC USA. [Meliker, Jaymie R.] SUNY Stony Brook, Dept Preventat Med, Stony Brook, NY 11794 USA. [Meliker, Jaymie R.] SUNY Stony Brook, Grad Program Publ Hlth, Stony Brook, NY 11794 USA. [Bonner, Matthew R.] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Wallace, Robert B.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Sch Med, Div Epidemiol, San Diego, CA 92103 USA. RP Schinasi, LH (reprint author), Drexel Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth, Philadelphia, PA 19104 USA. EM lhs36@drexel.edu OI Parks, Christine/0000-0002-5734-3456 FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; NIH, National Institute of Environmental Health Sciences FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 32 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD NOV PY 2015 VL 25 IS 11 BP 803 EP 810 DI 10.1016/j.annepidem.2015.08.002 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CU5WI UT WOS:000363602300001 PM 26365305 ER PT J AU Saidha, S Al-Louzi, O Ratchford, JN Bhargava, P Oh, J Newsome, SD Prince, JL Pham, D Roy, S van Zijl, P Balcer, LJ Frohman, EM Reich, DS Crainiceanu, C Calabresi, PA AF Saidha, Shiv Al-Louzi, Omar Ratchford, John N. Bhargava, Pavan Oh, Jiwon Newsome, Scott D. Prince, Jerry L. Pham, Dzung Roy, Snehashis van Zijl, Peter Balcer, Laura J. Frohman, Elliot M. Reich, Daniel S. Crainiceanu, Ciprian Calabresi, Peter A. TI Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study SO ANNALS OF NEUROLOGY LA English DT Article ID NERVE-FIBER LAYER; MICROCYSTIC MACULAR EDEMA; INNER NUCLEAR LAYER; PATHOLOGY; THICKNESS; NEURITIS; MS; SEGMENTATION; DEGENERATION; METAANALYSIS AB ObjectiveThe aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). MethodsCirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. ResultsRates of ganglion cell+inner plexiform layer (GCIP) and whole-brain (r=0.45; p<0.001), gray matter (GM; r=0.37; p<0.001), white matter (WM; r=0.28; p=0.007), and thalamic (r=0.38; p<0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r=0.67; p<0.001) than relapsing-remitting MS (RRMS; r=0.33; p=0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r=-0.30; p=0.02) and inner nuclear layer (r=-0.25; p=0.04) atrophy rates. InterpretationOver time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials. Ann Neurol 2015;78:Ann Neurol 2015;78:679-696 C1 [Saidha, Shiv; Al-Louzi, Omar; Ratchford, John N.; Bhargava, Pavan; Oh, Jiwon; Newsome, Scott D.; Reich, Daniel S.; Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Prince, Jerry L.; Pham, Dzung; Roy, Snehashis] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21287 USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21287 USA. [Prince, Jerry L.; Pham, Dzung; Roy, Snehashis; van Zijl, Peter; Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Pham, Dzung; Roy, Snehashis] Henry M Jackson Fdn Adv Mil Med, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Balcer, Laura J.] NYU, Dept Neurol, Langone Med Ctr, New York, NY 10016 USA. [Frohman, Elliot M.] Univ Texas Southwestern, Dept Neurol & Ophthalmol, Dallas, TX USA. [Reich, Daniel S.; Crainiceanu, Ciprian] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21287 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. RP Saidha, S (reprint author), Johns Hopkins Univ, 600 North Wolfe St,Pathol 627, Baltimore, MD 21287 USA. EM ssaidha2@jhmi.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Roy, Snehashis/0000-0002-7997-3993 FU Race to Erase MS; National Institutes of Health [5R01NS082347-02, R01NS070906]; National Multiple Sclerosis Society [TR 3760-A-3, RG 4212-A-4]; National Eye Institute [R01 EY 014993, R01 EY 019473]; Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund; Intramural Research Program of NINDS FX This study was funded by the Race to Erase MS (to S.S.), National Institutes of Health (5R01NS082347-02 [to P.A.C.] and R01NS070906 [to D.P.]), National Multiple Sclerosis Society (TR 3760-A-3 [to P.A.C.] and RG 4212-A-4 [to L.J.B. subcontracted to P.A.C.]), National Eye Institute (R01 EY 014993 and R01 EY 019473 [to L.J.B. subcontracted to P.A.C.]), Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund (to P.A.C., E.M.F., and L.J.B.), and the Intramural Research Program of NINDS (to D.S.R.). NR 53 TC 25 Z9 25 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD NOV PY 2015 VL 78 IS 5 BP 801 EP 813 DI 10.1002/ana.24487 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CU7NP UT WOS:000363727900014 PM 26190464 ER PT J AU Boufraqech, M Kebebew, E AF Boufraqech, Myriem Kebebew, Electron TI New genomic somatic amplifications and deletions in papillary thyroid cancer SO ENDOCRINE LA English DT Editorial Material ID RISK C1 [Boufraqech, Myriem; Kebebew, Electron] NCI, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016 FU Intramural NIH HHS [ZIA BC011275-03] NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD NOV PY 2015 VL 50 IS 2 BP 270 EP 271 DI 10.1007/s12020-015-0704-9 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU4HP UT WOS:000363488800003 PM 26224588 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects SO ENDOCRINE LA English DT Editorial Material ID MCCUNE-ALBRIGHT-SYNDROME; PITUITARY-ADENOMAS; MOLECULAR-GENETICS; CARNEY COMPLEX; MUTATIONS; CDKN1B; AIP; TUMORS; MEN1 C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet SEGEN, NIH,East Labs, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet SEGEN, NIH,East Labs, CRC Rm 1-3330,Bldg 10-CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD008920-04] NR 17 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD NOV PY 2015 VL 50 IS 2 BP 272 EP 275 DI 10.1007/s12020-015-0645-3 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU4HP UT WOS:000363488800004 PM 26054904 ER PT J AU Gelinas, L AF Gelinas, Luke TI Frames, Choice-Reversal, and Consent SO ETHICAL THEORY AND MORAL PRACTICE LA English DT Article DE Consent; Framing effects; Autonomy; Rights AB Recently Jason Hanna has argued that a particular type of susceptibility to framing effects-namely, the tendency to reverse one's choice between certain logically equivalent frames-invalidates actual tokens of consent. Here I argue that this claim is false: proneness to choice-reversal per se between the relevant types of frames does not invalidate consent. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Gelinas, L (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM lukegelinas@gmail.com NR 9 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-2820 EI 1572-8447 J9 ETHICAL THEORY MORAL JI Ethical Theory Moral Pract. PD NOV PY 2015 VL 18 IS 5 BP 1049 EP 1057 DI 10.1007/s10677-015-9581-9 PG 9 WC Philosophy SC Philosophy GA CU4GO UT WOS:000363485800011 ER PT J AU Prasad, V Bilal, U AF Prasad, Vinay Bilal, Usama TI The role of censoring on progression free survival: Oncologist discretion advised SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material DE Censoring; Progression free survival; Informative censoring; BOLERO-2; Randomised trial design; Surrogacy ID TRIALS AB Censoring is increasingly appreciated as a potential bias affecting estimates of progression free survival (PFS) in randomised trials. In this commentary, we explore the central assumption of censoring. Censored patients are considered no more or less likely to undergo the event of interest than those who remain in the analysis. Instead however, if one makes alternate assumptions, that censored patients are different than those who remain on the trial, estimates of PFS change. Using the example of the recent BOLERO-2 trial of exemestane and everolimus, we show that by altering the assumptions for censoring, the major conclusions of clinical trials may change. As such, the number of censored patients at each time interval should be routinely reported in randomised trials to better understand the implications of censoring. Published by Elsevier Ltd. C1 [Prasad, Vinay] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Bilal, Usama] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Prasad, V (reprint author), NCI, Med Oncol Serv, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Bilal, Usama/0000-0002-9868-7773 NR 8 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2015 VL 51 IS 16 BP 2269 EP 2271 DI 10.1016/j.ejca.2015.07.005 PG 3 WC Oncology SC Oncology GA CU3ZY UT WOS:000363466800001 PM 26259493 ER PT J AU Prasad, V AF Prasad, Vinay TI Non-invasive, serum DNA pregnancy testing leading to incidental discovery of cancer: A good thing? SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material DE Non-invasive pregnancy tests; Genetic testing; Unintended consequences; Lead-time bias; Overdiagnosis AB Cell-free DNA for perinatal screening is a growing industry. Non-invasive prenatal testing (NIPT) is based on the premise that foetal DNA is able to cross the placental barrier and enter the mother's circulation, where it can be examined for chromosomal abnormalities, such as trisomy 13, 18 or 21. Such tests are expected to be widely used by pregnant women, with the annual market expected to surpass $1 billion. Recently, a number of case reports have emerged in the haematology-oncology literature. The routine use of NIPT has led to the discovery of maternal neoplasms. Most writers have concluded that this is yet another benefit of the test; however, a closer examination of the cases reveals that this incidental detection may not improve patient outcomes. In some cases, early detection provides lead time bias, but does not change the ultimate clinical outcome, and in other cases, detection constitutes earlier knowledge of a cancer whose natural history cannot be altered. Here, we explore in detail cases where cancer was incidentally discovered among women undergoing routine non-invasive pregnancy testing, and investigate whether or not these women were benefitted by the discovery. Published by Elsevier Ltd. C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 7 TC 1 Z9 1 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2015 VL 51 IS 16 BP 2272 EP 2274 DI 10.1016/j.ejca.2015.07.029 PG 3 WC Oncology SC Oncology GA CU3ZY UT WOS:000363466800002 PM 26278647 ER PT J AU Giaccone, G Bazhenova, LA Nemunaitis, J Tan, M Juhasz, E Ramlau, R van den Heuvel, MM Lal, R Kloecker, GH Eaton, KD Chu, Q Dunlop, DJ Jain, M Garon, EB Davis, CS Carrier, E Moses, SC Shawler, DL Fakhrai, H AF Giaccone, G. Bazhenova, L. A. Nemunaitis, J. Tan, M. Juhasz, E. Ramlau, R. van den Heuvel, M. M. Lal, R. Kloecker, G. H. Eaton, K. D. Chu, Q. Dunlop, D. J. Jain, M. Garon, E. B. Davis, C. S. Carrier, E. Moses, S. C. Shawler, D. L. Fakhrai, H. TI A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Non-small cell lung cancer; Cancer vaccine; Cancer immunotherapy; Cancer gene therapy; TGF-beta ID CLINICAL-TRIAL; CHEMOTHERAPY; CISPLATIN; PEPTIDE; MULTICENTER; VINORELBINE; INDUCTION; RESPONSES; DURATION; EFFICACY AB Background: Treatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-beta 2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment. Methods: Stage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival. Results: This phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p = 0.594). There were also no differences in progression-free survival (4.3 months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p = 0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p = 0.002) and that prior radiation was a positive prognostic factor (median survival 28.4 months with belagenpumatucel-L versus 16.0 months with placebo; HR 0.61, p = 0.032). Conclusions: Although the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12 weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted. (C) 2015 Published by Elsevier Ltd. C1 [Giaccone, G.] NCI, Bethesda, MD 20892 USA. [Bazhenova, L. A.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Nemunaitis, J.] Mary Crowley Canc Res Ctr, Dallas, TX USA. [Tan, M.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Juhasz, E.] Koranyi Natl Inst TB & Pulmonol, Budapest, Hungary. [Ramlau, R.] Poznan Univ Med Sci, Wielkopolskie Ctr Pulmonol & Torakochirurg, Poznan, Poland. [van den Heuvel, M. M.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Thorac Oncol, Amsterdam, Netherlands. [Lal, R.] Kings Hlth Partners, Guys Hosp, London, England. [Kloecker, G. H.] Univ Louisville, James Graham Brown Canc, Louisville, KY 40292 USA. [Eaton, K. D.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Chu, Q.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Dunlop, D. J.] Royal Infirm, Glasgow G31 2ER, Lanark, Scotland. [Jain, M.] Noble Hosp, Pune, Maharashtra, India. [Garon, E. B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Davis, C. S.] CSD Biostat, Tucson, AZ USA. [Carrier, E.; Moses, S. C.; Shawler, D. L.; Fakhrai, H.] NovaRx Corp, San Diego, CA USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NCI NIH HHS [R44 CA096025] NR 38 TC 25 Z9 28 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2015 VL 51 IS 16 BP 2321 EP 2329 DI 10.1016/j.ejca.2015.07.035 PG 9 WC Oncology SC Oncology GA CU3ZY UT WOS:000363466800009 PM 26283035 ER PT J AU Jaskolski, M Miller, M Rao, JKM Gustchina, A Wlodawer, A AF Jaskolski, Mariusz Miller, Maria Rao, J. K. Mohana Gustchina, Alla Wlodawer, Alexander TI Elucidation of the structure of retroviral proteases: areminiscence SO FEBS JOURNAL LA English DT Editorial Material DE crystal structures; drug design; HIV; inhibitors; protease ID HUMAN-IMMUNODEFICIENCY-VIRUS; SYNTHETIC HIV-1 PROTEASE; RESOLUTION X-RAY; CRYSTAL-STRUCTURE; ASPARTIC PROTEINASES; DRUG DESIGN; INHIBITOR; COMPLEX; AIDS; EVOLUTIONARY AB Determinations of only a very few protein structures had consequences comparable to the impact exerted by the structure of the protease encoded by HIV-1, published just over 25years ago. The structure of this relatively small protein and its cousins from other retroviruses provided a clear target for a spectacularly successful structure-assisted drug design effort that offered new hope for controlling the then-escalating AIDS epidemic. This reminiscence is limited primarily to work conducted at the National Cancer Institute, and is not meant to be a comprehensive history of the field, but is rather an attempt to provide a very personal account of how the structures of this most thoroughly studied crystallographic target were determined. C1 [Jaskolski, Mariusz] Polish Acad Sci, A Mickiewicz Univ & Ctr Biocrystallog Res, Fac Chem, Inst Bioorgan Chem,Dept Crystallog, PL-61704 Poznan, Poland. [Miller, Maria; Rao, J. K. Mohana; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Jaskolski, M (reprint author), Polish Acad Sci, A Mickiewicz Univ & Ctr Biocrystallog Res, Fac Chem, Inst Bioorgan Chem,Dept Crystallog, Ul Noskowskiego 12-14, PL-61704 Poznan, Poland. EM mariuszj@amu.edu.pl; wlodawer@nih.gov RI Miller, Maria/I-1636-2013 OI Miller, Maria/0000-0003-0252-5348 NR 36 TC 2 Z9 2 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD NOV PY 2015 VL 282 IS 21 BP 4059 EP 4066 DI 10.1111/febs.13397 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU5RG UT WOS:000363589100001 PM 26258480 ER PT J AU El Haj, M Antoine, P Kapogiannis, D AF El Haj, Mohamad Antoine, Pascal Kapogiannis, Dimitrios TI Flexibility decline contributes to similarity of past and future thinking in Alzheimer's disease SO HIPPOCAMPUS LA English DT Article DE Alzheimer's disease; binding; flexibility; future thinking; hippocampus ID MEDIAL TEMPORAL-LOBE; MILD COGNITIVE IMPAIRMENT; MEMORY BINDING DEFICITS; MENTAL TIME-TRAVEL; AUTOBIOGRAPHICAL MEMORY; EPISODIC MEMORY; NEURODEGENERATIVE DISEASES; AUTONOETIC CONSCIOUSNESS; HIPPOCAMPAL DYSFUNCTION; ASSOCIATIVE MEMORY AB A striking similarity has been suggested between past and future thinking in Alzheimer's Disease (AD), a similarity attributable to abnormalities in common modular cognitive functions and neuroanatomical substrates. This study extends this literature by identifying specific executive function deficits underlying past and future thinking in AD. Twenty-four participants with a clinical diagnosis of probable (mild) AD and 26 older controls generated past and future events and underwent tests of binding and the executive functions of flexibility, inhibition, and updating. AD patients showed similar autobiographical performances in past and future event generation, and so did control participants. In each group, the similarity of past and future thinking was predicted by flexibility. Furthermore, AD patients with low flexibility showed higher similarity of past and future thinking than those with high flexibility. These findings are interpreted in terms of involvement of the hippocampus and frontal lobes in future thinking. Deficits in these brain regions in AD are likely to compromise the ability to recombine episodic information into novel and flexible configurations as scenarios for the future. (c) 2015 Wiley Periodicals, Inc. C1 [El Haj, Mohamad; Antoine, Pascal] Univ Lille, Res Unit Cognit & Affect Sci, Lab SCALab CNRS UMR 9193, Dept Psychol, Lille, France. [Kapogiannis, Dimitrios] NIA, Neurosci Lab, Dept Neurosci, Baltimore, MD 21224 USA. RP El Haj, M (reprint author), Univ Lille 3, Dept Psychol, BP 60149, F-59653 Villeneuve Dascq, France. EM mohamad.elhaj@univ-lille3.fr OI el haj, mohamad/0000-0001-7635-7557 FU LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer disease); National Institute on Aging; National Institutes of Health FX Grant sponsors: LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer disease), and intramural Program of the National Institute on Aging; National Institutes of Health. NR 75 TC 11 Z9 11 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD NOV PY 2015 VL 25 IS 11 BP 1447 EP 1455 DI 10.1002/hipo.22465 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CU6YW UT WOS:000363682300024 PM 25850800 ER PT J AU Chen, BA Panther, L Marzinke, MA Hendrix, CW Hoesley, CJ van der Straten, A Husnik, MJ Soto-Torres, L Nel, A Johnson, S Richardson-Harman, N Rabe, LK Dezzutti, CS AF Chen, Beatrice A. Panther, Lori Marzinke, Mark A. Hendrix, Craig W. Hoesley, Craig J. van der Straten, Ariane Husnik, Marla J. Soto-Torres, Lydia Nel, Annalene Johnson, Sherri Richardson-Harman, Nicola Rabe, Lorna K. Dezzutti, Charlene S. CA Microbicide Trials Network TI Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE microbicide; pre-exposure prophylaxis; dapivirine; maraviroc; vaginal rings; ex vivo challenge assay ID REVERSE-TRANSCRIPTASE INHIBITOR; FEMALE GENITAL-TRACT; HIV-NEGATIVE WOMEN; PREEXPOSURE PROPHYLAXIS; MICROBICIDE GEL; MS/MS METHOD; HUMAN PLASMA; INFECTION; PREVENTION; QUANTIFICATION AB Background:Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.Methods:MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.Results:There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log(10) greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.Conclusions:In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed. C1 [Chen, Beatrice A.; Dezzutti, Charlene S.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Chen, Beatrice A.; Rabe, Lorna K.; Dezzutti, Charlene S.] Magee Womens Res Inst, Pittsburgh, PA USA. [Panther, Lori] Fenway Inst, Dept Med & Infect Dis, Boston, MA USA. [Marzinke, Mark A.; Hendrix, Craig W.] Johns Hopkins Univ, Dept Pathol & Med, Baltimore, MD USA. [Hoesley, Craig J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [van der Straten, Ariane] Womens Global Hlth Imperat WGHI RTI Int, San Francisco, CA USA. [van der Straten, Ariane] Univ Calif San Francisco, Ctr AIDS Prevent Studies, Dept Med, San Francisco, CA USA. [Husnik, Marla J.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Soto-Torres, Lydia] NIAID, DAIDS, Bethesda, MD 20892 USA. [Nel, Annalene] Int Partnership Microbicides, Silver Spring, MD USA. [Johnson, Sherri] FHI 360, Durham, NC USA. [Richardson-Harman, Nicola] Alpha StatConsult, Damascus, MD USA. RP Chen, BA (reprint author), Magee Womens Hosp, 300 Halket St, Pittsburgh, PA 15213 USA. EM chenba@upmc.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health; National Institute of Mental Health of the U.S. National Institutes of Health; Gilead Sciences FX The study was designed and implemented by the Microbicide Trials Network (MTN). The MTN is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The vaginal rings used in this study were supplied by the IND sponsor, International Partnership for Microbicides (IPM).; N.R.-H. was a paid consultant for the pharmacodynamic data analysis. C.W.H. has received research support from Gilead Sciences managed through Johns Hopkins University. The remaining authors have no conflicts of interest to disclose. NR 33 TC 23 Z9 23 U1 1 U2 7 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 NOV 1 PY 2015 VL 70 IS 3 BP 242 EP 249 DI 10.1097/QAI.0000000000000702 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CU6ID UT WOS:000363634600004 PM 26034880 ER PT J AU Onabajo, OO Porter-Gill, P Paquin, A Rao, NN Liu, LY Tang, W Brand, N Prokunina-Olsson, L AF Onabajo, Olusegun O. Porter-Gill, Patricia Paquin, Ashley Rao, Nina Liu, Luyang Tang, Wei Brand, Nathan Prokunina-Olsson, Ludmila TI Expression of Interferon Lambda 4 Is Associated with Reduced Proliferation and Increased Cell Death in Human Hepatic Cells SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID C VIRUS-INFECTION; SPONTANEOUS CLEARANCE; ANTIVIRAL ACTIVITY; GENETIC-VARIATION; STIMULATED GENES; VIRAL CLEARANCE; HCV; GENOTYPE; IL28B; IFN-LAMBDA-4 AB Interferon lambda 4 (IFN-4) is a novel type-III interferon that can be generated only in individuals carrying a G frame-shift allele of an exonic genetic variant (rs368234815-G/TT). The rs368234815-G allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-4 expressed in human hepatic cellsa hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-4 but also detected secreted IFN-4 in the culture media of expressing cells. Secreted IFN-4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-4-induced phenotypesactivation of ISGs, decreased proliferation, and increased cell deathcould be inhibited by an anti-IFN-4-specific antibody. Our study offers new insights into biology of IFN-4 and its possible role in HCV clearance. C1 [Onabajo, Olusegun O.; Porter-Gill, Patricia; Paquin, Ashley; Rao, Nina; Liu, Luyang; Tang, Wei; Brand, Nathan; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM prokuninal@mail.nih.gov FU Intramural Research Program (IRP) of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US; NCI Director's Innovation Award; NCI Director's Career Development Award FX The work has been supported by the Intramural Research Program (IRP) of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US, by the NCI Director's Innovation Award to L.P.-O., and the NCI Director's Career Development Award to O.O.O. The authors thank Adeola Obajemu for technical help and staff of the Protein Expression Laboratory and Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research for help with development of stable inducible HepG2 cell lines. NR 42 TC 7 Z9 8 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD NOV 1 PY 2015 VL 35 IS 11 BP 888 EP 900 DI 10.1089/jir.2014.0161 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CU8BL UT WOS:000363766000006 PM 26134097 ER PT J AU Robbins, HA Clarke, CA Arron, ST Tatalovich, Z Kahn, AR Hernandez, BY Paddock, L Yanik, EL Lynch, CF Kasiske, BL Snyder, J Engels, EA AF Robbins, Hilary A. Clarke, Christina A. Arron, Sarah T. Tatalovich, Zaria Kahn, Amy R. Hernandez, Brenda Y. Paddock, Lisa Yanik, Elizabeth L. Lynch, Charles F. Kasiske, Bertram L. Snyder, Jon Engels, Eric A. TI Melanoma Risk and Survival among Organ Transplant Recipients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; SKIN-CANCER; RENAL-TRANSPLANTATION; MELANOCYTIC NEVI; KIDNEY; EXPOSURE; EXCESS; IMMUNOSUPPRESSION AB Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked US transplant-cancer registry data (1987-2010). We used standardized incidence ratios (SIRs) to compare incidence with the general population and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (n=182) and non-recipients (n=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (n=519) was elevated (SIR= 2.20, 95% Cl 2.01-2.39), especially for regional stage tumors (SIR= 4.11, 95% Cl 3.27-5.09). Risk of localized tumors was stable over time after transplantation but higher with azathioprine maintenance therapy (IRR= 1.35, 95% Cl 1.03-1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95% Cl 1.02-2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (hazard ratio 2.98, 95% CI 2.26-3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with UV radiation, whereas T-cell depleting induction therapies may promote late-stage tumors. Our findings support sun safety practices and skin screening for transplant recipients. C1 [Robbins, Hilary A.; Yanik, Elizabeth L.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Clarke, Christina A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Clarke, Christina A.] Stanford Canc Inst, Palo Alto, CA USA. [Arron, Sarah T.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Tatalovich, Zaria] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Kahn, Amy R.] New York State Canc Registry, Albany, NY USA. [Hernandez, Brenda Y.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Paddock, Lisa] New Jersey State Canc Registry, Trenton, NJ USA. [Paddock, Lisa] Rutgers Sch Publ Hlth, Piscataway, NJ USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Kasiske, Bertram L.] Univ Minnesota, Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Snyder, Jon] Minneapolis Med Res Fdn Inc, Sci Registry Transplant Recipients, Minneapolis, MN USA. RP Robbins, HA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6-E228, Bethesda, MD 20892 USA. EM hilary.robbins@jhmi.edu OI Yanik, Elizabeth/0000-0002-5835-0201 FU National Cancer Institute; Minneapolis Medical Research Foundation, Minneapolis, MN, USA [HHSH250201000018C]; Arbor Research Collaborative for Health in Ann Arbor, MI, USA [HHSH234200537009C]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000-034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201-000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201300021I, N01-PC-2013-00021]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN26120-13000171]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Illinois [5U58DP003883-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Maryland [U58DP12-1205 3919-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Michigan [5U58DP003921-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New York [U58DP003879]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement) [5458DP003920]; state of New Jersey; state of New York; state of Cancer Surveillance Initiative; state of Texas; state of Utah; state of Washington; state of University of Utah; state of Fred Hutchinson Cancer Research Center in Seattle, WA, USA FX This research was supported in part by the Intramural Research Program of the National Cancer Institute. We gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Paul Newkirk), and the following cancer registries: the states of California, Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii, Iowa, and Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu), New York and North Carolina (Chandrika Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry, and Ruth Parsons). The SRTR is currently operated under the contract number HHSH250201000018C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN, USA. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI, USA (contract number HHSH234200537009C). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contract numbers HHSN261201000036C, HHSN261201000035C, and HHSN261201000-034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201-000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN26120-13000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832), and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Initiative), Texas, Utah, and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA, USA. NR 50 TC 11 Z9 11 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2015 VL 135 IS 11 BP 2657 EP 2665 DI 10.1038/jid.2015.312 PG 9 WC Dermatology SC Dermatology GA CV1DM UT WOS:000363993600017 PM 26270022 ER PT J AU Dao, L Glancy, B Lucotte, B Chang, LC Balaban, RS Hsu, LY AF Dao, Lam Glancy, Brian Lucotte, Bertrand Chang, Lin-Ching Balaban, Robert S. Hsu, Li-Yueh TI A Model-based approach for microvasculature structure distortion correction in two-photon fluorescence microscopy images SO JOURNAL OF MICROSCOPY LA English DT Article DE Distortion Correction; image deconvolution and restoration; vascular Imaging ID POINT-SPREAD FUNCTIONS; IN-VIVO; CONFOCAL MICROSCOPY; BLIND DECONVOLUTION; EXCITATION; RESTORATION; CAPILLARIES AB This paper investigates a postprocessing approach to correct spatial distortion in two-photon fluorescence microscopy images for vascular network reconstruction. It is aimed at in vivo imaging of large field-of-view, deep-tissue studies of vascular structures. Based on simple geometric modelling of the object-of-interest, a distortion function is directly estimated from the image volume by deconvolution analysis. Such distortion function is then applied to subvolumes of the image stack to adaptively adjust for spatially varying distortion and reduce the image blurring through blind deconvolution. The proposed technique was first evaluated in phantom imaging of fluorescent microspheres that are comparable in size to the underlying capillary vascular structures. The effectiveness of restoring three-dimensional (3D) spherical geometry of the microspheres using the estimated distortion function was compared with empirically measured point-spread function. Next, the proposed approach was applied to in vivo vascular imaging of mouse skeletal muscle to reduce the image distortion of the capillary structures. We show that the proposed method effectively improve the image quality and reduce spatially varying distortion that occurs in large field-of-view deep-tissue vascular dataset. The proposed method will help in qualitative interpretation and quantitative analysis of vascular structures from fluorescence microscopy images. Lay Description Image distortion in fluorescence microscopy affects qualitative interpretation and particularly quantitative comparison of biological structures. Conventional image deconvolution approaches using empirically measured point-spread function (PSF) from submicron beads have limitations in correcting for large structural distortion in in vivo deep-tissue scans that require spatially varying models of the PSF. In this paper, we present a model-based image restoration approach to reduce spatial distortion and image blurring of microvascular structures in two-photon fluorescence microscopy images. Our results showed significant improvement in quantitative geometry measurements of the microsphere phantom compared to conventional measured PSF approach. We also showed that the method improve the image quality of vessel structures in mouse skeletal muscle. This image restoration approach can assist in qualitative and quantitative analysis of large field-of-view deep-tissue two photon fluorescence microscopy images. C1 [Dao, Lam; Glancy, Brian; Lucotte, Bertrand; Balaban, Robert S.; Hsu, Li-Yueh] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Dao, Lam; Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. RP Hsu, LY (reprint author), NHLBI, NIH, Bldg 10,Rm B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM lyhsu@mail.nih.gov RI Glancy, Brian/P-3163-2016 OI Glancy, Brian/0000-0002-8571-244X FU Intramural NIH HHS [Z99 HL999999] NR 35 TC 0 Z9 0 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-2720 EI 1365-2818 J9 J MICROSC-OXFORD JI J. Microsc.. PD NOV PY 2015 VL 260 IS 2 BP 180 EP 193 DI 10.1111/jmi.12281 PG 14 WC Microscopy SC Microscopy GA CU4UH UT WOS:000363525400008 PM 26224257 ER PT J AU Avenevoli, S Blader, JC Leibenluft, E AF Avenevoli, Shelli Blader, Joseph C. Leibenluft, Ellen TI Irritability in Youth: An Update SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material C1 [Avenevoli, Shelli] NIMH, Dev Trajectories Mental Disorders Branch, Div Translat Res, Bethesda, MD 20892 USA. [Blader, Joseph C.] Meadows Fdn, San Antonio, TX USA. [Blader, Joseph C.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Avenevoli, S (reprint author), 6001 Execut Blvd, Bethesda, MD USA. FU National Institutes of Health; Texas State Health and Human Service Commission FX Dr. Blader has received research grant support from the National Institutes of Health and has received research and service funding from the Texas State Health and Human Service Commission. He is employed by the State of Texas and is affiliated with the State University of New York at Stony Brook and with the North Shore-LIJ Health System. Drs. Avenevoli and Leibenluft report no biomedical financial interests or potential conflicts of interest. NR 6 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2015 VL 54 IS 11 BP 881 EP 883 DI 10.1016/j.jaac.2015.08.012 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CU8ZA UT WOS:000363831400002 PM 26506577 ER PT J AU Zou, MJ Baitei, EY Al-Rijjal, RA Parhar, RS Al-Mohanna, FA Kimura, S Pritchard, C BinEssa, H Alanazi, AA Alzahrani, AS Akhtar, M Assiri, AM Meyer, BF Shi, YF AF Zou, Minjing Baitei, Essa Y. Al-Rijjal, Roua A. Parhar, Ranjit S. Al-Mohanna, Futwan A. Kimura, Shioko Pritchard, Catrin BinEssa, Huda Alanazi, Azizah A. Alzahrani, All S. Akhtar, Mohammed Assiri, Abdullah M. Meyer, Brian F. Shi, Yufei TI KRAS(G12D)-mediated oncogenic transformation of thyroid follicular cells requires long-term TSH stimulation and is regulated by SPRY1 SO LABORATORY INVESTIGATION LA English DT Article ID MTS1 GENE OVEREXPRESSION; TRANSGENIC MICE; PHOSPHATIDYLINOSITOL 3-KINASE; THYROGLOBULIN PROMOTER; THYROTROPIN RECEPTOR; SIGNALING PATHWAY; TUMOR INITIATION; RAS ONCOGENE; MOUSE MODEL; MAP KINASE AB KRAS(G12D) can cause lung cancer rapidly, but is not sufficient to induce thyroid cancer. It is not clear whether long-term serum thyroid stimulating hormone (TSH) stimulation can promote KRAS(G12D)-mediated thyroid follicular cell transformation. In the present study, we investigated the effect of long-term TSH stimulation in KRAS(G12D) knock-in mice and the role of Sprouty1 (SPRY1) in KRAS(G12D)-mediated signaling. We used TPO-KRAS(G12D) mice for thyroid-specific expression of KRAS(G12D) under the endogenous KRAS promoter. Twenty TPO-KRAS(G12D) mice were given anti-thyroid drug propylthiouracil (PTU, 0.1% w/v) in drinking water to induce serum TSH and 20 mice were without PTU treatment. Equal number of wild-type littermates (TPO-KRAS(WT)) was given the same treatment. The expression of SPRY1, a negative regulator of receptor tyrosine kinase (RTK) signaling, was analyzed in both KRAS(G12D)-and BRAF(V600E)-induced thyroid cancers. Without PTU treatment, only mild thyroid enlargement and hyperplasia were observed in TPO-KRAS(G12D) mice. With PTU treatment, significant thyroid enlargement and hyperplasia occurred in both TPO-KRAS(G12D) and TPO-KRAS(WT) littermates. Thyroids from TPO-KRAS(G12D) mice were six times larger than TPO-KRAS(WT) littermates. Distinct thyroid histology was found between TPO-KRAS(G12D) and TPO-KRAS(WT) mice: thyroid from TPO-KRAS(G12D) mice showed hyperplasia with well-maintained follicular architecture whereas in TPO-KRAS(WT) mice this structure was replaced by papillary hyperplasia. Among 10 TPO-KRAS(G12D) mice monitored for 14 months, two developed follicular thyroid cancer (FTC), one with pulmonary metastasis. Differential SPRY1 expression was demonstrated: increased in FTC and reduced in papillary thyroid cancer (PTC). The increased SPRY1 expression in FTC promoted TSH-RAS signaling through PI3K/AKT pathway whereas downregulation of SPRY1 by BRAF(V600E) in PTC resulted in both MAPK and PI3K/AKT activation. We conclude that chronic TSH stimulation can enhance KRAS(G12D)-mediated oncogenesis, leading to FTC. SPRY1 may function as a molecular switch to control MAPK signaling and its downregulation by BRAF(V600E) favors PTC development. C1 [Zou, Minjing; Baitei, Essa Y.; Al-Rijjal, Roua A.; BinEssa, Huda; Meyer, Brian F.; Shi, Yufei] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Parhar, Ranjit S.] King Faisal Specialist Hosp & Res Ctr, Dept Cell Biol, Riyadh 11211, Saudi Arabia. [Al-Mohanna, Futwan A.; Alanazi, Azizah A.; Alzahrani, All S.] King Faisal Specialist Hosp & Res Ctr, Dept Med, Riyadh 11211, Saudi Arabia. [Kimura, Shioko] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pritchard, Catrin] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. [Akhtar, Mohammed] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia. [Assiri, Abdullah M.] King Faisal Specialist Hosp & Res Ctr, Dept Comparat Med, Riyadh 11211, Saudi Arabia. RP Shi, YF (reprint author), King Faisal Specialist Hosp & Res Ctr, Dept Genet, POB 3354, Riyadh 11211, Saudi Arabia. EM yufei@kfshrc.edu.sa FU KACST grants [11-BIO1434-20, PL-10-0051] FX The study is supported by KACST grants (11-BIO1434-20 and PL-10-0051). We would like to thank Dr Mario Encinas for critical discussions. NR 48 TC 0 Z9 0 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD NOV PY 2015 VL 95 IS 11 BP 1269 EP 1277 DI 10.1038/labinvest.2015.90 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CU8ZB UT WOS:000363831500005 PM 26146959 ER PT J AU Li, MF Toombes, GES Silberberg, SD Swartz, KJ AF Li, Mufeng Toombes, Gilman E. S. Silberberg, Shai D. Swartz, Kenton J. TI Physical basis of apparent pore dilation of ATP-activated P2X receptor channels SO NATURE NEUROSCIENCE LA English DT Article ID ION-CHANNEL; PERMEABILITY DYNAMICS; POTASSIUM CHANNEL; MEMBRANE PATCHES; CYTOSOLIC DOMAIN; OPEN STATE; SELECTIVITY; CELLS; PERMEATION; MECHANISM AB The selectivity of ion channels is fundamental for their roles in electrical and chemical signaling and in ion homeostasis. Although most ion channels exhibit stable ion selectivity, the prevailing view of purinergic P2X receptor channels, transient receptor potential V1 (TRPV1) channels and acid-sensing ion channels (ASICs) is that their ion conduction pores dilate upon prolonged activation. We investigated this mechanism in P2X receptors and found that the hallmark shift in equilibrium potential observed with prolonged channel activation does not result from pore dilation, but from time-dependent alterations in the concentration of intracellular ions. We derived a physical model to calculate ion concentration changes during patch-clamp recordings, which validated our experimental findings and provides a quantitative guideline for effectively controlling ion concentration. Our results have fundamental implications for understanding ion permeation and gating in P2X receptor channels, as well as more broadly for using patch-clamp techniques to study ion channels and neuronal excitability. C1 [Li, Mufeng; Toombes, Gilman E. S.; Silberberg, Shai D.; 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, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM kenton.swartz@nih.gov OI Toombes, Gilman/0000-0001-8346-1790 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health; K99 Pathway [NS070954] FX We thank M. Mayer, J. Minden, A. Jara-Osequera and members of the Swartz lab for discussions. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health (K.J.S.) and by K99 Pathway to Independence award NS070954 (M.L.). NR 50 TC 18 Z9 18 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD NOV PY 2015 VL 18 IS 11 BP 1577 EP 1583 DI 10.1038/nn.4120 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CU8YT UT WOS:000363830700015 PM 26389841 ER PT J AU Marquardt, JU Andersen, JB Thorgeirsson, SS AF Marquardt, Jens U. Andersen, Jesper B. Thorgeirsson, Snorri S. TI Functional and genetic deconstruction of the cellular origin in liver cancer SO NATURE REVIEWS CANCER LA English DT Review ID GROWTH-FACTOR RECEPTOR; FACTOR-KAPPA-B; FIBROLAMELLAR HEPATOCELLULAR-CARCINOMA; HEPATIC STELLATE CELLS; INTRAHEPATIC CHOLANGIOCARCINOMA; STEM-CELLS; PROGENITOR-CELL; HEPATOCYTE DIFFERENTIATION; HUMAN HEPATOCARCINOGENESIS; INACTIVATING MUTATIONS AB During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis. C1 [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Dept Med 1, D-55131 Mainz, Germany. [Andersen, Jesper B.] Univ Copenhagen, BRIC, DK-2200 Copenhagen N, Denmark. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244 FU Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA; German Research Foundation [MA 4443/2-1]; German Cancer Aid [DKH 110989]; Volkswagen Foundation (Lichtenberg program); Danish Cancer Society (Knaek cancer program); Novo Nordisk Foundation (Hallas-Moller fellowship); Danish Medical Research Council (Sapere Aude program); A.P. Moller Foundation FX This project was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA (to S.S.T.). J.U.M. is supported by grants from the German Research Foundation (MA 4443/2-1), German Cancer Aid (DKH 110989) and the Volkswagen Foundation (Lichtenberg program). J.B.A. is supported by grants from the Danish Cancer Society (Knaek cancer program), the Novo Nordisk Foundation (Hallas-Moller fellowship), the Danish Medical Research Council (Sapere Aude program) and the A.P. Moller Foundation. NR 146 TC 29 Z9 29 U1 6 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD NOV PY 2015 VL 15 IS 11 BP 653 EP 667 DI 10.1038/nrc4017 PG 15 WC Oncology SC Oncology GA CU7BV UT WOS:000363691100006 PM 26493646 ER PT J AU O'Shea, J AF O'Shea, John TI A FIRST LOOK AT T-H CELL TRANSCRIPTOMES SO NATURE REVIEWS IMMUNOLOGY LA English DT News Item C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP O'Shea, J (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM John.Oshea@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2015 VL 15 IS 11 BP 668 EP 668 DI 10.1038/nri3913 PG 1 WC Immunology SC Immunology GA CU7CG UT WOS:000363692400005 PM 26403100 ER PT J AU Viani, RM Alvero, C Fenton, T Acosta, EP Hazra, R Townley, E Steimers, D Min, S Wiznia, A AF Viani, Rolando M. Alvero, Carmelita Fenton, Terry Acosta, Edward P. Hazra, Rohan Townley, Ellen Steimers, Debra Min, Sherene Wiznia, Andrew CA P1093 Study Team TI Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents Forty-eight-week Results from IMPAACT P1093 SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE antiretroviral agents; dolutegravir; HIV integrase inhibitors; pediatric HIV; adolescent HIV ID HIV-INFECTED CHILDREN; ACTIVE ANTIRETROVIRAL THERAPY; ONCE-DAILY DOLUTEGRAVIR; NAIVE ADULTS; DOUBLE-BLIND; COMBINATION THERAPY; RALTEGRAVIR; RESISTANCE; ELVITEGRAVIR; TRIAL AB Objective: To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment-experienced adolescents. Methods: Children older than 12 to younger than 18 years received dolutegravir weight-based fixed doses at approximately 1.0mg/kg once daily in a phase I/II multicenter open label 48-week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through week 48. Results: Twenty-three adolescents were enrolled and 22 (96%) completed the 48-week study visit. Median age and weight were 15 years and 52kg, respectively. Median [interquartile range (IQR)] baseline CD4+ cell count was 466 cells/L (297, 771). Median (IQR) baseline HIV-1 RNA log(10) was 4.3 log(10) copies/mL (3.9, 4.6). Dolutegravir geometric mean of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC(0-24)) and 24 hour postdose concentration (C-24) were 46.0 g hours/mL and 0.90 g/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA <400 copies/mL was achieved in 74% [95% confidence interval (CI): 52-90%] at week 48. Additionally, 61% (95% CI: 39-80%) had an HIV RNA <50 copies/mL at week 48. Median (IQR) gain in CD4 cell count at week 48 was 84 cells/L (-81, 238). Dolutegravir was well tolerated, with no grade 4 adverse events, serious adverse events or discontinuations because of serious adverse events. Conclusions: Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48. C1 [Viani, Rolando M.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Viani, Rolando M.] Rady Childrens Hosp San Diego, La Jolla, CA USA. [Alvero, Carmelita; Fenton, Terry] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Acosta, Edward P.] Univ Alabama Birmingham, Birmingham, AL USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Townley, Ellen] NIAID, HJF DAIDS, Div Aids, Bethesda, MD 20892 USA. [Steimers, Debra; Min, Sherene] GlaxoSmithKline, Res Triangle Pk, NC USA. [Wiznia, Andrew] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. RP Viani, RM (reprint author), Univ Calif San Diego, Sch Med, Div Infect Dis, Dept Pediat, 9500 Gilman Dr,MC 0672, La Jolla, CA 92093 USA. EM rolandoviani1@gmail.com FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); ViiV Healthcare FX Overall support for the International Maternal Adolescent AIDS Clinical Trials (IMPAACT) Group was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding support was provided by ViiV Healthcare. The authors have no conflict of interest or funding to disclose, except for Debra Steimers and Sherene Min who are GSK employees and own stock and/or stock options in the company. NR 31 TC 1 Z9 1 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2015 VL 34 IS 11 BP 1207 EP 1213 DI 10.1097/INF.0000000000000848 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CU4WF UT WOS:000363530500012 PM 26244832 ER PT J AU Vrentas, C Ghirlando, R Keefer, A Hu, ZL Tomczak, A Gittis, AG Murthi, A Garboczi, DN Gottesman, S Leppla, SH AF Vrentas, Catherine Ghirlando, Rodolfo Keefer, Andrea Hu, Zonglin Tomczak, Aurelie Gittis, Apostolos G. Murthi, Athulaprabha Garboczi, David N. Gottesman, Susan Leppla, Stephen H. TI Hfqs in Bacillus anthracis: Role of protein sequence variation in the structure and function of proteins in the Hfq family SO PROTEIN SCIENCE LA English DT Article DE Hfq; small RNA; sRNA; Bacillus anthracis; anthrax; pXO1 ID RNA-BINDING PROPERTIES; ESCHERICHIA-COLI HFQ; SM-LIKE PROTEIN; CLOSTRIDIUM-DIFFICILE; CHAPERONE HFQ; LSM PROTEINS; BACTERIA; HEXAMER; IMPACT AB Hfq proteins in Gram-negative bacteria play important roles in bacterial physiology and virulence, mediated by binding of the Hfq hexamer to small RNAs and/or mRNAs to post-transcriptionally regulate gene expression. However, the physiological role of Hfqs in Gram-positive bacteria is less clear. Bacillus anthracis, the causative agent of anthrax, uniquely expresses three distinct Hfq proteins, two from the chromosome (Hfq1, Hfq2) and one from its pXO1 virulence plasmid (Hfq3). The protein sequences of Hfq1 and 3 are evolutionarily distinct from those of Hfq2 and of Hfqs found in other Bacilli. Here, the quaternary structure of each B. anthracis Hfq protein, as produced heterologously in Escherichia coli, was characterized. While Hfq2 adopts the expected hexamer structure, Hfq1 does not form similarly stable hexamers in vitro. The impact on the monomer-hexamer equilibrium of varying Hfq C-terminal tail length and other sequence differences among the Hfqs was examined, and a sequence region of the Hfq proteins that was involved in hexamer formation was identified. It was found that, in addition to the distinct higher-order structures of the Hfq homologs, they give rise to different phenotypes. Hfq1 has a disruptive effect on the function of E. coli Hfq in vivo, while Hfq3 expression at high levels is toxic to E. coli but also partially complements Hfq function in E. coli. These results set the stage for future studies of the roles of these proteins in B. anthracis physiology and for the identification of sequence determinants of phenotypic complementation. C1 [Vrentas, Catherine; Keefer, Andrea; Hu, Zonglin; Murthi, Athulaprabha; Leppla, Stephen H.] NIAID, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Bethesda, MD 20892 USA. [Tomczak, Aurelie] NIAID, Bethesda, MD 20892 USA. [Gittis, Apostolos G.; Garboczi, David N.] NIAID, Struct Biol Sect, Res Technol Branch, NIH, Rockville, MD USA. [Gottesman, Susan] NCI, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health FX Grant sponsor: Intramural research programs of the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Cancer Institute, National Institutes of Health. NR 34 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2015 VL 24 IS 11 BP 1808 EP 1819 DI 10.1002/pro.2773 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU7NK UT WOS:000363727200011 PM 26271475 ER PT J AU Redd, AD Newell, K Patel, EU Nalugoda, F Ssebbowa, P Kalibbala, S Frank, MA Tobian, AAR Gray, RH Quinn, TC Serwadda, D Reynolds, SJ AF Redd, Andrew D. Newell, Kevin Patel, Eshan U. Nalugoda, Fred Ssebbowa, Paschal Kalibbala, Sarah Frank, Melanie A. Tobian, Aaron A. R. Gray, Ronald H. Quinn, Thomas C. Serwadda, David Reynolds, Steven J. TI Decreased monocyte activation with daily acyclovir use in HIV-1/HSV-2 coinfected women SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID SIMPLEX-VIRUS TYPE-2; PLACEBO-CONTROLLED TRIAL; DISEASE PROGRESSION; CROSSOVER TRIAL; HIV-1; VALACYCLOVIR; TRANSMISSION; REPLICATION; INFECTION; THERAPY AB Objectives Several clinical trials have demonstrated that daily treatment of HIV-infected individuals with the antiherpes drug acyclovir slightly decreases HIV-1 viral load and slows disease progression. This study examines if this slowing in clinical progression is a direct cause of the decrease in viral load or an indirect effect of lower immune activation due to lower levels of herpetic reactivation. Methods Women who participated in a randomised clinical trial of daily acyclovir use (n=301) were monitored every 6 months for changes in immune activation. Soluble CD14 (sCD14), a marker for monocyte activation, and C-reactive protein (CRP), a marker for general immune activation, were measured by ELISA. Results Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multivariant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels. Conclusions These data suggest that decreased monocyte activation may play a minor role in the ability of daily acyclovir use to slow HIV disease progression. C1 [Redd, Andrew D.; Patel, Eshan U.; Frank, Melanie A.; Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Newell, Kevin] Leidos Biomed Res, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Nalugoda, Fred; Ssebbowa, Paschal; Kalibbala, Sarah; Serwadda, David] Rakai Hlth Sci Program, Entebbe, Uganda. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. RP Reynolds, SJ (reprint author), US Embassy, NIAID NIH ICER Program, POB 7007, Kampala, Uganda. EM sjreynolds@niaid.nih.gov OI Patel, Eshan/0000-0003-2174-5004 FU Intramural NIH HHS; NIAID NIH HHS [AI001040] NR 14 TC 4 Z9 4 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD NOV PY 2015 VL 91 IS 7 BP 485 EP 488 DI 10.1136/sextrans-2014-051867 PG 4 WC Infectious Diseases SC Infectious Diseases GA CU4CO UT WOS:000363474100008 PM 25904747 ER PT J AU Abdelmohsen, K Gorospe, M AF Abdelmohsen, Kotb Gorospe, Myriam TI Noncoding RNA control of cellular senescence SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review ID ONCOGENE-INDUCED SENESCENCE; HUMAN-DIPLOID FIBROBLASTS; LUNG-CANCER CELLS; REPLICATIVE SENESCENCE; TUMOR-GROWTH; CYCLE ARREST; STEM-CELLS; MULTIPLE MICRORNAS; HUMAN TELOMERASE; PROSTATE-CANCER AB Senescent cells accumulate in normal tissues with advancing age and arise by long-term culture of primary cells. Senescence develops following exposure to a range of stress-causing agents and broadly influences the physiology and pathology of tissues, organs, and systems in the body. While many proteins are known to control senescence, numerous noncoding (nc)RNAs are also found to promote or repress the senescent phenotype. Here, we review the regulatory ncRNAs (primarily microRNAs and lncRNAs) identified to-date as key modulators of senescence. We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence-associated secretory phenotype (SASP) and other senescence-associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence. WIREs RNA 2015, 6:615-629. doi: 10.1002/wrna.1297 For further resources related to this article, please visit the . C1 [Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov; myriam-gor-ospe@nih.gov FU NIA-IRP, NIH FX This work was supported by the NIA-IRP, NIH. NR 168 TC 8 Z9 8 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD NOV-DEC PY 2015 VL 6 IS 6 BP 615 EP 629 DI 10.1002/wrna.1297 PG 15 WC Cell Biology SC Cell Biology GA CU9NK UT WOS:000363871000002 PM 26331977 ER PT J AU Huestis, MA AF Huestis, Marilyn A. TI Deterring driving under the influence of cannabis SO ADDICTION LA English DT Editorial Material DE Blood; cannabis; driving; driving under the influence; impairment; marijuana; oral fluid ID MARIJUANA; ALCOHOL; BLOOD; DRIVERS; CRASHES; DRUGS C1 Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Chem & Drug Metab, Baltimore, MD 21235 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Chem & Drug Metab, Baltimore, MD 21235 USA. EM mhuestis@intra.nida.nih.gov NR 16 TC 2 Z9 2 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD NOV PY 2015 VL 110 IS 11 BP 1697 EP 1698 DI 10.1111/add.13041 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CU2CG UT WOS:000363329100001 PM 26264558 ER PT J AU Cherpitel, CJ Ye, Y Bond, J Borges, G Monteiro, M Chou, P Hao, W AF Cherpitel, Cheryl J. Ye, Yu Bond, Jason Borges, Guilherme Monteiro, Maristela Chou, Patricia Hao, Wei TI Alcohol Attributable Fraction for Injury Morbidity from the Dose-Response Relationship of Acute Alcohol Consumption: Emergency Department Data from 18 Countries SO ADDICTION LA English DT Article DE Alcohol; alcohol attributable fraction; dose-response; emergency department; gender; injury; motor vehicle; violence ID CASE-CROSSOVER DESIGN; GENERAL-POPULATION; NONFATAL INJURIES; RISK-FACTORS; RECALL BIAS; DRINKING; PATTERNS; DISEASE; BURDEN; ROOM AB AimsTo calculate the alcohol-attributable fraction (AAF) of injury morbidity by volume of consumption prior to injury based on newly reported relative risk (RR) estimates. DesignAAF estimates based on the dose-response RR estimates obtained from previous pair-matched case-crossover fractional polynomial analysis of mean volume in volume categories were calculated from the prevalence of drinking prior to injury in each volume category. SettingThirty-seven emergency departments (EDs) across 18 countries. ParticipantsProbability samples of patients, with equal representation of each shift for each day of the week, totaling 14,026 who arrived at the ED within six hours of injury from ED studies conducted between 2001 and 2011. MeasurementsAAF was analyzed by gender, age (18-30; >30), cause of injury (traffic, assault, fall, other), and country detrimental drinking pattern (DDP). FindingsFor the EDs analyzed, 16.4% of all injuries were estimated to be attributable to alcohol, and the AAF did not vary by age but was over twice as large for males (20.6%; 19.3-21.8) than for females (8.6%; 7.5-9.7%). While females were at greater risk of injury than males at higher volume levels, lower prevalence of women drinking at higher levels contributed to overall lower AAF for women. Assault-related injuries showed the largest AAF (44.1%; 37.6-42.6). AAF was slightly higher for injuries from falls (14.3%; 12.9-15.7) than motor vehicle crashes (11.1%; 9.3-12.9). AAF was higher in those countries with a DDP of 3 (18.6; 17.5-19.7) and 4 (19.4%; 17.3-21.6) than those with a DDP of 2 (12.0%; 10.5-13.5). ConclusionsAlcohol-attributable injuries presenting in emergency departments are higher for males than females, for violence-related injuries compared with other types of injury, and for countries with more detrimental drinking patterns compared with those with less detrimental patterns. C1 [Cherpitel, Cheryl J.; Ye, Yu; Bond, Jason] Alcohol Res Grp, Emeryville, CA 94608 USA. [Borges, Guilherme] Univ Autonoma Metropolitana, Inst Nacl Psiquiatria, Mexico City, DF, Mexico. [Monteiro, Maristela] Pan Amer Hlth Org, Washington, DC USA. [Chou, Patricia] Natl Inst Alcohol Abuse & Alcoholism, Washington, DC USA. [Hao, Wei] Hunan Med Univ, Changsha, Peoples R China. RP Cherpitel, CJ (reprint author), Alcohol Res Grp, 6475 Christie Ave,Suite 400, Emeryville, CA 94608 USA. EM ccherpitel@arg.org OI Borges, Guilherme/0000-0002-3269-0507 FU World Health Organization; U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA) [RO1 2 AA013750-04] FX The paper is based, in part on data collected by the following collaborators participating in the Emergency Room Collaborative Alcohol Analysis Project (ERCAAP) (C. J. Cherpitel, P.I., USA): W. Cook (USA), G. Gmel (Switzerland), A. Hope (Ireland); and collaborators participating in the WHO Collaborative Study on Alcohol and Injuries, sponsored by the World Health Organization and implemented by the WHO Collaborative Study Group on Alcohol and Injuries under the direction of V. Poznyak and M. Peden (WHO, Switzerland): V. Benegal (India); G. Borges (Mexico); S. Casswell (New Zealand); M. Cremonte (Argentina); R. Evsegneev (Belarus); N. Figlie and R. Larajeira (Brazil); N. Giesbrecht and S. Macdonald (Canada); W. Hao (China); S. Larsson and M. Stafstrom (Sweden); H. Sovinova (Czech Republic. A list of other staff contributing to the project can be found in the Main Report of the Collaborative Study on Alcohol and Injuries, WHO, Geneva.; Supported by a grant from the U.S. National Institute on Alcohol Abuse and Alcoholism (NIAAA) (RO1 2 AA013750-04) NR 38 TC 9 Z9 9 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD NOV PY 2015 VL 110 IS 11 BP 1724 EP 1732 DI 10.1111/add.13031 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA CU2CG UT WOS:000363329100009 PM 26119350 ER PT J AU Addissie, YA Kotecha, U Hart, RA Martinez, AF Kruszka, P Muenke, M AF Addissie, Yonit A. Kotecha, Udhaya Hart, Rachel A. Martinez, Ariel F. Kruszka, Paul Muenke, Maximilian TI Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Noonan syndrome; KRAS; craniosynostosis; RAS-MAPK; RASopathy ID RAS/MAPK SIGNALING PATHWAY; FACIO-CUTANEOUS SYNDROME; LOOSE ANAGEN HAIR; GERMLINE KRAS; HYPERTROPHIC CARDIOMYOPATHY; DEVELOPMENTAL DISORDERS; COSTELLO-SYNDROME; BRAF MUTATIONS; GENE; PROTEIN AB Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. (c) 2015 Wiley Periodicals, Inc. C1 [Addissie, Yonit A.; Hart, Rachel A.; Martinez, Ariel F.; Kruszka, Paul; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Kotecha, Udhaya] Sir Ganga Ram Hosp, Ctr Med Genet, New Delhi, India. RP Kruszka, P (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM paul.kruszka@nih.gov FU Division of Intramural Research of the National Human Genome Research Institute FX Grant sponsor: Division of Intramural Research of the National Human Genome Research Institute. NR 56 TC 5 Z9 5 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2015 VL 167 IS 11 BP 2657 EP 2663 DI 10.1002/ajmg.a.37259 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CU1LB UT WOS:000363281900027 PM 26249544 ER PT J AU Weiss, K Applegate, C Wang, T Batista, DAS AF Weiss, Karin Applegate, Carolyn Wang, Tao Batista, Denise A. S. TI Familial TAB2 microdeletion and congenital heart defects including unusual valve dysplasia and tetralogy of fallot SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE cardiac outflow tract; congenital heart defect; deletion 6q; myxomatous cardiac valves; TAB2 ID GROWTH FAILURE; DISEASE; DELETION AB Haploinsufficiency of TAB2 was recently implicated as a cause for a variety of congenital heart defects. Reported cases have genomic deletions of 2-10Mbs including TAB2 at 6q24-25 are almost always de novo and show variable cardiac and extra cardiac phenotype. We report on an inherited, 281kb deletion in a three generation family. This is the smallest reported deletion involving TAB2 that segregates with congenital heart defects. Three affected individuals in this family present with myxomatous cardiac valves in addition to structural heart defects commonly associated with TAB2 deletions. Findings from this family support a key role of TAB2 haploinsufficiency in congenital heart defects and expand the phenotypic spectrum of TAB2-microdeletion syndrome. (c) 2015 Wiley Periodicals, Inc. C1 [Weiss, Karin] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Applegate, Carolyn; Wang, Tao; Batista, Denise A. S.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. [Wang, Tao] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [Batista, Denise A. S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Batista, Denise A. S.] Kennedy Krieger Inst, Cytogenet & Microarray Lab, Baltimore, MD USA. RP Batista, DAS (reprint author), Johns Hopkins Univ, Cytogenet Lab, 600 N Wolfe St,Pk Bldg SB 202, Baltimore, MD 21287 USA. EM dbatist1@jhmi.edu NR 21 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2015 VL 167 IS 11 BP 2702 EP 2706 DI 10.1002/ajmg.a.37210 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CU1LB UT WOS:000363281900034 PM 26139517 ER PT J AU Burgemeister, AL Zirn, B Oeffner, F Kaler, SG Lemm, G Rossier, E Buttel, HM AF Burgemeister, Anna Lena Zirn, Birgit Oeffner, Frank Kaler, Stephen G. Lemm, Gunther Rossier, Eva Buettel, Hans-Martin TI Menkes disease with discordant phenotype in female monozygotic twins SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Menkes disease; female monozygotic twins; discordant phenotype; ATP7A ID MUSCULAR-DYSTROPHY; GROWTH AB Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene. This neurodegenerative disorder typically affects males and is characterized by impaired copper distribution and the malfunction of several copper-dependent enzymes. We report clinically discordant female monozygotic twins (MZT) with a heterozygous ATP7A mutation. One twin girl is healthy at the current age of 4 years, whereas the other twin girl developed classical MD, showed disease stabilization under copper histidine treatment but died at the age of 3 years. Presumably, the affected girl developed MD due to skewed X inactivation, although this could not be demonstrated in two tissues (blood, buccal mucosa). This case is a rare example of an affected girl with MD and shows the possibility of a discordant phenotype in MZT girls. As speculated in other X-linked diseases, the process of monozygotic twinning may be associated with skewed X inactivation leading to a discordant phenotype. (c) 2015 Wiley Periodicals, Inc. C1 [Burgemeister, Anna Lena; Zirn, Birgit; Oeffner, Frank; Rossier, Eva] Genetikum, Genet Counseling & Diagnost, D-70174 Stuttgart, Germany. [Burgemeister, Anna Lena; Zirn, Birgit; Oeffner, Frank; Rossier, Eva] Genetikum, Genet Counseling & Diagnost, Neu Ulm, Germany. [Zirn, Birgit] Univ Med, Dept Pediat & Neuropediat, Gottingen, Germany. [Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Translat Neurosci, Program Mol Med, NIH, Bethesda, MD USA. [Lemm, Gunther] SLK Klinikum, Dept Radiol, Heilbronn, Germany. [Buettel, Hans-Martin] SLK Klinikum, Dept Pediat & Neuropediat, Heilbronn, Germany. RP Burgemeister, AL (reprint author), Genetikum, Genet Counseling & Diagnost, Buchsenstr 20, D-70174 Stuttgart, Germany. EM burgemeister@genetikum.de NR 20 TC 0 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD NOV PY 2015 VL 167 IS 11 BP 2826 EP 2829 DI 10.1002/ajmg.a.37276 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA CU1LB UT WOS:000363281900054 PM 26239182 ER PT J AU Taylor, CL Thomas, PR Aloia, JF Millard, PS Rosen, CJ AF Taylor, Christine L. Thomas, Paul R. Aloia, John F. Millard, Peter S. Rosen, Clifford J. TI Questions About Vitamin D for Primary Care Practice: Input From an NIH Conference SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE 25-hydroxyvitamin D; 25(OH)D; Laboratory testing; Screening; Supplementation; Vitamin D; Vitamin D status ID CLINICAL-PRACTICE; D DEFICIENCY AB There is considerable consumer and physician interest in vitamin D as a possible therapeutic agent for a range of clinical conditions and, despite mixed evidence, the interest does not appear to lessen. Some clinicians believe that consumption of vitaminD is inadequate and, in turn, advocate vitamin D supplementation to increase serum levels of the nutrient. However, evidence concerning the role of vitamin D in health and disease is conflicting, and primary care physicians have little time to sort through the data and may find it difficult to advise their patients. To better understand the challenges that primary care physicians face regarding vitamin D, and to help inform those who provide guidance for clinical decision-making, the Office of Dietary Supplements at the National Institutes of Health, with co-sponsorship from other federal health agencies, held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in Primary Care in December 2014. More than 20 invited presenters and panelists considered laboratory methods for measuring vitamin D status, discussed how clinical studies of vitamin D should be evaluated and used in developing recommendations, noted the role of values and preferences in clinical decision-making, debated the current science related to at-risk groups, and described emerging data about health risks of excessive intakes of vitamin D. Eight questions about vitamin D stem from the Conference presentations as well as other expert sources. Published by Elsevier Inc. C1 [Taylor, Christine L.; Thomas, Paul R.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Aloia, John F.] Winthrop Univ Hosp, Bone Mineral Res Ctr, Mineola, NY 11501 USA. [Millard, Peter S.] Seaport Community Hlth Ctr, Belfast, ME USA. [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Ctr Clin & Translat Res, Scarborough, ME USA. RP Taylor, CL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01,MSC 7517, Bethesda, MD 20892 USA. EM TaylorCL3@od.nih.gov FU National Center for Complementary and Integrative Health; NCCIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute on Aging (NIA); Agency for Healthcare Research and Quality (AHRQ); Division for Heart Health and Stroke Prevention of the Centers for Disease Control and Prevention (CDC); National Institute of Standards and Technology (NIST); Office of Disease Prevention and Health Promotion (ODPHP) at the Department of Health and Human Services; US Food and Drug Administration FX This review was prepared from a conference held at the National Institutes of Health (NIH) on December 2-3, 2014 titled "Vitamin D: Moving Toward Evidence-based Decision Making in Primary Care." At the NIH, the primary sponsor was the Office of Dietary Supplements, with co-sponsorship by the National Center for Complementary and Alternative Medicine (now the National Center for Complementary and Integrative Health; NCCIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute on Aging (NIA). Additional co-sponsorship was provided by the Agency for Healthcare Research and Quality (AHRQ), Division for Heart Health and Stroke Prevention of the Centers for Disease Control and Prevention (CDC), National Institute of Standards and Technology (NIST), Office of Disease Prevention and Health Promotion (ODPHP) at the Department of Health and Human Services, and the US Food and Drug Administration. NR 9 TC 0 Z9 0 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD NOV PY 2015 VL 128 IS 11 BP 1167 EP 1170 DI 10.1016/j.amjmed.2015.05.025 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CU3VI UT WOS:000363453500027 PM 26071820 ER PT J AU Dettmer, AM Hambright, MK Novak, MF AF Dettmer, A. M. Hambright, M. K. Novak, M. F. TI ASP EDUCATION COMMITTEE PRE-CONFERENCE EDUCATIONAL OUTREACH SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Dettmer, A. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD 20837 USA. [Hambright, M. K.] Coll Coastal Georgia, Brunswick, GA USA. [Novak, M. F.] Cent Oregon Community Coll, Bend, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 3 BP 37 EP 37 PG 1 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500003 ER PT J AU Dettmer, AM Woodward, RA Rosenberg, K Suomi, SJ Novak, MA Meyer, JS AF Dettmer, A. M. Woodward, R. A. Rosenberg, K. Suomi, S. J. Novak, M. A. Meyer, J. S. TI HAIR CORTISOL IS ASSOCIATED WITH CHANGES IN HAIR LOSS AND BODY CONDITION ACROSS PUBERTY IN MALE RHESUS MONKEYS SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Dettmer, A. M.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD 20837 USA. [Woodward, R. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Res Anim Management Branch, Div Intramural Res, NIH, Poolesville, MD 20837 USA. [Rosenberg, K.; Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 37 BP 46 EP 46 PG 1 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500020 ER PT J AU Hamel, AF Dettmer, AM Miller, MM Suomi, SJ Meyer, JS Novak, MA AF Hamel, A. F. Dettmer, A. M. Miller, M. M. Suomi, S. J. Meyer, J. S. Novak, M. A. TI EARLY REARING EXPERIENCE MODULATES TEMPERAMENT AND ACTIVITY OF THE OXYTOCIN SYSTEM AND HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS IN INFANT RHESUS MONKEYS (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Hamel, A. F.] Univ Massachusetts, Neurosci & Behav Grad Program, Amherst, MA 01003 USA. [Dettmer, A. M.; Miller, M. M.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Poolesville, MD USA. [Meyer, J. S.; Novak, M. A.] Univ Massachusetts, Psychol & Brain Sci, Amherst, MA 01003 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 53 BP 53 EP 54 PG 2 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500035 ER PT J AU Aston, SA O'Connell, PH Schwandt, ML Barr, CS Lindell, SG Suomi, SJ Higley, JD AF Aston, S. A. O'Connell, P. H. Schwandt, M. L. Barr, C. S. Lindell, S. G. Suomi, S. J. Higley, J. D. TI A C-TO-T SNP IN THE PROMOTER REGION OF THE RHESUS MACAQUE (MACACA MULATTA) CRH GENE INTERACTS WITH EARLY REARING EXPERIENCES INFLUENCING ANXIOUS BEHAVIOR SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Aston, S. A.; O'Connell, P. H.; Higley, J. D.] Brigham Young Univ, Dept Psychol, SWKT 1042, Provo, UT 84602 USA. [Schwandt, M. L.; Barr, C. S.; Lindell, S. G.; Suomi, S. J.] NIAAA, NIH, NICHD, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 66 BP 60 EP 60 PG 1 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500048 ER PT J AU Peterson, EJ Worlein, JM Lee, GH Dettmer, AM Varner, EK Novak, MA AF Peterson, E. J. Worlein, J. M. Lee, G. H. Dettmer, A. M. Varner, E. K. Novak, M. A. TI LABORATORY HOUSED RHESUS MACAQUES (MACACA MULATTA) WITH SELF INJURIOUS BEHAVIOR SHOW A BLUNTED BEHAVIORAL RESPONSE TO THE HUMAN INTRUDER TEST SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Peterson, E. J.] Univ Massachusetts, Neurosci & Behav Grad Program, Amherst, MA 01003 USA. [Worlein, J. M.; Lee, G. H.] Washington Natl Primate Res Ctr, Seattle, WA USA. [Varner, E. K.; Novak, M. A.] Univ Massachusetts, Psychol & Brain Sci, Amherst, MA 01003 USA. [Dettmer, A. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 92 BP 73 EP 74 PG 2 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500074 ER PT J AU Paukner, A Simpson, EA Ferrari, PF Suomi, SJ AF Paukner, A. Simpson, E. A. Ferrari, P. F. Suomi, S. J. TI FACE-TO-FACE INTERACTIONS INCREASE SOCIAL VIEWING PREFERENCES IN INFANT RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Paukner, A.; Simpson, E. A.; Suomi, S. J.] NIH, Lab Comparat Ethol, Anim Ctr, Poolesville, MD 20837 USA. [Simpson, E. A.; Ferrari, P. F.] Univ Parma, I-43100 Parma, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 161 BP 104 EP 104 PG 1 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500131 ER PT J AU Madrid, JE Mandalaywala, TM Coyne, SP Garner, JP Barr, CS Maestripieri, D Parker, KJ AF Madrid, J. E. Mandalaywala, T. M. Coyne, S. P. Garner, J. P. Barr, C. S. Maestripieri, D. Parker, K. J. TI SEROTONIN TRANSPORTER AND MATERNAL CARE: A SEX-SPECIFIC G X E EFFECT ON JUVENILE SOCIAL PLAY IN FREE-RANGING RHESUS MACAQUES OF CAYO SANTIAGO SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Madrid, J. E.; Garner, J. P.; Parker, K. J.] Stanford Univ, MSLS, Stanford, CA 94305 USA. [Mandalaywala, T. M.; Coyne, S. P.; Maestripieri, D.] Univ Chicago, Chicago, IL 60637 USA. [Barr, C. S.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 169 BP 107 EP 108 PG 2 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500138 ER PT J AU Hutchinson, EK AF Hutchinson, E. K. TI A REVIEW OF DRUG THERAPIES FOR SELF-INJURIOUS BEHAVIOR SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-of-Primatologists CY JUN 18-21, 2015 CL Bend, OR SP Amer Soc Primatologists, Chimps Inc, Primate Conservat Inc, Purina LabDiet, Res Diets Inc, Carter 2 Syst Inc, S Karger Publishers Inc, Cambridge Univ Press, Unifab Corp, Van Hoang Dao C1 [Hutchinson, E. K.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD NOV PY 2015 VL 77 SU 1 MA 170 BP 108 EP 108 PG 1 WC Zoology SC Zoology GA CU5GQ UT WOS:000363560500139 ER PT J AU Giubellino, A Lara, K Martucci, V Huynh, T Agarwal, P Pacak, K Merino, MJ AF Giubellino, Alessio Lara, Karlena Martucci, Victoria Than Huynh Agarwal, Piyush Pacak, Karel Merino, Maria J. TI Urinary Bladder Paragangliomas How Immunohistochemistry Can Assist to Identify Patients With SDHB Germline and Somatic Mutations SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE bladder paraganglioma; SDHB; somatic mutation ID PHEOCHROMOCYTOMA; SPECIMENS; NEOPLASMS AB Urinary bladder paraganglioma (paraganglioma) is a rare tumor of chromaffin cells of the sympathetic system of the urinary bladder wall. We studied 14 cases of this entity and investigated the usefulness of SDHB protein staining by immunohistochemistry (IHC) as a diagnostic tool to identify patients with bladder paragangliomas that could be associated with SDHB gene mutations, as these patients have a more aggressive disease. Eleven tumors from these patients were stained by IHC. Six of 11 tumors were negative for SDHB staining by IHC with no cytoplasmic staining in tumor cells when compared with normal tissues. Five of these 6 negative cases were confirmed to be positive for germline SDHB mutations. One case showed negative staining and no germline SDHB mutation; however, further investigation of the tumor revealed a somatic SDHB gene deletion. The remaining 5 cases showed strong cytoplasmic staining, but they were negative for the presence of SDHB mutation. They were found to be either sporadic tumors or part of von Hippel-Lindau syndrome. Staining for SDHA was positive in all cases. Our study confirms that there is very good correlation between the presence of an SDHB mutation, whether germline or sporadic, and negative SDHB IHC staining in urinary bladder paragangliomas, and this is the first study to demonstrate that somatic mutations can be recognized by IHC staining. C1 [Giubellino, Alessio; Lara, Karlena; Merino, Maria J.] NCI, Translat Surg Pathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Martucci, Victoria; Than Huynh; Pacak, Karel] NICHHD, Bethesda, MD 20892 USA. [Agarwal, Piyush] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giubellino, A (reprint author), NCI, 10 Ctr Dr,Bldg 10,Room 2B38, Bethesda, MD 20892 USA. EM giubella@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2015 VL 39 IS 11 BP 1488 EP 1492 DI 10.1097/PAS.0000000000000534 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA CU2TH UT WOS:000363375900005 PM 26457353 ER PT J AU Blau, JE Abegg, MR Flegel, WA Zhao, X Harlan, DM Rother, KI AF Blau, J. E. Abegg, M. R. Flegel, W. A. Zhao, X. Harlan, D. M. Rother, K. I. TI Long-Term Immunosuppression After Solitary Islet Transplantation Is Associated With Preserved C-Peptide Secretion for More Than a Decade SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID INTENSIVE MEDICAL THERAPY; 5-YEAR FOLLOW-UP; QUALITY-OF-LIFE; INSULIN-INDEPENDENCE; CELL TRANSPLANTATION; HLA ANTIBODIES; TYPE-1; PROGRESSION; RECIPIENTS AB We report on two patients with type 1 diabetes (T1D) after solitary islet transplantation in 2001. They received steroid-sparing immunosuppression (daclizumab, sirolimus, and tacrolimus according to the Edmonton protocol). Both patients became insulin independent for 2 years: Patient A, a 42-year-old female with a 12-year history of T1D, received two islet infusions; patient B, a 53-year-old female with a 40-year T1D history, received one islet infusion. Pretransplant, both had undetectable C-peptide concentrations and frequent and severe hypoglycemia. Pretransplant, hemoglobin A1c (HbA1c) was 7.8% and 8.8% and insulin requirements were 0.47 and 0.33units/kg/day, respectively. Posttransplant, C-peptide levels remained detectable while immunosuppression was continued, but decreased over time. Insulin was re-started 2 years posttransplant in both patients. Since patient A's glycemia and insulin requirements trended toward pretransplant levels, immunosuppression was discontinued after 13 years. This resulted in a sudden cessation of C-peptide secretion. Patient B continues on immunosuppression, has better HbA1c, and half the insulin requirement compared to pretransplant. Both patients no longer experience severe hypoglycemia. Herein, we document blood glucose concentrations over time (>30000 measurements per patient) and cell function based on C-peptide secretion. Despite renewed insulin dependence, both patients express satisfaction with having undergone the procedure. C1 [Blau, J. E.; Abegg, M. R.; Zhao, X.; Rother, K. I.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Flegel, W. A.] NIH, Dept Transfus Med, NIH Clin Ctr, Bethesda, MD 20892 USA. [Harlan, D. M.] Univ Massachusetts, Sch Med, Dept Internal Med, Div Diabet Endocrinol & Nutr,Diabet Ctr Excellenc, North Worcester, MA USA. RP Rother, KI (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov FU Intramural Research Program of the NIH Clinical Center FX We would like to thank Sharon D. Adams, from the Department of Transfusion Medicine, NIH Clinical Center, for HLA testing. This work was supported by the Intramural Research Program of the NIH Clinical Center. NR 24 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2015 VL 15 IS 11 BP 2995 EP 3001 DI 10.1111/ajt.13383 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA CU1FG UT WOS:000363264800025 PM 26184712 ER PT J AU Marcum, ZA Perera, S Thorpe, JM Switzer, GE Gray, SL Castle, NG Strotmeyer, ES Simonsick, EM Bauer, DC Shorr, RI Studenski, SA Hanlon, JT AF Marcum, Zachary A. Perera, Subashan Thorpe, Joshua M. Switzer, Galen E. Gray, Shelly L. Castle, Nicholas G. Strotmeyer, Elsa S. Simonsick, Eleanor M. Bauer, Douglas C. Shorr, Ronald I. Studenski, Stephanie A. Hanlon, Joseph T. CA Hlth ABC Study USA TI Anticholinergic Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE cholinergic antagonist; accidental falls; older adults; pharmacoepidemiology ID BODY-COMPOSITION; PEOPLE; COHORT; ASSOCIATIONS; MEDICATIONS; BURDEN; ELDERS; RISK; CARE AB Background: Although it is generally accepted that anticholinergic use may lead to a fall, results from studies assessing the association between anticholinergic use and falls are mixed. In addition, direct evidence of an association between use of anticholinergic medications and recurrent falls among community-dwelling elders is not available. Objective: To assess the association between anticholinergic use across multiple anticholinergic subclasses, including over-the-counter medications, and recurrent falls. Methods: This was a longitudinal analysis of 2948 participants, with data collected via interview at year 1 from the Health, Aging and Body Composition study and followed through year 7 (1997-2004). Self-reported use of anticholinergic medication was identified at years 1, 2, 3, 5, and 6 as defined by the list from the 2015 American Geriatrics Society Beers Criteria. Dosage and duration were also examined. The main outcome was recurrent falls (2) in an ensuing 12-month period from each medication data collection. Results: Using multivariable generalized estimating equation models, controlling for demographic, health status/behaviors, and access-to-care factors, a 34% increase in likelihood of recurrent falls in anticholinergic users (adjusted odds ratio = 1.34; 95% CI = 0.93-1.93) was observed, but the results were not statistically significant; similar results were found with higher doses and longer duration of use. Conclusion: Increased point estimates suggest an association of anticholinergic use with recurrent falls, but the associations did not reach statistical significance. Future studies are needed for more definitive evidence and to examine other measures of anticholinergic burden and associations with more intermediate adverse effects such as cognitive function. C1 [Marcum, Zachary A.; Gray, Shelly L.] Univ Washington, Seattle, WA 98102 USA. [Perera, Subashan; Thorpe, Joshua M.; Switzer, Galen E.; Castle, Nicholas G.; Strotmeyer, Elsa S.; Hanlon, Joseph T.] Univ Pittsburgh, Pittsburgh, PA USA. [Thorpe, Joshua M.; Switzer, Galen E.; Hanlon, Joseph T.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Simonsick, Eleanor M.; Studenski, Stephanie A.] NIA, Baltimore, MD 21224 USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shorr, Ronald I.] Vet Affairs Med Ctr, Gainesville, FL 32608 USA. RP Marcum, ZA (reprint author), Univ Washington, Sch Pharm, Dept Pharm, 1959 NE Pacific St,H375G,Box 357630, Seattle, WA 98102 USA. EM zmarcum@uw.edu OI Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institute on Aging (NIA) [P30AG024827, T32 AG021885, K07AG033174, R01AG028050]; National Institutes of Health, NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing research grant [R01NR012459] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was primarily supported by National Institute on Aging (NIA) grants and contracts (P30AG024827, T32 AG021885, K07AG033174, R01AG028050). This research was also supported in part by the Intramural Research program of the National Institutes of Health, NIA (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106), and a National Institute of Nursing research grant (R01NR012459). NR 29 TC 2 Z9 2 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD NOV PY 2015 VL 49 IS 11 BP 1214 EP 1221 DI 10.1177/1060028015596998 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU0OW UT WOS:000363217800005 PM 26228936 ER PT J AU Laugsand, LE Ix, JH Bartz, TM Djousse, L Kizer, JR Tracy, RP Dehghan, A Rexrode, K Lopez, OL Rimm, EB Siscovick, DS O'Donnell, CJ Newman, A Mukamal, KJ Jensen, MK AF Laugsand, Lars E. Ix, Joachim H. Bartz, Traci M. Djousse, Luc Kizer, Jorge R. Tracy, Russell P. Dehghan, Abbas Rexrode, Kathryn Lopez, Oscar L. Rimm, Eric B. Siscovick, David S. O'Donnell, Christopher J. Newman, Anne Mukamal, Kenneth J. Jensen, Majken K. TI Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies SO ATHEROSCLEROSIS LA English DT Article DE Fetuin-A; Single nucleotide polymorphisms; Coronary heart disease; Mendelian randomization; Meta-analysis ID ALPHA(2)-HEREMANS-SCHMID GLYCOPROTEIN/FETUIN-A; INCIDENT DIABETES-MELLITUS; CARDIOVASCULAR HEALTH; OLDER-ADULTS; INSULIN-RECEPTOR; TYROSINE KINASE; ASSOCIATION; ATHEROSCLEROSIS; INHIBITOR; CALCIFICATION AB Background and aims: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Methods: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993. Results: Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048). Conclusion: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Laugsand, Lars E.] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway. [Laugsand, Lars E.; Rimm, Eric B.; Jensen, Majken K.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Djousse, Luc; Rexrode, Kathryn] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT 05405 USA. [Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Kizer, Jorge R.; Rimm, Eric B.; Jensen, Majken K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Siscovick, David S.] Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David S.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Newman, Anne] UPMC, Univ Pittsburgh, Sch Hlth Sci, Pittsburgh, PA USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Jensen, MK (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RI Djousse, Luc/F-5033-2017; Newman, Anne B./C-6408-2013; OI Djousse, Luc/0000-0002-9902-3047; Newman, Anne B./0000-0002-0106-1150; Rexrode, Kathryn/0000-0003-3387-8429; Dehghan, Abbas/0000-0001-6403-016X FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL094555]; NHLBI CARe project (Broad Institute of Massachusetts Institute of Technology and Harvard) [N01HC65226]; NHLBI [HL080295]; National Institute on Aging (NIA) [R01AG023629]; Liaison Committee; National Institutes of Health, Bethesda, MD [HL35464, CA55075, CA87969, HL34594]; NIH [N01-AG-12100]; NIA Intramural Research Program; Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Netherlands Organization for Scientific Research (NWO) [916.12.154]; EUR Fellowship; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; National Institutes of Aging; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Hjartavernd (the Icelandic Heart Association); Erasmus Medical Center; [HHSN268201200036C]; [HHSN268200800007C]; [N01HC55222]; [N01HC85079]; [N01HC85080]; [N01HC85081]; [N01HC85082]; [N01HC85083]; [NO1HC85086] FX The manuscript was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) (R01 HL094555 to LD, J.R.K.J.H.I, and K.J.M) and genotyping was funded by the NHLBI CARe project (Broad Institute of Massachusetts Institute of Technology and Harvard, N01HC65226). The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and NO1HC85086, and by grant HL080295 from NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A complete list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. Lars E. Laugsand received a research fellowship grant from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology.; Replication studies; The HPFS CHD case-control study was supported by HL35464, and CA55075 from the National Institutes of Health, Bethesda, MD, with additional support for genotyping from Merck/Rosetta Research Laboratories, North Wales, PA. NHS: The NHS CHD case-control study was supported by CA87969 and HL34594 from the National Institutes of Health, Bethesda, MD, with additional support for genotyping from Merck/Rosetta Research Laboratories, North Wales, PA.; CHARGE cohorts: AGES study was funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ARIC is supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. FHS was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (N02-HL-6-4278). Abbas Dehghan is supported by Netherlands Organization for Scientific Research (NWO) grant (veni, 916.12.154) and the EUR Fellowship. Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. Health ABC was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). NR 38 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 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2015 VL 243 IS 1 BP 44 EP 52 DI 10.1016/j.atherosclerosis.2015.08.031 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CU1FQ UT WOS:000363266000006 PM 26343871 ER PT J AU Lucero, D Sviridov, D Freeman, L Lopez, GI Fassio, E Remaley, AT Schreier, L AF Lucero, Diego Sviridov, Denis Freeman, Lita Lopez, Graciela I. Fassio, Eduardo Remaley, Alan T. Schreier, Laura TI Increased cholesterol efflux capacity in metabolic syndrome: Relation with qualitative alterations in HDL and LCAT (vol 224, pg 236, 2015) SO ATHEROSCLEROSIS LA English DT Correction C1 [Lucero, Diego; Lopez, Graciela I.; Schreier, Laura] Univ Buenos Aires, Fac Pharm & Biochem, Dept Clin Biochem, Lab Lipids & Atherosclerosis,INFIBIOC, Buenos Aires, DF, Argentina. [Lucero, Diego; Sviridov, Denis; Freeman, Lita; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20892 USA. [Fassio, Eduardo] Natl Hosp Prof A Posadas, Dept Gastroenterol, Buenos Aires, DF, Argentina. RP Lucero, D (reprint author), Univ Buenos Aires, Fac Pharm & Biochem, Dept Clin Biochem, Junin 956 C1113AAD, Buenos Aires, DF, Argentina. EM dmlucero@ffyb.uba.ar NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2015 VL 243 IS 1 BP 59 EP 59 DI 10.1016/j.atherosclerosis.2015.08.041 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CU1FQ UT WOS:000363266000008 ER PT J AU Im, A Pavletic, SZ AF Im, Annie Pavletic, Steven Z. TI Deciphering the Mystery: Extracorporeal Photopheresis in Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material ID PEDIATRIC-PATIENTS; PHOTOCHEMOTHERAPY; TRANSPLANTATION C1 [Im, Annie] Univ Pittsburgh, Med Ctr, Div Hematol Oncol, Pittsburgh, PA USA. [Pavletic, Steven Z.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Graft Versus Host Dis & Autoimmun Unit, Expt Transplantat & Immunol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room CRC 4-3130, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov OI Im, Annie/0000-0002-0973-7100 NR 12 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2015 VL 21 IS 11 BP 1861 EP 1862 DI 10.1016/j.bbmt.2015.09.011 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CU2MI UT WOS:000363357200002 PM 26386319 ER PT J AU Torres, HA Chong, PP De Lima, M Friedman, MS Giralt, S Hammond, SP Kiel, PJ Masur, H McDonald, GB Wingard, JR Gambarin-Gelwan, M AF Torres, Harrys A. Chong, Pearlie P. De Lima, Marcos Friedman, Mark S. Giralt, Sergio Hammond, Sarah P. Kiel, Patrick J. Masur, Henry McDonald, George B. Wingard, John R. Gambarin-Gelwan, Maya TI Hepatitis C Virus Infection among Hematopoietic Cell Transplant Donors and Recipients: American Society for Blood and Marrow Transplantation Task Force Recommendations SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article ID GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; LIVER-TRANSPLANTATION; TRANSIENT ELASTOGRAPHY; PEGYLATED INTERFERON; ACUTE EXACERBATION; LIVING-DONOR; FOLLOW-UP; B-VIRUS; HCV C1 [Torres, Harrys A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chong, Pearlie P.] Univ N Carolina, Chapel Hill, NC USA. [De Lima, Marcos] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [De Lima, Marcos] Case Western Reserve Univ, Univ Hosp Seidman Canc Ctr, Cleveland, OH 44106 USA. [Friedman, Mark S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Giralt, Sergio; Gambarin-Gelwan, Maya] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hammond, Sarah P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hammond, Sarah P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kiel, Patrick J.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Masur, Henry] NIH, Ctr Clin, Bethesda, MD 20892 USA. [McDonald, George B.] Univ Washington, Seattle, WA 98195 USA. [McDonald, George B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. RP Torres, HA (reprint author), Univ Texas MD Anderson Canc Ctr, Unit 1460, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM htorres@mdanderson.org FU University of Texas MD Anderson Cancer Center; Gilead Sciences; Merck Co., Inc.; Vertex Pharmaceuticals; Ansun Biopharma; Hoffman-La Roche; Coley Pharmaceutical; GlaxoSmithKline; LabCorp Corporation; Conatus Pharmaceuticals; Bristol-Myers Squibb FX H.A.T. is a consultant for Janssen Pharmaceuticals, Inc., Gilead Sciences, Merck & Co., Inc., Vertex Pharmaceuticals, Novartis, Genentech, Astellas, Pfizer, and Theravance, Inc. and has received research grants from The University of Texas MD Anderson Cancer Center, Gilead Sciences, Merck & Co., Inc., and Vertex Pharmaceuticals. S.P.H. has received research grants from Merck & Co., Inc. and Ansun Biopharma. J.R.W. is a consultant for Ansun, Gilead Sciences, Merck & Co, and Astellas; speaker for Pfizer; and has received royalties from UpToDate Inc. M.G.G. is a consultant for Gilead Sciences, Bristol-Myers Squibb and has received research grants from Hoffman-La Roche, Coley Pharmaceutical, GlaxoSmithKline, LabCorp Corporation, Conatus Pharmaceuticals, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors have no conflicts of interest to declare. NR 69 TC 9 Z9 10 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2015 VL 21 IS 11 BP 1870 EP 1882 DI 10.1016/j.bbmt.2015.07.033 PG 13 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CU2MI UT WOS:000363357200004 PM 26256943 ER PT J AU Kiselev, E Balasubramanian, R Uliassi, E Brown, KA Trujillo, K Katritch, V Hammes, E Stevens, RC Harden, TK Jacobson, KA AF Kiselev, Evgeny Balasubramanian, Ramachandran Uliassi, Elisa Brown, Kyle A. Trujillo, Kevin Katritch, Vsevolod Hammes, Eva Stevens, Raymond C. Harden, T. Kendall Jacobson, Kenneth A. TI Design, synthesis, pharmacological characterization of a fluorescent agonist of the P2Y(14) receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE G protein-coupled receptor; Nucleotides; Pyrimidines; Homology modeling; Docking; P2Y receptor ID HUMAN NEUTROPHILS; MOLECULAR PROBES; DERIVATIVES; ANTAGONISTS; CHEMOTAXIS; TEMPLATE; POTENT; MICE AB The P2Y(14)R is a G(i/o)-coupled receptor of the P2Y family of purinergic receptors that is activated by extracellular UDP and UDP-glucose (UDPG). In an earlier report we described a P2Y(14)R fluorescent probe, MRS4174, based on the potent and selective antagonist PPTN, a naphthoic acid derivative. Here, we report the design, preparation, and activity of an agonist-based fluorescent probe MRS4183 (11) and a shorter P2Y(14)R agonist congener, which contain a UDP-glucuronic acid pharmacophore and BODIPY fluorophores conjugated through diaminoalkyl linkers. The design relied on both docking in a P2Y(14)R homology model and established structure activity relationship (SAR) of nucleotide analogs. 11 retained P2Y(14)R potency with EC50 value of 0.96 nM (inhibition of adenylyl cyclase), compared to parent UDPG (EC50 47 nM) and served as a tracer for microscopy and flow cytometry, displaying minimal nonspecific binding. Binding saturation analysis gave an apparent binding constant for 11 in whole cells of 21.4 +/- 1.1 nM, with a t(1/2) of association at 50 nM 11 of 23.9 min. Known P2Y(14)R agonists and PPTN inhibited cell binding of 11 with the expected rank order of potency. The success in the identification of a new P2Y(14)R fluorescent agonist with low nonspecific binding illustrates the advantages of rational design based on recently determined GPCR X-ray structures. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. Published by Elsevier Ltd. C1 [Kiselev, Evgeny; Balasubramanian, Ramachandran; Uliassi, Elisa; Trujillo, Kevin; Hammes, Eva; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Brown, Kyle A.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Katritch, Vsevolod; Stevens, Raymond C.] Univ So Calif, Bridge Inst, Dept Biol Sci, Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. [Stevens, Raymond C.] Univ So Calif, Bridge Inst, Dept Chem, Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Katritch, Vsevolod/Q-8357-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; FU National Institutes of Health (Intramural Research Program of the NIDDK) [Z01 DK031116]; NIGMS Postdoctoral Research Associate (PRAT) Program [GM38213, U54GM094618] FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the National Institutes of Health (Intramural Research Program of the NIDDK, Z01 DK031116), NIGMS Postdoctoral Research Associate (PRAT) Program and Grant nos. GM38213 to T.K.H. and U54GM094618 to V.K. and R.C.S. NR 25 TC 4 Z9 4 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2015 VL 25 IS 21 BP 4733 EP 4739 DI 10.1016/j.bmcl.2015.08.021 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CU1IV UT WOS:000363275400007 PM 26303895 ER PT J AU Gupta, P Rastede, EE Appella, DH AF Gupta, Pankaj Rastede, Elizabeth E. Appella, Daniel H. TI Multivalent K-L gamma-PNA oligomers bind to a human telomere DNA G-rich sequence to form quadruplexes SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Quadruplex; DNA; PNA ID PEPTIDE NUCLEIC-ACIDS; COMPLEMENTARY; RNA; HYBRIDIZATION; OLIGONUCLEOTIDES; RECOGNITION; TRANSLATION; SELECTIVITY; STABILITY; PROMOTER AB We report G-quadruplex formation between peptide nucleic acids (PNAs) composed of K-L gamma-PNA-G monomers and a known portion of human telomeric DNA that adopts three G3 tracts via intramolecular hydrogen bonding. The resulting complex is a bimolecular PNA-DNA heteroquadruplex. In this Letter, we show that introduction of a gamma-modification and addition of a peptide ligand does not disrupt the heteroquadruplex. Although the unmodified PNA1 forms a quadruplex with itself, the gamma-substituted PNAs (PNA2-PNA6) do not form G-quadruplexes on their own, at even high concentrations. The selectivity of these PNAs could influence the design of new quadruplex-targeting molecules or allow the quadruplex structure to be used as a scaffold for multivalent display of protein binding ligands. Published by Elsevier Ltd. C1 [Gupta, Pankaj; Rastede, Elizabeth E.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov FU Intramural Research Program of NIDDK, NIH FX This research was supported by the Intramural Research Program of NIDDK, NIH. NR 48 TC 0 Z9 0 U1 3 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2015 VL 25 IS 21 BP 4757 EP 4760 DI 10.1016/j.bmcl.2015.07.075 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CU1IV UT WOS:000363275400010 PM 26259805 ER PT J AU Stratton, CF Newman, DJ Tan, DS AF Stratton, Christopher F. Newman, David J. Tan, Derek S. TI Cheminformatic comparison of approved drugs from natural product versus synthetic origins SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Natural products; Synthetic drugs; Physicochemical properties; Cheminformatics; Principal component analysis ID DIVERSITY-ORIENTED SYNTHESIS; SMALL MOLECULES; CHEMICAL SPACE; ORAL BIOAVAILABILITY; RING EXPANSION; DISCOVERY; LIBRARY; TARGETS; DISTRIBUTIONS; PERMEABILITY AB Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981 and 2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Stratton, Christopher F.; Tan, Derek S.] Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, New York, NY 10065 USA. [Newman, David J.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Ft Detrick, MD 21702 USA. [Tan, Derek S.] Mem Sloan Kettering Canc Ctr, Chem Biol Program, New York, NY 10065 USA. [Tan, Derek S.] Mem Sloan Kettering Canc Ctr, Triinst Res Program, New York, NY 10065 USA. RP Tan, DS (reprint author), Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, 1275 York Ave,Box 422, New York, NY 10065 USA. FU NIH [P41 GM076267]; Tri-Institutional Stem Cell Initiative; Commonwealth Foundation for Cancer Research; MSKCC Experimental Therapeutics Center FX This work is dedicated to the memory of our mentor and colleague, Professor David Y. Gin (1967-2011). Instant JChem was generously provided by ChemAxon. Financial support from the NIH (P41 GM076267 to D.S.T.), Tri-Institutional Stem Cell Initiative, William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the MSKCC Experimental Therapeutics Center is gratefully acknowledged. NR 48 TC 8 Z9 9 U1 7 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2015 VL 25 IS 21 BP 4802 EP 4807 DI 10.1016/j.bmcl.2015.07.014 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CU1IV UT WOS:000363275400020 PM 26254944 ER PT J AU Ghosh, AK Takayama, J Kassekert, LA Ella-Menye, JR Yashchuk, S Agniswamy, J Wang, YF Aoki, M Amano, M Weber, IT Mitsuya, H AF Ghosh, Arun K. Takayama, Jun Kassekert, Luke A. Ella-Menye, Jean-Rene Yashchuk, Sofiya Agniswamy, Johnson Wang, Yuan-Fang Aoki, Manabu Amano, Masayuki Weber, Irene T. Mitsuya, Hiroaki TI Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV-1 protease; Inhibitors; Design; Synthesis; Antiviral; Isophthalamide ID ACTIVE ANTIRETROVIRAL THERAPY; RESOLUTION CRYSTAL-STRUCTURES; BETA-SECRETASE INHIBITORS; COMBAT DRUG-RESISTANCE; LIGAND; INFECTION; COMPLEXES; MUTANTS AB We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme K-i of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11 angstrom resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ghosh, Arun K.; Takayama, Jun; Kassekert, Luke A.; Ella-Menye, Jean-Rene; Yashchuk, Sofiya] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Takayama, Jun; Kassekert, Luke A.; Ella-Menye, Jean-Rene; Yashchuk, Sofiya] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. [Aoki, Manabu; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ Med, Dept Hematol, Kumamoto 8608556, Japan. [Aoki, Manabu; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ Med, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Shinjuku Ku, Tokyo 1628655, Japan. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU National Institutes of Health [GM53386, GM62920]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho FX This research was supported by the National Institutes of Health (Grant GM53386, A.K.G. and Grant GM62920, I.T.W.). X-ray data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22BM at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. The authors would like to thank the Purdue University Center for Cancer Research, which supports the shared NMR and mass spectrometry facilities. NR 34 TC 3 Z9 3 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2015 VL 25 IS 21 BP 4903 EP 4909 DI 10.1016/j.bmcl.2015.05.052 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CU1IV UT WOS:000363275400041 PM 26096678 ER PT J AU Jensen, JD Ratcliff, C Weaver, J Krakow, MM Payton, W Loewen, S AF Jensen, Jakob D. Ratcliff, Chelsea Weaver, Jeremy Krakow, Melinda M. Payton, William Loewen, Sherrie TI Explicating perceived barriers to mammography for the USCREEN project: concerns about breast implants, faith violations, and perceived recommendations SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Perceived barriers; Health belief model; Mammography; Breast implants; Faith; News coverage ID SERVICES TASK-FORCE; HEALTH BELIEF MODEL; AFRICAN-AMERICAN WOMEN; CHURCH ATTENDANCE; SELF-EFFICACY; CANCER; PREDICTORS; VARIABLES; BENEFITS; SCALE AB In line with the health belief model, perceived barriers have proven to be a key determinant of intentions to screen for breast cancer. The standard measure of perceived barriers to breast cancer screening is an 11 item scale developed by Victoria Champion. However, perceived barriers emerge and change over time, and Champion's perceived barriers scale was last revised in 1999. Moreover, the original scale did not address barriers which may be more pronounced in particular populations, such as congruity of action with faith. As part of the Utah Screening Project, a sample of women 40-74 (N = 341, Mage = 51.19, SD = 8.11) were recruited from four Utah counties in 2014 to complete a survey. The results revealed that the four new perceived barrier items explained 6.4 % of intentions to screen, above and beyond other predictors. In addition to barriers identified in past research, the current study identified several novel barriers including (a) concerns about negative effects to breast implants, (b) perceived conflict with faith, and the (c) perception that mammography is no longer recommended. The new perceived barriers items are useful to researchers interested in exploring barriers not addressed by the original instrument. The barriers also suggest potential belief-based targets and channels (e.g., plastic surgery clinics, faith-based interventions) for delivering mammography interventions. C1 [Jensen, Jakob D.; Ratcliff, Chelsea; Weaver, Jeremy; Payton, William; Loewen, Sherrie] Univ Utah, Dept Commun, Salt Lake City, UT 84112 USA. [Jensen, Jakob D.] Huntsman Canc Inst, Salt Lake City, UT USA. [Krakow, Melinda M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Jensen, JD (reprint author), Univ Utah, Dept Commun, 2423 LNCO,255 S Cent Campus Dr, Salt Lake City, UT 84112 USA. EM jakobdjensen@gmail.com FU Utah Department of Health FX Jakob D. Jensen is an Associate Professor in the Department of Communication and the Huntsman Cancer Institute at the University of Utah. Chelsea Ratcliff, Jeremy Weaver, William Payton, and Sherrie Loewen are graduate students in the Department of Communication at the University of Utah. Melinda Krakow is a post-doctoral fellow at the National Cancer Institute. This research was funded by a grant from the Utah Department of Health. NR 30 TC 0 Z9 0 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2015 VL 154 IS 1 BP 201 EP 207 DI 10.1007/s10549-015-3581-2 PG 7 WC Oncology SC Oncology GA CU4YP UT WOS:000363538100023 PM 26424166 ER PT J AU Morgan, RJ Synold, TW Longmate, JA Quinn, DI Gandara, D Lenz, HJ Ruel, C Xi, BX Lewis, MD Colevas, AD Doroshow, J Newman, EM AF Morgan, Robert J. Synold, Timothy W. Longmate, Jeffrey A. Quinn, David I. Gandara, David Lenz, Heinz-Josef Ruel, Christopher Xi, Bixin Lewis, Michael D. Colevas, A. Dimitrios Doroshow, James Newman, Edward M. TI Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pharmacodynamics; Pharmacokinetics; Eribulin; Halichondrin B analog; Phase I trial ID CELL LUNG-CANCER; MARINE NATURAL-PRODUCTS; MESYLATE E7389; BREAST-CANCER; PACLITAXEL RESISTANCE; HOMOHALICHONDRIN-B; TUBULIN MUTATIONS; VINCA DOMAIN; DRUGS; SENSITIVITY AB The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of beta-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for > 72 h. C1 [Morgan, Robert J.; Doroshow, James] City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. [Synold, Timothy W.; Xi, Bixin; Newman, Edward M.] City Hope Comprehens Canc Ctr, Dept Canc Biol, Duarte, CA 91010 USA. [Longmate, Jeffrey A.; Ruel, Christopher] City Hope Comprehens Canc Ctr, Dept Biostat, Duarte, CA 91010 USA. [Quinn, David I.; Lenz, Heinz-Josef] Univ So Calif, Div Med Oncol, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Gandara, David] Univ Calif Davis, Ctr Canc, Div Med Oncol, Sacramento, CA 95817 USA. [Lewis, Michael D.] Eisai Res Inst, Andover, MA 01810 USA. [Colevas, A. Dimitrios] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Morgan, RJ (reprint author), City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM rmorgan@coh.org FU National Cancer Institute [P30CA033572, UM1CA186717, U01CA062505, M01RR000043] FX This study was supported in part by National Cancer Institute Grants P30CA033572, UM1CA186717, U01CA062505, and M01RR000043. NR 37 TC 3 Z9 3 U1 2 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2015 VL 76 IS 5 BP 897 EP 907 DI 10.1007/s00280-015-2868-7 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CU0YR UT WOS:000363245800002 PM 26362045 ER PT J AU Gulley, JL Marte, J Heery, CR Madan, RA Steinberg, SM Leitman, SF Tsang, KY Schlom, J AF Gulley, James L. Marte, Jennifer Heery, Christopher R. Madan, Ravi A. Steinberg, Seth M. Leitman, Susan F. Tsang, Kwong Y. Schlom, Jeffrey TI The impact of leukapheresis on immune-cell number and function in patients with advanced cancer SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Apheresis; Vaccine; Immunotherapy; Clinical trial ID RESISTANT PROSTATE-CANCER; RE INTERDISCIPLINARY CRITIQUE; COLONY-STIMULATING FACTOR; SIPULEUCEL-T; PHASE-I; METASTATIC CARCINOMA; VACCINE; IMMUNOTHERAPY; ANTIGEN; CEA AB Leukapheresis is often performed in cancer patients to harvest stem cells, manufacture therapeutic vaccines, or follow immunologic response to therapy. We have recently described the minimal impact of leukapheresis on normal donors. Here we provide additional immunologic data from patients with advanced cancer who underwent leukapheresis. Using data from cancer patients on clinical trials who had leukapheresis (n = 64) or peripheral blood draws only (n = 90) as controls for immune analysis, we evaluated the impact of leukapheresis on number and function of lymphocytes. In the leukapheresis group, median age was 63.5 (range 38-82); 87.5 % were male. Comparing pre- and post-leukapheresis values within the groups, with each patient as its own control, there was no significant difference in enzyme-linked immunosorbent spot (ELISPOT), antivector humoral response, absolute lymphocyte count (ALC), or T cell number. Twelve patients completed three leukaphereses with subsequent ELISPOT analysis; seven had increased responses to flu (1.1- to 2.3-fold) with an even distribution around no change. Nineteen patients had matched ALC values after completing three leukaphereses with no significant change from baseline. These data provide evidence that leukapheresis has no detectable effects on a cancer patient's immune system in terms of number or function. These results contribute to a growing body of evidence refuting the hypothesis that a patient's immune competence is meaningfully affected by the procedure. Limitations include a restriction to 2-L leukapheresis procedure and small sample size. C1 [Gulley, James L.; Marte, Jennifer; Madan, Ravi A.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, James L.; Heery, Christopher R.; Tsang, Kwong Y.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Leitman, Susan F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The authors acknowledge the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research for their support of this study. We also express appreciation to the professionals at the NIH Clinical Center Department of Transfusion Medicine for their part in performing apheresis procedures in study patients and to the medical oncology fellows at the NCI for their attention to patient care. Finally, we thank Bonnie L. Casey and Debra Weingarten for their editorial assistance in the preparation of this manuscript. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 24 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD NOV PY 2015 VL 64 IS 11 BP 1429 EP 1435 DI 10.1007/s00262-015-1738-9 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA CU0ZE UT WOS:000363247400007 PM 26243387 ER PT J AU Jones, GC Kehrer, JD Kahn, J Koneru, BN Narayan, R Thomas, TO Camphausen, K Mehta, MP Kaushal, A AF Jones, Guy C. Kehrer, Jason D. Kahn, Jenna Koneru, Bobby N. Narayan, Ram Thomas, Tarita O. Camphausen, Kevin Mehta, Minesh P. Kaushal, Aradhana TI Primary Treatment Options for High-Risk/Medically Inoperable Early Stage NSCLC Patients SO CLINICAL LUNG CANCER LA English DT Review DE Intraoperative brachytherapy; Microwave ablation; Percutaneous cryotherapy; Photodynamic therapy; Radiofrequency ablation; SBRT; Stereotactic body radiotherapy ID CELL LUNG-CANCER; BODY RADIATION-THERAPY; HIGH-RISK PATIENTS; PERCUTANEOUS RADIOFREQUENCY ABLATION; PROSPECTIVE PHASE-II; CLINICAL-PRACTICE GUIDELINES; PHOTODYNAMIC THERAPY; SUBLOBAR RESECTION; LIMITED RESECTION; WEDGE RESECTION AB Lung cancer is among the most common cancers worldwide and is the leading cause of cancer death in both men and women. For patients with early stage (American Joint Committee on Cancer T1-2, N0) non-small-cell lung cancer, the current standard of care is lobectomy with systematic lymph node evaluation. Unfortunately, patients with lung cancer often have medical comorbities, which may preclude the option of surgical resection. In such cases, a number of minimally invasive to noninvasive treatment options have gained popularity in the treatment of these high-risk patients. These modalities provide significant advantages, including patient convenience, treatment in an outpatient setting, and acceptable toxicities, including reduced impact on lung function and a modest risk of postprocedure chest wall pain. We provide a comprehensive review of the literature, including reported outcomes, complications, and limitations of sublobar resection with or without intraoperative brachytherapy, radiofrequency ablation, microwave ablation, percutaneous cryoablation, photodynamic therapy, and stereotactic body radiotherapy. C1 [Jones, Guy C.; Kehrer, Jason D.; Kahn, Jenna; Koneru, Bobby N.; Narayan, Ram; Thomas, Tarita O.; Camphausen, Kevin; Mehta, Minesh P.; Kaushal, Aradhana] NCI, Bethesda, MD 20892 USA. RP Jones, GC (reprint author), NCI, Radiat Oncol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM guy.jones@nih.gov OI mehta, minesh/0000-0002-4812-5713 FU Intramural NIH HHS [Z99 CA999999] NR 128 TC 3 Z9 4 U1 2 U2 7 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 EI 1938-0690 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD NOV PY 2015 VL 16 IS 6 BP 413 EP 430 DI 10.1016/j.cllc.2015.04.001 PG 18 WC Oncology SC Oncology GA CU1GD UT WOS:000363267500019 PM 26027433 ER PT J AU Potter, WZ AF Potter, W. Z. TI Biomarkers of Brain Structure and Function for Neurodegenerative Disorders: Are They Adequate for Go/No Go Decisions in Drug Development? SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB Given the high risk of developing drugs for neurodegenerative diseases if post-phase I decisions to go into efficacy studies were made with quantitative knowledge of an agent's action in brain, the risks should be diminished. Furthermore, if biomarkers were compelling, they could be utilized during a lengthy trial as an early measure of futility. What follows is one perspective on the adequacy of current and emerging measures to be applied to such decision making. C1 NIMH, Bethesda, MD 20892 USA. RP Potter, WZ (reprint author), NIMH, Bethesda, MD 20892 USA. EM bill.potter@nih.gov NR 9 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD NOV PY 2015 VL 98 IS 5 BP 472 EP 474 DI 10.1002/cpt.196 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3DU UT WOS:000363405000011 PM 26418882 ER PT J AU Mahnke, YD Beddall, MH Roederer, M AF Mahnke, Yolanda D. Beddall, Margaret H. Roederer, Mario TI OMIP-029: Human NK-cell phenotypization SO CYTOMETRY PART A LA English DT Article DE NK cells; immunophenotyping; NK receptors; FcR receptors ID NATURAL-KILLER-CELLS; RECEPTOR C1 [Mahnke, Yolanda D.; Beddall, Margaret H.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mahnke, YD (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM yolanda.mahnke@gmail.com NR 10 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD NOV PY 2015 VL 87A IS 11 BP 986 EP 988 DI 10.1002/cyto.a.22728 PG 3 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CU1FS UT WOS:000363266200005 PM 26228006 ER PT J AU Bassig, BA Cerhan, JR Au, WY Kim, HN Sangrajrang, S Hu, W Tse, J Berndt, S Zheng, TZ Zhang, HP Pornsopone, P Lee, JJ Kim, HJ Skibola, CF Vijai, J Burdette, L Yeager, M Brennan, P Shin, MH Liang, R Chanock, S Lan, Q Rothman, N AF Bassig, Bryan A. Cerhan, James R. Au, Wing-Yan Kim, Hee Nam Sangrajrang, Suleeporn Hu, Wei Tse, Jovic Berndt, Sonja Zheng, Tongzhang Zhang, Heping Pornsopone, Pattarapong Lee, Je-Jung Kim, Hyeoung-Joon Skibola, Christine F. Vijai, Joseph Burdette, Laurie Yeager, Meredith Brennan, Paul Shin, Min-Ho Liang, Raymond Chanock, Stephen Lan, Qing Rothman, Nathaniel TI Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE Diffuse large B-cell lymphoma; Eastern Asians; lymphoma; genetic susceptibility to DLBCL ID GENOME-WIDE ASSOCIATION; HEALTH-ORGANIZATION CLASSIFICATION; NON-HODGKIN-LYMPHOMA; CHINESE POPULATION; NEOPLASMS; THAILAND; RISK; LOCI AB ObjectivesDiffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. MethodsTo evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. ResultsThree of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR=2.04, 95% CI=1.63-2.56; p(trend)=3.9x10(-10)). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR=1.34, 95% CI=1.19-1.52; p(trend)=2.1x10(-6)), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR=3.05, 95% CI=1.32-7.05; p(trend)=0.009). ConclusionsOur study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. C1 [Bassig, Bryan A.; Hu, Wei; Berndt, Sonja; Burdette, Laurie; Yeager, Meredith; Chanock, Stephen; Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. [Cerhan, James R.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Au, Wing-Yan; Tse, Jovic; Liang, Raymond] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Kim, Hee Nam; Kim, Hyeoung-Joon] Chonnam Natl Univ, Hwasun Hosp, Genome Res Ctr Hematopoiet Dis, Hwasun, Jeollanam Do, South Korea. [Kim, Hee Nam; Shin, Min-Ho] Chonnam Natl Univ, Ctr Creat Biomed Scientists, Gwangju, South Korea. [Sangrajrang, Suleeporn] Natl Canc Inst, Div Res, Bangkok, Thailand. [Zheng, Tongzhang; Zhang, Heping] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Pornsopone, Pattarapong] Natl Canc Inst, Dept Med Oncol, Bangkok, Thailand. [Lee, Je-Jung; Kim, Hyeoung-Joon] Chonnam Natl Univ, Sch Med, Res Inst Med Sci, Dept Hematol Oncol, Gwangju, South Korea. [Skibola, Christine F.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Burdette, Laurie; Yeager, Meredith] NCI, Canc Genom Res Lab, DHHS, NIH, Gaithersburg, MD USA. [Brennan, Paul] IARC, Genet Epidemiol Grp, Lyon, France. [Shin, Min-Ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwangju, South Korea. RP Bassig, BA (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, NIH, 9609 Med Ctr Dr MSC 9776,Room 6E634, Bethesda, MD 20892 USA. EM bryan.bassig@mail.nih.gov OI Joseph, Vijai/0000-0002-7933-151X FU Intramural Research Program of the NIH; NCI; National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea [A111218-11-GM06]; NCI (Thailand); Ministry of Public Health; Hong Kong University Carol Chau Ting Tong Research Fund; Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology (MEST) [NRF-2011-0030034] FX Supported in part by the Intramural Research Program of the NIH, NCI, a grant from the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (A111218-11-GM06), the NCI (Thailand), Ministry of Public Health, and the Hong Kong University Carol Chau Ting Tong Research Fund. This research was also supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (MEST) (NRF-2011-0030034). We would like to thank all participants in these studies. NR 15 TC 4 Z9 4 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 EI 1600-0609 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD NOV PY 2015 VL 95 IS 5 BP 442 EP 448 DI 10.1111/ejh.12513 PG 7 WC Hematology SC Hematology GA CU2CD UT WOS:000363328800009 PM 25611436 ER PT J AU Shah, RV Murthy, VL Abbasi, SA Eng, J Wu, CL Ouyang, P Kwong, RY Goldfine, A Bluemke, DA Lima, J Jerosch-Herold, M AF Shah, Ravi V. Murthy, Venkatesh L. Abbasi, Siddique A. Eng, John Wu, Colin Ouyang, Pamela Kwong, Raymond Y. Goldfine, Allison Bluemke, David A. Lima, Joao Jerosch-Herold, Michael TI Weight loss and progressive left ventricular remodelling: The Multi-Ethnic Study of Atherosclerosis (MESA) SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Obesity; cardiac magnetic resonance; weight loss ID INCIDENT CARDIOVASCULAR EVENTS; WHITE ADULT MEN; BARIATRIC SURGERY; OBESITY CARDIOMYOPATHY; INSULIN-RESISTANCE; RISK-FACTORS; MASS; GEOMETRY; DISEASE; IMPACT AB Aims Impact of weight loss on cardiac structure has not been extensively investigated in large, multi-ethnic, community-based populations. We investigated the longitudinal impact of weight loss on cardiac structure by cardiac magnetic resonance (CMR). Methods and results 2351 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent CMR at Exam 1 (2002) and Exam 5 (2011) were included. Primary outcomes were percentage change in LV mass (indexed to height) and LV mass-to-volume ratio (concentric LV remodelling). Multivariable linear regression was used to measure the association between outcomes and weight change. At median 9.4 years' follow-up, 639 individuals (27%) experienced >5% weight loss (median 6.9kg) and 511 (22%) had >5% weight gain (median 6.4kg). A >5% weight gain was associated with the greatest increase in LV mass (+5.4% median) and LV mass-to-volume ratio (+12.2% median). Adjusting for medications, hypertension/diabetes (and change in these risk factors), age, race and other risk factors, every 5% weight loss was associated with a 1.3% decrease in height-indexed LV mass and 1.3% decrease in LV mass-to-volume ratio (p<0.0001). There was no effect modification/confounding by age, race, gender or baseline BMI. Change in LV mass-to-volume ratio was roughly linear, specifically for modest degrees of weight loss (-10% to +10%). Change in LV mass was linear with weight loss, suggesting no threshold of weight loss is needed for LV mass regression. Conclusions In a large multi-ethnic population, weight loss is associated with beneficial effects on cardiac structure, independent of age, race, gender, BMI and obesity-related cardiometabolic risk. There is no threshold of weight loss required to produce these effects. C1 [Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Div Nucl Med, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Cardiothorac Imaging Div, Ann Arbor, MI 48109 USA. [Abbasi, Siddique A.; Kwong, Raymond Y.; Jerosch-Herold, Michael] Brigham & Womens Hosp, Noninvas Cardiovasc Imaging, Boston, MA 02115 USA. [Eng, John; Wu, Colin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Ouyang, Pamela] Johns Hopkins Bayview Med Ctr, Div Cardiol, Baltimore, MD USA. [Goldfine, Allison] Joslin Diabet Ctr, Boston, MA 02215 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Radiol & Imaging Sci, NIH, Ctr Clin, Bethesda, MD USA. [Lima, Joao] Johns Hopkins Med Ctr, Dept Cardiol & Med, Baltimore, MD USA. RP Jerosch-Herold, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St,L1-RA050, Boston, MA 02115 USA. EM mjerosch-herold@partners.org RI Murthy, Venkatesh/B-3448-2013; OI Murthy, Venkatesh/0000-0002-7901-1321; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [NO1-HC-95159, NO1-HC-95160, NO1-HC-95161, NO1-HC-95162, NO1-HC-95163, NO1-HC-95164, NO1-HC-95165, NO1-HC-95166, NO1-HC-95167, NO1-HC-95168, N01-HC-95169]; American Heart Association Post-Doctoral Fellowship Award [11POST000002]; Heart Failure National Institutes of Health Clinical Research Network [U01-HL084877]; [R01-HL-65580] FX MESA is supported by contracts NO1-HC-95159 to N01-HC-95169 from the National Heart, Lung, and Blood Institute. Dr Shah was supported by an American Heart Association Post-Doctoral Fellowship Award (11POST000002) and a training grant from the Heart Failure National Institutes of Health Clinical Research Network (U01-HL084877). Dr Jerosch-Herold receives support through R01-HL-65580. All other authors have no financial disclosures relevant to the content of this manuscript. NR 31 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD NOV PY 2015 VL 22 IS 11 BP 1408 EP 1418 DI 10.1177/2047487314541731 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CT7LE UT WOS:000362995400005 PM 25009171 ER PT J AU Bailey-Wilson, JE Simpson, CL Musolf, AM Pinney, SM De Andrade, M Gaba, CR Yang, P You, M Schwartz, AG Mandal, D Liu, YH Spitz, MR Kupert, EY Amos, CI Anderson, M AF Bailey-Wilson, Joan E. Simpson, Claire L. Musolf, Anthony M. Pinney, Susan M. De Andrade, Mariza Gaba, Colette R. Yang, Ping You, Ming Schwartz, Ann G. Mandal, Diptasri Liu, Yanhong Spitz, Margaret R. Kupert, Elena Y. Amos, Christopher I. Anderson, MarshallW. TI Linkage methods used to evaluate EYA4 as a candidate risk locus in GELCC familial lung cancer families linked to 6q SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Bailey-Wilson, Joan E.; Simpson, Claire L.; Musolf, Anthony M.] NHGRI, NIH, Baltimore, MD USA. [Pinney, Susan M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [De Andrade, Mariza; Yang, Ping] Mayo Clin, Rochester, MN USA. [Gaba, Colette R.] Univ Toledo, Dana Canc Ctr, Toledo, OH 43606 USA. [You, Ming] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Liu, Yanhong; Spitz, Margaret R.] Baylor Coll Med, Houston, TX 77030 USA. [Kupert, Elena Y.; Anderson, MarshallW.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03756 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 8 BP 531 EP 532 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500012 ER PT J AU Bureau, A Sampson, J Yanek, LR Mathias, R Ruczinski, I AF Bureau, Alexandre Sampson, Joshua Yanek, Lisa R. Mathias, Rasika Ruczinski, Ingo TI Extension of a rare variant sharing exact test to sharing patterns involving a subset of affected relatives SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Bureau, Alexandre] Univ Laval, Quebec City, PQ G1K 7P4, Canada. [Sampson, Joshua] NCI, Bethesda, MD 20892 USA. [Yanek, Lisa R.; Mathias, Rasika] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 19 BP 536 EP 536 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500023 ER PT J AU Chen, F Szymanski, EP Olivier, KN Liu, XY Tettelin, H Holland, SM Duggal, P AF Chen, Fei Szymanski, Eva P. Olivier, Kenneth N. Liu, Xinyue Tettelin, Herve Holland, Steven M. Duggal, Priya TI Whole exome sequencing and linkage analysis of patients with pulmonary nontuberculous mycobacterial infection SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Chen, Fei; Duggal, Priya] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Szymanski, Eva P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Liu, Xinyue; Tettelin, Herve] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 22 BP 537 EP 537 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500026 ER PT J AU Chen, H Wang, CL Conomos, MP Stilp, AM Li, ZL Sofer, T Szpiro, AA Chen, W Brehm, JM Celedon, JC Redline, SS Papanicolaou, GJ Thornton, TA AF Chen, Han Wang, Chaolong Conomos, Matthew P. Stilp, Adrienne M. Li, Zilin Sofer, Tamar Szpiro, Adam A. Chen, Wei Brehm, John M. Celedon, Juan C. Redline, Susan S. Papanicolaou, George J. Thornton, Timothy A. TI GMMAT: logistic mixed models to control for population stratification and relatedness in genetic association studies with binary traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Chen, Han; Li, Zilin] Harvard Univ, TH Chan Sch Publ Hlth, Cambridge, MA 02138 USA. [Wang, Chaolong] Genome Inst Singapore, Singapore, Singapore. [Conomos, Matthew P.; Stilp, Adrienne M.; Sofer, Tamar; Szpiro, Adam A.; Thornton, Timothy A.] Univ Washington, Seattle, WA 98195 USA. [Chen, Wei; Brehm, John M.; Celedon, Juan C.] Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Redline, Susan S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Papanicolaou, George J.] NHLBI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 23 BP 537 EP 537 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500027 ER PT J AU Childs, EJ Chaffee, KG Gallinger, S Syngal, S Schwartz, AG Cote, ML Bondy, M Goggins, MG Hruban, RH Chanock, S Hoover, R Fuchs, C Rider, DN Amundadottir, L Stolzenberg-Solomon, R Wolpin, B Risch, HA Petersen, GM Klein, AP AF Childs, Erica J. Chaffee, Kari G. Gallinger, Steven Syngal, Sapna Schwartz, Ann G. Cote, Michele L. Bondy, Melissa Goggins, Michael G. Hruban, Ralph H. Chanock, Stephen Hoover, Robert Fuchs, Charles Rider, David N. Amundadottir, Laufey Stolzenberg-Solomon, Rachael Wolpin, Brian Risch, Harvey A. Petersen, Gloria M. Klein, Alison P. TI Examination of established cancer risk variants in putatively high-risk pancreatic cancer patients: A PACGENE study SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Childs, Erica J.] Johns Hopkins Sch Med, Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [Chaffee, Kari G.; Rider, David N.; Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Syngal, Sapna] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Schwartz, Ann G.; Cote, Michele L.] Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Schwartz, Ann G.; Cote, Michele L.] Wayne State Univ, Detroit, MI USA. [Bondy, Melissa] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Goggins, Michael G.; Hruban, Ralph H.] Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD USA. [Chanock, Stephen; Hoover, Robert; Amundadottir, Laufey] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fuchs, Charles; Wolpin, Brian] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Fuchs, Charles; Wolpin, Brian] Harvard Univ, Sch Med, Boston, MA USA. [Stolzenberg-Solomon, Rachael] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Wolpin, Brian] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Klein, Alison P.] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [Klein, Alison P.] Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 27 BP 538 EP 539 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500031 ER PT J AU Chiu, CY Jung, J Weeks, D Wilson, AF Bailey-Wilson, J Amos, CI Xiong, MM Mills, J Fan, RZ AF Chiu, Chi-Yang Jung, Jeesun Weeks, Daniel Wilson, Alexander F. Bailey-Wilson, Joan Amos, Christopher I. Xiong, Momiao Mills, James Fan, Ruzong TI A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Chiu, Chi-Yang; Mills, James; Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jung, Jeesun] NIAAA, NIH, Bethesda, MD USA. [Weeks, Daniel] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Wilson, Alexander F.; Bailey-Wilson, Joan] NHGRI, NIH, Bethesda, MD USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Xiong, Momiao] Univ Texas Houston, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 28 BP 539 EP 539 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500032 ER PT J AU Fan, RZ Amos, CI Wang, YF Weeks, D Li, Y Ren, HB Lobach, I Xiong, MM Moore, JH Boehnke, M AF Fan, Ruzong Amos, Christopher I. Wang, Yifan Weeks, Daniel Li, Yun Ren, Haobo Lobach, Iryna Xiong, Momiao Moore, Jason H. Boehnke, Michael TI Meta-analysis of Complex Diseases at Gene Level by Functional Regression Models SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Amos, Christopher I.; Moore, Jason H.] Univ Dartmouth, Hanover, NH USA. [Wang, Yifan] FDA, Silver Spring, MD USA. [Weeks, Daniel] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Li, Yun] Univ N Carolina, Chapel Hill, NC 27515 USA. [Ren, Haobo] Regeneron Pharmaceut Inc, Tarrytown, NY USA. [Lobach, Iryna] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Xiong, Momiao] Univ Texas Houston, Houston, TX USA. [Boehnke, Michael] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 49 BP 547 EP 548 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500053 ER PT J AU Goldin, LR Rotunno, M McMaster, ML Yeager, M Hicks, BD Burdette, L Goldstein, AM Fontaine, L Tucker, MA Marti, GE Chanock, SJ Caporaso, NE AF Goldin, Lynn R. Rotunno, Melissa McMaster, Mary L. Yeager, Meredith Hicks, Belynda D. Burdette, Laurie Goldstein, Alisa M. Fontaine, Laura Tucker, Margaret A. Marti, Gerald E. Chanock, Stephen J. Caporaso, Neil E. TI Whole exome sequencing in high-risk chronic lymphocytic leukemia families: do rare germline variants in somatically altered genes or GWAS genes contribute to susceptibility? SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Goldin, Lynn R.; Rotunno, Melissa; McMaster, Mary L.; Goldstein, Alisa M.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Yeager, Meredith; Hicks, Belynda D.; Burdette, Laurie] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fontaine, Laura] Westat Corp, Rockville, MD USA. [Tucker, Margaret A.] NCI, Human Genet Program, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Marti, Gerald E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 62 BP 553 EP 553 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500066 ER PT J AU Goldstein, AM Fraser, MC Yang, XHR Tucker, MA AF Goldstein, Alisa M. Fraser, Mary C. Yang, Xiaohong R. Tucker, Margaret A. TI Gene discovery obstacles in familial melanoma, a complex disease SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Goldstein, Alisa M.; Fraser, Mary C.; Yang, Xiaohong R.; Tucker, Margaret A.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 63 BP 553 EP 554 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500067 ER PT J AU Holzinger, ER Malley, J Li, Q Bailey-Wilson, JE AF Holzinger, Emily R. Malley, James Li, Qing Bailey-Wilson, Joan E. TI r2VIM: A variable selection method for identifying complex genetic models associated with human traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Holzinger, Emily R.; Li, Qing; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. [Malley, James] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 70 BP 556 EP 556 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500074 ER PT J AU Li, Q Holzinger, E Hetmanski, JB Marazita, ML Beaty, TH Bailey-Wilson, JE AF Li, Qing Holzinger, Emily Hetmanski, Jacqueline B. Marazita, Mary L. Beaty, Terri H. Bailey-Wilson, Joan E. TI Modified Random Forest Algorithm to Identify gene-gene Interaction in Case-Parent Trios Studies of Oral Cleft SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Li, Qing; Holzinger, Emily; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. [Hetmanski, Jacqueline B.; Marazita, Mary L.; Beaty, Terri H.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 92 BP 563 EP 564 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500096 ER PT J AU Mechanic, LE Lindstrom, S Chen, HS Daily, K Feuer, EJ Green, T Hodgson, J Kaefer, CM Kern, A McTigue, K Norman, T Sieberts, S Wellons, A Gillanders, EM AF Mechanic, Leah E. Lindstroem, Sara Chen, Huann-Sheng Daily, Kenneth Feuer, Eric J. Green, Tiffany Hodgson, Jay Kaefer, Christine M. Kern, Anna McTigue, Kevin Norman, Thea Sieberts, Solly Wellons, Audrey Gillanders, Elizabeth M. TI Up For A Challenge (U4C) - Stimulating Innovation in Breast Cancer Genetic Epidemiology SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Mechanic, Leah E.; Chen, Huann-Sheng; Feuer, Eric J.; Green, Tiffany; Kaefer, Christine M.; Kern, Anna; McTigue, Kevin; Wellons, Audrey; Gillanders, Elizabeth M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lindstroem, Sara] Harvard Univ, TH Chan Sch Publ Hlth, Cambridge, MA 02138 USA. [Daily, Kenneth; Hodgson, Jay; Norman, Thea; Sieberts, Solly] Sage Bionetworks, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 106 BP 568 EP 569 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500110 ER PT J AU Musolf, A Simpson, CL Pinney, SM de Andrade, M Gaba, C Yang, P You, M Schwartz, AG Mandal, D Kupert, EY Amos, CI Anderson, MW Bailey-Wilson, JE AF Musolf, Anthony Simpson, Claire L. Pinney, Susan M. de Andrade, Mariza Gaba, Collette Yang, Ping You, Ming Schwartz, Ann G. Mandal, Diptasri Kupert, Elena Y. Amos, Christopher I. Anderson, Marshall W. Bailey-Wilson, Joan E. TI Reproducibility in MCMC-based Linkage Analyses using Dense Marker Maps SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Musolf, Anthony; Simpson, Claire L.; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD USA. [Pinney, Susan M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [de Andrade, Mariza; Yang, Ping] Mayo Clin, Rochester, MN USA. [Gaba, Collette] Univ Toledo, Dana Canc Ctr, Toledo, OH 43606 USA. [You, Ming; Kupert, Elena Y.; Anderson, Marshall W.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03756 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 114 BP 571 EP 572 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500118 ER PT J AU Sabourin, JA Sorant, AJM Wilson, AF AF Sabourin, Jeremy A. Sorant, Alexa J. M. Wilson, Alexander F. TI Getting the most from your data: Comparing analyses using qualitative traits and related quantitative traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Sabourin, Jeremy A.; Sorant, Alexa J. M.; Wilson, Alexander F.] NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 127 BP 577 EP 577 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500131 ER PT J AU Schwantes-An, TH Sung, H Justice, CM Wilson, AF AF Schwantes-An, Tae-Hwi Sung, Heejong Justice, Cristina M. Wilson, Alexander F. TI No such thing as a free lunch: Assessing consistency of genotype imputation SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Schwantes-An, Tae-Hwi; Sung, Heejong; Justice, Cristina M.; Wilson, Alexander F.] NHGRI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 131 BP 578 EP 578 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500135 ER PT J AU Schwender, H Li, Q Neumann, C Taub, MA Younkin, SG Berger, P Scharpf, RB Beaty, TH Ruczinski, I AF Schwender, Holger Li, Qing Neumann, Christoph Taub, Margaret A. Younkin, Samuel G. Berger, Philipp Scharpf, Robert B. Beaty, Terri H. Ruczinski, Ingo TI Analyzing case-parent trio data with the R package trio SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Schwender, Holger; Berger, Philipp] Univ Dusseldorf, Math Inst, Dusseldorf, Germany. [Li, Qing] NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. [Neumann, Christoph] TU Dortmund Univ, Fac Stat, Dortmund, Germany. [Taub, Margaret A.; Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Younkin, Samuel G.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Scharpf, Robert B.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Beaty, Terri H.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 132 BP 578 EP 579 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500136 ER PT J AU Sheppard, B Benke, KS Daniels, J Croen, LA Schendel, D Ladd-Acosta, C Fallin, MD AF Sheppard, Brooke Benke, Kelly S. Daniels, Julie Croen, Lisa A. Schendel, Diana Ladd-Acosta, Christine Fallin, M. Daniele TI Polygene - by - Prenatal Environment Interaction in Autism Spectrum Disorder using Copy Number Variant Burden SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Sheppard, Brooke; Ladd-Acosta, Christine] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sheppard, Brooke; Benke, Kelly S.; Ladd-Acosta, Christine; Fallin, M. Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Wendy Klag Ctr Autism & Dev Disabil, Baltimore, MD USA. [Sheppard, Brooke] NIH, Genet Epidemiol Res Branch, Bethesda, MD USA. [Benke, Kelly S.; Fallin, M. Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Daniels, Julie] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Croen, Lisa A.] Kaiser Permanente No Calif, Autism Res Program, Div Res, Harbor City, CA USA. [Schendel, Diana] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark. [Schendel, Diana] Aarhus Univ, Natl Ctr Register Based Res, Dept Econ & Business, DK-8000 Aarhus C, Denmark. [Schendel, Diana] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Marion, SA, Australia. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 134 BP 579 EP 580 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500138 ER PT J AU Shi, M Umbach, DM Weinberg, CR AF Shi, Min Umbach, David M. Weinberg, Clarice R. TI Using parental phenotypes in case-parent studies SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Shi, Min; Umbach, David M.; Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 135 BP 580 EP 580 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500139 ER PT J AU Shriner, D Bentley, AR Doumatey, AP Chen, GJ Zhou, J Adeyemo, A Rotimi, CN AF Shriner, Daniel Bentley, Amy R. Doumatey, Ayo P. Chen, Guanjie Zhou, Jie Adeyemo, Adebowale Rotimi, Charles N. TI Phenotypic variance explained by ancestry in admixed African Americans SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Shriner, Daniel; Bentley, Amy R.; Doumatey, Ayo P.; Chen, Guanjie; Zhou, Jie; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 137 BP 580 EP 580 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500141 ER PT J AU Simpson, CL Musolf, A Bailey-Wilson, JE AF Simpson, Claire L. Musolf, Anthony Bailey-Wilson, Joan E. TI The Renaissance of Linkage Analysis and Effects of Extreme High Density Genotype Data on Linkage Algorithms SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Simpson, Claire L.; Musolf, Anthony; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 138 BP 580 EP 581 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500142 ER PT J AU Sung, H Schwantes-An, TH Sorant, AJM Sabourin, JA Justice, CM Wilson, AF AF Sung, Heejong Schwantes-An, Tae-Hwi Sorant, Alexa J. M. Sabourin, Jeremy A. Justice, Cristina M. Wilson, Alexander F. TI Correlation structure of the genome SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Sung, Heejong; Schwantes-An, Tae-Hwi; Sorant, Alexa J. M.; Sabourin, Jeremy A.; Justice, Cristina M.; Wilson, Alexander F.] NHGRI, Genometr Sect, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 146 BP 583 EP 584 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500150 ER PT J AU Weinberg, CR Shi, M Wise, A Umbach, DM Li, LP AF Weinberg, Clarice R. Shi, Min Wise, Alison Umbach, David M. Li, Leping TI A stochastic search algorithm for finding multi-SNP effects using nuclear families SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society (IGES) CY OCT 04-06, 2015 CL Baltimore, MD SP Int Genet Epidemiol Soc C1 [Weinberg, Clarice R.; Shi, Min; Umbach, David M.; Li, Leping] NIEHS, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2015 VL 39 IS 7 MA 170 BP 592 EP 592 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA CU2FZ UT WOS:000363340500174 ER PT J AU Khalili, M Lombardero, M Chung, RT Terrault, NA Ghany, MG Kim, WR Lau, D Lisker-Melman, M Sanyal, A Lok, AS AF Khalili, Mandana Lombardero, Manuel Chung, Raymond T. Terrault, Norah A. Ghany, Marc G. Kim, W. Ray Lau, Daryl Lisker-Melman, Mauricio Sanyal, Arun Lok, Anna S. CA HBRN TI Diabetes and prediabetes in patients with hepatitis B residing in North America SO HEPATOLOGY LA English DT Article ID METABOLIC SYNDROME INCREASES; IMPAIRED FASTING GLUCOSE; COUNTRY-OF-ORIGIN; BODY-MASS INDEX; VIRUS INFECTION; UNITED-STATES; HEPATOCELLULAR-CARCINOMA; INSULIN-RESISTANCE; VIRAL-HEPATITIS; LIVER FIBROSIS AB Diabetes is associated with liver disease progression and increased hepatocellular carcinoma risk, but factors associated with diabetes in patients with chronic hepatitis B virus (HBV) infection in North America are unknown. We aimed to determine factors predictive of diabetes and impaired fasting glucose (IFG) in a large HBV-infected multiethnic cohort. Adults with chronic HBV not receiving antiviral therapy were enrolled from 21 centers in North America. Diabetes was defined by history/medication use or fasting glucose 126 mg/dL and IFG as fasting glucose 100-125 mg/dL. Of 882 patients included, 47.2% were female, 71.3% Asian, 83.7% foreign born, median age was 44 years, and median body mass index BMI 24.3 kg/m(2). In this cohort, 26.0% were hepatitis B envelope antigen (HBeAg) positive, 43.9% had HBV DNA 20,000 IU/mL, and 26.7% alanine aminotransferase (ALT) 2x upper limit of normal (40 U/L women, 60 U/L men). Overall, 12.5% had diabetes and 7.8% IFG. The combined prevalence of diabetes or IFG was highest among blacks (36.7%) and those either born in the United States/Canada or foreign born with migration >20 years ago (25.5%). Obesity (odds ratio [OR]: 2.13), hyperlipidemia (OR, 4.13), hypertension (OR, 3.67), high ALT level (OR, 1.86), and family history of diabetes (OR, 3.43) were associated with diabetes. Factors associated with IFG were obesity (OR, 4.13) and hypertension (OR, 3.27), but also HBeAg positivity (OR, 0.39). Recent migration was negatively associated with diabetes among non-Asians (OR, 0.30). Conclusions: Diabetes is more prevalent in HBV-infected North American adults than the general population and is associated with known metabolic risk factors and liver damage, as determined by ALT levels. Among the foreign born, longer duration of North America residence predicted diabetes risk in non-Asians. These results highlight the opportunities for interventions to prevent diabetes especially among at-risk ethnic groups with HBV. (Hepatology 2015;62:1364-1374) C1 [Khalili, Mandana; Terrault, Norah A.] Univ Calif San Francisco, San Francisco, CA 94110 USA. [Lombardero, Manuel] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ghany, Marc G.] NIH, Bethesda, MD USA. [Kim, W. Ray] Stanford Univ, Stanford, CA 94305 USA. [Lau, Daryl] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lisker-Melman, Mauricio] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Sanyal, Arun] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Lok, Anna S.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Khalili, M (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, 1001 Potrero Ave,NH-3D, San Francisco, CA 94110 USA. EM Mandana.Khalili@ucsf.edu OI Cloonan, Yona/0000-0003-3893-3693; Wahed, Abdus/0000-0001-6911-7221 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK 082843, DK082863, DK082864, DK082866, DK082867, DK082871U01, DK082872, DK082874, DK082919, DK082923, DK082927, DK082943, U01 DK082944]; NIDDK [A-DK-3002-001]; NIDDK, National Institutes of Health (NIH); Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases) [P30DK50306]; Immunology Center (NIH Public Health Service Research) [M01-RR00040, UL1TR000058]; CTSA [UL1TR000004, UL1TR001111, UL1RR024986]; Gilead Sciences, Inc. FX The HBRN was funded by a U01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to the following investigators: Lewis R. Roberts, M.B., Ch.B., Ph.D. (DK 082843); Anna Suk-Fong Lok, M.D. (DK082863); Steven H. Belle, Ph.D., MScHyg (DK082864); Kyong-Mi Chang, M.D. (DK082866); Michael W. Fried, M.D. (DK082867); Adrian M. Di Bisceglie, M.D. (DK082871); William M. Lee, M.D. (U01 DK082872); Harry L.A. Janssen, M.D., Ph.D. (DK082874); Daryl T.-Y. Lau, M.D., M.P.H. (DK082919); Richard K. Sterling, M.D., M.Sc. (DK082923); Steven-Huy B. Han, M.D. (DK082927); Robert C. Carithers, M.D. (DK082943); Norah A. Terrault, M.D., M.P.H. (U01 DK082944); an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, Ph.D. (A-DK-3002-001) and support from the intramural program, NIDDK, National Institutes of Health (NIH): Marc G. Ghany, M.D. Additional funding to support this study was provided to Kyong-Mi Chang, M.D., the Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040), Richard K. Sterling, M.D., M.Sc. (UL1TR000058, NCATS [National Center for Advancing Translational Sciences], NIH), Norah A. Terrault, M.D., M.P.H. (CTSA grant no: UL1TR000004), Michael W. Fried, M.D. (CTSA grant no.: UL1TR001111), and Anna Suk-Fong Lok (CTSA grant no.: UL1RR024986). Additional support was provided by Gilead Sciences, Inc., and Roche Molecular Systems by a CRADA through the NIDDK. NR 40 TC 8 Z9 8 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD NOV PY 2015 VL 62 IS 5 BP 1364 EP 1374 DI 10.1002/hep.28110 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU1EZ UT WOS:000363264100008 PM 26390278 ER PT J AU Bloom, MS Whitcomb, BW Chen, Z Ye, A Kannan, K Louis, GMB AF Bloom, M. S. Whitcomb, B. W. Chen, Z. Ye, A. Kannan, K. Louis, G. M. Buck TI Associations between urinary phthalate concentrations and semen quality parameters in a general population SO HUMAN REPRODUCTION LA English DT Article DE endocrine disrupting chemicals; phthalates; plasticizers; semen; sperm ID ENDOCRINE-DISRUPTING CHEMICALS; FETAL TESTIS XENOGRAFTS; SEXUAL-DIFFERENTIATION; OXIDATIVE METABOLITES; REPRODUCTIVE FUNCTION; MULTIPLE COMPARISONS; SPERM MORPHOLOGY; SERUM COTININE; UNITED-STATES; MALE-RAT AB STUDY QUESTION: Are urinary phthalate concentrations associated with altered semen quality parameters among males recruited from the general population? SUMMARY ANSWER: Urinary levels of metabolites of phthalate diesters are associated with lower total sperm counts, larger sperm head sizes, and higher percentages of morphologically abnormal sperm. WHAT IS KNOWN ALREADY: High dose experiments in rats implicate phthalates as anti-androgens. Studies involving infertile men seeking care suggest that phthalates influence measures of semen quality raising concern about the implications for men in the general population. STUDY DESIGN, SIZE, DURATION: This prospective cohort study comprised 501 male partners in couples discontinuing contraception to become pregnant, who were recruited from 16 US counties using population-based sampling frameworks from 2005 to 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Urine and semen samples were obtained at baseline from 473 (94%) men, of whom 378 (80%) men provided a second sample the following month. Urine was analyzed for 14 monoester metabolites of phthalate diesters by high-performance liquid chromatography coupled to tandem mass spectrometry. Semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-benzyl phthalate (MBzP), and mono-isononyl phthalate (MNP) were significantly associated with lower total sperm counts and concentrations, larger sperm head sizes, higher proportions of megalo head sperm morphology, and/or other morphological changes. Urinary mono-methyl phthalate (MMP) and mono-cyclohexyl phthalate (MCPP) were significantly associated with lower sperm motility, and urine mono-2-ethylhexyl phthalate (MEHP) was significantly associated with higher sperm motility. LIMITATIONS, REASONS FOR CAUTION: While adverse associations were observed, the implications of the findings for couple fecundity and fertility remain to be established. Cautious interpretation is needed in light of reliance on a single measurement of phthalate measure and no correction for multiple comparisons. C1 [Bloom, M. S.; Kannan, K.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12144 USA. [Bloom, M. S.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12144 USA. [Whitcomb, B. W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Chen, Z.; Ye, A.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20892 USA. [Kannan, K.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. RP Bloom, MS (reprint author), Sch Publ Hlth, Rm 157,One Univ Pl, Rensselaer, NY 12144 USA. EM mbloom@albany.edu OI Bloom, Michael/0000-0002-0028-5494; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). NR 70 TC 14 Z9 14 U1 9 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2015 VL 30 IS 11 BP 2645 EP 2657 DI 10.1093/humrep/dev219 PG 13 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CT8GQ UT WOS:000363053400022 PM 26350610 ER PT J AU Ojukwu, M Mbizo, J Leyva, B Olaku, O Zia, F AF Ojukwu, Mary Mbizo, Justice Leyva, Bryan Olaku, Oluwadamilola Zia, Farah TI Complementary and Alternative Medicine Use Among Overweight and Obese Cancer Survivors in the United States SO INTEGRATIVE CANCER THERAPIES LA English DT Article DE alternative; cancer; complementary; medicine; obese; overweight; survivors ID BREAST-CANCER; RADICAL PROSTATECTOMY; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; NATIONAL-SURVEY; POOR-PROGNOSIS; WEIGHT CONTROL; CAM USE; THERAPIES; DIAGNOSIS AB Purpose. The purpose of the study was to determine the prevalence of complementary and alternative medicine (CAM) use among US cancer survivors; examine whether use varies by underweight/normal weight, overweight, and obese body mass index status; determine reasons for use; and document disclosure rates of CAM use to medical professionals. Methods. Data for 1785 cancer survivors were obtained from the 2007 National Health Interview Survey and CAM supplement. The prevalence and associations of CAM use in the previous 12 months were compared among underweight/normal weight, overweight, and obese adult cancer survivors. Results. Nearly 90% of cancer survivors used at least one type of CAM therapy in the 12 months preceding the survey. Those who were overweight, but not obese, were more likely to use a CAM modality compared to normal/underweight respondents. Over two thirds (71%) reported using CAM therapy for general health and wellness and 39.3% used CAM because a health care provider recommended it. Disclosure rates of CAM use to conventional medical professionals varied widely by CAM modality. Conclusions. An overwhelming majority of US cancer survivors use CAM for a variety of reasons. Overweight cancer survivors may be more likely to use CAM than those who are underweight, normal weight, or obese. Cancer survivors should be screened by medical providers for the use of CAM therapies; furthermore, prospective clinical research evaluating the efficacy and safety of biologically based CAM therapies, often used by cancer survivors, is important and necessary for the well-being of this population. C1 [Ojukwu, Mary; Olaku, Oluwadamilola; Zia, Farah] NCI, Off Canc Complementary & Alternat Med, Bethesda, MD 20892 USA. [Mbizo, Justice] Univ W Florida, Pensacola, FL 32514 USA. [Leyva, Bryan] NCI, Proc Care Res Branch, Bethesda, MD 20892 USA. [Olaku, Oluwadamilola] Kelly Serv Inc, Rockville, MD USA. RP Olaku, O (reprint author), NCI, Off Canc Complementary & Alternat Med, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM Olakuo@mail.nih.gov FU National Cancer Institute (NCI) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this manuscript was provided by the National Cancer Institute (NCI). The NCI did not participate in the design, analysis, interpretation of data and writing of manuscript. NR 71 TC 2 Z9 2 U1 3 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1534-7354 EI 1552-695X J9 INTEGR CANCER THER JI Integr. Cancer Ther. PD NOV PY 2015 VL 14 IS 6 BP 503 EP 514 DI 10.1177/1534735415589347 PG 12 WC Oncology; Integrative & Complementary Medicine SC Oncology; Integrative & Complementary Medicine GA CT8JW UT WOS:000363063200002 PM 26044767 ER PT J AU Poniewierska-Baran, A Suszynska, M Sun, WY Abdelbaset-Ismail, A Schneider, G Barr, FG Ratajczak, MZ AF Poniewierska-Baran, Agata Suszynska, Malwina Sun, Wenyue Abdelbaset-Ismail, Ahmed Schneider, Gabriela Barr, Frederic G. Ratajczak, Mariusz Z. TI Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE rhabdomyosarcoma; erythropoietin; erythropoietin receptor; metastasis ID TISSUE-LEVELS INCREASE; ALVEOLAR RHABDOMYOSARCOMA; PROMETASTATIC FACTORS; METASTATIC BEHAVIOR; HUMAN NEUROBLASTOMA; INHIBITORY FACTOR; BIOACTIVE LIPIDS; GENE-EXPRESSION; CANCER CELLS; GERMLINE AB The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. C1 [Poniewierska-Baran, Agata; Suszynska, Malwina; Abdelbaset-Ismail, Ahmed; Schneider, Gabriela; Ratajczak, Mariusz Z.] Univ Louisville, James Graham Brown Canc Ctr, Stem Cell Inst, Louisville, KY 40202 USA. [Poniewierska-Baran, Agata; Suszynska, Malwina] Pomeranian Med Univ, Dept Physiol, Szczecin, Poland. [Sun, Wenyue; Ratajczak, Mariusz Z.] Med Univ Warsaw, Dept Regenerat Med, Warsaw, Poland. [Barr, Frederic G.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Ratajczak, MZ (reprint author), Univ Louisville, James Graham Brown Canc Ctr, Stem Cell Inst, 500 S Floyd St,Room 107, Louisville, KY 40202 USA. EM mzrata01@louisville.edu OI Abdelbaset Ismail, Ahmed/0000-0002-2135-1753 FU NIH [2R01 DK074720, R01HL112788]; Stella and Henry Endowment; Maestro grant [2011/02/A/NZ4/00035]; National Cancer Institute FX The present study was supported by NIH grants (nos. 2R01 DK074720 and R01HL112788), the Stella and Henry Endowment, and the Maestro grant 2011/02/A/NZ4/00035 awarded to M.-Z.R. Work by F.-G.B. and W.S. was supported by the Intramural Research Program of the National Cancer Institute. NR 34 TC 2 Z9 2 U1 0 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD NOV PY 2015 VL 47 IS 5 BP 1989 EP 1997 DI 10.3892/ijo.2015.3184 PG 9 WC Oncology SC Oncology GA CU2LV UT WOS:000363355900040 PM 26412593 ER PT J AU Gafni, RI Guthrie, LC Kelly, MH Brillante, BA Christie, CM Reynolds, JC Yovetich, NA James, R Collins, MT AF Gafni, Rachel I. Guthrie, Lori C. Kelly, Marilyn H. Brillante, Beth A. Christie, C. Michele Reynolds, James C. Yovetich, Nancy A. James, Robert Collins, Michael T. TI Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE PARATHYROID-RELATED DISORDERS; PTH; BIOCHEMICAL MARKERS OF BONE TURNOVER; DXA; HORMONE REPLACEMENT ID BONE-MINERAL DENSITY; LONG-TERM TREATMENT; PRIMARY HYPERPARATHYROIDISM; POSTMENOPAUSAL WOMEN; VITAMIN-D; OSTEOPOROSIS; TURNOVER; SKELETON; DIFFERENTIATION; PTH(1-84) AB Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon. (c) 2015 American Society for Bone and Mineral Research. C1 [Gafni, Rachel I.; Guthrie, Lori C.; Kelly, Marilyn H.; Brillante, Beth A.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Christie, C. Michele] Kaiser Permanente, Dept Pediat, Springfield, VA USA. [Reynolds, James C.] NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. [Yovetich, Nancy A.; James, Robert] Rho Inc, Chapel Hill, NC USA. RP Gafni, RI (reprint author), NIDCR, NIH, Bldg 30,Room 228,30 Convent Dr MSC 4320, Bethesda, MD 20892 USA. EM gafnir@mail.nih.gov FU DIR, NIDCR, a part of the Intramural Research Program of the NIH, DHHS FX This research was supported, in part, by the DIR, NIDCR, a part of the Intramural Research Program of the NIH, DHHS. NR 33 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2015 VL 30 IS 11 BP 2112 EP 2118 DI 10.1002/jbmr.2555 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU1MV UT WOS:000363286900018 PM 25990370 ER PT J AU Whitehead, TR Ward, MH Colt, JS Dahl, G Ducore, J Reinier, K Gunier, RB Hammond, SK Rappaport, SM Metayer, C AF Whitehead, Todd P. Ward, Mary H. Colt, Joanne S. Dahl, Gary Ducore, Jonathan Reinier, Kyndaron Gunier, Robert B. Hammond, S. Katharine Rappaport, Stephen M. Metayer, Catherine TI Dust metal loadings and the risk of childhood acute lymphoblastic leukemia SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE childhood acute lymphoblastic leukemia; dust; environmental exposure; lead; metals ID IN-HOUSE DUST; POLYCYCLIC AROMATIC-HYDROCARBONS; POLYBROMINATED DIPHENYL ETHERS; PARENTAL OCCUPATIONAL-EXPOSURE; RESIDENTIAL DUST; TEMPORAL VARIABILITY; DRINKING-WATER; LEAD LEVELS; CHILDREN; CANCER AB We evaluated the relationship between the risk of childhood acute lymphoblastic leukemia (ALL) and the levels of metals in carpet dust A dust sample was collected from the homes of 142 ALL cases and 187 controls participating in the California Childhood Leukemia Study using a high volume small surface sampler (2001-2006). Samples were analyzed using microwave-assisted acid digestion in combination with inductively coupled plasma mass spectrometry for arsenic, cadmium, chromium, copper, lead, nickel, tin, tungsten, and zinc. Eight metals were detected in at least 85% of the case and control homes; tungsten was detected in <15% of homes. Relationships between dust metal loadings (mu g metal per m(2) carpet) and ALL risk were modeled using multivariable logistic regression, adjusting for the child's age, sex, and race/ethnicity and confounders, including household annual income. A doubling of dust metal loadings was not associated with significant changes in ALL risk (odds ratio (95% confidence interval): arsenic: 0.96 (0.86, 1.07), cadmium: 0.92 (0.81, 1.05), chromium: 1.01 (0.90, 1.14), copper: 0.97 (0.91, 1.03), lead: 1.01 (0.93, 1.10), nickel: 0.95 (0.82, 1.09), tin: 0.96 (0.86, 1.08), and zinc: 0.94 (0.84, 1.05)). Our findings do not support the hypothesis that metals in carpet dust are risk factors for childhood ALL. C1 [Whitehead, Todd P.; Gunier, Robert B.; Hammond, S. Katharine; Rappaport, Stephen M.; Metayer, Catherine] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. [Ward, Mary H.; Colt, Joanne S.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Dahl, Gary] Stanford Univ, Dept Pediat, Lucile Salter Packard Childrens Hosp, Palo Alto, CA 94304 USA. [Ducore, Jonathan] Univ Calif Davis, Sch Med, Dept Pediat, Sacramento, CA 95817 USA. [Reinier, Kyndaron] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Los Angeles, CA 90048 USA. RP Whitehead, TR (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM toddpwhitehead@berkeley.edu FU National Institute of Environmental Health Sciences (NIEHS) [R01ES009137, P42ES0470518]; Intramural Research Program of the National Cancer Institute (NCI), National Institute of Health [7590-S-04, 7590-S-01]; NCI [N02-CP-11015] FX This work was supported in part by the National Institute of Environmental Health Sciences (NIEHS, grant numbers R01ES009137 and P42ES0470518); by the Intramural Research Program of the National Cancer Institute (NCI), National Institute of Health (Subcontracts 7590-S-04,7590-S-01); and by the NCI (Contract N02-CP-11015). We thank the families for their participation. We also thank the clinical investigators at the following collaborating hospitals for the help in recruiting patients: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Drs. Mignon Loh and Katherine Matthay), Children's Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children's Hospital (Dr. Gary Dahl), Children's Hospital Oakland (Dr. James Feusner), Kaiser Permanente Oakland (Drs. Daniel Kronish and Stacy Month), Kaiser Permanente Roseville (Drs. Kent Jolly and Vincent Kiley), Kaiser Permanente Santa Clara (Drs. Carolyn Russo, Denah Taggart, and Alan Wong), and Kaiser Permanente San Francisco (Dr. Kenneth Leung). We thank Mr. Adam Abbgy of the Battelle Memorial Institute for his contribution as an analytical chemist. We acknowledge the late Dr. Patricia Buffler, the founding principal investigator of the California Childhood Leukemia Study, and her leadership of the study for nearly 20 years. Finally, we acknowledge the study staff for their effort and dedication. NR 56 TC 0 Z9 0 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD NOV-DEC PY 2015 VL 25 IS 6 BP 593 EP 598 DI 10.1038/jes.2015.9 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CU0QX UT WOS:000363224900007 PM 25736162 ER PT J AU O'Brien, TR Pfeiffer, RM Paquin, A Kuhs, KAL Chen, S Bonkovsky, HL Edlin, BR Howell, CD Kirk, GD Kuniholm, MH Morgan, TR Strickler, HD Thomas, DL Prokunina-Olsson, L AF O'Brien, Thomas R. Pfeiffer, Ruth M. Paquin, Ashley Kuhs, Krystle A. Lang Chen, Sabrina Bonkovsky, Herbert L. Edlin, Brian R. Howell, Charles D. Kirk, Gregory D. Kuniholm, Mark H. Morgan, Timothy R. Strickler, Howard D. Thomas, David L. Prokunina-Olsson, Ludmila TI Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance SO JOURNAL OF HEPATOLOGY LA English DT Article DE Genetics; IL28B; IFNL3; IFNL4; Innate immunity; Interferon lambda; Treatment; Viral clearance ID HEPATITIS-C VIRUS; INTERFERON-LAMBDA FAMILY; GENOME-WIDE ASSOCIATION; INJECTION-DRUG USERS; GENOTYPE 1 INFECTION; PEGYLATED INTERFERON; GENETIC-VARIATION; RIBAVIRIN TREATMENT; VIRAL CLEARANCE; IL28B AB Background & Aims: Genetic polymorphisms within the interferon lambda (IFN-lambda) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-Delta G/TT (rs368234815) polymorphism, which controls the generation of IFN-lambda 4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. Methods: We compared IFNL4-Delta G/TT and rs4803217 for association with response to pegylated-IFN-alpha/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-Delta G/TT and rs4803217 genotypes by a bootstrap approach. Results: Among European Americans, linkage disequilibrium between IFNL4-Delta G/TT and rs4803217 was strong (r(2) = 0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-Delta G/TT than rs4803217 (p = 0.003); the IFNL4-Delta G:rs48 03217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p = 0.03, comparison to IFNL4-Delta G:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-Delta G/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p = 0.03) and week 20 in HALT-C (p = 0.03), as well as for spontaneous HCV clearance (p = 0.048). Conclusion: IFNL4-Delta G/TT is the primary IFN-lambda region polymorphism for impaired HCV clearance. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [O'Brien, Thomas R.; Pfeiffer, Ruth M.; Kuhs, Krystle A. Lang] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Paquin, Ashley; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chen, Sabrina] Informat Management Serv Inc, Calverton, MD USA. [Bonkovsky, Herbert L.] Carolinas HealthCare Syst, Dept Med, Charlotte, NC USA. [Bonkovsky, Herbert L.] Carolinas HealthCare Syst, Liver Biliary Pancreat Ctr, Charlotte, NC USA. [Edlin, Brian R.] Natl Dev & Res Inst, New York, NY USA. [Edlin, Brian R.] Weill Cornell Med Coll, New York, NY USA. [Howell, Charles D.] Howard Univ, Coll Med, Dept Med, Washington, DC USA. [Kirk, Gregory D.; Thomas, David L.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kuniholm, Mark H.; Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Long Beach, CA USA. RP O'Brien, TR (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E108,MSC 9767, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov FU Intramural Research Program of the US National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics) [DA R01 013324]; ALIVE cohort [U01-DA-036297, R01-DA-04334, R01-DA-12568]; US National Institutes of Health [R15 HL117199, U01 DK 065201, U54 DK 083909, R01-DA09532, R01-DA12109, R01-DA13245, R01-DA16159]; National Cancer Institute [N02-CP-91027, N01-CO-12400]; Substance Abuse and Mental Health Services Administration grant [H79-TI12103]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases [U01-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI grant) [UL1 RR024131] FX This research was supported by the Intramural Research Program of the US National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics), as well as the following grants: DA R01 013324 (D.L.T.); ALIVE cohort (G.D.K), U01-DA-036297, R01-DA-04334 and R01-DA-12568, and US National Institutes of Health grants R15 HL117199, U01 DK 065201, U54 DK 083909 (H.L.B.); R01-DA09532, R01-DA12109, R01-DA13245, and R01-DA16159 (B.R.E.); National Cancer Institute contracts N02-CP-91027 and N01-CO-12400 (B.R.E.); Substance Abuse and Mental Health Services Administration grant H79-TI12103 (B.R.E.). The VIRAHEP-C and HALT-C studies were conducted, respectively, by the VIRAHEP-C and HALT-C Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The data and samples from the VIRAHEP-C and HALT-C studies reported here were supplied by the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories. This manuscript was not prepared in collaboration with the VIRAHEP-C study group or the HALT-C study group and does not necessarily reflect the opinions or views of the VIRAHEP-C Trial and HALT-C Trial, the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories or the National Institute of Diabetes and Digestive and Kidney Diseases. Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) located at: New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Analysis Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (U01-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The WIHS is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant UL1 RR024131). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US government. NR 43 TC 14 Z9 14 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2015 VL 63 IS 5 BP 1103 EP 1110 DI 10.1016/j.jhep.2015.06 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU1US UT WOS:000363307600009 PM 26186989 ER PT J AU Subleski, JJ Scarzello, AJ Alvord, WG Jiang, Q Stauffer, JK Kronfli, A Saleh, B Back, T Weiss, JM Wiltrout, RH AF Subleski, Jeff J. Scarzello, Anthony J. Alvord, W. Gregory Jiang, Qun Stauffer, Jimmy K. Kronfli, Anthony Saleh, Bahara Back, Timothy Weiss, Jonathan M. Wiltrout, Robert H. TI Serum-based tracking of de novo initiated liver cancer progression reveals early immunoregulation and response to therapy SO JOURNAL OF HEPATOLOGY LA English DT Article DE Sleeping Beauty Transposition; HCC; HCA; Gaussia Luciferase; Real-time tracking; Treatment ID CYTOTOXIC T-LYMPHOCYTES; HEPATOCELLULAR-CARCINOMA; SOMATIC MUTATIONS; CELLS; ACTIVATION; SYSTEM; TUMORS; PD-1 AB Background & Aims: Liver inflammatory diseases associated with cancer promoting somatic oncogene mutations are increasing in frequency. Preclinical cancer models that allow for the study of early tumor progression are often protracted, which limits the experimental study parameters due to time and expense. Here we report a robust inexpensive approach using Sleeping Beauty transposition (SBT) delivery of oncogenes along with Gaussia Luciferase expression vector GLuc, to assess de novo liver tumor progression, as well as the detection of innate immune responses or responses induced by therapeutic intervention. Methods: Tracking de novo liver tumor progression with GLuc was demonstrated in models of hepatocellular carcinoma (HCC) or adenoma (HCA) initiated by hydrodynamic delivery of SBT oncogenes. Results: Rising serum luciferase levels correlated directly with increasing liver tumor burden and eventual morbidity. Early detection of hepatocyte apoptosis from mice with MET+CAT transfected hepatocytes was associated with a transient delay in HCC growth mediated by a CD8(+) T-cell response against transformed hepatocytes. Furthermore, mice that lack B cells or macrophages had an increase in TUNEL+ hepatocytes following liver MET transfection demonstrating that these cells provide protection from MET-induced hepatocyte apoptosis. Treatment with IL-18+IL-12 of mice displaying established HCC decreased tumor burden which was associated with decreased levels of serum luciferase. Conclusions: Hydrodynamic delivery of the SBT vector GLuc to hepatocytes serves as a simple blood-based approach for real-time tracking of pathologically distinct types of liver cancer. This revealed tumor-induced immunologic responses and was beneficial in monitoring the efficacy of therapeutic interventions. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Subleski, Jeff J.; Scarzello, Anthony J.; Jiang, Qun; Stauffer, Jimmy K.; Kronfli, Anthony; Saleh, Bahara; Back, Timothy; Weiss, Jonathan M.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Alvord, W. Gregory] Data Management Serv Inc, Stat Consulting, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Wiltrout, RH (reprint author), NCI, Expt Therapeut Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM wiltrour@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health (NCI/NIH), United States FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (NCI/NIH), United States. NR 32 TC 3 Z9 3 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2015 VL 63 IS 5 BP 1181 EP 1189 DI 10.1016/j.jhep.2015.06.021 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU1US UT WOS:000363307600019 PM 26143441 ER PT J AU Wigren, M Nilsson, J Kaplan, MJ AF Wigren, M. Nilsson, J. Kaplan, M. J. TI Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention SO JOURNAL OF INTERNAL MEDICINE LA English DT Review DE CVD; immune mechanisms; immunotherapy; SLE ID CORONARY-ARTERY-DISEASE; RECEPTOR-DEFICIENT MICE; REGULATORY T-CELLS; MIGRATION INHIBITORY FACTOR; TRADITIONAL RISK-FACTORS; CARDIOVASCULAR-DISEASE; DENSITY-LIPOPROTEIN; I INTERFERON; ACCELERATED ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION AB Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies. C1 [Wigren, M.; Nilsson, J.] Lund Univ, Dept Clin Sci Malmo, S-20502 Malmo, Sweden. [Kaplan, M. J.] NIAMSD, System Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Wigren, M (reprint author), Lund Univ, Dept Clin Sci, Jan Waldenstroms Gata 35, S-20502 Malmo, Sweden. EM maria.wigren@med.lu.se FU Intramural NIH HHS [ZIA AR041199-01] NR 104 TC 2 Z9 2 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-6820 EI 1365-2796 J9 J INTERN MED JI J. Intern. Med. PD NOV PY 2015 VL 278 IS 5 BP 494 EP 506 DI 10.1111/joim.12357 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA CU1JX UT WOS:000363278500006 PM 25720452 ER PT J AU Cachia, D Kamiya-Matsuoka, C Mandel, JJ Olar, A Cykowski, MD Armstrong, TS Fuller, GN Gilbert, MR De Groot, JF AF Cachia, David Kamiya-Matsuoka, Carlos Mandel, Jacob J. Olar, Adriana Cykowski, Matthew D. Armstrong, Terri S. Fuller, Gregory N. Gilbert, Mark R. De Groot, John F. TI Primary and secondary gliosarcomas: clinical, molecular and survival characteristics SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Gliosarcoma; Primary gliosarcoma; Secondary gliosarcoma; TP53 mutation; IDH mutation ID NEWLY-DIAGNOSED GLIOBLASTOMA; CEREBRAL GLIOSARCOMA; BRAIN-TUMORS; FEATURES; TEMOZOLOMIDE; BEVACIZUMAB; MUTATIONS; IDH1; OSTEOSARCOMA; METASTASES AB Gliosarcoma is classified by the World Health Organization as a variant of glioblastoma. These tumors exhibit biphasic histologic and immunophenotypic features, reflecting both glial and mesenchymal differentiation. Gliosarcomas can be further classified into primary (de novo) tumors, and secondary gliosarcomas, which are diagnosed at recurrence after a diagnosis of glioblastoma. Using a retrospective review, patients seen at MD Anderson Cancer Center between 2004 and 2014 with a pathology-confirmed diagnosis of gliosarcoma were identified. 34 patients with a diagnosis of gliosarcoma seen at the time of initial diagnosis or at recurrence were identified (24 primary gliosarcomas (PGS), 10 secondary gliosarcomas (SGS)). Molecular analysis performed on fourteen patients revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH mutations. Median overall survival (OS) for all patients was 17.5 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 6.4 months. Comparing PGS with SGS, the median OS was 24.7 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GB was 25 months, with a PFS of 10.7 months. Molecular analysis revealed a higher than expected rate of TP53 mutations in GS patients and, typical of primary glioblastoma, IDH mutations were uncommon. Though our data shows improved outcomes for both PGS and SGS when compared to the literature, this is most likely a reflection of selection bias of patients treated on clinical trials at a quaternary center. C1 [Cachia, David] Med Univ S Carolina, Dept Neurosurg, Charleston, SC 29425 USA. [Kamiya-Matsuoka, Carlos; Armstrong, Terri S.; De Groot, John F.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Mandel, Jacob J.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Olar, Adriana; Fuller, Gregory N.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Cykowski, Matthew D.] Houston Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Armstrong, Terri S.] Univ Texas Houston, Dept Family Hlth, Hlth Sci Ctr, Sch Nursing, Houston, TX USA. [Gilbert, Mark R.] NCI, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cachia, D (reprint author), Med Univ S Carolina, Dept Neurosurg, 96 Jonathan Lucas St, Charleston, SC 29425 USA. EM cachia@musc.edu RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; Fuller, Gregory/0000-0001-9447-2647 FU Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy; MD Anderson Cancer Center Support grant [P30 CA016672]; National Institutes of Health/National Cancer Institute [5T32CA163185]; Merck; Genentech; Glaxo Smith Kline; Sanofi-Aventis; AstraZeneca; EMD-Serono; Eli Lilly; Novartis; Deciphera Pharmaceuticals FX We thank Dr Funda Meric-Bernstam MD and Dr Kenna R Shaw PhD for their invaluable support in preparation of this manuscript. This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672). A Olar was supported by the National Institutes of Health/National Cancer Institute (Training Grant No. 5T32CA163185). T.S. Armstrong serves as consultant for Immuno-cellular therapeutics; is on the advisory board for Roche; receives research support from Merck and Genentech. M.R. Gilbert reports research support from Genentech, Merck, Glaxo Smith Kline; receives honoraria from Merck, Genentech, AbbVie; and serves on the advisory board for Genetech, AbbVie, Heron Therapeutics. JF de Groot serves as a consultant for Celldex and Deciphera Pharmaceuticals; serves on the advisory board for Genentech, Novartis, Celldex, is on the Data and Safety Monitoring Board for VBL Therapeutics and receives research support from Sanofi-Aventis, AstraZeneca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmaceuticals. NR 50 TC 2 Z9 2 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2015 VL 125 IS 2 BP 401 EP 410 DI 10.1007/s11060-015-1930-y PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CU0YN UT WOS:000363245300020 PM 26354773 ER PT J AU Pujol, S Wells, W Pierpaoli, C Brun, C Gee, J Cheng, G Vemuri, B Commowick, O Prima, S Stamm, A Goubran, M Khan, A Peters, T Neher, P Maier-Hein, KH Shi, Y Tristan-Vega, A Veni, G Whitaker, R Styner, M Westin, CF Gouttard, S Norton, I Chauvin, L Mamata, H Gerig, G Nabavi, A Golby, A Kikinis, R AF Pujol, Sonia Wells, William Pierpaoli, Carlo Brun, Caroline Gee, James Cheng, Guang Vemuri, Baba Commowick, Olivier Prima, Sylvain Stamm, Aymeric Goubran, Maged Khan, Ali Peters, Terry Neher, Peter Maier-Hein, Klaus H. Shi, Yundi Tristan-Vega, Antonio Veni, Gopalkrishna Whitaker, Ross Styner, Martin Westin, Carl-Fredrik Gouttard, Sylvain Norton, Isaiah Chauvin, Laurent Mamata, Hatsuho Gerig, Guido Nabavi, Arya Golby, Alexandra Kikinis, Ron TI The DTI Challenge: Toward Standardized Evaluation of Diffusion Tensor Imaging Tractography for Neurosurgery SO JOURNAL OF NEUROIMAGING LA English DT Article DE Diffusion MRI; diffusion tensor imaging (DTI); tractography; brain gliomas; neurosurgery ID BRAIN-TUMOR SURGERY; VISUALIZATION; TRACT; MRI AB BACKGROUND AND PURPOSEDiffusion tensor imaging (DTI) tractography reconstruction of white matter pathways can help guide brain tumor resection. However, DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established. To address this issue, we initiated the DTI Challenge, an international working group of clinicians and scientists whose goal was to provide standardized evaluation of tractography methods for neurosurgery. The purpose of this empirical study was to evaluate different tractography techniques in the first DTI Challenge workshop. METHODSEight international teams from leading institutions reconstructed the pyramidal tract in four neurosurgical cases presenting with a glioma near the motor cortex. Tractography methods included deterministic, probabilistic, filtered, and global approaches. Standardized evaluation of the tracts consisted in the qualitative review of the pyramidal pathways by a panel of neurosurgeons and DTI experts and the quantitative evaluation of the degree of agreement among methods. RESULTSThe evaluation of tractography reconstructions showed a great interalgorithm variability. Although most methods found projections of the pyramidal tract from the medial portion of the motor strip, only a few algorithms could trace the lateral projections from the hand, face, and tongue area. In addition, the structure of disagreement among methods was similar across hemispheres despite the anatomical distortions caused by pathological tissues. CONCLUSIONSThe DTI Challenge provides a benchmark for the standardized evaluation of tractography methods on neurosurgical data. This study suggests that there are still limitations to the clinical use of tractography for neurosurgical decision making. C1 [Pujol, Sonia; Wells, William; Mamata, Hatsuho; Kikinis, Ron] Harvard Univ, Sch Med, Dept Radiol, Surg Planning Lab,Brigham & Womens Hosp, Boston, MA 02115 USA. [Pierpaoli, Carlo] NICHHD, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Brun, Caroline; Gee, James] Univ Penn, Penn Image Comp & Sci Lab, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cheng, Guang; Vemuri, Baba] Univ Florida, Dept Comp & Informat Sci & Engn, Gainesville, FL USA. [Commowick, Olivier; Prima, Sylvain; Stamm, Aymeric] Univ Rennes 1, VISAGES INSERM U746 CNRS UMR6074 INRIA, Rennes, France. [Goubran, Maged; Khan, Ali; Peters, Terry] Western Univ, Robarts Res Inst, Imaging Labs, London, ON, Canada. [Neher, Peter; Maier-Hein, Klaus H.] Jr Grp Med Image Comp, Div Med & Biol Informat, German Canc Res Ctr, Heidelberg, Germany. [Shi, Yundi; Styner, Martin] Univ N Carolina, Dept Psychiat & Comp Sci, Chapel Hill, NC USA. [Tristan-Vega, Antonio] Univ Valladolid, Dept Mech Engn, Valladolid, Spain. [Veni, Gopalkrishna; Whitaker, Ross; Gouttard, Sylvain; Gerig, Guido] Univ Utah, Sci Comp & Imaging Inst, Salt Lake City, UT USA. [Westin, Carl-Fredrik] Harvard Univ, Brigham & Womens Hosp, Lab Math Imaging, Sch Med, Boston, MA 02115 USA. [Norton, Isaiah; Golby, Alexandra] Harvard Univ, Brigham & Womens Hosp, Dept Neurosurg, Sch Med, Boston, MA 02115 USA. [Chauvin, Laurent] Harvard Univ, Brigham & Womens Hosp, Surg Nav & Robot Lab, Dept Radiol,Med Sch, Boston, MA 02115 USA. [Nabavi, Arya] INI, Hannover, Germany. RP Pujol, S (reprint author), Brigham & Womens Hosp, Surg Planning Lab, Radiol ASBI L1 050, 75 Francis St, Boston, MA 02115 USA. EM spujol@bwh.harvard.edu RI Tristan-Vega, Antonio/D-5609-2016; Maier-Hein, Klaus/M-6250-2016; Khan, Ali/P-1353-2014; OI Tristan-Vega, Antonio/0000-0002-4614-2501; Maier-Hein, Klaus/0000-0002-6626-2463; Khan, Ali/0000-0002-0760-8647; Gerig, Guido/0000-0002-9547-6233 FU National Alliance for Medical Image Computing (NIH) [U54EB005149]; Neuroimage Analysis Center (NIH) [P41RR013218]; National Center for Image-Guided Therapy (NIH) [NCIGT P41EB015898] FX This work was partially funded by the National Alliance for Medical Image Computing (NIH Grant U54EB005149), the Neuroimage Analysis Center (NIH Grant P41RR013218), and the National Center for Image-Guided Therapy (NIH Grant NCIGT P41EB015898). NR 20 TC 9 Z9 9 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD NOV-DEC PY 2015 VL 25 IS 6 BP 875 EP 882 DI 10.1111/jon.12283 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CU2DW UT WOS:000363334100004 PM 26259925 ER PT J AU Gomez-Castillo, BJ Hirsch, R Groninger, H Baker, K Cheng, MJ Phillips, J Pollack, J Berger, AM AF Gomez-Castillo, Blanca J. Hirsch, Rosemarie Groninger, Hunter Baker, Karen Cheng, M. Jennifer Phillips, Jayne Pollack, John Berger, Ann M. TI Increasing the Number of Outpatients Receiving Spiritual Assessment: A Pain and Palliative Care Service Quality Improvement Project SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Spirituality; spiritual assessment; quality improvement; palliative care AB Background. Spirituality is a patient need that requires special attention from the Pain and Palliative Care Service team. This quality improvement project aimed to provide spiritual assessment for all new outpatients with serious life-altering illnesses. Measures. Percentage of new outpatients receiving spiritual assessment (Faith, Importance/Influence, Community, Address/Action in care, psychosocial evaluation, chaplain consults) at baseline and postinterventions. Intervention. Interventions included encouraging clinicians to incorporate adequate spiritual assessment into patient care and implementing chaplain covisits for all initial outpatient visits. Outcomes. The quality improvement interventions increased spiritual assessment (baseline vs. postinterventions): chaplain covisits (25.5% vs. 50%), Faith, Importance/Influence, Community, Address/Action in care completion (49% vs. 72%), and psychosocial evaluation (89% vs. 94%). Conclusions/Lessons Learned. Improved spiritual assessment in an outpatient palliative care clinic setting can occur with a multidisciplinary approach. This project also identifies data collection and documentation processes that can be targeted for improvement. Published by Elsevier Inc. on behalf of American Academy of Hospice and Palliative Medicine. C1 [Gomez-Castillo, Blanca J.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Gomez-Castillo, Blanca J.; Hirsch, Rosemarie; Groninger, Hunter; Baker, Karen; Cheng, M. Jennifer; Phillips, Jayne; Pollack, John; Berger, Ann M.] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Berger, AM (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 2-1733, Bethesda, MD 20892 USA. EM aberger@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 9 TC 1 Z9 1 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD NOV PY 2015 VL 50 IS 5 BP 724 EP 729 DI 10.1016/j.jpainsymman.2015.05.012 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA CU3NX UT WOS:000363433200018 PM 26166183 ER PT J AU Nathan, N Wang, JA Li, SW Cowen, EW Haughey, M Moss, J Darling, TN AF Nathan, Neera Wang, Ji-an Li, Shaowei Cowen, Edward W. Haughey, Mary Moss, Joel Darling, Thomas N. TI Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE angiofibromas; lymphangioleiomyomatosis; mechanistic target of rapamycin inhibitor; shagreen patch; sirolimus; tuberous sclerosis complex; ungual fibroma ID GIANT-CELL ASTROCYTOMA; SPORADIC LYMPHANGIOLEIOMYOMATOSIS; PHASE-3 TRIAL; EVEROLIMUS; ANGIOMYOLIPOMA; EFFICACY; EXIST-1; SAFETY; ANGIOFIBROMAS; MULTICENTER AB Background: Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC). Objective: We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects. Methods: A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. Results: Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment). Limitations: This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis. Conclusion: Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated. C1 [Nathan, Neera; Wang, Ji-an; Li, Shaowei; Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Nathan, Neera; Haughey, Mary; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NIH, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM thomas.darling@usuhs.edu OI Darling, Thomas/0000-0002-5161-1974 FU Intramural NIH HHS [Z01 HL002541-12]; NIAMS NIH HHS [R01 AR062080, R01AR062080] NR 26 TC 7 Z9 8 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD NOV PY 2015 VL 73 IS 5 BP 802 EP 808 DI 10.1016/j.jaad.2015.07.018 PG 7 WC Dermatology SC Dermatology GA CU1HL UT WOS:000363271400022 PM 26365597 ER PT J AU Mahar, AL Compton, C McShane, LM Halabi, S Asamura, H Rami-Porta, R Groome, PA AF Mahar, Alyson L. Compton, Carolyn McShane, Lisa M. Halabi, Susan Asamura, Hisao Rami-Porta, Ramon Groome, Patti A. CA Amer Joint Comm Canc TI Refining Prognosis in Lung Cancer A Report on the Quality and Relevance of Clinical Prognostic Tools SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung cancer; Prognosis; Clinical prediction tools; Prediction models; Prognostic model ID MULTIVARIABLE PREDICTION MODEL; TNM CLASSIFICATION; STAGING PROJECT; EXTERNAL VALIDATION; LABORATORY PARAMETERS; INDIVIDUAL PROGNOSIS; SALVAGE TREATMENT; MALIGNANT-TUMORS; DIAGNOSIS TRIPOD; 7TH EDITION AB Introduction: Accurate, individualized prognostication for lung cancer patients requires the integration of standard patient and pathologic factors, biological, genetic, and other molecular characteristics of the tumor. Clinical prognostic tools aim to aggregate information on an individual patient to predict disease outcomes such as overall survival, but little is known about their clinical utility and accuracy in lung cancer. Methods: A systematic search of the scientific literature for clinical prognostic tools in lung cancer published from January 1, 1996 to January 27, 2015 was performed. In addition, web-based resources were searched. A priori criteria determined by the Molecular Modellers Working Group of the American Joint Committee on Cancer were used to investigate the quality and usefulness of tools. Criteria included clinical presentation, model development approaches, validation strategies, and performance metrics. Results: Thirty-two prognostic tools were identified. Patients with metastases were the most frequently considered population in non-small-cell lung cancer. All tools for small-cell lung cancer covered that entire patient population. Included prognostic factors varied considerably across tools. Internal validity was not formally evaluated for most tools and only 11 were evaluated for external validity. Two key considerations were highlighted for tool development: identification of an explicit purpose related to a relevant clinical population and clear decision points and prioritized inclusion of established prognostic factors over emerging factors. Conclusions: Prognostic tools will contribute more meaningfully to the practice of personalized medicine if better study design and analysis approaches are used in their development and validation. C1 [Mahar, Alyson L.; Groome, Patti A.] Queens Univ, Div Canc Care & Epidemiol, Canc Res Inst, Kingston, ON K7L 3N6, Canada. [Compton, Carolyn] Arizona State Univ, Phoenix, AZ USA. [Compton, Carolyn] Mayo Clin, Sch Med, Lab Med & Pathol, Rochester, MN USA. [McShane, Lisa M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Halabi, Susan] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Halabi, Susan] Alliance Stat & Data Ctr, Durham, NC USA. [Asamura, Hisao] Natl Canc Ctr, Div Thorac Surg, Tokyo, Japan. [Rami-Porta, Ramon] Hosp Univ Mutua Terrassa, Dept Thorac Surg, Barcelona, Spain. RP Groome, PA (reprint author), Queens Canc Res Inst, Canc Res Inst, Div Canc Care & Epidemiol, Level 2,10 Stuart St, Kingston, ON K7L 3N6, Canada. EM groomep@queensu.ca FU Intramural NIH HHS [Z99 CA999999] NR 71 TC 6 Z9 6 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2015 VL 10 IS 11 BP 1576 EP 1589 DI 10.1097/JTO.0000000000000652 PG 14 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CU1WL UT WOS:000363312700010 PM 26313682 ER PT J AU Sardo, L Hatch, SC Chen, JB Nikolaitchik, O Burdick, RC De Chen Westlake, CJ Lockett, S Pathak, VK Hu, WS AF Sardo, Luca Hatch, Steven C. Chen, Jianbo Nikolaitchik, Olga Burdick, Ryan C. De Chen Westlake, Christopher J. Lockett, Stephen Pathak, Vinay K. Hu, Wei-Shau TI Dynamics of HIV-1 RNA Near the Plasma Membrane during Virus Assembly SO JOURNAL OF VIROLOGY LA English DT Article ID ESCRT PROTEIN RECRUITMENT; VIRAL PARTICLES; GAG; ENCAPSIDATION; GENOMES; VIRION; IDENTIFICATION; VISUALIZATION; SPECIFICITY; SITE AB To increase our understanding of the events that lead to HIV-1 genome packaging, we examined the dynamics of viral RNA and Gag-RNA interactions near the plasma membrane by using total internal reflection fluorescence microscopy. We labeled HIV-1 RNA with a photoconvertible Eos protein via an RNA-binding protein that recognizes stem-loop sequences engineered into the viral genome. Near-UV light exposure causes an irreversible structural change in Eos and alters its emitted fluorescence from green to red. We studied the dynamics of HIV-1 RNA by photoconverting Eos near the plasma membrane, and we monitored the population of photoconverted red-Eos-labeled RNA signals over time. We found that in the absence of Gag, most of the HIV-1 RNAs stayed near the plasma membrane transiently, for a few minutes. The presence of Gag significantly increased the time that RNAs stayed near the plasma membrane: most of the RNAs were still detected after 30 min. We then quantified the proportion of HIV-1 RNAs near the plasma membrane that were packaged into assembling viral complexes. By tagging Gag with blue fluorescent protein, we observed that only a portion, similar to 13 to 34%, of the HIV-1 RNAs that reached the membrane were recruited into assembling particles in an hour, and the frequency of HIV-1 RNA packaging varied with the Gag expression level. Our studies reveal the HIV-1 RNA dynamics on the plasma membrane and the efficiency of RNA recruitment and provide insights into the events leading to the generation of infectious HIV-1 virions. IMPORTANCE Nascent HIV-1 particles assemble on plasma membranes. During the assembly process, HIV-1 RNA genomes must be encapsidated into viral complexes to generate infectious particles. To gain insights into the RNA packaging and virus assembly mechanisms, we labeled and monitored the HIV-1 RNA signals near the plasma membrane. Our results showed that most of the HIV-1 RNAs stayed near the plasma membrane for only a few minutes in the absence of Gag, whereas most HIV-1 RNAs stayed at the plasma membrane for 15 to 60 min in the presence of Gag. Our results also demonstrated that only a small proportion of the HIV-1 RNAs, approximately 1/10 to 1/3 of the RNAs that reached the plasma membrane, was incorporated into viral protein complexes. These studies determined the dynamics of HIV-1 RNA on the plasma membrane and obtained temporal information on RNA-Gag interactions that lead to RNA encapsidation. C1 [Sardo, Luca; Hatch, Steven C.; Chen, Jianbo; Nikolaitchik, Olga; Hu, Wei-Shau] NCI, Viral Recombinat Sect, Frederick, MD 21701 USA. [Burdick, Ryan C.] NCI, Viral Mutat Sect, Frederick, MD 21701 USA. [Westlake, Christopher J.] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Westlake, Christopher J.] NCI, Membrane Trafficking & Signaling Sect, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. [De Chen; Lockett, Stephen] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Image Anal Lab, Frederick, MD USA. RP Hu, WS (reprint author), NCI, Viral Recombinat Sect, Frederick, MD 21701 USA. EM Wei-Shau.Hu@nih.gov FU Intramural Research Program of the NIH; NCI; CCR; Intramural AIDS Targeted Antiviral Program; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the NIH, NCI, CCR, by Intramural AIDS Targeted Antiviral Program grant funding to W.-S.H. and V.K.P., and, in part, by federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 34 TC 9 Z9 9 U1 2 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2015 VL 89 IS 21 BP 10832 EP 10840 DI 10.1128/JVI.01146-15 PG 9 WC Virology SC Virology GA CU3ZP UT WOS:000363465900009 PM 26292321 ER PT J AU Gjessing, MC Yutin, N Tengs, T Senkevich, T Koonin, E Ronning, HP Alarcon, M Ylving, S Lie, KI Saure, B Tran, L Moss, B Dale, OB AF Gjessing, Mona C. Yutin, Natalya Tengs, Torstein Senkevich, Tania Koonin, Eugene Ronning, Hans Petter Alarcon, Marta Ylving, Sonja Lie, Kai-Inge Saure, Britt Tran, Linh Moss, Bernard Dale, Ole Bendik TI Erratum for Gjessing et al., Salmon Gill Poxvirus, the Deepest Representative of the Chordopoxvirinae (vol 89, pg 9348, 2015) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Gjessing, Mona C.; Tengs, Torstein; Alarcon, Marta; Ylving, Sonja; Lie, Kai-Inge; Saure, Britt; Tran, Linh; Dale, Ole Bendik] Norwegian Vet Inst, Oslo, Norway. [Yutin, Natalya; Koonin, Eugene] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Senkevich, Tania; Moss, Bernard] NIH, NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Ronning, Hans Petter] Sisomar AS, Trollbukta, Straumen, Norway. RP Gjessing, MC (reprint author), Norwegian Vet Inst, Oslo, Norway. NR 1 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2015 VL 89 IS 21 BP 11174 EP 11174 DI 10.1128/JVI.02125-15 PG 1 WC Virology SC Virology GA CU3ZP UT WOS:000363465900041 PM 26432522 ER PT J AU Huang, SW Tai, CH Fonville, JM Lin, CH Wang, SM Liu, CC Su, IJ Smith, DJ Wang, JR AF Huang, Sheng-Wen Tai, Ching-Hui Fonville, Judith M. Lin, Chin-Hui Wang, Shih-Min Liu, Ching-Chung Su, Ih-Jen Smith, Derek J. Wang, Jen-Ren TI Mapping Enterovirus A71 Antigenic Determinants from Viral Evolution SO JOURNAL OF VIROLOGY LA English DT Article ID A H3N2 VIRUSES; SYNTHETIC PEPTIDES; GENETIC EVOLUTION; INFLUENZA-VIRUS; CAPSID PROTEIN; STRAINS; IDENTIFICATION; ANTIBODIES; RECEPTOR; BINDING AB Human enterovirus A71 (EV-A71) belongs to the Enterovirus A species in the Picornaviridae family. Several vaccines against EV-A71, a disease causing severe neurological complications or even death, are currently under development and being tested in clinical trials, and preventative vaccination programs are expected to start soon. To characterize the potential for antigenic change of EV-A71, we compared the sequences of two antigenically diverse genotype B4 and B5 strains of EV-A71 and identified substitutions at residues 98, 145, and 164 in the VP1 capsid protein as antigenic determinants. To examine the effects of these three substitutions on antigenicity, we constructed a series of recombinant viruses containing different mutation combinations at these three residues with a reverse genetics system and then investigated the molecular basis of antigenic changes with antigenic cartography. We found that a novel EV-A71 mutant, containing lysine, glutamine, and glutamic acid at the respective residues 98, 145, and 164 in the VP1 capsid protein, exhibited neutralization reduction against patients' antisera and substantially increased virus binding ability to human cells. These observations indicated that this low-neutralization-reactive EV-A71 VP1-98K/145Q/164E mutant potentially increases viral binding ability and that surveillance studies should look out for these mutants, which could compromise vaccine efficacy. IMPORTANCE Emerging and reemerging EV-A71 viruses can cause severe neurological etiology, primarily affecting children, especially around Asia-Pacific countries. We identified a set of mutations in EV-A71 that both reduced neutralization activity against humoral immunity in antisera of patients and healthy adults and greatly increased the viral binding ability to cells. These findings provide important insights for EV-A71 antigenic determinants and emphasize the importance of continuous surveillance, especially after EV-A71 vaccination programs begin. C1 [Huang, Sheng-Wen; Wang, Shih-Min; Liu, Ching-Chung; Wang, Jen-Ren] Natl Cheng Kung Univ, Ctr Infect Dis & Signaling Res, Tainan 70101, Taiwan. [Lin, Chin-Hui; Wang, Jen-Ren] Natl Cheng Kung Univ, Dept Med Lab Sci & Biotechnol, Tainan 70101, Taiwan. [Wang, Shih-Min] Natl Cheng Kung Univ, Dept Emergency Med, Tainan 70101, Taiwan. [Liu, Ching-Chung] Natl Cheng Kung Univ, Dept Pediat, Tainan 70101, Taiwan. [Wang, Jen-Ren] Natl Hlth Res Inst, Natl Inst Infect Dis & Vaccinol, Tainan, Taiwan. [Smith, Derek J.] Univ Cambridge, Cambridge, England. [Smith, Derek J.] Erasmus MC, Rotterdam, Netherlands. [Fonville, Judith M.] WHO, Collaborating Ctr Modeling Evolut & Control Emerg, Cambridge, England. [Smith, Derek J.] NIH, Bethesda, MD 20892 USA. RP Smith, DJ (reprint author), Natl Cheng Kung Univ, Ctr Infect Dis & Signaling Res, Tainan 70101, Taiwan. EM dsmith@zoo.cam.ac.uk; jrwang@mail.ncku.edu.tw RI Wang, Ren-Jen/F-5254-2011; OI Wang, Jen-Ren/0000-0002-4127-4046 FU Center of Infectious Disease and Signaling Research, National Cheng Kung University, Aim for the Top University Project, Ministry of Education; Centers for Disease Control, Ministry of Health and Welfare; National Health Research Institute grant; Ministry of Science and Technology, Taiwan [101-2321-B-006-027-MY2, 103-2321-B-006-011, 104-2321-B-006-002]; Medical Research Council UK [MR/K021885/1]; Homerton College, Cambridge, United Kingdom FX This work was financially supported by the Center of Infectious Disease and Signaling Research, National Cheng Kung University, Aim for the Top University Project, Ministry of Education; by a Centers for Disease Control, Ministry of Health and Welfare, grant; by a National Health Research Institute grant; and by Ministry of Science and Technology, Taiwan, grants 101-2321-B-006-027-MY2, 103-2321-B-006-011, and 104-2321-B-006-002. J.M.F. is supported by a Fellowship in Biomedical Informatics from the Medical Research Council UK (MR/K021885/1) and a Junior Research Fellowship from Homerton College, Cambridge, United Kingdom. NR 34 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2015 VL 89 IS 22 BP 11500 EP 11506 DI 10.1128/JVI.02035-15 PG 7 WC Virology SC Virology GA CU4AC UT WOS:000363467200027 PM 26339057 ER PT J AU Zaritsky, LA Bedsaul, JR Zoon, KC AF Zaritsky, Luna A. Bedsaul, Jacquelyn R. Zoon, Kathryn C. TI Virus Multiplicity of Infection Affects Type I Interferon Subtype Induction Profiles and Interferon-Stimulated Genes SO JOURNAL OF VIROLOGY LA English DT Article ID POSITIVE FEEDBACK; EXPRESSION; ALPHA; CELLS; ACTIVATION; RESPONSES; IRF-7; AMPLIFICATION; TRANSCRIPTION; RECOGNITION AB Type I interferons (IFNs) are induced upon viral infection and important mediators of innate immunity. While there is 1 beta interferon (IFN-beta) protein, there are 12 different IFN-alpha subtypes. It has been reported extensively that different viruses induce distinct patterns of IFN subtypes, but it has not been previously shown how the viral multiplicity of infection (MOI) can affect IFN induction. In this study, we discovered the novel finding that human U937 cells infected with 2 different concentrations of Sendai virus (SeV) induce 2 distinct type I IFN subtype profiles. Cells infected at the lower MOI induced more subtypes than cells infected at the higher MOI. We found that this was due to the extent of signaling through the IFN receptor (IFNAR). The cells infected at the lower viral MOI induced the IFNAR2-dependent IFN-alpha subtypes 4, 6, 7, 10, and 17, which were not induced in cells infected at higher virus concentrations. IFN-beta and IFN-alpha 1, -2, and -8 were induced in an IFNAR-independent manner in cells infected at both virus concentrations. IFN-alpha 5, -14, -16, and -21 were induced in an IFNAR-dependent manner in cells infected at lower virus concentrations and in an IFNAR-independent manner in cells infected at higher virus concentrations. These differences in IFN subtype profiles in the 2 virus concentrations also resulted in distinct interferon-stimulated gene induction. These results present the novel finding that different viral MOIs differentially activate JAK/STAT signaling through the IFNAR, which greatly affects the profile of IFN subtypes that are induced. IMPORTANCE Type I IFNs are pleiotropic cytokines that are instrumental in combating viral diseases. Understanding how the individual subtypes are induced is important in developing strategies to block viral replication. Many studies have reported that different viruses induce distinct type I IFN subtype profiles due to differences in the way viruses are sensed in different cell types. However, we report in our study the novel finding that the amount of virus used to infect a system can also affect which type I IFN subtypes are induced due to the extent of activation of certain signaling pathways. These distinct IFN subtype profiles in cells infected at different MOIs are correlated with differences in interferon-stimulated gene induction, indicating that the same virus can induce distinct antiviral responses depending on the MOI. Because type I IFNs are used as therapeutic agents to treat viral diseases, understanding their antiviral mechanisms can enhance clinical treatments. C1 [Zaritsky, Luna A.; Bedsaul, Jacquelyn R.; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM KZoon@niaid.nih.gov FU Division of Intramural Research (DIR) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Intramural Research Training Program (IRTA) FX This work was supported by the Intramural Research Training Program (IRTA) and the Division of Intramural Research (DIR) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 30 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2015 VL 89 IS 22 BP 11534 EP 11548 DI 10.1128/JVI.01727-15 PG 15 WC Virology SC Virology GA CU4AC UT WOS:000363467200030 PM 26355085 ER PT J AU Chien, WW McDougald, DS Roy, S Fitzgerald, TS Cunningham, LL AF Chien, Wade W. McDougald, Devin S. Roy, Soumen Fitzgerald, Tracy S. Cunningham, Lisa L. TI Cochlear gene transfer mediated by adeno-associated virus: Comparison of two surgical approaches SO LARYNGOSCOPE LA English DT Article DE Gene therapy; adeno-associated virus; round window; cochleostomy; hearing loss ID GUINEA-PIG COCHLEA; IN-VIVO DELIVERY; HAIR-CELLS; TRANSGENE EXPRESSION; MURINE COCHLEA; MOUSE; THERAPY; TRANSDUCTION; ADENOVIRUS; HEARING AB Objectives/HypothesisGene therapy offers the possibility of delivering corrective genetic materials to the cochlea, potentially improving hearing. In animals, the most commonly used surgical methods for viral gene therapy delivery to the cochlea are the round window and the cochleostomy approaches. However, the patterns of viral infection and the effects on hearing have not been directly compared between these two approaches. In this study, we compare the patterns of cochlear infection and effects on hearing between these two surgical approaches using adeno-associated virus serotype 2/8 (AAV8) as the gene delivery vehicle. Study DesignAnimal study and basic science research. MethodsOne- to two-month-old CBA/J mice were used in this study. AAV8-green fluorescent protein (GFP) was delivered to the cochlea by either the round window or the cochleostomy approach (described below). Auditory brainstem response was used to examine hearing thresholds before and after surgery. Animals were examined at 1, 2, 3, and 4 weeks after surgery for the patterns of cochlear infection and hearing loss. ResultsCochlear gene transfer was successful through both surgical approaches. In both approaches, AAV8-GFP mostly infected the inner hair cells. There was occasional low-level infection of the outer hair cells and supporting cells. The two surgical approaches resulted in comparable viral infection efficiencies. The round window approach resulted in less surgical trauma, as indicated by hearing loss, than the cochleostomy approach. ConclusionsAdeno-associated virus-mediated gene transfer to the cochlea can be accomplished using either the round window or the cochleostomy surgical approach. The round window approach resulted in less hearing loss compared to the cochleostomy approach. C1 [Chien, Wade W.; McDougald, Devin S.; Roy, Soumen; Fitzgerald, Tracy S.; Cunningham, Lisa L.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Chien, WW (reprint author), Johns Hopkins Hlth Care & Surg Ctr, 6420 Rockledge Dr,Suite 4920, Bethesda, MD 20817 USA. EM wchien1@jhmi.edu FU National Institute on Deafness and Other Communication Disorders [Z01-DC-000079-03, Z01-DC-000082-02] FX This study was supported by National Institute on Deafness and Other Communication Disorders intramural research funds Z01-DC-000079-03 (L.L.C.) and Z01-DC-000082-02 (W.W.C) NR 22 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2015 VL 125 IS 11 BP 2557 EP 2564 DI 10.1002/lary.25317 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CU2XO UT WOS:000363387200033 PM 25891801 ER PT J AU Park, JW Park, DM Choi, BK Kwon, BS Seong, JK Green, JE Kim, DY Kim, HK AF Park, Jun Won Park, Dong Min Choi, Beom K. Kwon, Byoung S. Seong, Je Kyung Green, Jeffrey E. Kim, Dae-Yong Kim, Hark Kyun TI Establishment and characterization of metastatic gastric cancer cell lines from murine gastric adenocarcinoma lacking Smad4, p53, and E-cadherin SO MOLECULAR CARCINOGENESIS LA English DT Article DE cell line; EMT; gastric cancer; mouse; beta-catenin pathway ID MOUSE MODEL; STOMACH AB There is a strong need for murine gastric cancer cell line models recapitulating human gastric cancers. Here, we describe two murine gastric cancer cell lines designated as NCC-S1 and NCC-S3. They were generated from gastric adenocarcinomas that formed in a Villin-cre, Smad4(F/F), Trp53(F/F), Cdh1(F/wt) mouse and a Pdx1-cre, Trp53(F/F), Cdh1(F/F) mouse, respectively. Molecular profiles of both cell lines were very similar to human gastric cancer. NCC-S1M and NCC-S3M subpopulation clones were isolated from pulmonary metastasis of heterotopic allografts of NCC-S1 and NCC-S3 cells, respectively. NCC-S1M and NCC-S3M showed enhanced in vivo growth rates and metastatic potentials and exhibited epithelial-to-mesenchymal transition features. NCC-S1M cells developed orthotopic and heterotopic tumors in immunocompetent mice in predictable manner, and were useful for testing the efficacy of an immunotherapeutic agent, anti-4-1BB antibody. NCC-S1M and NCC-S3M cells demonstrated Wnt/-catenin pathway activation, and knockdown of Ctnnb1 reversed the metastatic phenotype of NCC-S1M. These results underscore the role of Wnt/-catenin pathway in metastatic phenotype of gastric cancer. Taken together, our novel metastatic gastric cancer cell lines are useful resources for drug development and metastasis research. (c) 2014 Wiley Periodicals, Inc. C1 [Park, Jun Won; Park, Dong Min; Choi, Beom K.; Kwon, Byoung S.; Kim, Hark Kyun] Natl Canc Ctr, Goyang, Gyeonggi, South Korea. [Park, Jun Won; Seong, Je Kyung; Kim, Dae-Yong] Seoul Natl Univ, Coll Vet Med, Seoul 151742, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kim, DY (reprint author), Seoul Natl Univ, Dept Vet Pathol, Coll Vet Med, 599 Gwanank Ro, Seoul 151742, South Korea. FU National Cancer Center [1210051, 1410850]; Proteogenomic Research Program FX Grant sponsor: National Cancer Center; Grant numbers: 1210051; 1410850; Grant sponsor: Proteogenomic Research Program NR 15 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD NOV PY 2015 VL 54 IS 11 BP 1521 EP 1527 DI 10.1002/mc.22226 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CU0PX UT WOS:000363220700027 PM 25307412 ER PT J AU Frederick, AL Yano, H Trifilieff, P Vishwasrao, HD Biezonski, D Meszaros, J Urizar, E Sibley, DR Kellendonk, C Sonntag, KC Graham, DL Colbran, RJ Stanwood, GD Javitch, JA AF Frederick, A. L. Yano, H. Trifilieff, P. Vishwasrao, H. D. Biezonski, D. Meszaros, J. Urizar, E. Sibley, D. R. Kellendonk, C. Sonntag, K. C. Graham, D. L. Colbran, R. J. Stanwood, G. D. Javitch, J. A. TI Evidence against dopamine D1/D2 receptor heteromers SO MOLECULAR PSYCHIATRY LA English DT Article ID MEDIUM SPINY NEURONS; BAC TRANSGENIC MICE; ADENYLATE-CYCLASE; BASAL GANGLIA; RAT STRIATUM; PHOSPHOINOSITIDE HYDROLYSIS; COMPARTMENTAL ORGANIZATION; NUCLEUS-ACCUMBENS; PHOSPHOLIPASE-C; GENE-EXPRESSION AB Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to G(alpha q) proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate G(alpha q) and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect G(alpha q) or G(alpha 11) protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and G(alpha q) KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKII alpha that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through G(alpha q) or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies. C1 [Frederick, A. L.] Vanderbilt Univ, Sch Med, Grad Program Neurosci, Nashville, TN 37232 USA. [Yano, H.; Biezonski, D.; Meszaros, J.; Urizar, E.; Kellendonk, C.; Javitch, J. A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10025 USA. [Yano, H.; Biezonski, D.; Meszaros, J.; Urizar, E.; Kellendonk, C.; Javitch, J. A.] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10025 USA. [Trifilieff, P.] Univ Bordeaux, INRA UMR 1286, Nutr & Integrat Neurobiol, Bordeaux, France. [Trifilieff, P.; Vishwasrao, H. D.] Columbia Univ, Dept Neurosci, New York, NY USA. [Sibley, D. R.] Natl Inst Neurol Disorders & Stroke, NIH, Mol Neuropharmacol Sect, Bethesda, MD USA. [Kellendonk, C.; Javitch, J. A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Sonntag, K. C.] Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. [Graham, D. L.; Stanwood, G. D.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. [Colbran, R. J.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Colbran, R. J.; Stanwood, G. D.] Vanderbilt Univ, Sch Med, Vanderbilt Kennedy Ctr, Nashville, TN 37212 USA. [Colbran, R. J.; Stanwood, G. D.] Vanderbilt Univ, Sch Med, Vanderbilt Brain Inst, Nashville, TN 37212 USA. RP Stanwood, GD (reprint author), Vanderbilt Univ, Sch Med, Dept Pharmacol, 8405 MRBIV,2213 Garland Ave, Nashville, TN 37232 USA. EM gregg.stanwood@vanderbilt.edu; jaj2@columbia.edu FU NIH [RO1MH086629, F31DA029499, TL1 RR024158-04, K05DA022413, R01MH54137, RO1MH093672, R01NS078291]; Research Foundation for Mental Hygiene; Lieber Center for Schizophrenia Research and Treatment; [P30HD15052] FX This work was supported by NIH grants RO1MH086629 (GDS), F31DA029499 (to ALF), TL1 RR024158-04 (to HY), K05DA022413 and R01MH54137 (to JAJ), RO1MH093672 (to CK), R01NS078291 (to RJC), a Research scientist award from the Research Foundation for Mental Hygiene (to PT) and the Lieber Center for Schizophrenia Research and Treatment. Behavioral work was performed at the Vanderbilt Mouse Neurobehavioral Core, which is supported in part by P30HD15052. We thank Dr Celine Gales (Institut National de la Sante et de la Recherche Medicale, Toulouse, France) and Dr Nevin Lambert (Georgia Health Sciences University, Augusta, Georgia) for kindly sharing Rluc and Venus fusion G protein constructs, Dr Stefan Offermanns (University of Heidelberg, Germany) for supplying the Galpha q mutant line and Dr Nicole Calakos (Duke University) for the Drd1a-tdTomato reporter line. We also thank Matt Buendia, Heather Durai and Dr John Allison for excellent technical assistance. NR 70 TC 19 Z9 19 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2015 VL 20 IS 11 BP 1373 EP 1385 DI 10.1038/mp.2014.166 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CU3ZK UT WOS:000363465300012 PM 25560761 ER PT J AU Yang, J Wang, S Yang, Z Hodgkinson, CA Iarikova, P Ma, JZ Payne, TJ Goldman, D Li, MD AF Yang, J. Wang, S. Yang, Z. Hodgkinson, C. A. Iarikova, P. Ma, J. Z. Payne, T. J. Goldman, D. Li, M. D. TI The contribution of rare and common variants in 30 genes to risk nicotine dependence SO MOLECULAR PSYCHIATRY LA English DT Article ID AFRICAN-AMERICAN SMOKERS; RECEPTOR SUBUNIT NR3A; YOUNG-WOMEN SMOKE; SIGNIFICANT ASSOCIATION; EUROPEAN-AMERICANS; NMDA-RECEPTOR; FUNCTIONAL POLYMORPHISM; GLUTAMATE-RECEPTOR; PROTEIN FUNCTION; LOW-FREQUENCY AB Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case-Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerstrom Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ranging from 2.42 x 10(-3) to 1.31 x 10(-4) after 106 phenotype rearrangements. We also observed a significant excess of rare nonsynonymous variants exclusive to EA smokers in NRXN1, CHRNA9, TAS2R38, GRIN3A, DBH, ANKK1/DRD2, NRXN3 and CDH13 with WSS P-values between 3.5 x 10(-5) and 1 x 10(-6). Variants rs142807401 (A432T) and rs139982841 (A452V) in CHRNA9 and variants V132L, V389L, rs34755188 (R480H) and rs75981117 (N549S) in GRIN3A are of particular interest because they are found in both the AA and EA samples. A significant aggregate contribution of rare and common coding variants in CHRNA9 to the risk for ND (SKAT-C: P = 0.0012) was detected by applying the combined sum test in MSTCC EAs. Together, our results indicate that rare variants alone or combined with common variants in a subset of 30 biological candidate genes contribute substantially to the risk of ND. C1 [Yang, J.; Wang, S.; Yang, Z.; Li, M. D.] Univ Virginia, Dept Psychiat & Neurobehav Sci, Charlottesville, VA 22903 USA. [Hodgkinson, C. A.; Iarikova, P.; Goldman, D.] NIAAA, Lab Neurogenet, NIH, Bethesda, MD USA. [Ma, J. Z.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Payne, T. J.] Univ Mississippi, Med Ctr, Dept Otolaryngol & Communicat Sci, ACT Ctr Tobacco Treatment Educ & Res, Jackson, MS 39216 USA. RP Li, MD (reprint author), Univ Virginia, Dept Psychiat & Neurobehav Sci, 450 Ray C Hunt Dr, Charlottesville, VA 22903 USA. EM ml2km@virginia.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institutes of Health [R01 DA012844] FX We acknowledge the invaluable contributions of personal information and blood samples by all participants in the study. This project was supported by National Institutes of Health grant R01 DA012844 to MDL. NR 67 TC 9 Z9 9 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2015 VL 20 IS 11 BP 1467 EP 1478 DI 10.1038/mp.2014.156 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CU3ZK UT WOS:000363465300021 PM 25450229 ER PT J AU Arrowsmith, CH Audia, JE Austin, C Baell, J Bennett, J Blagg, J Bountra, C Brennan, PE Brown, PJ Bunnage, ME Buser-Doepner, C Campbell, RM Carter, AJ Cohen, P Copeland, RA Cravatt, B Dahlin, JL Dhanak, D Edwards, AM Frederiksen, M Frye, SV Gray, N Grimshaw, CE Hepworth, D Howe, T Huber, KVM Jin, J Knapp, S Kotz, JD Kruger, RG Lowe, D Mader, MM Marsden, B Mueller-Fahrnow, A Muller, S O'Hagan, RC Overington, JP Owen, DR Rosenberg, SH Ross, R Roth, B Schapira, M Schreiber, SL Shoichet, B Sundstrom, M Superti-Furga, G Taunton, J Toledo-Sherman, L Walpole, C Walters, MA Willson, TM Workman, P Young, RN Zuercher, WJ AF Arrowsmith, Cheryl H. Audia, James E. Austin, Christopher Baell, Jonathan Bennett, Jonathan Blagg, Julian Bountra, Chas Brennan, Paul E. Brown, Peter J. Bunnage, Mark E. Buser-Doepner, Carolyn Campbell, Robert M. Carter, Adrian J. Cohen, Philip Copeland, Robert A. Cravatt, Ben Dahlin, Jayme L. Dhanak, Dashyant Edwards, Aled M. Frederiksen, Mathias Frye, Stephen V. Gray, Nathanael Grimshaw, Charles E. Hepworth, David Howe, Trevor Huber, Kilian V. M. Jin, Jian Knapp, Stefan Kotz, Joanne D. Kruger, Ryan G. Lowe, Derek Mader, Mary M. Marsden, Brian Mueller-Fahrnow, Anke Mueller, Susanne O'Hagan, Ronan C. Overington, John P. Owen, Dafydd R. Rosenberg, Saul H. Ross, Ruth Roth, Bryan Schapira, Matthieu Schreiber, Stuart L. Shoichet, Brian Sundstroem, Michael Superti-Furga, Giulio Taunton, Jack Toledo-Sherman, Leticia Walpole, Chris Walters, Michael A. Willson, Timothy M. Workman, Paul Young, Robert N. Zuercher, William J. TI The promise and peril of chemical probes (vol 11, pg 536, 2015) SO NATURE CHEMICAL BIOLOGY LA English DT Correction C1 [Roth, Bryan] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Act Drug Screening Program NIMH PDSP,De, Chapel Hill, NC USA. [Roth, Bryan] Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Frederiksen, Mathias] Novartis, Novartis Inst BioMed Res, Basel, Switzerland. RI Baell, Jonathan/E-5844-2017 OI Baell, Jonathan/0000-0003-2114-8242 FU Cancer Research UK [11566] NR 1 TC 3 Z9 3 U1 7 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD NOV PY 2015 VL 11 IS 11 BP 887 EP 887 DI 10.1038/nchembio.1931 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU1HS UT WOS:000363272100017 PM 26485080 ER PT J AU Beringer, DX Kleijwegt, FS Wiede, F van der Slik, AR Loh, KL Petersen, J Dudek, NL Duinkerken, G Laban, S Joosten, A Vivian, JP Chen, ZJ Uldrich, AP Godfrey, DI McCluskey, J Price, DA Radford, KJ Purcell, AW Nikolic, T Reid, HH Tiganis, T Roep, BO Rossjohn, J AF Beringer, Dennis X. Kleijwegt, Fleur S. Wiede, Florian van der Slik, Arno R. Loh, Khai Lee Petersen, Jan Dudek, Nadine L. Duinkerken, Gaby Laban, Sandra Joosten, Antoinette Vivian, Julian P. Chen, Zhenjun Uldrich, Adam P. Godfrey, Dale I. McCluskey, James Price, David A. Radford, Kristen J. Purcell, Anthony W. Nikolic, Tatjana Reid, Hugh H. Tiganis, Tony Roep, Bart O. Rossjohn, Jamie TI T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex SO NATURE IMMUNOLOGY LA English DT Article ID HUMAN DENDRITIC CELLS; STRUCTURAL BASIS; THYMIC SELECTION; GERMLINE BIAS; AMINO-ACIDS; CLASS-I; MHC; TCR; PEPTIDE; TOLERANCE AB Central to adaptive immunity is the interaction between the alpha beta T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 1800 polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR alpha-chain and beta-chain are overlaid with the alpha-chain and beta-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition. C1 [Beringer, Dennis X.; Wiede, Florian; Loh, Khai Lee; Petersen, Jan; Dudek, Nadine L.; Vivian, Julian P.; Purcell, Anthony W.; Reid, Hugh H.; Tiganis, Tony; Rossjohn, Jamie] Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic, Australia. [Beringer, Dennis X.; Wiede, Florian; Loh, Khai Lee; Petersen, Jan; Dudek, Nadine L.; Vivian, Julian P.; Purcell, Anthony W.; Reid, Hugh H.; Tiganis, Tony; Rossjohn, Jamie] Monash Univ, Dept Biochem & Mol Biol, Biomed Discovery Inst, Clayton, Vic, Australia. [Kleijwegt, Fleur S.; van der Slik, Arno R.; Duinkerken, Gaby; Laban, Sandra; Joosten, Antoinette; Nikolic, Tatjana; Roep, Bart O.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. [Petersen, Jan; Vivian, Julian P.; Reid, Hugh H.; Rossjohn, Jamie] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic, Australia. [Chen, Zhenjun; Uldrich, Adam P.; Godfrey, Dale I.; McCluskey, James] Univ Melbourne, Australian Res Council Ctr Excellence Adv Mol Ima, Parkville, Vic 3052, Australia. [Uldrich, Adam P.; Godfrey, Dale I.] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Parkville, Vic 3052, Australia. [Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Radford, Kristen J.] Univ Queensland, Mater Res Inst, Brisbane, Qld, Australia. [Radford, Kristen J.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. RP Reid, HH (reprint author), Monash Univ, Infect & Immun Program, Biomed Discovery Inst, Clayton, Vic, Australia. EM tony.tiganis@monash.edu; B.O.Roep@lumc.nl; jamie.rossjohn@monash.edu RI Price, David/C-7876-2013; McCluskey, James/A-1291-2007; OI Price, David/0000-0001-9416-2737; McCluskey, James/0000-0002-8597-815X; Purcell, Anthony/0000-0003-0532-8331; Rossjohn, Jamie/0000-0002-2020-7522 FU Australian Research Council (ARC); National Health and Medical Research Council of Australia (NHMRC); Netherlands Organization for Scientific Research [VICI 918.86.611]; European Union [241447]; National Diabetes Expert Center - Dutch Diabetes Research Foundation (DEN); Diabetes Research Netherlands (DON) Foundation FX We thank staff at the Australian synchrotron, the Leiden University Medical Center, the Monash Macromolecular Crystallization Facility, T. Beddoe, J. Teeler, C. van der Torren, S. Scally, M. Tran, S. Gras, K. Ladell, G. Dolton, R. Ayala-Perez and R. Berry for assistance. This work was supported by the Australian Research Council (ARC) and the National Health and Medical Research Council of Australia (NHMRC). A.P.U. is an ARC Future Fellow, D.I.G. is an NHMRC Senior Principal Research Fellow, D.A.P. is a Wellcome Trust Senior Investigator, K.J.R. is an NHMRC Career Development Fellow, A.W.P. is an NHMRC Senior Research Fellow, T.T. is an NHMRC Principal Research Fellow and K.J.R. is an NHMRC Australia Fellow. F.S.K., A.J. and B.O.R. are supported by the Netherlands Organization for Scientific Research (VICI 918.86.611), T.N. and S.L. are supported by the European Union 7th Framework Program (FP7/2007-2013) under Grant No. 241447 (Novel Immunotherapies for Type I Diabetes (NIAMIT)) and G.D. and A.R.v.d.S. are supported by the National Diabetes Expert Center funded by the Dutch Diabetes Research Foundation (DFN) and the Diabetes Research Netherlands (DON) Foundation. NR 39 TC 21 Z9 23 U1 4 U2 24 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 NOV PY 2015 VL 16 IS 11 BP 1153 EP 1161 DI 10.1038/ni.3271 PG 9 WC Immunology SC Immunology GA CT8VW UT WOS:000363096000009 PM 26437244 ER PT J AU Heindel, JJ Newbold, R Schug, TT AF Heindel, Jerrold J. Newbold, Retha Schug, Thaddeus T. TI Endocrine disruptors and obesity SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID EPIGENETIC TRANSGENERATIONAL INHERITANCE; POLYBROMINATED DIPHENYL ETHERS; EARLY-LIFE EXPOSURE; MESENCHYMAL STEM-CELLS; BISPHENOL-A EXPOSURE; ORAL DOSE TOXICITY; IN-UTERO EXPOSURE; AIR-POLLUTION; PRENATAL EXPOSURE; BODY-WEIGHT AB The increasing incidence of obesity is a serious global public health challenge. Although the obesity epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated metabolic processes, especially if exposure occurs during early development. These chemicals, so-called 'obesogens' might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their modes of action. The research reviewed here provides knowledge that health scientists can use to inform their research and decision-making processes. C1 [Heindel, Jerrold J.; Schug, Thaddeus T.] Natl Inst Environm Sci, Div Extramural Res & Training, Populat Hlth Branch, Res Triangle Pk, NC 27709 USA. [Newbold, Retha] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Heindel, JJ (reprint author), Natl Inst Environm Sci, Div Extramural Res & Training, Populat Hlth Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM J.J.H.heindelj@niehs.nih.gov NR 139 TC 25 Z9 25 U1 17 U2 85 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD NOV PY 2015 VL 11 IS 11 BP 653 EP 661 DI 10.1038/nrendo.2015.163 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU4CQ UT WOS:000363474400008 PM 26391979 ER PT J AU Metti, AL Aizenstein, H Yaffe, K Boudreau, RM Newman, A Launer, L Gianaros, PJ Lopez, OL Saxton, J Ives, DG Kritchevsky, S Vallejo, AN Rosano, C AF Metti, Andrea L. Aizenstein, Howard Yaffe, Kristine Boudreau, Robert M. Newman, Anne Launer, Lenore Gianaros, Peter J. Lopez, Oscar L. Saxton, Judith Ives, Diane G. Kritchevsky, Stephen Vallejo, Abbe N. Rosano, Caterina TI Trajectories of peripheral interleukin-6, structure of the hippocampus, and cognitive impairment over 14 years in older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE Cognitive impairment; Interleukin-6; Hippocampal morphology; Aging; Epidemiology ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; CARDIOVASCULAR HEALTH; ALZHEIMERS-DISEASE; INFLAMMATORY MARKERS; BRAIN; RISK; DECLINE; MEMORY; IL-6 AB We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70-79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (beta = -0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline. (C) 2015 Elsevier Inc. All rights reserved. C1 [Metti, Andrea L.] Metti Consulting Co, Pittsburgh, PA 15207 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Boudreau, Robert M.; Newman, Anne; Ives, Diane G.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Gianaros, Peter J.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Lopez, Oscar L.; Saxton, Judith] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Kritchevsky, Stephen] Wake Forest Univ, Dept Internal Med, Winston Salem, NC 27109 USA. [Vallejo, Abbe N.] Univ Pittsburgh, Sch Med, UPMC Childrens Hosp Pittsburgh, Div Pediat Rheumatol, Pittsburgh, PA USA. [Vallejo, Abbe N.] Univ Pittsburgh, Sch Med, UPMC Childrens Hosp Pittsburgh, Dept Pediat & Immunol, Pittsburgh, PA USA. RP Metti, AL (reprint author), Metti Consulting Co, 4216 Lydia St, Pittsburgh, PA 15207 USA. EM andrealmetti@gmail.com RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187; Metti, Andrea/0000-0002-4467-5304 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01 AG028288]; National Institute of Nursing Research (NINR) [R01-NR012459]; Intramural Research Program on the National Institutes of Health (NIH), National Institute on Aging FX This work was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grants R01-AG028050 and R01 AG028288, and National Institute of Nursing Research (NINR) grant R01-NR012459. This research was supported in part by the Intramural Research Program on the National Institutes of Health (NIH), National Institute on Aging. NR 48 TC 2 Z9 2 U1 0 U2 4 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 NOV PY 2015 VL 36 IS 11 BP 3038 EP 3044 DI 10.1016/j.neurobiolaging.2015.07.025 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CU1LA UT WOS:000363281700014 PM 26279115 ER PT J AU Beydoun, MA Beydoun, HA Rostant, OS Dore, GA Fanelli-Kuczmarski, MT Evans, MK Zonderman, AB AF Beydoun, May A. Beydoun, Hind A. Rostant, Ola S. Dore, Greg A. Fanelli-Kuczmarski, Marie T. Evans, Michele K. Zonderman, Alan B. TI Thyroid hormones are associated with longitudinal cognitive change in an urban adult population SO NEUROBIOLOGY OF AGING LA English DT Article DE Thyroid hormones; Cognitive function; Longitudinal studies; Aging ID SUBCLINICAL HYPOTHYROIDISM; OLD-AGE; THYROXINE REPLACEMENT; STIMULATING HORMONE; DEPRESSED MOOD; US ADULTS; HEALTHY; MEMORY; IMPAIRMENT; DEMENTIA AB Recent evidence indicates that thyroid hormones may be closely linked to cognition among adults. We investigated associations between thyroid hormones and longitudinal cognitive change, within and outside of reference ranges, stratifying by sex and race. This longitudinal study used data from the Healthy Aging in Neighborhoods of Diversity Across the Lifespan study, set in Baltimore City, MD, 2004-2013, on adults aged 30-64 years at baseline visit, with a length of follow-up between visits 1 and 2 ranging from < 1 to 8 years; mean +/- standard deviation: 4.64 +/- 0.93. The final analytic sample sizes ranged from 1486 to 1602 participants with 1.6-1.7 visits per participant (total visits: 2496-2757), depending on the cognitive test. Eleven cognitive test scores spanning domains of learning or memory, language or verbal, attention, visuospatial and/or visuoconstruction, psychomotor speed, executive function, and mental status were used. Mixed-effects regression models were conducted, interacting time of follow-up with several thyroid exposures. Whites performed better than African Americans, with only 4 cognitive test scores of 11 declining significantly over time. Importantly, above reference range thyroid stimulating hormone (vs. reference range, thyroid stimulating hormone, above reference range [TSHarr]) was linked to faster rates of decline on the digits span backwards test, reflecting working memory (TSHarr x time gamma +/- standard error: -0.14 +/- 0.05, p = 0.006) and clock-command, at test of visuospatial and/or visuoconstruction abilities (TSHarr x Time gamma +/- standard error: -0.10 +/- 0.04, p = 0.004). The latter finding was replicated when comparing normal thyroid function to " subclinical hypothyroidism". Within-reference ranges, a higher thyroid stimulating hormone was related to faster decline on the clock-command test scores in women. In sum, higher baseline thyroid stimulating hormone was associated with faster cognitive decline over-time among urban US adults, specifically in domains of working memory and visuospatial and/or visuoconstruction abilities. Published by Elsevier Inc. C1 [Beydoun, May A.; Rostant, Ola S.; Dore, Greg A.; Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, Biomed Res Ctr, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Fanelli-Kuczmarski, Marie T.] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, Intramural Research Program (NIA/NIH/IRP) FX This study was entirely supported by the National Institute on Aging, Intramural Research Program (NIA/NIH/IRP). NR 47 TC 5 Z9 6 U1 2 U2 6 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 NOV PY 2015 VL 36 IS 11 BP 3056 EP 3066 DI 10.1016/j.neurobiolaging.2015.08.002 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CU1LA UT WOS:000363281700016 PM 26329688 ER PT J AU Pereira, IT Gallagher, M Rapp, PR AF Pereira, Ines Tomas Gallagher, Michela Rapp, Peter R. TI Head west or left, east or right: interactions between memory systems in neurocognitive aging SO NEUROBIOLOGY OF AGING LA English DT Article DE Prefrontal cortex; Hippocampus; Memory systems; Arc; Rat; Neuroadaptive aging ID SPATIAL-LEARNING IMPAIRMENT; MILD COGNITIVE IMPAIRMENT; EARLY GENE ARC; CAUDATE-NUCLEUS; AGED RATS; NAVIGATION STRATEGIES; PREFRONTAL CORTEX; WORKING-MEMORY; MESSENGER-RNA; ANIMAL-MODELS AB Cognitive aging is accompanied by decline in multiple domains of memory. Here, we developed a T-maze task that required rats to learn competing hippocampal, and striatal navigation strategies in succession, across days. A final session increased demands on cognitive flexibility and required within-day switching between strategies, emphasizing capacities that engage the prefrontal cortex. Background characterization in young and aged rats used a water maze protocol optimized for individual differences in hippocampal integrity. Consistent with earlier work, young adults acquired place strategies in the T-maze faster than response, whereas the opposite was observed in aged rats with impaired spatial memory. The novel result was that aged animals with preserved spatial memory displayed a qualitatively distinct pattern, acquiring place and response strategies equally rapidly, without disruption when switching between them. Subsequent in situ hybridization for the plasticity-related immediate-early gene Arc revealed that while increasing demands on cognitive flexibility and within-day strategy switching potently engaged the prefrontal cortex in young adult and aged-impaired rats, Arc expression was insensitive in aged rats with normal spatial memory and superior switching abilities. Together, the results indicate that cognitive aging is an emergent property of the interactions between memory systems, and that successful cognitive outcomes reflect a distinct neuroadaptive process rather than a slower rate of aging. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pereira, Ines Tomas; Rapp, Peter R.] NIA, Neurocognit Aging Sect, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. RP Rapp, PR (reprint author), 251 Bayview Blvd,Suite 100,Room 9C224, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov OI Tomas Pereira, Ines/0000-0003-2388-8164 FU NIH [AG09973]; NIA; Fundacao para a Ciencia e a Tecnologia [SFRH/BD/27758/2006] FX The authors would like to acknowledge Bonnie Fletcher, Pul Park, Rebecca P. Haberman, Robert McMahan, and members of the Neurocognitive Aging Section for helpful discussion and technical assistance. This research was supported by NIH grant AG09973, the Intramural Research Program of the NIA, and by grant SFRH/BD/27758/2006 from Fundacao para a Ciencia e a Tecnologia. NR 57 TC 2 Z9 2 U1 7 U2 11 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 NOV PY 2015 VL 36 IS 11 BP 3067 EP 3078 DI 10.1016/j.neurobiolaging.2015.07.024 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CU1LA UT WOS:000363281700017 ER PT J AU Volkow, ND Wang, GJ Smith, L Fowler, JS Telang, F Logan, J Tomasi, D AF Volkow, Nora D. Wang, Gene-Jack Smith, Lisa Fowler, Joanna S. Telang, Frank Logan, Jean Tomasi, Dardo TI Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release SO NEUROIMAGE LA English DT Article DE Addiction; Neurotoxicity; Dopamine terminal; Parkinson's disease ID POSITRON-EMISSION-TOMOGRAPHY; PLACEBO-CONTROLLED TRIAL; PARKINSONS-DISEASE; DOWN-REGULATION; DOUBLE-BLIND; NEUROTOXICITY; BRAIN; RAT; COCAINE; METHYLPHENIDATE AB Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [C-11] cocaine to measure DAT, and with [C-11]raclopride to measure dopamine release (assessed as changes in specific binding of [C-11] raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n = 16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum(except for a small decrease in left putamen), when compared to controls (n = 15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p = 0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n = 9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p = 0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals. Published by Elsevier Inc. C1 [Volkow, Nora D.; Wang, Gene-Jack; Telang, Frank; Logan, Jean; Tomasi, Dardo] NIAAA, Lab Neuroimaging, Intramural Program, Bethesda, MD USA. [Smith, Lisa] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Volkow, Nora D.] NIDA, Off Director, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov OI Logan, Jean/0000-0002-6993-9994 FU NIH intramural program (NIAAA); Brookhaven National Laboratory (BNL) [DE-AC02-98CH10886] FX This research was supported by the NIH intramural program (NIAAA) and carried out at Brookhaven National Laboratory (BNL) under contract DE-AC02-98CH10886. We thank C. Wong, C Shea, Y. Xu, D Alexoff, P. King, Karen Apelskog and Ruben Baler. NR 54 TC 9 Z9 9 U1 0 U2 9 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 NOV 1 PY 2015 VL 121 BP 20 EP 28 DI 10.1016/j.neuroimage.2015.07.035 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CT9FK UT WOS:000363122000003 PM 26208874 ER PT J AU Paulsen, JL Ozarslan, E Komlosh, ME Basser, PJ Song, YQ AF Paulsen, Jeffrey L. Oezarslan, Evren Komlosh, Michal E. Basser, Peter J. Song, Yi-Qiao TI Detecting compartmental non-Gaussian diffusion with symmetrized double-PFG MRI SO NMR IN BIOMEDICINE LA English DT Article DE non-Gaussian diffusion; Kurtosis; double wavevector; double diffusion encoding; microscopic anisotropy; compartment shape anisotroy; restricted diffusion; diffusion correlation ID SPIN-ECHO; MAGNETIC-RESONANCE; GRADIENT; NMR; KURTOSIS; VECTOR; TENSOR; ANISOTROPY AB Diffusion in tissue and porous media is known to be non-Gaussian and has been used for clinical indications of stroke and other tissue pathologies. However, when conventional NMR techniques are applied to biological tissues and other heterogeneous materials, the presence of multiple compartments (pores) with different Gaussian diffusivities will also contribute to the measurement of non-Gaussian behavior. Here we present symmetrized double PFG (sd-PFG), which can separate these two contributions to non-Gaussian signal decay as having distinct angular modulation frequencies. In contrast to prior angular d-PFG methods, sd-PFG can unambiguously extract kurtosis as an oscillation from samples with isotropic or uniformly oriented anisotropic pores, and can generally extract a combination of compartmental anisotropy and kurtosis. The method further fixes its sensitivity with respect to the time dependence of the apparent diffusion coefficient. We experimentally demonstrate the measurement of the fourth cumulant (kurtosis) of diffusion and find it consistent with theoretical predictions. By enabling the unambiguous identification of contributions of compartmental kurtosis to the signal, sd-PFG has the potential to help identify the underlying micro-structural changes corresponding to current kurtosis based diagnostics, and act as a novel source of contrast to better resolve tissue micro-structure. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Paulsen, Jeffrey L.; Song, Yi-Qiao] Schlumberger Doll Res Ctr, Cambridge, MA 02139 USA. [Oezarslan, Evren] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Oezarslan, Evren; Komlosh, Michal E.; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Oezarslan, Evren; Komlosh, Michal E.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Oezarslan, Evren] Bogazici Univ, Dept Phys, TR-34342 Istanbul, Turkey. RP Paulsen, JL (reprint author), Schlumberger Doll Res Ctr, Cambridge, MA 02139 USA. EM JPaulsen2@slb.com FU Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM); Henry M. Jackson Foundation (HJF); NIH [R01MH074794]; TUBITAK-EU Co-Funded Brain Circulation Scheme [114C015]; CNRM/HJF [G189BH]; Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD000266] FX Support for this work includes contributions from Schlumberger. Evren Ozsarslan was supported by (i) the Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) and the Henry M. Jackson Foundation (HJF), (ii) NIH R01MH074794, and (iii) TUBITAK-EU Co-Funded Brain Circulation Scheme, project 114C015. Michal Komlosh was supported by a grant for "Clinical Double Pulsed Field Gradient (dPFG) MRI for Mild TBI Assessment" under the auspices of the CNRM/HJF (#G189BH). Peter Basser was supported by funds derived from the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) underHD000266 (2015) "Imaging Water Diffusion in the Brain and in Other Soft Tissues". NR 29 TC 1 Z9 1 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD NOV PY 2015 VL 28 IS 11 BP 1550 EP 1556 DI 10.1002/nbm.3363 PG 7 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA CU4AE UT WOS:000363467400021 PM 26434812 ER PT J AU Chew, EY Schachat, AP AF Chew, Emily Y. Schachat, Andrew P. TI Should We Add Screening of Age-Related Macular Degeneration to Current Screening Programs for Diabetic Retinopathy? SO OPHTHALMOLOGY LA English DT Editorial Material ID COST-EFFECTIVENESS; CLINICAL-TRIAL; EYE DISEASE; PREVALENCE; ZINC C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2015 VL 122 IS 11 BP 2155 EP 2156 DI 10.1016/j.ophtha.2015.08.007 PG 2 WC Ophthalmology SC Ophthalmology GA CU4IQ UT WOS:000363491800012 PM 26498078 ER PT J AU Kelly, KA Hollingsworth, MA Brand, RE Liu, CH Singh, VK Srivastava, S Wasan, AD Yadav, D Andersen, DK AF Kelly, Kimberly A. Hollingsworth, Michael A. Brand, Randall E. Liu, Christina H. Singh, Vikesh K. Srivastava, Sudhir Wasan, Ajay D. Yadav, Dhiraj Andersen, Dana K. TI Advances in Biomedical Imaging, Bioengineering, and Related Technologies for the Development of Biomarkers of Pancreatic Disease Summary of a National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Biomedical Imaging and Bioengineering Workshop SO PANCREAS LA English DT Article DE biomarkers; chronic pancreatitis; pancreatic cancer; molecular imaging; exosomes; circulating tumor cells AB A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Biomedical Imaging and Bioengineering focused on research gaps and opportunities in the development of new biomarkers of pancreatic disease. The session was held on July 22, 2015, and structured into 6 sessions: 1) Introduction and Overview; 2) Keynote Address; 3) New Approaches to the Diagnosis of Chronic Pancreatitis; 4) Biomarkers of Pain and Inflammation; 5) New Approaches to the Detection of Pancreatic Cancer; and 6) Shed Exosomes, Shed Cells, and Shed Proteins. Recent advances in the fields of pancreatic imaging, functional markers of pancreatic disease, proteomics, molecular and cellular imaging, and detection of circulating cancer cells and exosomes were reviewed. Knowledge gaps and research needs were highlighted. The development of new methods for the noninvasive determination of pancreatic pathology; the use of cellular markers of pancreatic function, inflammation, pain, and malignancy; and the refinement of methods to identify cells and cellular constituents of pancreatic cancer were discussed. The further refinement of sophisticated technical methods and the need for clinical studies to validate these new approaches in large-scale studies of patients at risk for the development of pancreatic disease were repeatedly emphasized. C1 [Kelly, Kimberly A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. [Hollingsworth, Michael A.] Univ Nebraska, Sch Med, Eppley Canc Inst, Omaha, NE 68198 USA. [Brand, Randall E.; Wasan, Ajay D.; Yadav, Dhiraj] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. [Brand, Randall E.; Wasan, Ajay D.; Yadav, Dhiraj] Univ Pittsburgh, Sch Med, Dept Anesthesiol & Psychiat, Pittsburgh, PA USA. [Liu, Christina H.] NCI, Off Canc Nanotechnol Res, NIH, Bethesda, MD 20892 USA. [Liu, Christina H.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Singh, Vikesh K.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol, Baltimore, MD 21205 USA. [Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. RP Kelly, KA (reprint author), Univ Virginia, Dept Biomed Engn, Robert M Berne Cardiovasc Res Ctr, 415 Lane Rd,Bldg MR5,Rm 1214, Charlottesville, VA 22904 USA. EM kak3x@virginia.edu FU National Pancreas Foundation FX The authors and sponsors are grateful for the additional support of the National Pancreas Foundation and for the on-site assistance of Ms Patter Birsic, Mr Matthew Alsante, Ms Jessica Kruse, and Mr Dan Spracklen of the National Pancreas Foundation and for the assistance of Ms Joy Merusi of the University of Pittsburgh. NR 1 TC 4 Z9 4 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2015 VL 44 IS 8 BP 1185 EP 1194 DI 10.1097/MPA.0000000000000552 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU2AQ UT WOS:000363324000006 PM 26465948 ER PT J AU Lee, L Ito, T Igarashi, H Kawabe, K Oda, Y Jensen, RT AF Lee, L. Ito, T. Igarashi, H. Kawabe, K. Oda, Y. Jensen, R. T. TI Long-Term Outcomes and Prognostic Factors in 78 Japanese Patients With Advanced Pancreatic Neuroendocrine Tumors: A Single-Center Retrospective Study SO PANCREAS LA English DT Meeting Abstract C1 [Lee, L.; Ito, T.; Igarashi, H.; Kawabe, K.] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 812, Japan. [Oda, Y.] Kyushu Univ, Grad Sch Med Sci, Dept Anat Pathol, Fukuoka 812, Japan. [Jensen, R. T.] Natl Inst Diabet Digest & Kidney Dis, Digest Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2015 VL 44 IS 8 BP 1391 EP 1391 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU2AQ UT WOS:000363324000162 ER PT J AU Yamaguchi, H Dangol, G Ghosh, B Gutkind, JS Maitra, A AF Yamaguchi, H. Dangol, G. Ghosh, B. Gutkind, J. S. Maitra, A. TI Induction of R201C Mutant Gas Facilitates Murine Pancreatic Tumorigenesis in Cooperation With G12D Mutant Kras SO PANCREAS LA English DT Meeting Abstract C1 [Yamaguchi, H.; Dangol, G.; Ghosh, B.; Maitra, A.] Univ Texas MD Anderson Canc Ctr, Sheikh Ahmed Ctr Pancreat Canc Res, Houston, TX 77030 USA. [Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2015 VL 44 IS 8 BP 1427 EP 1427 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CU2AQ UT WOS:000363324000309 ER PT J AU Gotea, V Gartner, JJ Qutob, N Elnitski, L Samuels, Y AF Gotea, Valer Gartner, Jared J. Qutob, Nouar Elnitski, Laura Samuels, Yardena TI The functional relevance of somatic synonymous mutations in melanoma and other cancers SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE synonymous mutations; cancer; melanoma; gene splicing; miRNA regulation; secondary structure; protein translation; protein folding ID CONGENITAL MELANOCYTIC NEVI; CUTANEOUS MALIGNANT-MELANOMA; UV-RADIATION EXPOSURE; BRAF MUTATION; SPITZ NEVI; BLUE NEVI; N-RAS; TUMOR PROGRESSION; NRAS MUTATIONS; CONSTITUTIVE ACTIVATION AB Recent technological advances in sequencing have flooded the field of cancer research with knowledge about somatic mutations for many different cancer types. Most cancer genomics studies focus on mutations that alter the amino acid sequence, ignoring the potential impact of synonymous mutations. However, accumulating experimental evidence has demonstrated clear consequences for gene function, leading to a widespread recognition of the functional role of synonymous mutations and their causal connection to various diseases. Here, we review the evidence supporting the direct impact of synonymous mutations on gene function via gene splicing; mRNA stability, folding, and translation; protein folding; and miRNA-based regulation of expression. These results highlight the functional contribution of synonymous mutations to oncogenesis and the need to further investigate their detection and prioritization for experimental assessment. C1 [Gartner, Jared J.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Gartner, Jared J.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Qutob, Nouar; Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Samuels, Y (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. EM elnitski@mail.nih.gov; Yardena.samuels@weizmann.ac.il OI Gotea, Valer/0000-0001-7857-3309 FU Intramural Research Programs of the National Human Genome Research Institute; Israel Science Foundation [1604/13, 877/13]; ERC [StG-335377]; Knell Family; Peter and Patricia Gruber Award; Gideon Hamburger, Israel FX We thank F. Supek and B. Lehner for providing relevant data from their study (Supek et al., 2014). This work was supported by the Intramural Research Programs of the National Human Genome Research Institute (VG, LE). YS is supported by Israel Science Foundation grant numbers 1604/13 and 877/13 and by the ERC (StG-335377), the Knell Family, the Peter and Patricia Gruber Award, and Gideon Hamburger, Israel. NR 120 TC 4 Z9 4 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD NOV PY 2015 VL 28 IS 6 BP 673 EP 684 DI 10.1111/pcmr.12413 PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA CU3DL UT WOS:000363404000008 PM 26300548 ER PT J AU Markt, SC Shui, IM Unger, RH Urun, Y Berg, CD Black, A Brennan, P Bueno-De-Mesquita, HB Gapstur, SM Giovannucci, E Haiman, C Henderson, B Hoover, RN Hunter, DJ Key, TJ Khaw, KT Canzian, F Larranga, N Le Marchand, L Ma, J Naccarati, A Siddiq, A Stampfer, MJ Stattin, P Stevens, VL Stram, DO Tjonneland, A Travis, RC Trichopoulos, D Ziegler, RG Lindstrom, S Kraft, P Mucci, LA Choueiri, TK Wilson, KM AF Markt, Sarah C. Shui, Irene M. Unger, Robert H. Urun, Yuksel Berg, Christine D. Black, Amanda Brennan, Paul Bueno-de-Mesquita, H. Bas Gapstur, Susan M. Giovannucci, Edward Haiman, Christopher Henderson, Brian Hoover, Robert N. Hunter, David J. Key, Timothy J. Khaw, Kay-Tee Canzian, Federico Larranga, Nerea Le Marchand, Loic Ma, Jing Naccarati, Alessio Siddiq, Afshan Stampfer, Meir J. Stattin, Par Stevens, Victoria L. Stram, Daniel O. Tjonneland, Anne Travis, Ruth C. Trichopoulos, Dimitrios Ziegler, Regina G. Lindstrom, Sara Kraft, Peter Mucci, Lorelei A. Choueiri, Toni K. Wilson, Kathryn M. TI ABO Blood Group Alleles and Prostate Cancer Risk: Results from the Breast and Prostate Cancer Cohort Consortium (BPC3) SO PROSTATE LA English DT Article DE ABO; blood type; prostate cancer; genetic epidemiology ID ASSOCIATION AB BACKGROUND. ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer. METHODS. We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score >= 8 or locally advanced/metastatic disease (stage T3/T4/N1/M1). RESULTS. We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95% CI = 0.87-1.08; Type B: OR = 0.92, 95% CI = n0.77-1.09; Type AB: OR = 1.25, 95% CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk. CONCLUSIONS. ABO blood type was not associated with risk of aggressive prostate cancer. Prostate 75: 1677-1681, 2015. (C) 2015 Wiley Periodicals, Inc. C1 [Markt, Sarah C.; Shui, Irene M.; Unger, Robert H.; Giovannucci, Edward; Hunter, David J.; Ma, Jing; Stampfer, Meir J.; Trichopoulos, Dimitrios; Lindstrom, Sara; Kraft, Peter; Mucci, Lorelei A.; Wilson, Kathryn M.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Shui, Irene M.; Hunter, David J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Urun, Yuksel] Ankara Univ, Fac Med, Dept Med Oncol, TR-06100 Ankara, Turkey. [Berg, Christine D.] Johns Hopkins Med, Dept Radiat Oncol, Baltimore, MD USA. [Black, Amanda] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brennan, Paul; Hoover, Robert N.; Ziegler, Regina G.] Int Agcy Res Canc, F-69372 Lyon, France. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol, London, England. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Dept Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social, Kuala Lumpur, Malaysia. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Prevent Med, Kuala Lumpur, Malaysia. [Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Giovannucci, Edward; Stevens, Victoria L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Haiman, Christopher; Henderson, Brian; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hunter, David J.; Lindstrom, Sara; Kraft, Peter] Harvard Univ, TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Key, Timothy J.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Sch Clin Med, Cambridge, England. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Larranga, Nerea] BIODonostia Res Inst, Basque Hlth Dept, Publ Hlth Div Gipuzkoa, San Sebastian, Spain. [Larranga, Nerea] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA. [Ma, Jing; Stampfer, Meir J.; Mucci, Lorelei A.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir J.; Mucci, Lorelei A.] Harvard Univ, Sch Med, Boston, MA USA. [Naccarati, Alessio] HuGeF Fdn, Mol & Genet Epidemiol Unit, Turin, Italy. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci, Urol & Androl, S-90187 Umea, Sweden. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bureau Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellenic Hlth Fdn, Athens, Greece. [Choueiri, Toni K.] Dana Farber Canc Inst, Dept Genitourinary Oncol, Boston, MA 02115 USA. RP Markt, SC (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave Room 920A, Boston, MA 02115 USA. EM sec110@mail.harvard.edu FU US National Institutes of Health, National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758, R01 CA63464, P01 CA33619, R37 CA54281, UM1 CA164973]; Intramural Research Program of the Division of Cancer Epidemiology and Cancer Prevention (PLCO); Intramural Research Program of the Division of Cancer Epidemiology and Cancer Prevention (ATBC); Division of Cancer Epidemiology and Genetics; Danish Cancer (Danish study Diet, Cancer and Health); Cancer Research EPIC study of vitamin D and prostate cancer and the EPIC-UK cohorts; Medical Research Council (EPIC study of vitamin D and prostate cancer and the EPIC-UK cohorts); (EPIC-Greece) Foundation; Health Research Fund (EPIC-Spain); Regional Government of Andalucia [6236]; Regional Government of Asturias [6236]; Regional Government of Basque Country [6236]; Regional Government of Murcia [6236]; Navarra (EPIC-Spain); ISCIII (EPIC-Spain) [RD06/0020]; Sicilian government, Aire-Onlus Ragusa (Italy)(EPIC-Italy); European Commission (MORGEN-EPIC); International Agency for Research on (MORGEN-EPIC); Dutch Ministry of Public (MORGEN-EPIC); Welfare and Sports (MORGEN-EPIC); Statistics (MORGEN-EPIC); National Cancer Institute at the National Institutes of Health Training Grant; U.S. Army Department of Defense Prostate Cancer Post-doctoral Fellowship; Prostate Cancer Foundation Young Investigators FX Grant sponsor: US National Institutes of Health, National Cancer Institute; Grant numbers: U01-CA98233 (PHS, HPFS); U01-CA98710 (CPS2); U01-CA98216 (EPIC); U01-CA98758; R01 CA63464; P01 CA33619; R37 CA54281; UM1 CA164973 (MEC); Grant sponsor: Intramural Research Program of the Division of Cancer Epidemiology and Cancer Prevention (PLCO and ATBC); Grant sponsor: Division of Cancer Epidemiology and Genetics; Grant sponsor: Danish Cancer (Danish study Diet, Cancer and Health); Grant sponsor: Cancer Research EPIC study of vitamin D and prostate cancer and the EPIC-UK cohorts; Grant sponsor: Medical Research Council (EPIC study of vitamin D and prostate cancer and the EPIC-UK cohorts); Grant sponsor: (EPIC-Greece) Foundation; Grant sponsor: Health Research Fund (EPIC-Spain); Grant sponsor: Regional Governments of Andalucia, Asturias, Basque Country, Murcia (No. 6236) and Navarra (EPIC-Spain); Grant sponsor: ISCIII (EPIC-Spain); Grant number: RD06/0020; Grant sponsor: Sicilian government, Aire-Onlus Ragusa (Italy)(EPIC-Italy); Grant sponsor: European Commission (MORGEN-EPIC); Grant sponsor: International Agency for Research on (MORGEN-EPIC); Grant sponsor: Dutch Ministry of Public (MORGEN-EPIC); Grant sponsor: Welfare and Sports (MORGEN-EPIC); Grant sponsor: Statistics (MORGEN-EPIC); Grant sponsor: National Cancer Institute at the National Institutes of Health Training Grant; Grant number: (to SCM); Grant sponsor: U.S. Army Department of Defense Prostate Cancer Post-doctoral Fellowship; Grant number: (to IMS); Grant sponsor: Prostate Cancer Foundation Young Investigators; Grant number: (to LAM and KMW). NR 8 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD NOV 1 PY 2015 VL 75 IS 15 BP 1677 EP 1681 DI 10.1002/pros.23035 PG 5 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CU0PJ UT WOS:000363219200001 PM 26268879 ER PT J AU Barry, KH Moore, LE Liao, LM Huang, WY Andreotti, G Poulin, M Berndt, SI AF Barry, Kathryn Hughes Moore, Lee E. Liao, Linda M. Huang, Wen-Yi Andreotti, Gabriella Poulin, Matthew Berndt, Sonja I. TI Prospective Study of DNA Methylation at LINE-1 and Alu in Peripheral Blood and the Risk of Prostate Cancer SO PROSTATE LA English DT Article DE global DNA methylation; pre-diagnostic; prostate cancer; repetitive element ID BREAST-CANCER; LEUKOCYTE DNA; REPETITIVE ELEMENT; BLADDER-CANCER; CELL CARCINOMA; HYPOMETHYLATION; ASSOCIATION; TUMOR; HYPERMETHYLATION; POPULATION AB BACKGROUND. Evidence suggests that global blood DNA methylation levels may be associated with the risk of various cancers, but no studies have evaluated this relationship for prostate cancer. METHODS. We used pyrosequencing to quantify DNA methylation levels at the long interspersed nuclear element 1 (LINE-1) and Alu repetitive elements in pre-diagnostic blood samples from 694 prostate cancer cases and 703 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We evaluated prostate cancer risk associated with the mean methylation level for each element using logistic regression, adjusting for potential confounders. RESULTS. We did not observe a significant association with prostate cancer for LINE-1 [ odds ratio (OR) for the highest compared to the lowest quartile = 1.01, 95% confidence interval (CI): 0.73-1.39, P-trend = 0.99] or Alu (OR = 0.94, 95% CI: 0.68-1.29, P-trend = 0.69) methylation levels overall. However, for Alu, we observed that higher DNA methylation levels were associated with a significant increased risk for those diagnosed 4 or more years after blood draw (OR = 2.26, 95% CI: 1.27-4.00, P-trend = 4.4 x 10(-3)). In contrast, there was no association for those diagnosed 2 (OR = 1.13, 95% CI: 0.67-1.90, P-trend = 0.64) or 3 years after draw (OR = 1.22, 95% CI: 0.71-2.07, P-trend = 0.32), and a decreased risk for those diagnosed less than 2 years after draw (OR = 0.40, 95% CI: 0.25-0.65, P-trend = 3.8 x 10(-5); P-heterogeneity = 5.3 x 10(-6)). CONCLUSIONS. Although LINE-1 DNA methylation levels were not associated with prostate cancer, we observed an association for Alu that varied by time from blood draw to diagnosis. Our study suggests that elevated Alu blood DNA methylation levels several years before diagnosis may be associated with an increased prostate cancer risk. (C) 2015 Wiley Periodicals, Inc. C1 [Barry, Kathryn Hughes; Moore, Lee E.; Huang, Wen-Yi; Andreotti, Gabriella; Berndt, Sonja I.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liao, Linda M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Poulin, Matthew] EpigenDx Inc, Hopkinton, MA USA. RP Barry, KH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 6E116 MSC 9771, Bethesda, MD 20892 USA. EM barrykh@mail.nih.gov OI Liao, Linda/0000-0002-1923-5294 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX Grant sponsor: Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 26 TC 9 Z9 9 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD NOV 1 PY 2015 VL 75 IS 15 BP 1718 EP 1725 DI 10.1002/pros.23053 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CU0PJ UT WOS:000363219200005 PM 26250474 ER PT J AU Fang, MZ Ohman-Strickland, P Kelly-McNeil, K Kipen, H Crabtree, BF Lew, JP Zarbl, H AF Fang, Ming Zhu Ohman-Strickland, Pamela Kelly-McNeil, Kathie Kipen, Howard Crabtree, Benjamin F. Lew, Jenny Pan Zarbl, Helmut TI Sleep interruption associated with house staff work schedules alters circadian gene expression SO SLEEP MEDICINE LA English DT Article DE Circadian rhythm; Biomarker; Shift worker; PERIOD 2; Breast cancer ID NIGHT-SHIFT WORK; CANCER PREVENTION TRIAL; BREAST-CANCER; VITAMIN-E; URINARY MELATONIN; PROSTATE-CANCER; CLOCK; RISK; DISRUPTION; NURSES AB Background: Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor beta (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. Methods: Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. Results: The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p < 0.0001). Conclusion: Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies. (C) 2015 Elsevier B.V. All rights reserved. C1 [Fang, Ming Zhu; Kelly-McNeil, Kathie; Kipen, Howard; Zarbl, Helmut] Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ USA. [Fang, Ming Zhu; Ohman-Strickland, Pamela; Kelly-McNeil, Kathie; Kipen, Howard; Zarbl, Helmut] NIEHS, Ctr Environm Exposures & Dis, Environm & Occupat Hlth Sci Inst, Piscataway, NJ USA. [Fang, Ming Zhu; Crabtree, Benjamin F.; Zarbl, Helmut] Rutgers State Univ, Canc Inst New Jersey, Piscataway, NJ 08854 USA. [Ohman-Strickland, Pamela] Sch Publ Hlth, Dept Biostat, Piscataway, NJ USA. [Crabtree, Benjamin F.] Robert Wood Johnson Med Sch, Family Med, Piscataway, NJ USA. [Lew, Jenny Pan] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Zarbl, H (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, 170 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM zarbl@eohsi.rutgers.edu FU V Foundation for Cancer Research; National Institute of Environmental Health Sciences (NIEHS) [P30ES005022]; Environmental and Occupational Health Sciences Institute at Rutgers, The State University of New Jersey FX These studies were supported by a Translational Research Grant from the V Foundation for Cancer Research (H. Zarbl), an environmental health sciences center grant (P30ES005022) from the National Institute of Environmental Health Sciences (NIEHS) (H. Zarbl), and the Environmental and Occupational Health Sciences Institute at Rutgers, The State University of New Jersey (H. Zarbl). The authors thank the house staff in the departments of family medicine and pediatrics at Robert Wood Johnson University Hospital and the Clinical Research Center staff of Robert Wood Johnson Medical School, at Rutgers University. NR 37 TC 3 Z9 3 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD NOV PY 2015 VL 16 IS 11 BP 1388 EP 1394 DI 10.1016/j.sleep.2015.06.011 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CU4CL UT WOS:000363473700014 PM 26498241 ER PT J AU Hasin, DS Grant, BF AF Hasin, Deborah S. Grant, Bridget F. TI The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Waves 1 and 2: review and summary of findings SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Review DE Epidemiology; National survey; Alcohol and drugs; Mood disorders; Comorbidity; Anxiety disorders; Personality disorders ID SUBSTANCE-USE DISORDERS; DSM-IV ALCOHOL; DRUG-USE DISORDERS; MAJOR DEPRESSIVE DISORDER; POSTTRAUMATIC-STRESS-DISORDER; GENERAL-POPULATION SAMPLE; SOCIAL ANXIETY DISORDER; CANNABIS USE DISORDERS; BORDERLINE PERSONALITY-DISORDER; ANTISOCIAL BEHAVIORAL SYNDROMES AB The NESARC, a "third-generation" psychiatric epidemiologic survey that integrated detailed measures of alcohol and drug use and problems has been the data source for over > 850 publications. A comprehensive review of NESARC findings and their implications is lacking. NESARC was a survey of 43,093 participants that covered alcohol, drug and psychiatric disorders, risk factors, and consequences. Wave 1 of the NESARC was conducted in 2001-2002. Three years later, Wave 2 follow-up re-interviews were conducted with 34,653 of the original participants. Scopus and Pubmed were used to search for NESARC papers, which were sorted into topic areas and summarized. The most common disorders were alcohol and posttraumatic stress disorders, and major depression. Females had more internalizing disorders and males had more externalizing disorders, although the preponderance of males with alcohol disorders (the "gender gap") was less pronounced than it was in previous decades. A race/ethnic "paradox" (lower risk among disadvantaged minorities than whites) remains unexplained. Younger participants had higher risk for substance and personality disorders, but not unipolar depressive or anxiety disorders. Psychiatric comorbidity was extensive and often formed latent trans-diagnostic domains. Since 1991-1992, risk for marijuana and prescription drug disorders increased, while smoking decreased, although smoking decreases were less pronounced among those with comorbidity. A nexus of comorbidity, social support, and stress predicted transitions in diagnostic status between Waves 1 and 2. Childhood maltreatment predicted psychopathology. Alcohol and drug use disorders were seldom treated; attitudinal barriers (little perceived need, perceived alcoholism stigma, pessimism about efficacy) were more important in predicting non-treatment than financial barriers. Understanding comorbidity and the effects of early stressors will require research incorporating biologic components, e.g., genetic variants and brain imaging. The lack of treatment for alcohol and drug disorders, predicted by attitudinal rather than financial variables, suggests an urgent need for public and professional education to reduce the stigma associated with these disorders and increase knowledge of treatment options. C1 [Hasin, Deborah S.] Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane,Room 3077, Rockville, MD 20852 USA. EM bgrant@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Drug Abuse; NIAAA [U01AA018111]; Columbia University; New York State Psychiatric Institute; NIAAA, NIH FX The NESARC-III was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), with supplemental support from the National Institute on Drug Abuse. Support is acknowledged from NIAAA U01AA018111, Columbia University, and New York State Psychiatric Institute (Hasin). Support is also acknowledged from the intramural program, NIAAA, NIH. To obtain the NESARC datasets, contact Aaron White at NIAAA, whitea4@mail.nih.gov. NR 548 TC 25 Z9 25 U1 28 U2 61 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD NOV PY 2015 VL 50 IS 11 BP 1609 EP 1640 DI 10.1007/s00127-015-1088-0 PG 32 WC Psychiatry SC Psychiatry GA CU0ZY UT WOS:000363249700001 PM 26210739 ER PT J AU Holmberg, C Whitehouse, K Daly, M McCaskill-Stevens, W AF Holmberg, Christine Whitehouse, Katie Daly, Mary McCaskill-Stevens, Worta TI Gaining control over breast cancer risk: Transforming vulnerability, uncertainty, and the future through clinical trial participation - a qualitative study SO SOCIOLOGY OF HEALTH & ILLNESS LA English DT Article DE breast cancer; randomised controlled trials (RCT); narrative method ID SURGICAL ADJUVANT BREAST; PREVENTION TRIAL; BOWEL PROJECT; TAMOXIFEN; PHARMACEUTICALIZATION; RECRUITMENT; RALOXIFENE; EXPERIENCE; DISEASE; HEALTH AB Concepts of disease risk and its management are central to processes of medicalisation and pharmaceuticalisation. Through a narrative perspective, this paper aims to understand how such macro-level developments may (or may not) be experienced individually, and how an algorithm that is used for recruitment into a clinical trial may structure individual notions of being at risk' and in need of treatment'. We interviewed 31 women participating in the Study of Tamoxifen and Raloxifene (STAR), a chemoprevention trial conducted in the US between 1999 and 2006. Interviews were thematically analysed. Women in the study had experienced the threat of breast cancer and felt vulnerable to developing the disease prior to STAR participation. The diagnosis of being at risk' for cancer through an algorithm that determined risk-eligibility for STAR, opened up the possibility for the women to heal. The trial became a means to recognise and collectivise the women's experiences of vulnerability. Through medication intake, being cared for by study coordinators, and the sense of community with other STAR participants, trial participation worked to transform women's lives. Such transformative experiences may nevertheless have been temporary, enduring only as long as the close links to the medical institution through trial participation lasted. C1 [Holmberg, Christine; Whitehouse, Katie] Charite Univ Med Berlin, Berlin Sch Publ Hlth, Berlin, Germany. [Daly, Mary] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [McCaskill-Stevens, Worta] Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. RP Holmberg, C (reprint author), Dept Social Med Epidemiol & Hlth Econ, Luisenstr 57, D-10098 Berlin, Germany. EM christine.holmberg@charite.de FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 1 Z9 1 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0141-9889 EI 1467-9566 J9 SOCIOL HEALTH ILL JI Sociol. Health Ill. PD NOV PY 2015 VL 37 IS 8 BP 1373 EP 1387 DI 10.1111/1467-9566.12307 PG 15 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical; Sociology SC Public, Environmental & Occupational Health; Biomedical Social Sciences; Sociology GA CU1ZK UT WOS:000363320700016 PM 26235092 ER PT J AU Huang, YY Kaneko, KJ Pan, HY DePamphilis, ML AF Huang, Yi-Yuan Kaneko, Kotaro J. Pan, Haiyan DePamphilis, Melvin L. TI Geminin is Essential to Prevent DNA Re-Replication-Dependent Apoptosis in Pluripotent Cells, but not in Differentiated Cells SO STEM CELLS LA English DT Article DE Geminin; DNA re-replication; Apoptosis; Pluripotent; Embryonic stem cells; Embryonic fibroblasts ID EMBRYONIC STEM-CELLS; DAMAGE-INDUCED PHOSPHORYLATION; MESENCHYMAL TRANSITION; MAMMALIAN DEVELOPMENT; CELLULAR SENESCENCE; G(2)/M CHECKPOINT; FATE ACQUISITION; GENE-EXPRESSION; GERM LAYERS; IN-VIVO AB Geminin is a dual-function protein unique to multicellular animals with roles in modulating gene expression and preventing DNA re-replication. Here, we show that geminin is essential at the beginning of mammalian development to prevent DNA re-replication in pluripotent cells, exemplified by embryonic stem cells, as they undergo self-renewal and differentiation. Embryonic stem cells, embryonic fibroblasts, and immortalized fibroblasts were characterized before and after geminin was depleted either by gene ablation or siRNA. Depletion of geminin under conditions that promote either self-renewal or differentiation rapidly induced DNA re-replication, followed by DNA damage, then a DNA damage response, and finally apoptosis. Once differentiation had occurred, geminin was no longer essential for viability, although it continued to contribute to preventing DNA re-replication induced DNA damage. No relationship was detected between expression of geminin and genes associated with either pluripotency or differentiation. Thus, the primary role of geminin at the beginning of mammalian development is to prevent DNA re-replication-dependent apoptosis, a role previously believed essential only in cancer cells. These results suggest that regulation of gene expression by geminin occurs only after pluripotent cells differentiate into cells in which geminin is not essential for viability. C1 [Huang, Yi-Yuan; Kaneko, Kotaro J.; Pan, Haiyan; DePamphilis, Melvin L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 6A,Room 3A15,MSC 2753,9000 Rockville Pike, Bethesda, MD 20892 USA. EM de-pamphm@mail.nih.gov FU Eunice Shriver Kennedy National Institute of Child Health and Human Development (NICHD) FX We thank Dr. Alex Vassilev for help with Flow Cytometry and Xiaohong Zhang for maintaining our mouse colony. This work was supported by Eunice Shriver Kennedy National Institute of Child Health and Human Development (NICHD) intramural research program. K.J.K. is currently affiliated with the Division of Biotechnology and GRAS Notice Review, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, Maryland. NR 64 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD NOV PY 2015 VL 33 IS 11 BP 3239 EP 3253 DI 10.1002/stem.2092 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CU1FP UT WOS:000363265900009 PM 26140583 ER PT J AU Wu, TT Liu, Y Fan, ZP Xu, JJ Jin, LY Gao, ZH Wu, ZF Hu, L Wang, JS Zhang, CM Chen, WJ Wang, SL AF Wu, Tingting Liu, Yi Fan, Zhipeng Xu, Junji Jin, Luyuan Gao, Zhenhua Wu, Zhifang Hu, Lei Wang, Jinsong Zhang, Chunmei Chen, Wanjun Wang, Songlin TI miR-21 Modulates the Immunoregulatory Function of Bone Marrow Mesenchymal Stem Cells Through the PTEN/Akt/TGF-beta 1 Pathway SO STEM CELLS LA English DT Article DE miR-21; Immunoregulation; Mesenchymal stem cells; Transforming growth factor-beta 1; PTEN ID REGULATORY T-CELLS; TGF-BETA; NITRIC-OXIDE; CANCER; DIFFERENTIATION; PROLIFERATION; INDUCTION; MICRORNAS; MIR-146; GROWTH AB microRNAs (miRNAs) act as regulatory signals for maintaining stemness, self-renewal, and differentiation of mesenchymal stem cells (MSCs), but whether miRNAs modulate the immunoregulatory function of MSCs remains largely unknown. Here, we show that miR-21 negatively regulates the activity of immunoregulatory cytokine transforming growth factor-beta 1 (TGF-beta 1) in MSCs. Consistently, bone marrow MSCs (BMMSCs) from miR-21(-/-) mice show enhanced immunosuppressive function by more TGF-beta 1 secretion and induce more CD4(+)Foxp3(+) regulatory T cells compared with wild-type BMMSCs in vitro, which anti-TGF-beta 1 antibody abrogates. Mechanistically, miR-21 inhibits TGF-beta 1 expression by targeting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in BMMSCs. Downstream of PTEN, miR-21 promotes activation of Akt, and consequently increases activation of NF-kappa B pathway. Importantly, adoptive transfer of miR-21(-/-) BMMSCs into mice with experimental colitis more effectively ameliorates colonic inflammation in a TGF-beta 1-dependent manner. Thus, these findings indicate a previously uncovered mechanism of miR-21 control immunoregulatory function of BMMSCs through TGF-beta 1 inhibition. C1 [Wu, Tingting; Xu, Junji; Jin, Luyuan; Gao, Zhenhua; Wu, Zhifang; Hu, Lei; Wang, Jinsong; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Mol Lab Gene Therapy & Tooth Regenerat, Beijing 100050, Peoples R China. [Liu, Yi] Capital Med Univ, Sch Stomatol, Lab Tissue Regenerat & Immunol, Beijing 100050, Peoples R China. [Liu, Yi] Capital Med Univ, Sch Stomatol, Dept Periodont, Beijing 100050, Peoples R China. [Fan, Zhipeng] Capital Med Univ, Sch Stomatol, Lab Mol Signaling & Stem Cell Therapy, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Beijing 100050, Peoples R China. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Wang, Songlin] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100050, Peoples R China. RP Wang, SL (reprint author), Capital Med Univ, Mol Lab Gene Therapy & Tooth Regenerat, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Sch Stomatol, Beijing 100050, Peoples R China. EM slwang@ccmu.edu.cn FU Beijing Municipality Government [PXM2014_014226_000180, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, Z121100005212004, PXM 2013_014226_000021, PXM 2013_014226_07_000080, TJSHG201310025005]; National Basic Research Program of China [2010CB944801]; National Natural Science Foundation of China [NSFC81222011, 81470751]; NIH, NIDCR FX This work was supported by the Beijing Municipality Government Grants (Beijing Scholar Program-PXM2014_014226_000180, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, Z121100005212004, PXM 2013_014226_000021, PXM 2013_014226_07_000080, and TJSHG201310025005 [to S.W.]), the National Basic Research Program of China (2010CB944801 [to S.W.]), National Natural Science Foundation of China (NSFC81222011, 81470751 [to Y.L.]), and the Intramural Research Program of NIH, NIDCR (to W.C.). NR 37 TC 8 Z9 8 U1 3 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD NOV PY 2015 VL 33 IS 11 BP 3281 EP 3290 DI 10.1002/stem.2081 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CU1FP UT WOS:000363265900012 PM 26086742 ER PT J AU Marcus, PM Freedman, AN Khoury, MJ AF Marcus, Pamela M. Freedman, Andrew N. Khoury, Muin J. TI Targeted Cancer Screening in Average-Risk Individuals SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SERVICES TASK-FORCE; COLORECTAL-CANCER; PROSTATE-CANCER; LUNG-CANCER; RECOMMENDATION STATEMENT; NEGATIVE COLONOSCOPY; AMERICAN-COLLEGE; GUIDELINES; SUSCEPTIBILITY; STRATEGIES AB Targeted cancer screening refers to use of disease risk information to identify those most likely to benefit from screening. Researchers have begun to explore the possibility of refining screening regimens for average-risk individuals' using genetic and non-genetic risk factors and previous screening experience. Average-risk individuals are those not known to be at substantially elevated risk, including those without known inherited predisposition, without comorbidities known to increase cancer risk, and without previous diagnosis of cancer or pre-cancer. In this paper, we describe the goals of targeted cancer screening in average-risk individuals, present factors on which cancer screening has been targeted, discuss inclusion of targeting in screening guidelines issued by major U.S. professional organizations, and present evidence to support or question such inclusion. Screening guidelines for average-risk individuals currently target age; smoking (lung cancer only); and, in some instances, race; family history of cancer; and previous negative screening history (cervical cancer only). No guidelines include common genomic polymorphisms. RCTs suggest that targeting certain ages and smoking histories reduces disease-specific cancer mortality, although some guidelines extend ages and smoking histories based on statistical modeling. Guidelines that are based on modestly elevated disease risk typically have either no or little evidence of an ability to affect a mortality benefit. In time, targeted cancer screening is likely to include genetic factors and past screening experience as well as non-genetic factors other than age, smoking, and race, but it is of utmost importance that clinical implementation be evidence-based. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Marcus, Pamela M.; Freedman, Andrew N.; Khoury, Muin J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E608, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 3 Z9 3 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2015 VL 49 IS 5 BP 765 EP 771 DI 10.1016/j.amepre.2015.04.030 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CT7MK UT WOS:000362998600014 PM 26165196 ER PT J AU Basile, BM Moylan, EJ Charles, DP Murray, EA AF Basile, Benjamin M. Moylan, Emily J. Charles, David P. Murray, Elisabeth A. TI Two-item same/different discrimination in rhesus monkeys (Macaca mulatta) SO ANIMAL COGNITION LA English DT Article DE Categorization; Concept learning; Entropy; Perceptual variability ID SAME-DIFFERENT DISCRIMINATION; VARIABILITY DISCRIMINATION; FINDING DIFFERENCES; VISUAL-DISPLAYS; PIGEONS; AMYGDALA; LESIONS; BIRDS AB Almost all nonhuman animals can recognize when one item is the same as another item. It is less clear whether nonhuman animals possess abstract concepts of "same" and "different" that can be divorced from perceptual similarity. Pigeons and monkeys show inconsistent performance, and often surprising difficulty, in laboratory tests of same/different learning that involve only two items. Previous results from tests using multi-item arrays suggest that nonhumans compute sameness along a continuous scale of perceptual variability, which would explain the difficulty of making two-item same/different judgments. Here, we provide evidence that rhesus monkeys can learn a two-item same/different discrimination similar to those on which monkeys and pigeons have previously failed. Monkeys' performance transferred to novel stimuli and was not affected by perceptual variations in stimulus size, rotation, view, or luminance. Success without the use of multi-item arrays, and the lack of effect of perceptual variability, suggests a computation of sameness that is more categorical, and perhaps more abstract, than previously thought. C1 [Basile, Benjamin M.; Moylan, Emily J.; Charles, David P.; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Basile, BM (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr MSC 4415, Bethesda, MD 20892 USA. EM benjamin.basile@nih.gov FU Intramural Research Program of the National Institute of Mental Health FX David P. Charles passed away on October 17, 2006. We thank Luke Humphrey for help testing monkeys. We thank an anonymous reviewer for suggesting an additional analysis. This work was supported by the Intramural Research Program of the National Institute of Mental Health. The authors declare that they have no conflict of interest. All procedures were reviewed and approved by the NIMH Animal Care and Use Committee and complied with US law. NR 31 TC 1 Z9 1 U1 6 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1435-9448 EI 1435-9456 J9 ANIM COGN JI Anim. Cogn. PD NOV PY 2015 VL 18 IS 6 BP 1221 EP 1230 DI 10.1007/s10071-015-0891-z PG 10 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA CT6YS UT WOS:000362960200003 PM 26142053 ER PT J AU Krishnan, S Dhillon, PK Bhadelia, A Schurmann, A Basu, P Bhatla, N Birur, P Colaco, R Dey, S Grover, S Gupta, H Gupta, R Gupta, V Lewis, MA Mehrotra, R McMikel, A Mukherji, A Naik, N Nyblade, L Pati, S Pillai, MR Rajaraman, P Ramesh, C Rath, GK Reithinger, R Sankaranarayanan, R Selvam, J Shanmugam, MS Shridhar, K Siddiqi, M Squiers, L Subramanian, S Travasso, SM Verma, Y Vijayakumar, M Weiner, BJ Reddy, KS Knaul, FM AF Krishnan, Suneeta Dhillon, Preet K. Bhadelia, Afsan Schurmann, Anna Basu, Partha Bhatla, Neerja Birur, Praveen Colaco, Rajeev Dey, Subhojit Grover, Surbhi Gupta, Harmala Gupta, Rakesh Gupta, Vandana Lewis, Megan A. Mehrotra, Ravi McMikel, Ann Mukherji, Arnab Naik, Navami Nyblade, Laura Pati, Sanghamitra Pillai, M. Radhakrishna Rajaraman, Preetha Ramesh, Chalurvarayaswamy Rath, G. K. Reithinger, Richard Sankaranarayanan, Rengaswamy Selvam, Jerard Shanmugam, M. S. Shridhar, Krithiga Siddiqi, Maqsood Squiers, Linda Subramanian, Sujha Travasso, Sandra M. Verma, Yogesh Vijayakumar, M. Weiner, Bryan J. Reddy, K. Srinath Knaul, Felicia M. TI Report from a symposium on catalyzing primary and secondary prevention of cancer in India SO CANCER CAUSES & CONTROL LA English DT Article DE Cancer; Prevention; Policy; Advocacy; India; Symposium ID PRIMARY-HEALTH-CARE; CERVICAL-CANCER; HUMAN-PAPILLOMAVIRUS; RESOURCE COUNTRIES; RANDOMIZED-TRIAL; INCOME COUNTRIES; ORAL-CANCER; BREAST; BURDEN; MEXICO AB Oral, breast, and cervical cancers are amenable to early detection and account for a third of India's cancer burden. We convened a symposium of diverse stakeholders to identify gaps in evidence, policy, and advocacy for the primary and secondary prevention of these cancers and recommendations to accelerate these efforts. Indian and global experts from government, academia, private sector (health care, media), donor organizations, and civil society (including cancer survivors and patient advocates) presented and discussed challenges and solutions related to strategic communication and implementation of prevention, early detection, and treatment linkages. Innovative approaches to implementing and scaling up primary and secondary prevention were discussed using examples from India and elsewhere in the world. Participants also reflected on existing global guidelines and national cancer prevention policies and experiences. Symposium participants proposed implementation-focused research, advocacy, and policy/program priorities to strengthen primary and secondary prevention efforts in India to address the burden of oral, breast, and cervical cancers and improve survival. C1 [Krishnan, Suneeta] Res Triangle Inst Global India Pvt Ltd, Paharpur Business Ctr, New Delhi 110019, India. [Dhillon, Preet K.; Shridhar, Krithiga] Publ Hlth Fdn India, Ctr Chron Condit & Injuries, Sect 44, Gurgaon 122002, India. [Bhadelia, Afsan; Knaul, Felicia M.] Harvard Univ, Harvard Global Equity Initiat, Boston, MA 02115 USA. [Schurmann, Anna] Independent Publ Hlth Consultant, Bangalore 560025, Karnataka, India. [Basu, Partha] Chittaranjan Natl Canc Inst, Kolkata 700026, India. [Bhatla, Neerja] All India Inst Med Sci, Dept Obstet & Gynaecol, New Delhi 110029, India. [Birur, Praveen] Biocon Fdn, Bangalore 560100, Karnataka, India. [Colaco, Rajeev; Nyblade, Laura; Reithinger, Richard; Squiers, Linda] RTI Int, Washington, DC 20005 USA. [Dey, Subhojit] Indian Inst Publ Hlth Delhi, Publ Hlth Fdn India, Gurgaon 122002, India. [Grover, Surbhi] Univ Penn, Philadelphia, PA 19104 USA. [Gupta, Harmala] KanakDurgaBastiVikasKendra, CanSupport, New Delhi 110022, India. [Gupta, Rakesh] Rajasthan Canc Fdn, Jaipur 302018, Rajasthan, India. [Gupta, Vandana] Near Tata Mem Hosp, V Care Fdn, Bombay 400012, Maharashtra, India. [Lewis, Megan A.] RTI Int, Res Triangle Pk, NC 27709 USA. [Mehrotra, Ravi] Inst Cytol & Prevent Oncol ICMR, Noida 201301, India. [McMikel, Ann; Naik, Navami] Amer Canc Soc Inc, Atlanta, GA 30303 USA. [Mukherji, Arnab] IIM Bangalore, Ctr Publ Policy, Bangalore 560076, Karnataka, India. [Pati, Sanghamitra] Indian Inst Publ Hlth Bhubaneswar, Publ Hlth Fdn India, Bhubaneswar 751024, Orissa, India. [Pillai, M. Radhakrishna] Govt India Minist Sci & Technol, Rajiv Gandhi Ctr Biotechnol, Thiruvananthapuram 695014, Kerala, India. [Rajaraman, Preetha] NCI, Ctr Global Hlth, Rockville, MD 20892 USA. [Ramesh, Chalurvarayaswamy; Vijayakumar, M.] Kidwai Mem Inst Oncol, Bangalore 560029, Karnataka, India. [Rath, G. K.] All India Inst Med Sci, New Delhi 110029, India. [Sankaranarayanan, Rengaswamy] WHO IARC, F-69372 Lyon 08, France. [Selvam, Jerard; Shanmugam, M. S.] Tamil Nadu Hlth Syst Project, Madras 600006, Tamil Nadu, India. [Siddiqi, Maqsood] Canc Fdn India, Kolkata 700031, India. [Subramanian, Sujha] RTI Int, Waltham, MA 02451 USA. [Travasso, Sandra M.] St Johns Res Inst, Bangalore 560034, Karnataka, India. [Verma, Yogesh] STNM Hosp, Gangtok 737101, Sikkim, Sikkim. [Weiner, Bryan J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Reddy, K. Srinath] Publ Hlth Fdn India, Gurgaon 122003, Haryana, India. RP Krishnan, S (reprint author), Res Triangle Inst Global India Pvt Ltd, Paharpur Business Ctr, Suite 405,21 Nehru Pl, New Delhi 110019, India. EM skrishnan@rti.org; preet.dhillon@phfi.org FU RTI International; American Cancer Society FX This symposium was funded by RTI International and the American Cancer Society. Travel support was also provided by the Centre for Global Health, United States National Cancer Institute. NR 67 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2015 VL 26 IS 11 BP 1671 EP 1684 DI 10.1007/s10552-015-0637-x PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CT3CV UT WOS:000362685200013 PM 26335262 ER PT J AU Yang, YM Jacoby, E Fry, TJ AF Yang, Yinmeng Jacoby, Elad Fry, Terry J. TI Challenges and opportunities of allogeneic donor-derived CAR T cells SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE adoptive immunotherapy; allogeneic hematopoietic stem cell transplantation; chimeric antigen receptors; donor derived; graft-versus-host disease ID CHIMERIC-ANTIGEN-RECEPTOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; NATURAL-KILLER-CELLS; EPSTEIN-BARR-VIRUS; HEMATOPOIETIC STEM; CANCER-IMMUNOTHERAPY; ADOPTIVE IMMUNOTHERAPY AB Purpose of reviewAs T cells engineered with chimeric antigen receptors (CARs) are entering advanced phases of clinical trial testing with promising results, the potential implications of use in an allogeneic environment are emerging as an important consideration. This review discusses the use of allogeneic CAR therapy, the potential effects of T-cell receptor (TCR) signaling on CAR T-cell efficacy, and the potential for TCR elimination to generate an off-the-shelf product.Recent findingsThe majority of preclinical and clinical data regarding allogeneic T cells are focused on safety of their use given the potential for graft-versus-host disease (GVHD) mediated by the T-cell receptor expressed with the introduced CAR. Recent clinical trials using donor-derived CAR T cells are using either rigorous patient selection or T-cell selection (such as enrichment for virus-specific T cells). Although no GVHD has been reported, the efficacy of the allogeneic CAR treatment needs to be optimized. Several preclinical models limit allogeneic CAR-driven GVHD by utilizing memory T-cell selection, virus-specific T cells, gene-editing techniques, or suicide gene engineering.SummaryIn the allogeneic environment, the potential effects of TCR signaling on the efficacy of CAR could affect the clinical responses with the use of donor-derived CAR T cells. Better understanding of the functionality of donor-derived T cells for therapy is essential for the development of universal effector cells for CAR therapy. C1 [Yang, Yinmeng; Jacoby, Elad; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yang, Yinmeng] Georgetown Univ, Washington, DC 20057 USA. RP Fry, TJ (reprint author), BG 10-CRC RM 1-3952,10 Ctr Dr, Bethesda, MD 20814 USA. EM fryt@mail.nih.gov FU NIH FX This work was supported by the intramural research program at NIH. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 76 TC 4 Z9 4 U1 1 U2 39 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD NOV PY 2015 VL 22 IS 6 BP 509 EP 515 DI 10.1097/MOH.0000000000000181 PG 7 WC Hematology SC Hematology GA CT2OI UT WOS:000362641700008 PM 26390167 ER PT J AU Nellan, A Lee, DW AF Nellan, Anandani Lee, Daniel W. TI Paving the road ahead for CD19 CAR T-cell therapy SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE acute lymphoblastic leukemia; CD19; central nervous system leukemia; chimeric antigen receptor; cytokine release syndrome ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHIMERIC ANTIGEN RECEPTORS; ADVERSE EVENT; TRANSPLANTATION AB Purpose of reviewModern immunotherapies, most notably in the form of anti-CD19 chimeric antigen receptor (CAR) T cells, have produced significant clinical responses in otherwise refractory pre-B-cell acute lymphoblastic leukemia patients. Several groups have simultaneously reported robust response rates in children and adults alike. These early studies indicate an impending shift in paradigm for the treatment of acute lymphoblastic leukemia. Incorporating CD19 CAR T-cell therapy into upfront or salvage regimens has its challenges and opportunities.Recent findingsMost CD19 CAR T-cell products in trial today are excellent at inducing minimal residual disease negative remissions, and most responding patients experience cytokine release syndrome and/or neurotoxicity. The challenges facing the CAR community involve how best to minimize the severity of cytokine release syndrome and neurotoxicity while maximizing antitumor efficacy, determining what role this therapy will play for the prophylaxis and treatment of central nervous system leukemia, and its implications on subsequent hematopoietic stem cell transplant given the emergence of CD19-negative relapses.SummaryCD19 CAR T-cell therapy is a powerful new tool in the oncologist's arsenal. How it is incorporated into standard practice and how it will shift survival curves are the exciting questions that are waiting to be answered. C1 [Nellan, Anandani; Lee, Daniel W.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Lee, DW (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr Bldg 10,Room 1-3750,MSC 1104, Bethesda, MD 20892 USA. EM leed3@mail.nih.gov FU National Institutes of Health; St. Baldrick's Foundation; Hope From Harper Fund FX The authors receive funding from the National Institutes of Health. D.W.L.'s work was supported in part by a St. Baldrick's Foundation Scholar Award and with generous support from the Hope From Harper Fund. NR 16 TC 2 Z9 2 U1 1 U2 31 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD NOV PY 2015 VL 22 IS 6 BP 516 EP 520 DI 10.1097/MOH.0000000000000182 PG 5 WC Hematology SC Hematology GA CT2OI UT WOS:000362641700009 PM 26335422 ER PT J AU Luis, AD O'Shea, TJ Hayman, DTS Wood, JLN Cunningham, AA Gilbert, AT Mills, JN Webb, CT AF Luis, Angela D. O'Shea, Thomas J. Hayman, David T. S. Wood, James L. N. Cunningham, Andrew A. Gilbert, Amy T. Mills, James N. Webb, Colleen T. TI Network analysis of host-virus communities in bats and rodents reveals determinants of cross-species transmission SO ECOLOGY LETTERS LA English DT Article DE Chiroptera; ecological networks; emerging infectious disease; Rodentia; zoonoses ID EMERGING INFECTIOUS-DISEASES; EVOLUTION; PARASITES; PHYLOGENY; RESERVOIR; PATTERNS; MATRICES; ECOLOGY; PACKAGE AB Bats are natural reservoirs of several important emerging viruses. Cross-species transmission appears to be quite common among bats, which may contribute to their unique reservoir potential. Therefore, understanding the importance of bats as reservoirs requires examining them in a community context rather than concentrating on individual species. Here, we use a network approach to identify ecological and biological correlates of cross-species virus transmission in bats and rodents, another important host group. We show that given our current knowledge the bat viral sharing network is more connected than the rodent network, suggesting viruses may pass more easily between bat species. We identify host traits associated with important reservoir species: gregarious bats are more likely to share more viruses and bats which migrate regionally are important for spreading viruses through the network. We identify multiple communities of viral sharing within bats and rodents and highlight potential species traits that can help guide studies of novel pathogen emergence. C1 [Luis, Angela D.; Hayman, David T. S.; Webb, Colleen T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Luis, Angela D.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Luis, Angela D.] Univ Montana, Dept Ecosyst & Conservat Sci, Wildlife Biol Program, Missoula, MT 59812 USA. [O'Shea, Thomas J.] US Geol Survey, Ft Collins Sci Ctr, Ft Collins, CO 80526 USA. [Hayman, David T. S.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Hayman, David T. S.] Massey Univ, mEpiLab, Infect Dis Res Ctr IDReC, Hopkirk Res Inst,Inst Vet Anim & Biomed Sci, Palmerston North 4442, Manawatu, New Zealand. [Wood, James L. N.] Univ Cambridge, Dis Dynam Unit, Dept Vet Med, Cambridge CB3 0ES, England. [Cunningham, Andrew A.] Zool Soc London, Inst Zool, London NW1 4RY, England. [Gilbert, Amy T.] USDA, Natl Wildlife Res Ctr, Ft Collins, CO 80521 USA. [Mills, James N.] Emory Univ, Populat Biol Ecol & Evolut Program, Atlanta, GA 30322 USA. RP Luis, AD (reprint author), Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. EM angela.luis@umontana.edu RI Cunningham, Andrew/E-7536-2010; Wood, James/A-1626-2008 OI Wood, James/0000-0002-0258-3188 FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate (US Department of Homeland Security); Fogarty International Center (National Institutes of Health); David H. Smith post-doctoral fellowship; Royal Society Wolfson Research Merit award; Alborada Trust FX This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate (US Department of Homeland Security) and the Fogarty International Center (National Institutes of Health). D.T.S.H. acknowledges funding from a David H. Smith post-doctoral fellowship. A.A.C. is partially funded by a Royal Society Wolfson Research Merit award, and J.L.N.W. is supported by the Alborada Trust. Thanks to Paul Cryan and Michael O'Donnell of the USGS Fort Collins Science Center for help with species distribution analyses. NR 47 TC 8 Z9 8 U1 14 U2 66 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1461-023X EI 1461-0248 J9 ECOL LETT JI Ecol. Lett. PD NOV PY 2015 VL 18 IS 11 BP 1153 EP 1162 DI 10.1111/ele.12491 PG 10 WC Ecology SC Environmental Sciences & Ecology GA CT6IB UT WOS:000362915600002 ER PT J AU Freedman, LS Midthune, D Carroll, RJ Commins, JM Arab, L Baer, DJ Moler, JE Moshfegh, AJ Neuhouser, ML Prentice, RL Rhodes, D Spiegelman, D Subar, AF Tinker, LF Willett, W Kipnis, V AF Freedman, Laurence S. Midthune, Douglas Carroll, Raymond J. Commins, John M. Arab, Lenore Baer, David J. Moler, James E. Moshfegh, Alanna J. Neuhouser, Marian L. Prentice, Ross L. Rhodes, Donna Spiegelman, Donna Subar, Amy F. Tinker, Lesley F. Willett, Walter Kipnis, Victor TI Application of a New Statistical Model for Measurement Error to the Evaluation of Dietary Self-report Instruments SO EPIDEMIOLOGY LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; WITHIN-PERSON VARIATION; RECOVERY BIOMARKERS; NUTRITIONAL EPIDEMIOLOGY; ENERGY-EXPENDITURE; SODIUM-INTAKE; POTASSIUM INTAKE; 2 VALIDATION; PROTEIN; RECALLS AB Most statistical methods that adjust analyses for dietary measurement error treat an individual's usual intake as a fixed quantity. However, usual intake, if defined as average intake over a few months, varies over time. We describe a model that accounts for such variation and for the proximity of biomarker measurements to self-reports within the framework of a meta-analysis, and apply it to the analysis of data on energy, protein, potassium, and sodium from a set of five large validation studies of dietary self-report instruments using recovery biomarkers as reference instruments. We show that this time-varying usual intake model fits the data better than the fixed usual intake assumption. Using this model, we estimated attenuation factors and correlations with true longer-term usual intake for single and multiple 24-hour dietary recalls (24HRs) and food frequency questionnaires (FFQs) and compared them with those obtained under the fixed method. Compared with the fixed method, the estimates using the time-varying model showed slightly larger values of the attenuation factor and correlation coefficient for FFQs and smaller values for 24HRs. In some cases, the difference between the fixed method estimate and the new estimate for multiple 24HRs was substantial. With the new method, while four 24HRs had higher estimated correlations with truth than a single FFQ for absolute intakes of protein, potassium, and sodium, for densities the correlations were approximately equal. Accounting for the time element in dietary validation is potentially important, and points toward the need for longer-term validation studies. C1 [Freedman, Laurence S.; Commins, John M.; Moler, James E.] Informat Management Serv Inc, Rockville, MD USA. [Midthune, Douglas; Subar, Amy F.; Kipnis, Victor] NCI, Bethesda, MD 20892 USA. [Carroll, Raymond J.] Texas A&M Univ, College Stn, TX USA. [Arab, Lenore] Univ Calif Los Angeles, Los Angeles, CA USA. [Baer, David J.; Moshfegh, Alanna J.; Rhodes, Donna] USDA, Beltsville, MD 20705 USA. [Neuhouser, Marian L.; Prentice, Ross L.; Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Spiegelman, Donna; Willett, Walter] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Freedman, LS (reprint author), Sheba Med Ctr, Gertner Inst Epidemiol, IL-52621 Tel Hashomer, Israel. EM lsf@actcom.co.il OI Moler, James/0000-0001-8738-6898 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 39 TC 3 Z9 3 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2015 VL 26 IS 6 BP 925 EP 933 DI 10.1097/EDE.0000000000000377 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT1JF UT WOS:000362553900020 PM 26360372 ER PT J AU Mariosa, D Kamel, F Bellocco, R Ye, W Fang, F AF Mariosa, D. Kamel, F. Bellocco, R. Ye, W. Fang, F. TI Association between diabetes and amyotrophic lateral sclerosis in Sweden SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE amyotrophic lateral sclerosis; diabetes; epidemiology; insulin dependence; metabolic and endocrine disorders; motor neuron disease; neurological disorders; neuromuscular diseases; research methods ID RISK; MELLITUS AB Background and purposeEnergy metabolism is altered in patients with amyotrophic lateral sclerosis (ALS) but the role of diabetes is largely unknown. MethodsA population-based case-control study was conducted of 5108 ALS cases and 25540 individually matched population controls during 1991-2010. Information on ALS and pre-existing diabetes was retrieved from the Swedish Patient Register to explore the association of ALS with diabetes overall and with insulin-dependent or non-insulin-dependent diabetes specifically. Variation of the association by diabetes duration and age was also studied. ResultsIn total, 224 ALS cases (4.39%) and 1437 controls (5.63%) had diabetes before the index date, leading to an overall inverse association between diabetes and ALS risk [odds ratio (OR)0.79, 95% confidence interval (CI)0.68-0.91]. The association was strong for non-insulin-dependent diabetes (OR0.66, 95% CI0.53-0.81) but not for insulin-dependent diabetes (OR0.83, 95% CI0.60-1.15) and varied as a function of diabetes duration, with the strongest association observed around 6years after first ascertainment of diabetes. The association was age-specific; the inverse association was noted only amongst individuals aged 70 or older. In contrast, for younger individuals (<50years), pre-existing insulin-dependent diabetes was associated with a higher ALS risk (OR5.38, 95% CI1.87-15.51). ConclusionsOur study suggests that there is an association between diabetes and ALS, and highlights the importance of taking into account age, insulin dependence and diabetes duration. Future studies should explore whether the association is independent of body mass index. Click to view the accompanying paper in this issue. C1 [Mariosa, D.; Bellocco, R.; Ye, W.; Fang, F.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Kamel, F.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Bellocco, R.] Univ Milano Bicocca, Dept Stat & Quantitat Methods, Milan, Italy. RP Mariosa, D (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, S-17177 Stockholm, Sweden. EM Daniela.mariosa@ki.se OI Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615 FU Swedish Research Council; Swedish Society for Medical Research; Swedish Research Council for Health, Working Life and Welfare; Karolinska Institutet Partial Finance for PhD Students; NIH [Z01 ES 049005] FX This study was funded by the Swedish Research Council, the Swedish Society for Medical Research, the Swedish Research Council for Health, Working Life and Welfare, the Karolinska Institutet Partial Finance for PhD Students, and the Intramural Research Program of the NIH (Z01 ES 049005). NR 25 TC 10 Z9 11 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD NOV PY 2015 VL 22 IS 11 BP 1436 EP 1442 DI 10.1111/ene.12632 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT2YR UT WOS:000362673300004 PM 25600257 ER PT J AU Bluher, A Devan, WJ Holliday, EG Nalls, M Parolo, S Bione, S Giese, AK Boncoraglio, GB Maguire, JM Muller-Nurasyid, M Gieger, C Meschia, JF Rosand, J Rolfs, A Kittner, SJ Mitchell, BD O'Connell, JR Cheng, YC AF Bluher, A. Devan, W. J. Holliday, E. G. Nalls, M. Parolo, S. Bione, S. Giese, A. -K. Boncoraglio, G. B. Maguire, J. M. Mueller-Nurasyid, M. Gieger, C. Meschia, J. F. Rosand, J. Rolfs, A. Kittner, S. J. Mitchell, B. D. O'Connell, J. R. Cheng, Y. -C. TI Heritability of young- and old-onset ischaemic stroke SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE heritability; ischemic stroke; stroke ID HISTORY; WOMEN; RISK AB Background and purposeAlthough the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. MethodsThis analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age<55years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age55years). ResultsHeritabilities for young-onset stroke and old-onset stroke were estimated at 42% (8%, P<0.001) and 34% (+/- 10%, P<0.001), respectively. ConclusionsOur data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant. C1 [Bluher, A.; Kittner, S. J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Devan, W. J.; Rosand, J.] Univ Maryland, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Stroke Serv, Baltimore, MD 21201 USA. [Devan, W. J.; Rosand, J.] Univ Maryland, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Baltimore, MD 21201 USA. [Holliday, E. G.] Hunter Med Res Inst, Publ Hlth Program, Newcastle, NSW, Australia. [Holliday, E. G.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Nalls, M.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Parolo, S.; Bione, S.] CNR, Inst Mol Genet, Pavia, Italy. [Giese, A. -K.; Rolfs, A.] Univ Rostock, Albrecht Kossel Inst Neuroregenerat, Rostock, Germany. [Boncoraglio, G. B.] Ist Neurol Carlo Besta, Fdn IRCCS, Dept Cerebrovasc Dis, Milan, Italy. [Maguire, J. M.] Univ Newcastle, Sch Nursing & Midwifery, Newcastle, NSW 2300, Australia. [Mueller-Nurasyid, M.] Helmholtz Zentrum Munchen German Res Ctr Environm, Neuherberg, Germany. [Mueller-Nurasyid, M.] Univ Munich, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, M.] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovas Res, Munich, Germany. [Gieger, C.] Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, Neuherberg, Germany. [Gieger, C.] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany. [Meschia, J. F.] Mayo Clin, Dept Neurol, Jacksonville, FL USA. [Kittner, S. J.] Vet Affairs Maryland Hlth Care Syst, Dept Neurol, Baltimore, MD USA. [Mitchell, B. D.; O'Connell, J. R.; Cheng, Y. -C.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Mitchell, B. D.] Vet Affairs Maryland Hlth Care Syst, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Cheng, Y. -C.] Vet Affairs Maryland Hlth Care Syst, Res & Dev Program, Baltimore, MD USA. RP Mitchell, BD (reprint author), 685 W Baltimore St,MSTF 302, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu RI Boncoraglio, Giorgio/B-8647-2011; OI Bione, Silvia/0000-0002-3924-4606; Parolo, Silvia/0000-0002-3671-5353; Gieger, Christian/0000-0001-6986-9554; Mitchell, Braxton/0000-0003-4920-4744 FU US Department of Veterans Affairs [1IK2BX001823]; US National Institute of Health [U01 HG004436, U01 NS069208, P30 DK072488, 5U01NS069208]; US National Institute of Health (NIA) [Z01 AG-000954-06]; Australian National Health and Medical Research Council (NHMRC) [569257]; Australian National Heart Foundation (NHF) [G 04S 1623]; Cariplo Foundation [2010/0253]; Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8]; Australian Heart Foundation [100071]; National Stroke Foundation; [FP6 LSHM-CT-2007-037273] FX This work was supported in part by funding from the US Department of Veterans Affairs (1IK2BX001823 to Y.C. and a Merit Review Award to S.J.K), US National Institute of Health (grants U01 HG004436, U01 NS069208 and P30 DK072488, 5U01NS069208, NIA intramural project Z01 AG-000954-06), the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the Cariplo Foundation (grant no. 2010/0253) and the Italian Ministry of Health (grant no. RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8). The PROCARDIS control samples were funded by FP6 LSHM-CT-2007-037273. E.G.H. is supported by a fellowship (100071) from the Australian Heart Foundation and National Stroke Foundation. NR 10 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD NOV PY 2015 VL 22 IS 11 BP 1488 EP 1491 DI 10.1111/ene.12827 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT2YR UT WOS:000362673300011 PM 26333310 ER PT J AU Nita-Lazar, A Mann, JM Laky, K Fraser, IDC Li, N AF Nita-Lazar, Aleksandra Mann, Jessica M. Laky, Karen Fraser, Iain D. C. Li, Ning TI Analysis of protein O-fucosyltransferase 1 regulation of Toll-like receptor signaling in macrophages SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Nita-Lazar, Aleksandra; Mann, Jessica M.] NIAID, Cellular Networks Prote Unit, Lab Syst Biol, NIH, Bethesda, MD USA. [Fraser, Iain D. C.; Li, Ning] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD USA. [Laky, Karen] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD USA. NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 4 BP 1230 EP 1230 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500011 ER PT J AU Lingwood, D Villar, RF Patel, J Kanekiyo, M Wheatley, AK Nabel, GJ Mascola, JR Carr, SA AF Lingwood, Daniel Villar, Rina F. Patel, Jinal Kanekiyo, Masaru Wheatley, Adam K. Nabel, Gary J. Mascola, John R. Carr, Steven A. TI Viral lectin initiates B cell Activation and Signaling SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Lingwood, Daniel; Villar, Rina F.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Kanekiyo, Masaru; Wheatley, Adam K.; Nabel, Gary J.; Mascola, John R.] NIH, Vaccine Res Ctr, Stapleton, NY USA. [Patel, Jinal; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 23 BP 1235 EP 1236 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500026 ER PT J AU Gildersleeve, J AF Gildersleeve, Jeffrey TI Serum Anti-Glycan Antibodies as Immunotherapy Biomarkers SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Gildersleeve, Jeffrey] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 35 BP 1238 EP 1239 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500034 ER PT J AU Tabak, LA Beck, L Patel, K Ajinkya, M Rojas, R AF Tabak, Lawrence A. Beck, Lauren Patel, Kanishka Ajinkya, Monica Rojas, Raul TI Growth factors do not mediate Golgi-to-ER relocation of GalNAc-Ts SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Tabak, Lawrence A.; Beck, Lauren; Patel, Kanishka; Ajinkya, Monica; Rojas, Raul] Natl Inst Dent & Craniofacial Res, Sect Biol Chem, NIH, Bethesda, MD USA. NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 120 BP 1269 EP 1269 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500114 ER PT J AU Akan, I Hanover, JA AF Akan, Ilhan Hanover, John A. TI O-GlcNAcase is an epigenetic regulator of Drosophila development SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Akan, Ilhan; Hanover, John A.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 164 BP 1286 EP 1286 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500158 ER PT J AU Hanover, JA Cheng, CM Love, DC Bondy, C Gharib, AM AF Hanover, John A. Cheng, Clara M. Love, Dona C. Bondy, Carolyn Gharib, Ahmed M. TI Deregulated O-GlcNAc Cycling in Turner Syndrome SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Hanover, John A.; Love, Dona C.; Gharib, Ahmed M.] NIDDK, NIH, Bethesda, MD 20892 USA. [Cheng, Clara M.; Bondy, Carolyn] NICHD, NIH, Bethesda, MD USA. RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 166 BP 1286 EP 1287 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500160 ER PT J AU Bond, MR Hanover, JA AF Bond, Michelle R. Hanover, John A. TI O-GlcNAc transferase is required for fidelity in C. elegans development SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Bond, Michelle R.; Hanover, John A.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 167 BP 1287 EP 1287 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500161 ER PT J AU Huizing, M Okafor, O Zerfas, PM Bodine, S Starost, MF Gahl, WA Kopp, JB Malicdan, MCV AF Huizing, Marjan Okafor, Obiageri Zerfas, Patricia M. Bodine, Steven Starost, Matthew F. Gahl, William A. Kopp, Jeffrey B. Malicdan, May Christine V. TI N-Acetylmannosamine Mitigates Neuraminidase-induced Podocyte Injury in Mice SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Huizing, Marjan; Okafor, Obiageri; Bodine, Steven; Gahl, William A.; Malicdan, May Christine V.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.; Starost, Matthew F.] NIH, Off Res Serv, OD, Bethesda, MD 20892 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 212 BP 1303 EP 1304 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500206 ER PT J AU Zhang, LP ten Hagen, KG AF Zhang, Liping ten Hagen, Kelly G. TI O-glycosylation is required for peritrophic membrane formation to maintain gut homeostasis in Drosophila SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology on Glycobiology - Accelerating Impact across the Biomedical Sciences CY DEC 01-04, 2015 CL San Francisco, CA SP Soc Glycobiol C1 [Zhang, Liping; ten Hagen, Kelly G.] Natl Inst Dent & Craniofacial Res, Dev Glycobiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2015 VL 25 IS 11 MA 214 BP 1304 EP 1304 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT7JR UT WOS:000362991500208 ER PT J AU Liu, S Saloustros, E Mertz, EL Tsang, K Starost, MF Salpea, P Faucz, FR Szarek, E Nesterova, M Leikin, S Stratakis, CA AF Liu, Sisi Saloustros, Emmanouil Mertz, Edward L. Tsang, Kitman Starost, Matthew F. Salpea, Paraskevi Faucz, Fabio R. Szarek, Eva Nesterova, Maria Leikin, Sergey Stratakis, Constantine A. TI Haploinsufficiency for either one of the type-II regulatory subunits of protein kinase A improves the bone phenotype of Prkar1a(+/-) mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID DENTIN MATRIX PROTEIN-1; DIFFERENTIATION IN-VITRO; MCCUNE-ALBRIGHT SYNDROME; STIMULATORY G-PROTEIN; OSTEOBLAST DIFFERENTIATION; CARNEY COMPLEX; GENE-TRANSCRIPTION; SKELETAL DEVELOPMENT; ALPHA-SUBUNIT; STROMAL CELLS AB Carney Complex (CNC), a human genetic syndrome predisposing to multiple neoplasias, is associated with bone lesions such as osteochondromyxomas (OMX). The most frequent cause for CNC is PRKAR1A deficiency; PRKAR1A codes for type-I regulatory subunit of protein kinase A (PKA). Prkar1a(+/-) mice developed OMX, fibrous dysplasia-like lesions (FDL) and other tumors. Tumor tissues in these animals had increased PKA activity due to an unregulated PKA catalytic subunit and increased PKA type II (PKAII) activity mediated by the PRKAR2A and PRKAR2B subunits. To better understand the effect of altered PKA activity on bone, we studied Prkar2a and Prkar2b knock out (KO) and heterozygous mice; none of these mice developed bone lesions. When Prkar2a(+/-) and Prkar2b(+/-) mice were used to generate Prkar1a(+/-) Prkar2a(+/-) and Prkar1a(+/-) Prkar2b(+/-) animals, bone lesions formed that looked like those of the Prkar1a(+/-) mice. However, better overall bone organization and mineralization and fewer FDL lesions were found in both double heterozygote groups, indicating a partial restoration of the immature bone structure observed in Prkar1a(+/-) mice. Further investigation indicated increased osteogenesis and higher new bone formation rates in both Prkar1a(+/-) Prkar2a(+/-) and Prkar1a(+/-) Prkar2b(+/-) mice with some minor differences between them. The observations were confirmed with a variety of markers and studies. PKA activity measurements showed the expected PKA-II decrease in both double heterozygote groups. Thus, haploinsufficiency for either of PKA-II regulatory subunits improved bone phenotype of mice haploinsufficient for Prkar1a, in support of the hypothesis that the PRKAR2A and PRKAR2B regulatory subunits were in part responsible for the bone phenotype of Prkar1a(+/-) mice. C1 [Liu, Sisi; Saloustros, Emmanouil; Tsang, Kitman; Salpea, Paraskevi; Faucz, Fabio R.; Szarek, Eva; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, Bethesda, MD 20892 USA. [Mertz, Edward L.; Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, Off Sci Director, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, ORS, DVR, OD, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA FX This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA. NR 55 TC 2 Z9 2 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2015 VL 24 IS 21 BP 6080 EP 6092 DI 10.1093/hmg/ddv320 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7WA UT WOS:000363024000011 PM 26246497 ER PT J AU Bianchi, L Gagliardi, A Maruelli, S Besio, R Landi, C Gioia, R Kozloff, KM Khoury, BM Coucke, PJ Symoens, S Marini, JC Rossi, A Bini, L Forlino, A AF Bianchi, Laura Gagliardi, Assunta Maruelli, Silvia Besio, Roberta Landi, Claudia Gioia, Roberta Kozloff, Kenneth M. Khoury, Basma M. Coucke, Paul J. Symoens, Sofie Marini, Joan C. Rossi, Antonio Bini, Luca Forlino, Antonella TI Altered cytoskeletal organization characterized lethal but not surviving Brtl(+/-) mice: insight on phenotypic variability in osteogenesis imperfecta SO HUMAN MOLECULAR GENETICS LA English DT Article ID GROWTH-FACTOR-BETA; OSTEOBLAST DIFFERENTIATION; MURINE MODEL; MOUSE MODEL; I COLLAGEN; INTERMEDIATE-FILAMENTS; INTEGRIN RECEPTORS; ACTIN DYNAMICS; CELL-SHAPE; PROTEINS AB Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl(+/-) to investigate the molecular basis of OI phenotypic variability. Brtl(+/-) resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the alpha 1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl(+/-) mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl(+/-) lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-beta signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. C1 [Bianchi, Laura; Gagliardi, Assunta; Landi, Claudia; Bini, Luca] Univ Siena, Dept Life Sci, Funct Prote Lab, I-53100 Siena, Italy. [Maruelli, Silvia; Besio, Roberta; Gioia, Roberta; Rossi, Antonio; Forlino, Antonella] Univ Pavia, Biochem Unit, Dept Mol Med, I-27100 Pavia, Italy. [Kozloff, Kenneth M.; Khoury, Basma M.] Univ Michigan, Dept Orthopaed Surg, Orthopaed Res Labs, Ann Arbor, MI 48109 USA. [Coucke, Paul J.; Symoens, Sofie] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD USA. RP Forlino, A (reprint author), Univ Pavia, Biochem Unit, Dept Mol Med, Via Taramelli 3-B, I-27100 Pavia, Italy. EM aforlino@unipv.it FU Fondazione Cariplo [2013-0612]; Telethon [GGP13098]; European Community [602300] FX The work was supported by Fondazione Cariplo (grant No. 2013-0612), Telethon (grant No. GGP13098) and the European Community, FP7, 'Sybil' project (grant No. 602300). NR 53 TC 1 Z9 1 U1 0 U2 5 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 NOV 1 PY 2015 VL 24 IS 21 BP 6118 EP 6133 DI 10.1093/hmg/ddv328 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7WA UT WOS:000363024000014 PM 26264579 ER PT J AU Geiger, SS Fagundes, CT Siegel, RM AF Geiger, Sarah S. Fagundes, Caio T. Siegel, Richard M. TI Chrono-immunology: progress and challenges in understanding links between the circadian and immune systems SO IMMUNOLOGY LA English DT Review DE circadian; cytokines; immunity; metabolism; sleep ID FOOD-ANTICIPATORY ACTIVITY; NECROSIS-FACTOR-ALPHA; HIGH-FAT DIET; SUPRACHIASMATIC NUCLEUS; INFLAMMATORY CYTOKINES; RHEUMATOID-ARTHRITIS; DIURNAL-VARIATION; CLOCK PROTEIN; T-CELL; SLEEP AB Development of inflammatory diseases, such as metabolic syndrome and cancer, is prevalent in individuals that encounter continuous disruption of their internal clock. Further, daily oscillations in susceptibility to infection as well as a multitude of other immunological processes have been described. Much progress has been made and various mechanisms have been proposed to explain circadian variations in immunity; yet much is still unknown. Understanding the crosstalk between the circadian and the immune systems will allow us to manipulate clock outputs to prevent and treat inflammatory diseases in individuals at risk. This review briefly summarizes current knowledge about circadian rhythms and their role in the immune system and highlights progress and challenges in chrono-immunological research. C1 [Geiger, Sarah S.; Siegel, Richard M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Fagundes, Caio T.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Microbiol, Microorganism Host Interact, Belo Horizonte, MG, Brazil. RP Geiger, SS (reprint author), NIAMS, NIH, 9000 Rockville Pike,Bldg 10,Room 13C213, Bethesda, MD 20892 USA. EM sarah.sofia.geiger@gmail.com FU Wellcome Trust; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the U.S. National Institutes of Health FX This work was supported by the Wellcome Trust and the intramural research funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the U.S. National Institutes of Health. The authors thank the reviewer for helpful comments and Sahaana B Arumugam, Anthony C Cruz, John R Ferdinand, Christian Geiger and Arianne C Richard for critical reading of the manuscript. NR 84 TC 8 Z9 8 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD NOV PY 2015 VL 146 IS 3 BP 349 EP 358 DI 10.1111/imm.12525 PG 10 WC Immunology SC Immunology GA CT6EX UT WOS:000362906300001 PM 26301993 ER PT J AU Swindle, EJ Brown, JM Radinger, M DeLeo, FR Metcalfe, DD AF Swindle, Emily J. Brown, Jared M. Radinger, Madeleine DeLeo, Frank R. Metcalfe, Dean D. TI Interferon-gamma enhances both the anti-bacterial and the pro-inflammatory response of human mast cells to Staphylococcus aureus SO IMMUNOLOGY LA English DT Article DE bacteria; innate immunity; beta(1) integrin; interferon-gamma; mast cells ID FC-EPSILON-RI; NECROSIS-FACTOR-ALPHA; ESCHERICHIA-COLI; IFN-GAMMA; TNF-ALPHA; EPITHELIAL-CELLS; INNATE IMMUNITY; UP-REGULATION; IN-VITRO; ACTIVATION AB Human mast cells (huMCs) are involved in both innate and adaptive immune responses where they release mediators including amines, reactive oxygen species (ROS), eicosanoids and cytokines. We have reported that interferon- (IFN-gamma) enhances FcR-dependent ROS production. The aim of this study was to extend these observations by investigating the effect of IFN- on the biological responses of huMCs to Staphylococcus aureus. We found that exposure of huMCs to S.aureus generated intracellular and extracellular ROS, which were enhanced in the presence of IFN-gamma IFN-gamma also promoted bacteria killing, -hexosaminidase release and eicosanoid production. Interferon- similarly increased expression of mRNAs encoding CCL1 to CCL4, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor- and CXCL8 in S.aureus-stimulated huMCs. The ability of IFN- to increase CXCL8 and GM-CSF protein levels was confirmed by ELISA. Fibronectin or a beta(1) integrin blocking antibody completely abrogated IFN-gamma-dependent S.aureus binding and reduced S.aureus-dependent CXCL8 secretion. These data demonstrate that IFN-gamma primes huMCs for enhanced anti-bacterial and pro-inflammatory responses to S.aureus, partially mediated by beta(1) integrin. C1 [Swindle, Emily J.] Univ Southampton, Southampton Univ Hosp, Fac Med, Acad Unit Clin & Expt Sci, Southampton SO16 6YD, Hants, England. [Brown, Jared M.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO USA. [Radinger, Madeleine] Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden. [DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MA USA. [Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Swindle, EJ (reprint author), Univ Southampton, Southampton Univ Hosp, Fac Med, Acad Unit Clin & Expt Sci, Southampton SO16 6YD, Hants, England. EM e.j.swindle@soton.ac.uk; dmetcalfe@niaid.nih.gov FU Division of Intramural Research, NIAID/NIH FX EJS designed and performed experiments, analysed data and composed the manuscript. JB and MR provided some of the mast cell cultures and helped with PCRs and ELISAs and edited the manuscript. FRD and DD critically reviewed data and assisted in writing the manuscript. This work was supported by the Division of Intramural Research, NIAID/NIH. NR 41 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD NOV PY 2015 VL 146 IS 3 BP 470 EP 485 DI 10.1111/imm.12524 PG 16 WC Immunology SC Immunology GA CT6EX UT WOS:000362906300012 PM 26288256 ER PT J AU Jackson, JN Haas, CJ Fregly, BJ AF Jackson, Jennifer N. Haas, Chris J. Fregly, Benjamin J. TI Residual Elimination Algorithm Enhancements to Improve Foot Motion Tracking During Forward Dynamic Simulations of Gait SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE gait; walking; residual elimination algorithm; optimization; forward dynamic simulation; biomechanics ID UNITED-STATES; HUMAN WALKING; ADULTS; REHABILITATION; OSTEOARTHRITIS; POPULATION; PARAMETERS; FRAMEWORK; GRAVITY; IMPACT AB Patient-specific gait optimizations capable of predicting post-treatment changes in joint motions and loads could improve treatment design for gait-related disorders. To maximize potential clinical utility, such optimizations should utilize full-body three-dimensional patient-specific musculoskeletal models, generate dynamically consistent gait motions that reproduce pretreatment marker measurements closely, and achieve accurate foot motion tracking to permit deformable foot-ground contact modeling. This study enhances an existing residual elimination algorithm (REA) Remy, C. D., and Thelen, D. G., 2009, "Optimal Estimation of Dynamically Consistent Kinematics and Kinetics for Forward Dynamic Simulation of Gait," ASME J. Biomech. Eng., 131(3), p. 031005) to achieve all three requirements within a single gait optimization framework. We investigated four primary enhancements to the original REA: (1) manual modification of tracked marker weights, (2) automatic modification of tracked joint acceleration curves, (3) automatic modification of algorithm feedback gains, and (4) automatic calibration of model joint and inertial parameter values. We evaluated the enhanced REA using a full-body three-dimensional dynamic skeletal model and movement data collected from a subject who performed four distinct gait patterns: walking, marching, running, and bounding. When all four enhancements were implemented together, the enhanced REA achieved dynamic consistency with lower marker tracking errors for all segments, especially the feet (mean root-mean-square (RMS) errors of 3.1 versus 18.4 mm), compared to the original REA. When the enhancements were implemented separately and in combinations, the most important one was automatic modification of tracked joint acceleration curves, while the least important enhancement was automatic modification of algorithm feedback gains. The enhanced REA provides a framework for future gait optimization studies that seek to predict subject-specific post-treatment gait patterns involving large changes in foot-ground contact patterns made possible through deformable foot-ground contact models. C1 [Jackson, Jennifer N.; Fregly, Benjamin J.] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA. [Jackson, Jennifer N.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. [Haas, Chris J.] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL 32611 USA. [Fregly, Benjamin J.] Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL 32611 USA. RP Fregly, BJ (reprint author), Univ Florida, Dept Mech & Aerosp Engn, Gainesville, FL 32611 USA. EM fregly@ufl.edu RI Fregly, Benjamin/O-6860-2016 OI Fregly, Benjamin/0000-0003-1166-4358 FU NSF [CBET 1052754, CBET 1159735] FX This study was funded by NSF grant numbers CBET 1052754 and CBET 1159735. NR 35 TC 0 Z9 0 U1 0 U2 2 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD NOV PY 2015 VL 137 IS 11 AR 111002 DI 10.1115/1.4031418 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CT5IT UT WOS:000362842900002 PM 26299394 ER PT J AU Ladell, K Hazenberg, MD Fitch, M Emson, C Asgarian, BKMH Mold, JE Miller, C Busch, R Price, DA Hellerstein, MK McCune, JM AF Ladell, Kristin Hazenberg, Mette D. Fitch, Mark Emson, Claire Asgarian, Bridget K. McEvoy-Hein Mold, Jeff E. Miller, Corey Busch, Robert Price, David A. Hellerstein, Marc K. McCune, Joseph M. TI Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1 beta: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNE ACTIVATION; MICROBIAL TRANSLOCATION; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; REGULATORY CELLS; IN-VIVO; CD4(+); IMMUNODEFICIENCY; AIDS; PROLIFERATION AB Untreated HIV disease is associated with chronic immune activation and CD4(+) T cell depletion. A variety of mechanisms have been invoked to account for CD4(+) T cell depletion in this setting, but the quantitative contributions of these proposed mechanisms over time remain unclear. We turned to the DO11.10 TCR transgenic mouse model, where OVA is recognized in the context of H-2(d), to explore the impact of chronic antigenic stimulation on CD4(+) T cell dynamics. To model dichotomous states of persistent Ag exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, IL-1 beta. In both cases, circulating Ag-specific CD4(+) T cells were depleted. However, in the absence of IL-1 beta, there was limited proliferation and effector/memory conversion of Ag-specific T cells, depletion of peripheral CD4(+) T cells in hematolymphoid organs, and systemic induction of regulatory Foxp3(+)CD4(+) T cells, as often observed in late-stage HIV disease. By contrast, when OVA peptide was administered in the presence of IL-1 beta, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between Ag-stimulated DO11.10 TCR transgenic mice and HIV-infected humans, our data suggest that CD4(+) T cell depletion in the setting of HIV disease may reflect, at least in part, chronic Ag exposure in the absence of proinflammatory signals and/or appropriate APC functions. C1 [Ladell, Kristin; Mold, Jeff E.; Miller, Corey; McCune, Joseph M.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94110 USA. [Hazenberg, Mette D.] Univ Med Ctr Utrecht, Dept Immunol, NL-3584 EA Utrecht, Netherlands. [Fitch, Mark; Emson, Claire; Asgarian, Bridget K. McEvoy-Hein; Hellerstein, Marc K.] Univ Calif Berkeley, Dept Nutr Sci, Berkeley, CA 94720 USA. [Emson, Claire; Hellerstein, Marc K.] KineMed Inc, Emeryville, CA 94608 USA. [Busch, Robert] Univ Roehampton, Whitelands Coll, Dept Life Sci, London SW15 4JD, England. [Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP McCune, JM (reprint author), Univ Calif San Francisco, Dept Med, Div Expt Med, 1001 Potrero Ave,Bldg 3,Room 601, San Francisco, CA 94110 USA. EM ladellk@gmail.com; mike.mccune@ucsf.edu RI Ladell, Kristin/C-8301-2013; Price, David/C-7876-2013 OI Ladell, Kristin/0000-0002-9856-2938; Price, David/0000-0001-9416-2737 FU National Institutes of Health [RO1 AI43866, U01 AI43641, R37 AI40312]; European Molecular Biology Organization [ALTF 254-2002]; Burroughs Wellcome Fund Clinical Scientist Award in Translational Research; National Institutes of Health Director's Pioneer Award, National Institutes of Health Roadmap for Medical Research [DPI OD00329]; KineMed Inc.; National Center for Research Resources, a component of the National Institutes of Health [UL1 RR024131-01]; National Institutes of Health Roadmap for Medical Research FX This work was supported by National Institutes of Health Grant RO1 AI43866 (to M.K.H.); European Molecular Biology Organization Grant ALTF 254-2002 (to M.D.H.); National Institutes of Health Awards U01 AI43641 and R37 AI40312 (to J.M.M.); the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (to J.M.M.); and the National Institutes of Health Director's Pioneer Award (to J.M.M.), part of the National Institutes of Health Roadmap for Medical Research, through Grant DPI OD00329. Funding for the optimization of low-count techniques by mass spectrometry was provided by KineMed Inc. D.A.P. is a Wellcome Trust Senior Investigator. The Clinical and Translational Science Institute Clinical Research Center at the University of California, San Francisco was supported by Grant UL1 RR024131-01 from the National Center for Research Resources, a component of the National Institutes of Health, and the National Institutes of Health Roadmap for Medical Research. NR 39 TC 1 Z9 1 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2015 VL 195 IS 9 BP 4096 EP 4105 DI 10.4049/jimmunol.1500799 PG 10 WC Immunology SC Immunology GA CT7BQ UT WOS:000362968500007 PM 26416271 ER PT J AU Lu, Y Cao, X Zhang, XY Kovalovsky, D AF Lu, Ying Cao, Xin Zhang, Xianyu Kovalovsky, Damian TI PLZF Controls the Development of Fetal-Derived IL-17(+)V gamma 6(+) gamma delta T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR PLZF; ZINC-FINGER; CYCLE PROGRESSION; LINEAGE; DIFFERENTIATION; INNATE; PROLIFERATION; PROGRAM; INTERLEUKIN-17; INFLAMMATION AB Expression of promyelocytic leukemia zinc finger (PLZF) protein directs the effector differentiation of invariant NKT (iNKT) cells and IL-4(+) gamma delta NKT cells. In this study, we show that PLZF is also required for the development and function of IL-17(+) gamma delta T cells. We observed that PLZF is expressed in fetal-derived invariant V gamma 5(+) and V gamma 6(+) gamma delta T cells, which secrete IFN-gamma and IL-17, respectively. PLZF deficiency specifically affected the effector differentiation of V gamma 6(+) cells, leading to reduced numbers of mature CD27(-)CD44(+) phenotype capable of secreting IL-17. Although PLZF was not required for V gamma 5(+) gamma delta T cells to develop, when these cells were reprogrammed into IL-17-secreting cells in Skint-1 mutant mice, they required PLZF for their effector maturation, similarly to V gamma 6(+) gamma delta T cells. The impaired effector differentiation of PLZF-deficient V gamma 6(+) gamma delta T cells was not due to increased apoptosis and it was related to reduced proliferation of immature CD27(+)CD44(-) V gamma 6(+) gamma delta T cells, which was required for their differentiation into mature CD27(-)CD44(+) IL-17-secreting cells. Thus, the present study identifies that PLZF function is not restricted to NKT or IL-4(+) T cells, but it also controls the development of IL-17(+) gamma delta T cells. C1 [Lu, Ying; Cao, Xin; Zhang, Xianyu; Kovalovsky, Damian] NCI, Expt Immunol Branch, NIH, 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 National Institutes of Health intramural funds [1ZIABC011429] FX This work was supported by National Institutes of Health intramural funds (1ZIABC011429). NR 40 TC 2 Z9 2 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2015 VL 195 IS 9 BP 4273 EP 4281 DI 10.4049/jimmunol.1500939 PG 9 WC Immunology SC Immunology GA CT7BQ UT WOS:000362968500025 PM 26408661 ER PT J AU Bardina, SV Michlmayr, D Hoffman, KW Obara, CJ Sum, J Charo, IF Lu, WY Pletnev, AG Lim, JK AF Bardina, Susana V. Michlmayr, Daniela Hoffman, Kevin W. Obara, Christopher J. Sum, Janet Charo, Israel F. Lu, Wuyuan Pletnev, Alexander G. Lim, Jean K. TI Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CD8(+) T-CELLS; NATIVE CHEMICAL LIGATION; BONE-MARROW; MONONUCLEAR LEUKOCYTES; INFLAMMATORY MONOCYTES; ALPHA/BETA-INTERFERON; UP-REGULATION; ENCEPHALITIS; RECEPTOR AB West Nile virus (WNV) is a re-emerging pathogen and the leading cause of epidemic encephalitis in the United States. Inflammatory monocytes are a critical component of the cellular infiltrate found in the CNS duringWNVencephalitis, although the molecular cues involved in their migration are not fully understood. In mice, we previously showed that WNVinfection induces a CCR2-dependent monocytosis that precedes monocyte migration into the CNS. Currently, the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in directing monocyte mobilization and leukocyte migration into the CNS is unclear. In this study, we demonstrate that, although both CCL2 and CCL7 are required for efficient monocytosis and monocyte accumulation in the CNS, only CCL7 deficiency resulted in increased viral burden in the brain and enhanced mortality. The enhanced susceptibility in the absence of CCL7 was associated with the delayed migration of neutrophils and CD8(+) T cells into the CNS compared with WTor Ccl2(-/-) mice. To determine whether CCL7 reconstitution could therapeutically alter the survival outcome of WNV infection, we administered exogenous CCL7 i.v. to WNV-infected Ccl7(-/-) mice and observed a significant increase in monocytes and neutrophils, but not CD8(+) T cells, within the CNS, as well as an enhancement in survival compared with Ccl7(-/-) mice treated with a linear CCL7 control peptide. Our experiments suggest that CCL7 is an important protective signal involved in leukocyte trafficking during WNV infection, and it may have therapeutic potential for the treatment of acute viral infections of the CNS. C1 [Bardina, Susana V.; Michlmayr, Daniela; Hoffman, Kevin W.; Sum, Janet; Lim, Jean K.] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Obara, Christopher J.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Charo, Israel F.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. [Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Lu, Wuyuan] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lim, JK (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, One Gustave L Levy Pl,Box 1124, New York, NY 10029 USA. EM jean.lim@mssm.edu RI Lu, Wuyuan/B-2268-2010 FU National Institute of Allergy and Infectious Diseases [R01AI108715, F31AI110071]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health Research Training Award [T32AI007647] FX This work was supported by National Institute of Allergy and Infectious Diseases Grant R01AI108715 and in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.V.B. was supported in part by National Institutes of Health Research Training Award T32AI007647 and National Institute of Allergy and Infectious Diseases Grant F31AI110071. NR 66 TC 8 Z9 8 U1 1 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2015 VL 195 IS 9 BP 4306 EP 4318 DI 10.4049/jimmunol.1500352 PG 13 WC Immunology SC Immunology GA CT7BQ UT WOS:000362968500028 PM 26401006 ER PT J AU Hashimoto, M Nasser, H Bhuyan, F Kuse, N Satou, Y Harada, S Yoshimura, K Sakuragi, J Monde, K Maeda, Y Welbourn, S Strebel, K El-Wahab, EWA Miyazaki, M Hattori, S Chutiwitoonchai, N Hiyoshi, M Oka, S Takiguchi, M Suzu, S AF Hashimoto, Michihiro Nasser, Hesham Bhuyan, Farzana Kuse, Nozomi Satou, Yorifumi Harada, Shigeyoshi Yoshimura, Kazuhisa Sakuragi, Jun-ichi Monde, Kazuaki Maeda, Yosuke Welbourn, Sarah Strebel, Klaus El-Wahab, Ekram W. Abd Miyazaki, Mitsue Hattori, Shinichiro Chutiwitoonchai, Nopporn Hiyoshi, Masateru Oka, Shinichi Takiguchi, Masafumi Suzu, Shinya TI Fibrocytes Differ from Macrophages but Can Be Infected with HIV-1 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; HEMATOPOIETIC PROGENITOR CELLS; ACTIVE ANTIRETROVIRAL THERAPY; PERIPHERAL-BLOOD FIBROCYTES; VIRUS TYPE-1 VIREMIA; CIRCULATING FIBROCYTES; BONE-MARROW; PULMONARY-FIBROSIS; CHEMOKINE RECEPTOR; VIRAL RESERVOIRS AB Fibrocytes (fibroblastic leukocytes) are recently identified as unique hematopoietic cells with features of both macrophages and fibroblasts. Fibrocytes are known to contribute to the remodeling or fibrosis of various injured tissues. However, their role in viral infection is not fully understood. In this study, we show that differentiated fibrocytes are phenotypically distinguishable from macrophages but can be infected with HIV-1. Importantly, fibrocytes exhibited persistently infected cell-like phenotypes, the degree of which was more apparent than macrophages. The infected fibrocytes produced replication-competent HIV-1, but expressed HIV-1 mRNA at low levels and strongly resisted HIV-1-induced cell death, which enabled them to support an extremely long-term HIV-1 production at low but steady levels. More importantly, our results suggested that fibrocytes were susceptible to HIV-1 regardless of their differentiation state, in contrast to the fact that monocytes become susceptible to HIV-1 after the differentiation into macrophages. Our findings indicate that fibrocytes are the previously unreported HIV-1 host cells, and they suggest the importance of considering fibrocytes as one of the long-lived persistently infected cells for curing HIV-1. C1 [Hashimoto, Michihiro; Nasser, Hesham; Bhuyan, Farzana; Kuse, Nozomi; Satou, Yorifumi; El-Wahab, Ekram W. Abd; Miyazaki, Mitsue; Hattori, Shinichiro; Chutiwitoonchai, Nopporn; Hiyoshi, Masateru; Takiguchi, Masafumi; Suzu, Shinya] Kumamoto Univ, Ctr AIDS Res, Kumamoto 8600811, Japan. [Hashimoto, Michihiro; Nasser, Hesham; Bhuyan, Farzana; Satou, Yorifumi; El-Wahab, Ekram W. Abd; Miyazaki, Mitsue; Takiguchi, Masafumi; Suzu, Shinya] Kumamoto Univ, Int Res Ctr Med Sci, Kumamoto 8600811, Japan. [Harada, Shigeyoshi; Yoshimura, Kazuhisa] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo 1628640, Japan. [Sakuragi, Jun-ichi] Osaka Univ, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan. [Monde, Kazuaki; Maeda, Yosuke] Kumamoto Univ, Dept Med Virol, Kumamoto 8608556, Japan. [Welbourn, Sarah; Strebel, Klaus] NIAID, NIH, Bethesda, MD 20892 USA. [Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo 1620052, Japan. RP Suzu, S (reprint author), Kumamoto Univ, Int Res Ctr Med Sci, Ctr AIDS Res, Honjo 2-2-1, Kumamoto 8600811, Japan. EM ssuzu06@kumamoto-u.ac.jp RI Takiguchi, Masafumi/E-7468-2013; OI Satou, Yorifumi/0000-0002-1495-7810 FU Takeda Science Foundation; Senshin Medical Research Foundation; Science and Technology Development Fund, Egypt [6385] FX This work was supported by the grants from the Takeda Science Foundation and the Senshin Medical Research Foundation (to S.S.). E.W.A.E.-W. was supported by Science and Technology Development Fund, Egypt Grant 6385. NR 64 TC 1 Z9 1 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2015 VL 195 IS 9 BP 4341 EP 4350 DI 10.4049/jimmunol.1500955 PG 10 WC Immunology SC Immunology GA CT7BQ UT WOS:000362968500031 PM 26416279 ER PT J AU Singh, SP Foley, JF Zhang, HWH Hurt, DE Richards, JL Smith, CS Liao, F Farber, JM AF Singh, Satya P. Foley, John F. Zhang, Hongwei H. Hurt, Darrell E. Richards, Jennifer L. Smith, Craig S. Liao, Fang Farber, Joshua M. TI Selectivity in the Use of G(i/o) Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific SO MOLECULAR PHARMACOLOGY LA English DT Article ID BETA(2) ADRENERGIC-RECEPTOR; SITE-DIRECTED MUTAGENESIS; M1 MUSCARINIC RECEPTOR; COUPLED RECEPTORS; CRYSTAL-STRUCTURE; T-CELLS; BETA(2)-ADRENERGIC RECEPTOR; CONSTITUTIVE ACTIVATION; INTRACELLULAR DOMAINS; CHEMOKINE RECEPTORS AB CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the (DRY3.51)-R-3.49-Y-3.50 sequence, and all but two contain A(3.53) at the cytoplasmic terminus of the third transmembrane helix (H3C), a region within class A G protein-coupled receptors that contacts G proteins. In CXCR6, H3C contains (DRFIV3.53)-R-3.49-F-3.50-I-3.51-V-3.52 at positions 126-130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individualG(i/o) proteins; and the effects of mutations in H3C on receptor function and selectivity in G(i/o) protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available G(i/o) proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments. C1 [Singh, Satya P.; Foley, John F.; Zhang, Hongwei H.; Richards, Jennifer L.; Smith, Craig S.; Liao, Fang; Farber, Joshua M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Hurt, Darrell E.] NIAID, Bioinformat & Sci IT Program, Off Technol Informat Syst, NIH, Bethesda, MD 20892 USA. [Smith, Craig S.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Rm 11N112,MSC 1886, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov OI Foley, John/0000-0003-0395-5390 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 72 TC 1 Z9 1 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD NOV PY 2015 VL 88 IS 5 BP 894 EP 910 DI 10.1124/mol.115.099960 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CT8AO UT WOS:000363037400007 PM 26316539 ER PT J AU Capitanio, S Nanni, C Marini, C Bonfiglioli, R Martignani, C Dib, B Fuccio, C Boriani, G Picori, L Boschi, S Morbelli, S Fanti, S Sambuceti, G AF Capitanio, Selene Nanni, Cristina Marini, Cecilia Bonfiglioli, Rachele Martignani, Cristian Dib, Bassam Fuccio, Chiara Boriani, Giuseppe Picori, Lorena Boschi, Stefano Morbelli, Silvia Fanti, Stefano Sambuceti, Gianmario TI Heterogeneous response of cardiac sympathetic function to cardiac resynchronization therapy in heart failure documented by 11[C]-hydroxy-ephedrine and PET/CT SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Heart failure; Sympathetic innervation; Cardiac resynchronization therapy; C-11-hydroxyephedrine; PET/CT ID POSITRON-EMISSION-TOMOGRAPHY; DILATED CARDIOMYOPATHY; NERVOUS-SYSTEM; NOREPINEPHRINE; CARVEDILOL; CARBON-11-META-HYDROXYEPHEDRINE; HYPERTROPHY; INNERVATION; TRANSPORTER; RETENTION AB Introduction: Cardiac resynchronization therapy (CRT) is an accepted treatment in patients with end-stage heart failure. PET permits the absolute quantification of global and regional homogeneity in cardiac sympathetic innervation. We evaluated the variation of cardiac adrenergic activity in patients with idiopathic heart failure (IHF) disease (NYHA III-IV) after CRT using C-11-hydroxyephedrine (HED) PET/CT. Methods: Ten IHF patients (mean age = 68; range = 55-81; average left ventricular ejection fraction 26 +/- 4%) implanted with a resynchronization device underwent three HED PET/CT studies: PET 1 one week after inactive device implantation; PET 2, one week after PET 1 under stimulated rhythm; PET 3, at 3 months under active CRT. A dedicated software (PMOD 3.4 version) was used to estimate global and regional cardiac uptake of HED through 17 segment polar maps. Results: At baseline, HED uptake was heterogeneously distributed throughout the left ventricle with a variation coefficient of 18 +/- 5%. This variable markedly decreased after three months CRT (12 +/- 5%, p < 0.01). Interestingly, subdividing the 170 myocardial segments (17 segments of each patient multiplied by the number of patients) into two groups, according to the median value of tracer uptake expressed as % of maximal myocardial uptake (76%), we observed a different behaviour depending on baseline innervation: HED uptake significantly increased only in segments with "impaired innervation" (SUV 2.61 +/- 0.92 at PET1 and 3.05 +/- 1.67 at three months, p<0.01). Conclusion: As shown by HED PET/CT uptake and distribution, improvement in homogeneity of myocardial neuronal function reflected a selective improvement of tracer uptake in regions with more severe neuronal damage. Advances in Knowledge: These finding supported the presence of a myocardial regional variability in response of cardiac sympathetic system to CRT and a systemic response involving remote tissues with rich adrenergic innervation. Implication for patient care: This work might contribute to identify imaging parameters that could predict the response to CRT therapy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Capitanio, Selene; Dib, Bassam; Picori, Lorena; Morbelli, Silvia; Sambuceti, Gianmario] Univ Genoa, Dept Hlth Sci, IRCCS AOU San Martino IST, Nucl Med, I-16132 Genoa, Italy. [Nanni, Cristina; Bonfiglioli, Rachele; Fuccio, Chiara; Boschi, Stefano; Fanti, Stefano] Univ Bologna, Azienda Osped Univ Bologna Policlin St Orsola Mal, Hematol Oncol & Lab Med Dept, Nucl Med, I-40126 Bologna, Italy. [Marini, Cecilia] CNR, Inst Bioimages & Mol Physiol, Sect Genoa, I-20133 Milan, Italy. [Martignani, Cristian; Boriani, Giuseppe] Univ Bologna, Azienda Osped Univ Bologna Policlin St Orsola Mal, Ist Cardiol, I-40126 Bologna, Italy. RP Sambuceti, G (reprint author), Univ Genoa, IRCCS San Martino, Natl Canc Inst, Nucl Med, Lgo R Benzi 10, I-16132 Genoa, Italy. EM Sambuceti@unige.it RI Boriani, Giuseppe/A-4852-2015; OI Boriani, Giuseppe/0000-0002-9820-4815; Sambuceti, Gianmario/0000-0003-2979-6500 NR 35 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV PY 2015 VL 42 IS 11 BP 858 EP 863 DI 10.1016/j.nucmedbio.2015.07.002 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CT8NJ UT WOS:000363073000007 PM 26239084 ER PT J AU Lee, JH Kim, H Yao, ZS Lee, SJ Szajek, LP Grasso, L Pastan, I Paik, CH AF Lee, Jae-Ho Kim, Heejung Yao, Zhengsheng Lee, Sung-Jin Szajek, Lawrence P. Grasso, Luigi Pastan, Ira Paik, Chang H. TI Tumor and organ uptake of Cu-64-labeled MORAb-009 (amatuximab), an anti-mesothelin antibody, by PET imaging and biodistribution studies SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Cu-64 labeling; NOTA; Mesothelin; Amatuximab; Antibody; Tumor targeting ID IMMUNO-PET; MONOCLONAL-ANTIBODIES; EXPRESSING CANCERS; OVARIAN CANCERS; RADIOIMMUNOTHERAPY AB Objectives: To investigate the effect of the injection dose of MORAb-009 (amatuximab, an anti-mesothelin monoclonal antibody), the tumor size and the level of shed mesothelin on the uptake of the antibody in mesothelin-positive tumor and organs by biodistribution (BD) and positron emission tomography (PET) imaging studies. Methods: 2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacydononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to amatuximab and labeled with (CuCl2)-Cu-64 in 0.25 M acetate buffer, pH 4.2. The resulting Cu-64-NOTA-amatuximab was purified with a PD 10 column. To investigate the dose effect or the effect of tumor size, the BD was performed in groups of nude mice (n = 5) with mesothelin-expressing A431/H9 tumors (range, 80-300 mm(3)) one day after iv injection of Cu-64-NOTA-amatuximab (10 mu Ci) containing a total amatuximab dose of 2, 30, or 60 mu g. The BD and PET imaging were also investigated 3, 24 and 48 h after injecting a total dose of 30 mu g (10 mu Ci for BD), and 2 or 60 mu g (300 mu Ci for PET), respectively. Results: Comparing the results of the BDs from three different injection doses, the major difference was shown in the uptake (%ID/g) of the radiolabel in tumor, liver and blood. The tumor uptake and blood retention from 30 and 60 mu g doses were greater than those from 2 mu g dose, whereas the liver uptake was smaller. The BD studies also demonstrated a positive correlation between tumor size (or the level of shed mesothelin in blood) and liver uptake. However, there was a negative correlation between tumor size (or the shed mesothelin level) and tumor uptake and between tumor size and blood retention. These findings were confirmed by the PET imaging study, which clearly visualized the tumor uptake with the radiolabel concentrated in the tumor core and produced a tumor to liver ratio of 1.2 at 24 h post-injection with 60 mu g amatuximab, whereas the injection of 2 mu g amatuximab produced a tumor to liver ratio of 0.4 at 24 h post-injection. Conclusion: Our studies using a nude mouse model of A431/H9 tumor demonstrated that the injection of a high amatuximab dose (30 to 60 mu g) could provide a beneficial effect in maximizing tumor uptake while maintaining minimum liver and spleen uptakes of the radiolabel, and in facilitating its penetration into the tumor core. Published by Elsevier Inc. C1 [Lee, Jae-Ho; Kim, Heejung; Yao, Zhengsheng; Lee, Sung-Jin; Paik, Chang H.] NIH, Nucl Med, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Szajek, Lawrence P.] NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. [Grasso, Luigi] Morphotek Inc, Exton, PA 19341 USA. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lee, JH (reprint author), NIH, Nucl Med, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM leejaeho@mail.nih.gov; cpaik@mail.nih.gov FU intramural research program of Clinical Center, NIH FX We thank Ms. Eden Dejene for her editorial assistance with this manuscript. This research was supported by the intramural research program of Clinical Center, NIH. NR 28 TC 2 Z9 2 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV PY 2015 VL 42 IS 11 BP 880 EP 886 DI 10.1016/j.nucmedbio.2015.07.008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CT8NJ UT WOS:000363073000010 PM 26307499 ER PT J AU Kitahara, CM Linet, MS Drozdovitch, V Alexander, BH Preston, DL Simon, SL Freedman, DM Brill, AB Miller, JS Little, MP Rajaraman, P Doody, MM AF Kitahara, Cari M. Linet, Martha S. Drozdovitch, Vladimir Alexander, Bruce H. Preston, Dale L. Simon, Steven L. Freedman, D. Michal Brill, Aaron B. Miller, Jeremy S. Little, Mark P. Rajaraman, Preetha Doody, Michele M. TI Cancer and circulatory disease risks in US radiologic technologists associated with performing procedures involving radionuclides SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID ATOMIC-BOMB SURVIVORS; IONIZING-RADIATION; NUCLEAR-MEDICINE; UNITED-STATES; BRITISH RADIOLOGISTS; MORTALITY RISKS; EXPOSURE; WORKERS; REGISTRY; HEALTH AB Objectives The number of nuclear medicine procedures has increased substantially over the past several decades, with uncertain health risks to the medical workers who perform them. We estimated risks of incidence and mortality from cancer and circulatory disease associated with performing procedures involving the use of radionuclides. Methods From a nationwide cohort of 90 955 US radiologic technologists who completed a mailed questionnaire during 1994-1998, 22 039 reported ever performing diagnostic radionuclide procedures, brachytherapy, radioactive iodine therapy, or other radionuclide therapy. We calculated multivariable-adjusted HRs and 95% CIs for incidence (through 2003-2005) and mortality (through 2008) associated with performing these procedures. Results Ever (versus never) performing radionuclide procedures was not associated with risks for most end points examined. However, we observed increased risks for squamous cell carcinoma of the skin (HR=1.29, 95% CI 1.01 to 1.66) with ever performing diagnostic radionuclide procedures, for myocardial infarction incidence (HR=1.37, 95% CI 1.10 to 1.70), all-cause mortality (HR=1.10, 95% CI 1.00 to 1.20) and all-cancer mortality (HR=1.20, 95% CI 1.01 to 1.43) with ever performing brachytherapy, and for mortality from all causes (HR=1.14, 95% CI 1.01 to 1.30), breast cancer (HR=2.68, 95% CI 1.10 to 6.51), and myocardial infarction (HR=1.76, 95% CI 1.02 to 3.04) with ever performing other radionuclide therapy procedures (excluding brachytherapy and radioactive iodine); increasing risks were also observed with greater frequency of performing these procedures, particularly before 1980. Conclusions The modest health risks among radiologic technologists performing procedures using radionuclides require further examination in studies with individual dose estimates, more detailed information regarding types of procedures performed and radionuclides used, and longer follow-up. C1 [Kitahara, Cari M.; Linet, Martha S.; Drozdovitch, Vladimir; Simon, Steven L.; Freedman, D. Michal; Little, Mark P.; Rajaraman, Preetha; Doody, Michele M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA USA. [Brill, Aaron B.] Vanderbilt Univ, Dept Radiol & Radiol Sci, Nashville, TN 37235 USA. [Miller, Jeremy S.] Informat Management Syst Inc, Calverton, MD USA. RP Kitahara, CM (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM meinholdc@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Little, Mark/0000-0003-0980-7567 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA FX This research was funded by the intramural programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, USA. NR 33 TC 1 Z9 2 U1 4 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD NOV PY 2015 VL 72 IS 11 BP 770 EP 776 DI 10.1136/oemed-2015-102834 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CT6GA UT WOS:000362909900004 PM 26220810 ER PT J AU Thoreson, CK Chung, ST Ricks, M Reynolds, JC Remaley, AT Periwal, V Li, Y Sumner, AE AF Thoreson, C. K. Chung, S. T. Ricks, M. Reynolds, J. C. Remaley, A. T. Periwal, V. Li, Y. Sumner, A. E. TI Biochemical and clinical deficiency is uncommon in African immigrants despite a high prevalence of low vitamin D: the Africans in America study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE African immigrants; Bone mineral density; Parathyroid hormone; Vitamin D ID BONE-MINERAL DENSITY; D-BINDING PROTEIN; 25-HYDROXYVITAMIN D; SECONDARY HYPERPARATHYROIDISM; PARATHYROID-HORMONE; SEASONAL-VARIATION; D INSUFFICIENCY; FRACTURE RISK; WHITE WOMEN; BLACK-WOMEN AB African ancestry is associated with low vitamin D levels but high bone density. Fifty percent of African immigrants had low vitamin D levels, but < 10 % had evidence of deficiency. The value of providing vitamin D supplementation to African immigrants without evidence of deficiency needs to be determined. Introduction The Endocrine Society and Institute of Medicine (IOM) have concluded from studies in largely white populations that 25(OH)D is necessary for bone health. However, their definition of vitamin D insufficiency differs. The Endocrine Society recommends a 25(OH)D threshold of < 30 ng/mL. The IOM uses a lower threshold of 25(OH)D of < 20 ng/mL. As African ancestry is associated with decreased 25(OH)D but increased bone mineral density (BMD), the applicability of these thresholds to Africans is unknown. Therefore, we examined in African immigrants the relationship of 25(OH)D to parathyroid hormone (PTH) and BMD. Methods One hundred eighty-six African immigrants(69 % male, age 38 +/- 10 (mean +/- SD), range 20-64 years) living in metropolitan Washington, DC, were enrolled. BMD was determined from whole-body dual-energy X-ray absorptiometry (DXA) scans. Decreased BMD required T-scores a parts per thousand currency signa'1.0. The threshold for low 25(OH)D was the concentration of 25(OH)D at which PTH became suppressed. This is known as the inflection point. Biochemical deficiency required low 25(OH)D and PTH of > 65 pg/mL. Clinical deficiency required low 25(OH)D and T-scores a parts per thousand currency signa'1.0. Results 25(OH)D < 30 and < 20 ng/mL occurred in 83 and 46 % of African immigrants, respectively. PTH inversely correlated with 25(OH)D (r = -0.31, P = 0.002). The inflection point occurred at a 25(OH)D concentration of 20 ng/mL. Biochemical and clinical deficiency occurred in only 8 and 3 % of immigrants, respectively. Conclusion As PTH became suppressed at 25(OH)D of 20 ng/mL, the 25(OH)D < 20 ng/mL threshold for insufficiency may apply to African immigrants. However, similar to 50 % of African immigrants have 25(OH)D < 20 ng/mL, but only < 10 % had evidence of deficiency. The value of providing vitamin D supplementation to the large number of African immigrants with 25(OH)D < 20 ng/mL and no detectable evidence of deficiency needs to be determined. C1 [Thoreson, C. K.; Chung, S. T.; Ricks, M.; Sumner, A. E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Reynolds, J. C.] NIH, Div Nucl Med, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. [Remaley, A. T.] NHLBI, Lipoprot Metab Sect, Cardiopulmonary Branch, NIH, Bethesda, MD 20892 USA. [Periwal, V.; Li, Y.] NIDDK, Lab Biol Modeling, Computat Med Sect, NIH, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bld 10-CRC,Rm 6-5940,MSC 1612,9000 Rockville Pike, Bethesda, MD 20892 USA. EM annes@intra.niddk.nih.gov FU intramural program of National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Center; intramural program of National Heart, Lung, and Blood Institute FX Caroline K. Thoreson, Stephanie T. Chung, Madia Ricks, Vipul Periwal, Yanjun Li, and Anne E. Sumner were supported by the intramural program of National Institute of Diabetes and Digestive and Kidney Diseases. James C. Reynolds was supported in the Clinical Center and Alan T. Remaley was supported by the intramural program of National Heart, Lung, and Blood Institute. NR 39 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD NOV PY 2015 VL 26 IS 11 BP 2607 EP 2615 DI 10.1007/s00198-015-3169-z PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CT8CG UT WOS:000363042000007 PM 26001560 ER PT J AU Kessler, RC Stein, MB Bliese, PD Bromet, EJ Chiu, WT Cox, KL Colpe, LJ Fullerton, CS Gilman, SE Gruber, MJ Heeringa, SG Lewandowski-Romps, L Millikan-Bell, A Naifeh, JA Nock, MK Petukhova, MV Rosellini, AJ Sampson, NA Schoenbaum, M Zaslavsky, AM Ursano, RJ AF Kessler, R. C. Stein, M. B. Bliese, P. D. Bromet, E. J. Chiu, W. T. Cox, K. L. Colpe, L. J. Fullerton, C. S. Gilman, S. E. Gruber, M. J. Heeringa, S. G. Lewandowski-Romps, L. Millikan-Bell, A. Naifeh, J. A. Nock, M. K. Petukhova, M. V. Rosellini, A. J. Sampson, N. A. Schoenbaum, M. Zaslavsky, A. M. Ursano, R. J. CA Army STARRS Collaborators TI Occupational differences in US Army suicide rates SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Army; Army STARRS; deployment; resiliency factors; suicide ID HEALTH-CARE UTILIZATION; RISK-FACTORS; MENTAL-HEALTH; MILITARY OCCUPATION; U.S. ARMY; RESILIENCE; DEPLOYMENT; SOLDIERS; WAR; STARRS AB Background. Civilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate. Method. The joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009. Results. There were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2-39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2-22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [ odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1-4.1], less so when previously deployed (OR 1.6, 95% CI 1.1-2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8-1.8). Adjustment for a differential 'healthy warrior effect' cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status. Conclusions. Efforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk. C1 [Kessler, R. C.; Chiu, W. T.; Gruber, M. J.; Petukhova, M. V.; Rosellini, A. J.; Sampson, N. A.; Zaslavsky, A. M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Stein, M. B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, M. B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, M. B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Bliese, P. D.] Univ S Carolina, Darla Moore Sch Business, Columbia, SC 29208 USA. [Bromet, E. J.] SUNY Stony Brook, Dept Psychiat, Sch Med, Stony Brook, NY 11794 USA. [Cox, K. L.; Millikan-Bell, A.] US Army Publ Hlth Command, Aberdeen Proving Ground, MD USA. [Colpe, L. J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Fullerton, C. S.; Naifeh, J. A.; Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Sch Med, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, S. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Heeringa, S. G.; Lewandowski-Romps, L.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, M. K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Schoenbaum, M.] NIMH, Off Sci Policy Planning & Commun, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH 087981]; EPI-Q; Sanofi-Aventis Group; Walgreens Co.; Janssen FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH 087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, the NIMH, the Department of the Army or the DoD. As a cooperative agreement, scientists employed by the NIMH (L. J. Colpe and M. Schoenbaum) and Army liaisons/consultants [Col. Steven Cersovsky, M.D., M.P.H. (US Army Public Health Command; USAPHC) and K. L. Cox, M.D., M.P.H. (USAPHC)] collaborated to develop the study protocol and data collection instruments, supervise data collection, interpret results and prepare reports. Although a draft of this manuscript was submitted to the Army and NIMH for review and comment prior to submission, this was with the understanding that comments would be no more than advisory. R. C. Kessler has been a consultant over the past 3 years for J & J Wellness & Prevention, Inc., Lake Nona Institute, Ortho-McNeil Janssen Scientific Affairs, Sanofi-Aventis Group, Shire US Inc. and Transcept Pharmaceuticals Inc. and has had research support for his epidemiological studies over this time period from EPI-Q, Sanofi-Aventis Group, and Walgreens Co. R. C. Kessler owns stock in DataStat, Inc. M. B. Stein has been a consultant for Healthcare Management Technologies and had research support for pharmacological imaging studies from Janssen. The remaining authors report nothing to disclose. NR 48 TC 1 Z9 1 U1 3 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD NOV PY 2015 VL 45 IS 15 BP 3293 EP 3304 DI 10.1017/S0033291715001294 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CT7HZ UT WOS:000362986900015 PM 26190760 ER PT J AU Ballard, ED Van Eck, K Musci, RJ Hart, SR Storr, CL Breslau, N Wilcox, HC AF Ballard, E. D. Van Eck, K. Musci, R. J. Hart, S. R. Storr, C. L. Breslau, N. Wilcox, H. C. TI Latent classes of childhood trauma exposure predict the development of behavioral health outcomes in adolescence and young adulthood SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Childhood adverse experiences; latent class analysis; trauma; young adulthood ID POSTTRAUMATIC-STRESS-DISORDER; INTERNATIONAL DIAGNOSTIC INTERVIEW; NATIONAL-COMORBIDITY-SURVEY; HOUSEHOLD DYSFUNCTION; PSYCHIATRIC-DISORDERS; SUICIDE IDEATION; SUBSTANCE-ABUSE; FAMILY-HISTORY; TOXIC STRESS; RISK-FACTORS AB Background. To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative behavioral outcomes in adolescence and young adulthood. Method. A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences. Latent classes were used to predict psychiatric outcomes at age 513 years, criminal convictions, physical health problems and traumatic experiences reported in young adulthood. Results. Three latent classes of childhood traumatic experiences were supported by the data. One class (8% of sample), primarily female, was characterized by experiences of sexual assault and reported significantly higher rates of a range of psychiatric outcomes by young adulthood. Another class (8%), primarily male, was characterized by experiences of violence exposure and reported higher levels of antisocial personality disorder and post-traumatic stress. The final class (84%) reported low levels of childhood traumatic experiences. Parental psychopathology was related to membership in the sexual assault group. Conclusions. Classes of childhood traumatic experiences predict specific psychiatric and behavioral outcomes in adolescence and young adulthood. The long-term adverse effects of childhood traumas are primarily concentrated in victims of sexual and non-sexual violence. Gender emerged as a key covariate in the classes of trauma exposure and outcomes. C1 [Ballard, E. D.] NIMH, Expt & Pathophysiol Branch, Bethesda, MD 20892 USA. [Van Eck, K.; Musci, R. J.; Storr, C. L.; Wilcox, H. C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Van Eck, K.] Johns Hopkins Univ, Sch Med, Div Pediat, Baltimore, MD USA. [Hart, S. R.] Calif State Univ Chico, Dept Child Dev, Chico, CA 95929 USA. [Storr, C. L.] Univ Maryland, Sch Nursing, Dept Family & Community Hlth, Baltimore, MD 21201 USA. [Breslau, N.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Wilcox, H. C.] Johns Hopkins Univ, Sch Med, Child & Adolescent Psychiat, Baltimore, MD USA. RP Ballard, ED (reprint author), NIMH, Expt & Pathophysiol Branch, Bldg 10,CRC Room 7-3345,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. EM Elizabeth.Ballard@nih.gov FU National Institute of Health; National Institute of Mental Health [MH090480, MH71395, MH 71395, MH 48802]; National Institute on Drug Abuse [DA09897, DA04392, DA019805] FX This work was supported by several National Institute of Health grants over the span of the prospective study: National Institute of Mental Health (MH090480, MH71395, MH 71395, MH 48802) and National Institute on Drug Abuse (DA09897, DA04392, and DA019805). NR 52 TC 4 Z9 4 U1 10 U2 30 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD NOV PY 2015 VL 45 IS 15 BP 3305 EP 3316 DI 10.1017/S0033291715001300 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CT7HZ UT WOS:000362986900016 PM 26149665 ER PT J AU Dueck, AC Mendoza, TR Mitchell, SA Reeve, BB Castro, KM Rogak, LJ Atkinson, TM Bennett, AV Denicoff, AM O'Mara, AM Li, YL Clauser, SB Bryant, DM Bearden, JD Gillis, TA Harness, JK Siegel, RD Paul, DB Cleeland, CS Schrag, D Sloan, JA Abernethy, AP Bruner, DW Minasian, LM Basch, E AF Dueck, Amylou C. Mendoza, Tito R. Mitchell, Sandra A. Reeve, Bryce B. Castro, Kathleen M. Rogak, Lauren J. Atkinson, Thomas M. Bennett, Antonia V. Denicoff, Andrea M. O'Mara, Ann M. Li, Yuelin Clauser, Steven B. Bryant, Donna M. Bearden, James D., III Gillis, Theresa A. Harness, Jay K. Siegel, Robert D. Paul, Diane B. Cleeland, Charles S. Schrag, Deborah Sloan, Jeff A. Abernethy, Amy P. Bruner, Deborah W. Minasian, Lori M. Basch, Ethan CA Natl Canc Inst PRO-CTCAE Study Grp TI Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO JAMA ONCOLOGY LA English DT Article ID CLINICIAN; SYMPTOMS; CHEMOTHERAPY; INSTRUMENT; TOXICITIES; AGREEMENT; ONCOLOGY; QLQ-C30; TRIALS AB IMPORTANCE To integrate the patient perspective into adverse event reporting, the National Cancer Institute developed a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). OBJECTIVE To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items. DESIGN, SETTING, AND PARTICIPANTS A total of 975 adults with cancer undergoing outpatient chemotherapy and/or radiation therapy enrolled in this questionnaire-based study between January 2011 and February 2012. Eligible participants could read English and had no clinically significant cognitive impairment. They completed PRO-CTCAE items on tablet computers in clinic waiting rooms at 9 US cancer centers and community oncology practices at 2 visits 1 to 6 weeks apart. A subset completed PRO-CTCAE items during an additional visit 1 business day after the first visit. MAIN OUTCOMES AND MEASURES Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30). RESULTS A total of 940 of 975 (96.4%) and 852 of 940 (90.6%) participants completed PRO-CTCAE items at visits 1 and 2, respectively. At least 1 symptom was reported by 938 of 940 (99.8%) participants. Participants' median age was 59 years; 57.3% were female, 32.4% had a high school education or less, and 17.1% had an ECOG PS of 2 to 4. All PRO-CTCAE items had at least 1 correlation in the expected direction with a QLQ-C30 scale (111 of 124, P <.05 for all). Stronger correlations were seen between PRO-CTCAE items and conceptually related QLQ-C30 domains. Scores for 94 of 124 PRO-CTCAE items were higher in the ECOG PS 2 to 4 vs 0 to 1 group (58 of 124, P <.05 for all). Overall, 119 of 124 items met at least 1 construct validity criterion. Test-retest reliability was 0.7 or greater for 36 of 49 prespecified items (median [range] intraclass correlation coefficient, 0.76 [0.53-.96]). Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were statistically significant for 27 prespecified items (median [range] r = 0.43 [0.10-. 56]; all P <=.006). CONCLUSIONS AND RELEVANCE Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous US sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are under way to inform further development of PRO-CTCAE and its inclusion in cancer trials. C1 [Dueck, Amylou C.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ USA. [Mendoza, Tito R.; Cleeland, Charles S.] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Mitchell, Sandra A.; Castro, Kathleen M.; Clauser, Steven B.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Reeve, Bryce B.; Bennett, Antonia V.; Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Rogak, Lauren J.; Basch, Ethan] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Atkinson, Thomas M.; Li, Yuelin] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Denicoff, Andrea M.; Minasian, Lori M.] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [O'Mara, Ann M.] NCI, Canc Prevent Div, Rockville, MD USA. [Bryant, Donna M.] Canc Program Our Lady Lake & Mary Bird Perkins, Dept Clin Res, Baton Rouge, LA USA. [Bearden, James D., III] Gibbs Canc Ctr & Res Inst, Spartanburg, SC USA. [Gillis, Theresa A.] Christiana Care Hlth Syst, Helen Graham Canc Ctr, Newark, DE USA. [Gillis, Theresa A.] Christiana Care Hlth Syst, Res Inst, Newark, DE USA. [Harness, Jay K.] St Joseph Hosp Orange, Ctr Canc Prevent & Treatment, Orange, CA USA. [Siegel, Robert D.] Hartford Hosp, Helen & Harry Gray Canc Ctr, Hartford, CT 06115 USA. [Schrag, Deborah] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Sloan, Jeff A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Abernethy, Amy P.] Duke Univ, Dept Med, Med Ctr, Durham, NC USA. [Bruner, Deborah W.] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. RP Dueck, AC (reprint author), Mayo Clin, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM dueck@mayo.edu FU National Cancer Institute [HHSN261200800043C, HHSN261201000063C, HHSN261200800001E] FX This study was supported by contracts from the National Cancer Institute: HHSN261200800043C, HHSN261201000063C, and HHSN261200800001E. NR 31 TC 41 Z9 41 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1051 EP 1059 DI 10.1001/jamaoncol.2015.2639 PG 10 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700008 PM 26270597 ER PT J AU Landgren, O Shim, YK Michalek, J Costello, R Burton, D Ketchum, N Calvo, KR Caporaso, N Raveche, E Middleton, D Marti, G Vogt, RF AF Landgren, Ola Shim, Youn K. Michalek, Joel Costello, Rene Burton, Debra Ketchum, Norma Calvo, Katherine R. Caporaso, Neil Raveche, Elizabeth Middleton, Dan Marti, Gerald Vogt, Robert F., Jr. TI Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance An Operation Ranch Hand Veteran Cohort Study SO JAMA ONCOLOGY LA English DT Article ID EARLY TREATMENT STRATEGIES; PRECEDES MULTIPLE-MYELOMA; AGRICULTURAL-WORKERS; BIOLOGICAL INSIGHTS; PESTICIDE EXPOSURE; SIGNIFICANCE MGUS; CANCER INCIDENCE; UNITED-STATES; LIGHT-CHAINS; IOWA FARMERS AB IMPORTANCE Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans. OBJECTIVE To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans. DESIGN, SETTING, AND PARTICIPANTS This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS. EXPOSURES Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002. MAIN OUTCOMES AND MEASURES Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs. RESULTS The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1%(34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P =.007). CONCLUSIONS AND RELEVANCE Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma. C1 [Landgren, Ola; Costello, Rene; Burton, Debra; Caporaso, Neil] NCI, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Shim, Youn K.; Middleton, Dan] Agcy Tox Subst & Dis Registry, Atlanta, GA USA. [Michalek, Joel; Ketchum, Norma] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Calvo, Katherine R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Raveche, Elizabeth] Rutgers New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Vogt, Robert F., Jr.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org FU Intramural Program at the Agency for Toxic Substances and Disease Registry; Intramural Program at the National Cancer Institute; Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine FX This study was supported by the Intramural Program at the Agency for Toxic Substances and Disease Registry, the Intramural Program at the National Cancer Institute, and the Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine through an award to the Centers for Disease Control and Prevention (CDC) Foundation. NR 50 TC 4 Z9 5 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1061 EP 1068 DI 10.1001/jamaoncol.2015.2938 PG 8 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700010 PM 26335650 ER PT J AU Heery, CR Ibrahim, NK Arlen, PM Mohebtash, M Murray, JL Koenig, K Madan, RA McMahon, S Marte, JL Steinberg, SM Donahue, RN Grenga, I Jochems, C Farsaci, B Folio, LR Schlom, J Gulley, JL AF Heery, Christopher R. Ibrahim, Nuhad K. Arlen, Philip M. Mohebtash, Mahsa Murray, James L. Koenig, Kimberly Madan, Ravi A. McMahon, Sheri Marte, Jennifer L. Steinberg, Seth M. Donahue, Renee N. Grenga, Italia Jochems, Caroline Farsaci, Benedetto Folio, Les R. Schlom, Jeffrey Gulley, James L. TI Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer A Randomized Clinical Trial SO JAMA ONCOLOGY LA English DT Article ID RESISTANT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; POXVIRAL-BASED VACCINE; T-CELL RESPONSES; SIPULEUCEL-T; PHASE-II; IMMUNOTHERAPY; CEA; CARCINOMA; CHEMOTHERAPY AB IMPORTANCE Previous phase 1 and 2 trials of PANVAC, a poxviral-based cancer vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell-mediated killing. OBJECTIVE The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast cancer compared with docetaxel treatment alone. DESIGN, SETTING, AND PARTICIPANTS Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P <= .10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. RESULTS Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema (P = .02, likely related to greater median number of docetaxel cycles) and injection-site reactions (P < .001). In the final data analysis, median PFS was 7.9 months in arm A vs 3.9 months in arm B (hazard ratio, 0.65 [95% CI, 0.34-1.14]; P = .09). CONCLUSIONS AND RELEVANCE The results suggest that the combination of PANVAC with docetaxel in metastatic breast cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. C1 [Madan, Ravi A.; McMahon, Sheri; Marte, Jennifer L.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. [Heery, Christopher R.; Arlen, Philip M.; Mohebtash, Mahsa; Donahue, Renee N.; Grenga, Italia; Jochems, Caroline; Farsaci, Benedetto; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ibrahim, Nuhad K.; Murray, James L.; Koenig, Kimberly] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Div Canc Med, Houston, TX 77030 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Folio, Les R.] NCI, Radiol & Imaging Serv, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM gulleyj@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 28 TC 12 Z9 12 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD NOV PY 2015 VL 1 IS 8 BP 1087 EP 1095 DI 10.1001/jamaoncol.2015.2736 PG 9 WC Oncology SC Oncology GA DW5IO UT WOS:000383677700014 PM 26291768 ER PT J AU Keutgen, XM Glanville, J Kerkar, S Kebebew, E AF Keutgen, Xavier M. Glanville, Joanne Kerkar, Sid Kebebew, Electron TI Serous Cystadenoma of the Pancreas Causing Obstructive Jaundice in a Patient with Von Hippel-Lindau Disease SO JOURNAL OF THE PANCREAS LA English DT Article DE von Hippel-Lindau Disease; Cystadenoma, Serous ID COMMON BILE-DUCT; INVOLVEMENT; LESIONS AB Context Cystic lesions of the pancreas are a common finding in patients with von Hippel-Lindau disease (vHL). However, only twelve cases of pancreatic cystic lesions causing obstructive jaundice have been reported in vHL patients. Case report Herein we report the rare case of a massive serous cystadenoma of the pancreatic head causing obstructive jaundice in a fifty-one-year-old female with vHL. Preoperative biliary decompression was achieved via ERCP and stent placement. Since the whole pancreas showed cystic degenerations, a total pancreatectomy was performed. Final histopathology showed diffuse compression of the distal intrapancreatic common bile duct but no evidence of malignancy. Conclusion To our knowledge this is only the second case report of a total pancreatectomy performed in a patient with vHL for biliary obstruction caused by a serous cystadenoma of the pancreas. Surgical intervention in this rare scenario should be recommended, because of the inability to rule out malignancy and the necessity to address the biliary obstruction. C1 [Keutgen, Xavier M.; Glanville, Joanne; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kerkar, Sid] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Keutgen, XM (reprint author), NCI, EOB, NIH, 10 Ctr Dr,3W-5840, Bethesda, MD 20892 USA. EM xavier.keutgen@nih.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU E S BURIONI RICERCHE BIBLIOGRAFICHE PI GENOVA PA CORSO FIRENZE 41-2, GENOVA, 16136, ITALY SN 1590-8577 J9 J PANCREAS JI J. Pancreas PD NOV PY 2015 VL 16 IS 6 BP 616 EP 618 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DY6KS UT WOS:000385225400017 ER PT J AU Mensch, BS Gorbach, PM Kelly, C Kiepiela, P Gomez, K Ramjee, G Ganesh, S Morar, N Soto-Torres, L Parikh, UM AF Mensch, Barbara S. Gorbach, Pamina M. Kelly, Cliff Kiepiela, Photini Gomez, Kailazarid Ramjee, Gita Ganesh, Shayhana Morar, Neetha Soto-Torres, Lydia Parikh, Urvi M. TI Characteristics Associated with HIV Drug Resistance Among Women Screening for an HIV Prevention Trial in KwaZulu-Natal, South Africa SO AIDS AND BEHAVIOR LA English DT Article DE HIV drug resistance; KwaZulu-Natal; HIV-positive women screening for a prevention trial ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; PREEXPOSURE PROPHYLAXIS; SURVEILLANCE; TRANSMISSION; INFECTION AB While the expansion of antiretroviral therapy (ART) in sub-Saharan Africa has reduced morbidity and mortality from HIV/AIDS, it has increased concern about drug resistance. The Microbicide Trials Network 009 study assessed the prevalence of drug-resistance mutations among women at clinical sites in Durban, South Africa who tested seropositive for HIV-1 at screening for the VOICE trial. The objective of this paper was to identify characteristics and behaviors associated with drug resistance. Factors found to be significantly associated with increased resistance were high perceived risk of getting HIV and prior participation in a microbicide trial, a likely proxy for familiarity with the health care system. Two factors were found to be significantly associated with reduced resistance: having a primary sex partner and testing negative for HIV in the past year. Other variables hypothesized to be important in identifying women with resistant virus, including partner or friend on ART who shared with the participant and being given antiretrovirals during pregnancy or labor, or the proxy variable-number of times given birth in a health facility-were not significantly associated. The small number of participants with resistant virus and the probable underreporting of sensitive behaviors likely affected our ability to construct a comprehensive profile of the type of HIV-positive women at greatest risk of developing resistance mutations. C1 [Mensch, Barbara S.] Populat Council, New York, NY 10017 USA. [Gorbach, Pamina M.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA. [Kelly, Cliff] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Kiepiela, Photini; Ramjee, Gita; Ganesh, Shayhana; Morar, Neetha] South African Med Res Council, HIV Prevent Res Unit, Durban, South Africa. [Gomez, Kailazarid] FHI 360, Durham, NC USA. [Soto-Torres, Lydia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Parikh, Urvi M.] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. RP Mensch, BS (reprint author), Populat Council, One Dag Hammarskjold Plaza, New York, NY 10017 USA. EM bmensch@popcouncil.org FU National Institute of Allergy and Infectious Diseases [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health FX We gratefully acknowledge the study participants, the communities and all the sites at which the study took place, health service providers, the South African Medical Research Council Institutional Review Board, and all of the MTN-009 Study Team including the clinical research site leaders Sarita Naidoo, Zakir Gaffoor, Marwah Jenneker, Zola Msiska, Arendevi Pather, Charlene Harichund, Sharika Gappoo, Jessica Philip, Nicola Coumi, Samantha Sukhdeo, Yuki Sookrajh, Leith Kwaan, Vijayanand Guddera and Brodie Daniels. We acknowledge the contributions of Benoit Masse, Paul Edelfsen and Karen Patterson from the Statistical Center for HIV/AIDS Research & Prevention (SCHARP). We also thank Stan Mierzwa and the Population Council IT team that designed and implemented the ACASI software, and Beth Galaska-Burzuk and Judy Jones from the MTN Core for their support during protocol development. The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. NR 26 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2015 VL 19 IS 11 BP 2076 EP 2086 DI 10.1007/s10461-015-1056-4 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CT2TQ UT WOS:000362657300013 PM 25931240 ER PT J AU Marathe, S Liu, S Brai, E Kaczarowski, M Alberi, L AF Marathe, S. Liu, S. Brai, E. Kaczarowski, M. Alberi, L. TI Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID NEURAL STEM-CELLS; NEURONAL DEATH; ALZHEIMERS-DISEASE; ISCHEMIC-STROKE; POSTMITOTIC NEURONS; NERVOUS-SYSTEM; GENE KNOCKOUT; ADULT BRAIN; MOUSE-BRAIN; PATHWAY AB Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3 beta pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR. C1 [Marathe, S.; Brai, E.; Kaczarowski, M.; Alberi, L.] Univ Fribourg, Inst Anat, Dept Med, CH-1700 Fribourg, Switzerland. [Liu, S.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Alberi, L (reprint author), Univ Fribourg, Inst Anat, Dept Med, Route Gockel 1, CH-1700 Fribourg, Switzerland. EM lavinia.alberi@unifr.ch FU Swiss National Foundation; Swiss Heart Association; Synapsis Foundation FX This work was supported by funds from the Swiss National Foundation, Swiss Heart Association and Synapsis Foundation. We would like to thank Dr. Nicholas Gaiano for his continuous support to our lab. We thank T Honjo for sharing the RBPJKfloxed/floxed mouse line. F Calegari and B Artegiani for providing us the 4D construct. We are thankful to Dr. Solinas for providing the p110 gamma antibody. We thank P Clarke and J Puyal for their helpful scientific input on the study. NR 54 TC 6 Z9 6 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD NOV PY 2015 VL 22 IS 11 BP 1775 EP 1784 DI 10.1038/cdd.2015.23 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS9US UT WOS:000362438500005 PM 25822340 ER PT J AU Cohen, JS Levy, HP Sloan, J Dariotis, J Biesecker, BB AF Cohen, J. S. Levy, H. P. Sloan, J. Dariotis, J. Biesecker, B. B. TI Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life SO CLINICAL GENETICS LA English DT Article DE depression; neurofibromatosis; psychosocial burden; quality of life ID CHILDREN; ADOLESCENTS AB Neurofibromatosis type 1 (NF1) carries a significant psychosocial burden for affected individuals. The objective of this study was to measure the prevalence of depressive symptoms among a large sample of adults with NF1 and to quantify the impact of depressive symptoms on quality of life (QoL). This cross-sectional study used an Internet-based questionnaire to collect data from 498 adults who self-reported as having NF1. Using the Center for Epidemiologic Studies Depression (CESD) scale, 55% of all participants (61% of females and 43% of males) scored above 16, indicating a high likelihood of clinical depression. In a multivariate regression model controlling for demographics and potential confounders, depressive symptoms accounted for 32% of the variance in QoL as measured by the Quality of Life Index. This study is the largest to date and found the highest prevalence of depression compared to prior studies. Our data provide more compelling evidence that individuals with NF1 are at increased risk for psychiatric morbidity and suggest that this population should be routinely screened for depression. Because depression was found to be strongly associated with QoL and accounted for nearly one-third of the variance in QoL, it is likely that effectively treating depression may significantly enhance QoL for individuals with NF1. C1 [Cohen, J. S.] Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. [Levy, H. P.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Levy, H. P.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Sloan, J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Dariotis, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Dariotis, J.] Univ Cincinnati, Coll Educ Criminal Justice & Human Serv, Cincinnati, OH USA. [Biesecker, B. B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, JS (reprint author), Kennedy Krieger Inst, Dept Neurol & Dev Med, 801 North Broadway,Room 564, Baltimore, MD 21205 USA. EM cohenju@kennedykrieger.org FU National Human Genome Research Institute FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute. We thank the individuals with NF1 who participated in the study and the NF1 support organizations, Neurofibromatosis Inc and Children's Tumor Foundation, for assisting us with study recruitment. This research was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 26 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD NOV PY 2015 VL 88 IS 5 BP 425 EP 430 DI 10.1111/cge.12551 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA CT3BW UT WOS:000362682200003 PM 25534182 ER PT J AU Vasu, S Berg, M Davidson-Moncada, J Tian, X Cullis, H Childs, RW AF Vasu, Sumithira Berg, Maria Davidson-Moncada, Jan Tian, Xin Cullis, Herb Childs, Richard W. TI A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation SO CYTOTHERAPY LA English DT Article DE cryopreserved cord blood; expanded NK cells; ex vivo expansion; natural killer cells; umbilical cord blood ID HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; ACTIVATING RECEPTORS; BONE-MARROW; NK CELLS; T-CELLS; ALLOREACTIVITY; PROFILE; ADULTS; LIGAND AB Background aims. Umbilical cord blood transplantation (UCBT) is increasingly used to treat acute leukemias. UCB units are thawed and infused in their entirety at transplant, precluding later use as immunotherapy to prevent or treat leukemia relapse. Methods. We developed a device that selectively thaws only 1 mL of the UCB unit, leaving the remaining UCB unit cryopreserved for subsequent transplantation. We also show that large numbers of CD56(+) natural killer (NK) cells can be expanded from these 1-mL fractions of selectively accessed UCB. Immunomagnetic depletion of CD3(+) cells of the 1-mL fraction was performed, and the cells were subsequently stimulated with irradiated Epstein-Barr virus transformed lymphoblastoid cell lines (EBV-LCLs) and set to culture in media containing interleukin (IL)-2. Results. When a 1:20 ratio of total nucleated cells to EBV-LCL feeder cells was used, day-21 and day-35 NK cell cultures initiated from 1 mL of UCB contained a median of 430 x 10(6) (range: 44-4321 x 10(6)) and 6092 x 10(6) (range: 165-20947 x 10(6)) CD3(-)CD56(+) NK cells. These cells expressed high levels of CD161, LFA-1, CD69, NKG2D, NKp30, NKp44, NKp80 and NKp46. UCB-derived NK cells were highly cytotoxic against K562 leukemia cells, although cytotoxicity was slightly lower than in expanded PBMC-derived NK cells. Conclusions. We have developed and optimized a strategy to selectively access a small fraction from cryopreserved UCB and show that large numbers of CD56(+) cells can be expanded from this selectively accessed fraction. This strategy presents a method to explore whether early adoptive transfer of NK cells expanded from the same UCB unit used for transplantation can prevent leukemic relapse and decrease graft-versus-host disease after UCBT. C1 [Vasu, Sumithira] Ohio State Univ, Div Hematol, Columbus, OH 43210 USA. [Berg, Maria; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Davidson-Moncada, Jan] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Cullis, Herb] Amer Flouroseal Corp, Gaithersburg, MD USA. RP Childs, RW (reprint author), NHLBI, NIH, Bldg 10,Room 3E-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM childsr@nhlbi.nih.gov OI Tian, Xin/0000-0003-1896-2462 FU Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 49 TC 4 Z9 4 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD NOV PY 2015 VL 17 IS 11 BP 1582 EP 1593 DI 10.1016/j.jcyt.2015.07.020 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CT2DV UT WOS:000362613100009 PM 26432560 ER PT J AU Hirschfeld, S AF Hirschfeld, Steven TI A child is a child is a child? Paediatric terminology in a health context SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Editorial Material AB This commentary is on the systematic review by Clark et al. on pages 1011-1018 of this issue. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20852 USA. RP Hirschfeld, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20852 USA. RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 NR 1 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD NOV PY 2015 VL 57 IS 11 BP 985 EP 985 DI 10.1111/dmcn.12829 PG 1 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA CT3YG UT WOS:000362742200002 PM 26084814 ER PT J AU Morgun, A Dzutsev, A Dong, XX Greer, RL Sexton, DJ Ravel, J Schuster, M Hsiao, W Matzinger, P Shulzhenko, N AF Morgun, Andrey Dzutsev, Amiran Dong, Xiaoxi Greer, Renee L. Sexton, D. Joseph Ravel, Jacques Schuster, Martin Hsiao, William Matzinger, Polly Shulzhenko, Natalia TI Uncovering effects of antibiotics on the host and microbiota using transkingdom gene networks SO GUT LA English DT Article ID PSEUDOMONAS-AERUGINOSA; INTESTINAL MICROBIOTA; COMMENSAL BACTERIA; COEXPRESSION NETWORKS; IMMUNE-RESPONSES; GUT MICROBIOTA; PATHOGENESIS; PROTEIN; CANCER; LIFE AB Objective Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited. Design Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network. Results We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments. Conclusions In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics. C1 [Morgun, Andrey; Dong, Xiaoxi] Oregon State Univ, Coll Pharm, Corvallis, OR 97331 USA. [Dzutsev, Amiran] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick, MD 21701 USA. [Greer, Renee L.; Shulzhenko, Natalia] Oregon State Univ, Coll Vet Med, Corvallis, OR 97331 USA. [Sexton, D. Joseph; Schuster, Martin] Oregon State Univ, Dept Microbiol, Corvallis, OR 97331 USA. [Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Hsiao, William] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Morgun, Andrey; Matzinger, Polly; Shulzhenko, Natalia] NIAID, Ghost Lab, NIH, Bethesda, MD 20892 USA. RP Shulzhenko, N (reprint author), Oregon State Univ, 105 Dryden, Corvallis, OR 97331 USA. EM anemorgun@hotmail.com; natalia.shulzhenko@oregonstate.edu OI Ravel, Jacques/0000-0002-0851-2233 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Oregon State University Medical Research Foundation of Oregon FX Division of Intramural Research, National Institute of Allergy and Infectious Diseases. Oregon State University Medical Research Foundation of Oregon. NR 64 TC 16 Z9 16 U1 2 U2 34 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2015 VL 64 IS 11 BP 1732 EP 1743 DI 10.1136/gutjnl-2014-308820 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CT1WQ UT WOS:000362593700010 PM 25614621 ER PT J AU Zoulim, F Liang, TJ Gerbes, AL Aghemo, A Deuffic-Burban, S Dusheiko, G Fried, MW Pol, S Rockstroh, JK Terrault, NA Wiktor, S AF Zoulim, Fabien Liang, T. Jake Gerbes, Alexander L. Aghemo, Alessio Deuffic-Burban, Sylvie Dusheiko, Geoffrey Fried, Michael W. Pol, Stanislas Rockstroh, Juergen Kurt Terrault, Norah A. Wiktor, Stefan TI Hepatitis C virus treatment in the real world: optimising treatment and access to therapies SO GUT LA English DT Article ID SOFOSBUVIR PLUS RIBAVIRIN; GENOTYPE 1 INFECTION; SUSTAINED VIROLOGICAL RESPONSE; TREATMENT-EXPERIENCED PATIENTS; DIRECT-ACTING ANTIVIRALS; PROOF-OF-CONCEPT; PHASE 2A COHORT; OPEN-LABEL; LIVER-TRANSPLANTATION; COST-EFFECTIVENESS AB Chronic HCV infections represent a major worldwide public health problem and are responsible for a large proportion of liver related deaths, mostly because of HCV-associated hepatocellular carcinoma and cirrhosis. The treatment of HCV has undergone a rapid and spectacular revolution. In the past 5 years, the launch of direct acting antiviral drugs has seen sustained virological response rates reach 90% and above for many patient groups. The new treatments are effective, well tolerated, allow for shorter treatment regimens and offer new opportunities for previously excluded groups. This therapeutic revolution has changed the rules for treatment of HCV, moving the field towards an interferon-free era and raising the prospect of HCV eradication. This manuscript addresses the new challenges regarding treatment optimisation in the real world, improvement of antiviral efficacy in 'hard-to-treat' groups, the management of patients whose direct acting antiviral drug treatment was unsuccessful, and access to diagnosis and treatment in different parts of the world. C1 [Zoulim, Fabien] Univ Lyon 1, Canc Res Ctr Lyon, Hosp Civils Lyon, INSERM,U1052, F-69003 Lyon, France. [Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Gerbes, Alexander L.] Univ Hosp Munich, Klinikum LMU Munchen Grosshadern, Liver Ctr Munich, Munich, Germany. [Aghemo, Alessio] Fdn IRCCS Ca Granda Osped Maggiore Policlin, UO Gastroenterol & Epatol, Milan, Italy. [Deuffic-Burban, Sylvie] INSERM, IAME, UMR 1137, Paris, France. [Deuffic-Burban, Sylvie] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Deuffic-Burban, Sylvie] INSERM, LIRIC UMR995, Lille, France. [Deuffic-Burban, Sylvie] Univ Lille, Lille, France. [Dusheiko, Geoffrey] Royal Free Hosp, UCL Inst Liver & Digest Hlth, London NW3 2QG, England. [Fried, Michael W.] Univ N Carolina, UNC Liver Ctr, Chapel Hill, NC USA. [Pol, Stanislas] Univ Paris 05, INSERM, Inst Pasteur, USM20, Paris, France. [Pol, Stanislas] Univ Paris 05, Hop Cochin, AP HP, Dept Hepatol, Paris, France. [Rockstroh, Juergen Kurt] Univ Hosp Bonn, Dept Med 1, Bonn, Germany. [Terrault, Norah A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wiktor, Stefan] WHO, CH-1211 Geneva, Switzerland. RP Zoulim, F (reprint author), Univ Lyon 1, Canc Res Ctr Lyon, Hosp Civils Lyon, INSERM,U1052, F-69003 Lyon, France. EM fabien.zoulim@inserm.fr FU Gilead Sciences; Janssen; Merck; AbbVie; BMS; MSD; Bristol-Myers Squibb; Gilead; Glaxo; NIH; Roche; Boehringer Ingelheim; Vertex; Novartis; Sanofi; Glaxo Smith Kline; Abbott laboratories; Cipla; ViiV; NEAT-ID; Eisai; Biotest; Achillion; Gilead Sc FX AA received consulting and lecture fees from Gilead Sciences, Janssen, Merck, AbbVie, BMS, as well as grants and research support from Gilead Sciences. SD-B reports receiving research grants from Janssen and MSD; consultancy honoraria from AbbVie, Bristol-Myers Squibb, HEVA, Janssen, MSD and Public Health Expertise; and lecture fees from Bristol-Myers Squibb, Gilead and Janssen. GD acted as advisor to Gilead Sciences, Merck, Bristol Myers Squibb, Janssen and AbbVie. MWF reports research grant funding from AbbVie, Bristol-Myers Squibb, Gilead, Glaxo, Janssen, Merck, NIH and consultant funding from AbbVie, Bristol-Myers Squibb, Gilead, Glaxo, Janssen, Merck. ALG received grants from Gilead, MSD and Roche and advisory board fees from Bristol-Myers Squibb. SP has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, MSD, Novartis, Abbvie, Sanofi and Glaxo Smith Kline, and grants from Bristol-Myers Squibb, Gilead, Roche and MSD. JKR has received consulting and lecturing fees from Abbott laboratories, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Cipla, Gilead, Janssen, MSD, ViiV, and grants from NEAT-ID and Gilead. NAT received Grant support from Gilead, AbbVie, Eisai, Biotest, and consulting/advisory board fees from Bristol-Myers Squibb, MSD, Achillion, Janssen. FZ has received consulting and/or lecturing fees from Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Gilead Sc and MSD. NR 88 TC 30 Z9 30 U1 3 U2 11 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD NOV PY 2015 VL 64 IS 11 BP 1824 EP 1833 DI 10.1136/gutjnl-2015-310421 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CT1WQ UT WOS:000362593700022 PM 26449729 ER PT J AU Skinner, J Huang, CY Waisberg, M Felgner, PL Doumbo, OK Ongoiba, A Kayentao, K Traore, B Crompton, PD Williamson, KC AF Skinner, Jeff Huang, Chiung-Yu Waisberg, Michael Felgner, Philip L. Doumbo, Ogobara K. Ongoiba, Aissata Kayentao, Kassoum Traore, Boubacar Crompton, Peter D. Williamson, Kim C. TI Plasmodium falciparum Gametocyte-Specific Antibody Profiling Reveals Boosting through Natural Infection and Identifies Potential Markers of Gametocyte Exposure SO INFECTION AND IMMUNITY LA English DT Article ID TRANSMISSION-BLOCKING ANTIBODIES; SEXUAL STAGE ANTIGENS; IMMUNE-RESPONSES; VACCINE CANDIDATE; SEASONAL TRANSMISSION; MALARIA INFECTIONS; LIFE-CYCLE; PROTEIN; PFS230; EXPRESSION AB Malaria elimination efforts would benefit from vaccines that block transmission of Plasmodium falciparum gametocytes from humans to mosquitoes. A clear understanding of gametocyte-specific antibody responses in exposed populations could help determine whether transmission-blocking vaccines (TBV) would be boosted by natural gametocyte exposure, and also inform the development of serologic tools to monitor gametocyte exposure in populations targeted for malaria elimination. To this end, plasma was collected from Malian children and adults before and after the 6-month malaria season and probed against a microarray containing 1,204 P. falciparum proteins. Using publicly available proteomic data, we classified 91 proteins as gametocyte specific and 69 as proteins not expressed by gametocytes. The overall breadth and magnitude of gametocyte-specific IgG responses increased during the malaria season, although they were consistently lower than IgG responses to nongametocyte antigens. Notably, IgG specific for the TBV candidates Pfs48/45 and Pfs230 increased during the malaria season. In addition, IgGs specific for the gametocyte proteins Pfmdv1, Pfs16, PF3D7_1346400, and PF3D7_1024800 were detected in nearly all subjects, suggesting that seroconversion to these proteins may be a sensitive indicator of gametocyte exposure, although further studies are needed to determine the specificity and kinetics of these potential serologic markers. These findings suggest that TBV-induced immunity would be boosted through natural gametocyte exposure, and that antibody responses to particular antigens may reliably indicate gametocyte exposure. C1 [Skinner, Jeff; Waisberg, Michael; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Huang, Chiung-Yu] Johns Hopkins Univ, Div Biostat & Bioinformat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Felgner, Philip L.; Ongoiba, Aissata; Kayentao, Kassoum] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. [Felgner, Philip L.] Antigen Discovery Inc, Irvine, CA USA. [Doumbo, Ogobara K.; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Mali Int Ctr Excellence Res, Bamako, Mali. [Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60626 USA. RP Crompton, PD (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov; kwilli4@luc.edu RI Crompton, Peter/N-1130-2016; OI Skinner, Jeff/0000-0001-5697-0442 FU Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Public Health Service grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI069314, R43AI066791, U54AI065359, R01AI095916] FX This study was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by Public Health Service grants AI069314 (K.C.W.), R43AI066791 (P.L.F.), U54AI065359 (P.L.F.), and R01AI095916 (P.L.F.) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 50 TC 2 Z9 2 U1 3 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2015 VL 83 IS 11 BP 4229 EP 4236 DI 10.1128/IAI.00644-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NU UT WOS:000362494000006 PM 26283330 ER PT J AU Greenberg, DE Sturdevant, DE Marshall-Batty, KR Chu, J Pettinato, AM Virtaneva, K Lane, J Geller, BL Porcella, SF Gallin, JI Holland, SM Zarember, KA AF Greenberg, David E. Sturdevant, Daniel E. Marshall-Batty, Kimberly R. Chu, Jessica Pettinato, Anthony M. Virtaneva, Kimmo Lane, John Geller, Bruce L. Porcella, Stephen F. Gallin, John I. Holland, Steven M. Zarember, Kol A. TI Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCUS; GENE-EXPRESSION; POLYMORPHONUCLEAR LEUKOCYTES; CONSTITUTIVE APOPTOSIS; FRANCISELLA-TULARENSIS; ASPERGILLUS-FUMIGATUS; CYNOMOLGUS MACAQUES; BACTERIAL PATHOGENS; PERITONEAL-DIALYSIS; SEQUENCE-ANALYSIS AB Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation with G. bethesdensis and, simultaneously, in G. bethesdensis with normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation-and immunity-related genes were also altered. Upon interaction with PMN, G. bethesdensis altered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of Granulibacter growth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to Granulibacter. This study expands knowledge of microbial pathogenesis of Granulibacter in cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen. C1 [Greenberg, David E.; Marshall-Batty, Kimberly R.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Greenberg, David E.; Marshall-Batty, Kimberly R.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Greenberg, David E.; Marshall-Batty, Kimberly R.] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Sturdevant, Daniel E.; Virtaneva, Kimmo; Lane, John; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. [Chu, Jessica; Pettinato, Anthony M.; Gallin, John I.; Zarember, Kol A.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Geller, Bruce L.] Oregon State Univ, Dept Microbiol, Corvallis, OR 97331 USA. RP Zarember, KA (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kzarember@niaid.nih.gov OI Chu, Jessica/0000-0002-5763-873X FU Intramural Research Program of the NIH, NIAID FX This work was supported in part by the Intramural Research Program of the NIH, NIAID. NR 55 TC 1 Z9 1 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2015 VL 83 IS 11 BP 4277 EP 4292 DI 10.1128/IAI.00778-15 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NU UT WOS:000362494000011 PM 26283340 ER PT J AU Cash, DR Noinaj, N Buchanan, SK Cornelissen, CN AF Cash, Devin R. Noinaj, Nicholas Buchanan, Susan K. Cornelissen, Cynthia Nau TI Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae SO INFECTION AND IMMUNITY LA English DT Article ID BINDING PROTEIN-A; GONOCOCCAL TRANSFERRIN RECEPTOR; COMPLEMENT FACTOR-H; ENHANCED IMMUNOGENICITY; PATHOGENIC NEISSERIA; LIGAND-BINDING; IRON COMPOUNDS; GENITAL-TRACT; IDENTIFICATION; CEFTRIAXONE AB Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. However, the transferrin (Tf) receptor system, composed of TbpA and TbpB, is an ideal target for novel therapeutics and vaccine development. Using a three-dimensional structure of gonococcal TbpA, we investigated two hypotheses, i.e., that loop-derived antibodies can interrupt ligand-receptor interactions in the native bacterium and that the loop 3 helix is a critical functional domain. Preliminary loop-derived antibodies, as well as optimized second-generation antibodies, demonstrated similar modest ligand-blocking effects on the gonococcal surface but different effects in Escherichia coli. Mutagenesis of loop 3 helix residues was employed, generating 11 mutants. We separately analyzed the mutants' abilities to (i) bind Tf and (ii) internalize Tf-bound iron in the absence of the coreceptor TbpB. Single residue mutations resulted in up to 60% reductions in ligand binding and up to 85% reductions in iron utilization. All strains were capable of growing on Tf as the sole iron source. Interestingly, in the presence of TbpB, only a 30% reduction in Tf-iron utilization was observed, indicating that the coreceptor can compensate for TbpA impairment. Complete deletion of the loop 3 helix of TbpA eliminated the abilities to bind Tf, internalize iron, and grow with Tf as the sole iron source. Our studies demonstrate that while the loop 3 helix is a key functional domain, its function does not exclusively rely on any single residue. C1 [Cash, Devin R.; Cornelissen, Cynthia Nau] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Noinaj, Nicholas; Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cornelissen, CN (reprint author), Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. EM cncornel@vcu.edu FU Public Health Service grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 AI065555, R01 AI084400, U19 AI31496]; National Institute of Allergy and Infectious Diseases, National Institutes of Health [F30 AI112199]; intramural research program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases FX Funding for this work was provided to C.N.C. by Public Health Service grants R01 AI065555, R01 AI084400, and U19 AI31496 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. D.R.C. was supported by fellowship grant F30 AI112199 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. N.N. and S.K.B. were supported by the intramural research program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases. NR 49 TC 1 Z9 1 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2015 VL 83 IS 11 BP 4438 EP 4449 DI 10.1128/IAI.00762-15 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NU UT WOS:000362494000025 PM 26351283 ER PT J AU DuPont, RL Compton, WM McLellan, AT AF DuPont, Robert L. Compton, Wilson M. McLellan, A. Thomas TI Five-Year Recovery: A New Standard for Assessing Effectiveness of Substance Use Disorder Treatment SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Editorial Material ID HEALTH-PROGRAMS; OUTCOMES; PREDICTORS; DEPENDENCE C1 [DuPont, Robert L.] Inst Behav & Hlth Inc, Rockville, MD 20852 USA. [Compton, Wilson M.] NIDA, Rockville, MD 20852 USA. [McLellan, A. Thomas] Treatment Res Inst, Philadelphia, PA 19106 USA. RP Compton, WM (reprint author), NIDA, 6001 Execut Blvd, Rockville, MD 20852 USA. EM bobdupont@aol.com; wcompton@nida.nih.gov; TMcLellan@tresearch.org NR 21 TC 4 Z9 4 U1 0 U2 2 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 NOV PY 2015 VL 58 BP 1 EP 5 DI 10.1016/j.jsat.2015.06.024 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CS8BZ UT WOS:000362312000001 PM 26277423 ER PT J AU Shih, JH Albert, PS Mendola, P Grantz, KL AF Shih, Joanna H. Albert, Paul S. Mendola, Pauline Grantz, Katherine L. TI Modelling the type and timing of consecutive events: application to predicting preterm birth in repeated pregnancies SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Adverse pregnancy outcome; Normal copula; Polychotomous random-effects logistic model; Pre-eclampsia; Preterm birth; Repeated pregnancies ID COMPETING RISK; OUTCOMES AB Predicting the occurrence and timing of adverse pregnancy events such as preterm birth is an important analytical challenge in obstetrical practice. Developing statistical approaches that can be used to assess the risk and timing of these adverse events will provide clinicians with tools for individualized risk assessment that account for a woman's prior pregnancy history. Often adverse pregnancy outcomes are subject to competing events; for example, interest may focus on the occurrence of pre-eclampsia-related preterm birth, where preterm birth for other reasons may serve as a competing event. We propose modelling the type and timing of adverse outcomes in repeated pregnancies. We formulate a joint model, where types of adverse outcomes across repeated pregnancies are modelled by using a polychotomous logistic regression model with random effects, and gestational ages at delivery are modelled conditionally on the types of adverse outcome. The correlation between gestational ages conditional on the adverse pregnancies is modelled by the semiparametric normal copula function. We present a two-stage estimation method and develop the asymptotic theory for the estimators proposed. The model and estimation procedure proposed are applied to the National Institute of Child Health and Human Development consecutive pregnancies study data and evaluated by simulations. C1 [Shih, Joanna H.] NCI, Bethesda, MD 20892 USA. [Albert, Paul S.; Mendola, Pauline; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Shih, JH (reprint author), NCI, Biometr Res Branch, Room 5W124,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM jshih@mail.nih.gov OI Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU NICHD NIH HHS [HHSN275200800002I] NR 13 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 EI 1467-9876 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD NOV PY 2015 VL 64 IS 5 BP 711 EP 730 DI 10.1111/rssc.12100 PG 20 WC Statistics & Probability SC Mathematics GA CT3FL UT WOS:000362692500001 PM 27239073 ER PT J AU Tietbohl, CK Rendle, KAS Halley, MC May, SG Lin, GA Frosch, DL AF Tietbohl, Caroline K. Rendle, Katharine A. S. Halley, Meghan C. May, Suepattra G. Lin, Grace A. Frosch, Dominick L. TI Implementation of Patient Decision Support Interventions in Primary Care: The Role of Relational Coordination SO MEDICAL DECISION MAKING LA English DT Article DE relational coordination; decision support interventions; patient engagement; implementation; qualitative methodologies ID CLINICAL-PRACTICE; AIDS AB Background. The benefits of patient decision support interventions (DESIs) have been well documented. However, DESIs remain difficult to incorporate into clinical practice. Relational coordination (RC) has been shown to improve performance and quality of care in health care settings. This study aims to demonstrate how applying RC theory to DESI implementation could elucidate underlying issues limiting widespread uptake. Methods. Five primary care clinics in Northern California participated in a DESI implementation project. We used a deductive thematic approach guided by behaviors outlined in RC theory to analyze qualitative data collected from ethnographic field notes documenting the implementation process and focus groups with health care professionals. We then systematically compared the qualitative findings with quantitative DESI distribution data. Results. Based on DESI distribution rates, clinics were placed into 3 performance categories: high, middle, and low. Qualitative data illustrated how each clinic's performance related to RC behaviors. Consistent with RC theory, the high-performing clinic exhibited frequent, timely, and accurate communication and positive working relationships. The 3 middle-performing clinics exhibited high-quality communication within physician-staff teams but limited communication regarding DESI implementation across the clinic. The lowest-performing clinic was characterized by contentious relationships and inadequate communication. Limitations. Limitations of the study include nonrandom selection of clinics and limited geographic diversity. In addition, ethnographic data collected documented only DESI implementation practices and not larger staff interactions contributing to RC. Conclusions. These findings suggest that a high level of RC within clinical settings may be a key component and facilitator of successful DESI implementation. Future attempts to integrate DESIs into clinical practice should consider incorporating interventions designed to increase positive RC behaviors as a potential means to improve uptake. C1 [Tietbohl, Caroline K.; Frosch, Dominick L.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Tietbohl, Caroline K.; Rendle, Katharine A. S.; Halley, Meghan C.; May, Suepattra G.; Frosch, Dominick L.] Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. [Rendle, Katharine A. S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [May, Suepattra G.] Precis Hlth Econ, Los Angeles, CA USA. [Lin, Grace A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Frosch, Dominick L.] Gordon & Betty Moore Fdn, Palo Alto, CA USA. RP Tietbohl, CK (reprint author), Univ Calif Los Angeles, 405 Hilgard Ave, Los Angeles, CA 90095 USA. EM ctietbohl@ucla.edu FU Informed Medical Decisions Foundation FX This study was funded by a grant from the Informed Medical Decisions Foundation. The funders did not influence data collection, interpretation, or publication. The authors also thank Harold S. Luft, PhD, Laurel Trujillo, MD, and R. Adams Dudley, MD, MBA, for their assistance in designing the project and Carla Arellano-Bravo for her contributions to data collection. NR 22 TC 1 Z9 1 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD NOV PY 2015 VL 35 IS 8 BP 987 EP 998 DI 10.1177/0272989X15602886 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA CS9YT UT WOS:000362450800007 PM 26314727 ER PT J AU Holmberg, C Waters, EA Whitehouse, K Daly, M McCaskill-Stevens, W AF Holmberg, Christine Waters, Erika A. Whitehouse, Katie Daly, Mary McCaskill-Stevens, Worta TI My Lived Experiences Are More Important Than Your Probabilities: The Role of Individualized Risk Estimates for Decision Making about Participation in the Study of Tamoxifen and Raloxifene (STAR) SO MEDICAL DECISION MAKING LA English DT Article DE individualized risk information; lived experiences; narrative interviews; decision making; chemoprevention; breast cancer risk ID BREAST-CANCER CHEMOPREVENTION; SURGICAL ADJUVANT BREAST; BOWEL PROJECT; PRIMARY-CARE; P-2 TRIAL; US WOMEN; PREVENTION; HEALTH; INFORMATION; PERCEPTIONS AB Background: Decision-making experts emphasize that understanding and using probabilistic information are important for making informed decisions about medical treatments involving complex risk-benefit tradeoffs. Yet empirical research demonstrates that individuals may not use probabilities when making decisions. Objectives: To explore decision making and the use of probabilities for decision making from the perspective of women who were risk-eligible to enroll in the Study of Tamoxifen and Raloxifene (STAR). Methods: We conducted narrative interviews with 20 women who agreed to participate in STAR and 20 women who declined. The project was based on a narrative approach. Analysis included the development of summaries of each narrative, and thematic analysis with developing a coding scheme inductively to code all transcripts to identify emerging themes. Results: Interviewees explained and embedded their STAR decisions within experiences encountered throughout their lives. Such lived experiences included but were not limited to breast cancer family history, a personal history of breast biopsies, and experiences or assumptions about taking tamoxifen or medicines more generally. Conclusions: Women's explanations of their decisions about participating in a breast cancer chemoprevention trial were more complex than decision strategies that rely solely on a quantitative risk-benefit analysis of probabilities derived from populations In addition to precise risk information, clinicians and risk communicators should recognize the importance and legitimacy of lived experience in individual decision making. C1 [Holmberg, Christine; Whitehouse, Katie] Charite, Berlin Sch Publ Hlth, D-13347 Berlin, Germany. [Waters, Erika A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Daly, Mary] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [McCaskill-Stevens, Worta] NCI, Rockville, MD USA. RP Holmberg, C (reprint author), Charite, Berlin Sch Publ Hlth, Seestr 73 Haus 10, D-13347 Berlin, Germany. EM Christine.holmberg@charite.de FU Public Health Service from the National Cancer Institute, Department of Health and Human Services [UG1-189867]; Barnes-Jewish Hospital Foundation FX Supported by Public Health Service Grant UG1-189867 from the National Cancer Institute, Department of Health and Human Services. This research was conducted while Holmberg and Waters were cancer prevention fellows at the National Cancer Institute. Waters was also supported by the Barnes-Jewish Hospital Foundation. Revision accepted for publication 7 June 2015. NR 50 TC 2 Z9 2 U1 4 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD NOV PY 2015 VL 35 IS 8 BP 1010 EP 1022 DI 10.1177/0272989X15594382 PG 13 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA CS9YT UT WOS:000362450800009 PM 26183166 ER PT J AU Radin, RG Rothman, KJ Hatch, EE Mikkelsen, EM Sorensen, HT Riis, AH Fox, MP Wise, LA AF Radin, Rose G. Rothman, Kenneth J. Hatch, Elizabeth E. Mikkelsen, Ellen M. Sorensen, Henrik T. Riis, Anders H. Fox, Matthew P. Wise, Lauren A. TI Maternal Recall Error in Retrospectively Reported Time-to-Pregnancy: an Assessment and Bias Analysis SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Bias (Epidemiology); Cohort Studies; Fertility Determinants ID COHORT PROFILE; FECUNDABILITY; QUESTIONNAIRE; VALIDITY; FERTILITY AB BackgroundEpidemiologic studies of fecundability often use retrospectively measured time-to-pregnancy (TTP), thereby introducing potential for recall error. Little is known about how recall error affects the bias and precision of the fecundability odds ratio (FOR) in such studies. MethodsUsing data from the Danish Snart-Gravid Study (2007-12), we quantified error for TTP recalled in the first trimester of pregnancy relative to prospectively measured TTP among 421 women who enrolled at the start of their pregnancy attempt and became pregnant within 12 months. We defined recall error as retrospectively measured TTP minus prospectively measured TTP. Using linear regression, we assessed mean differences in recall error by maternal characteristics. We evaluated the resulting bias in the FOR and 95% confidence interval (CI) using simulation analyses that compared corrected and uncorrected retrospectively measured TTP values. ResultsRecall error (mean=-0.11 months, 95% CI -0.25, 0.04) was not appreciably associated with maternal age, gravidity, or recent oral contraceptive use. Women with TTP>2 months were more likely to underestimate their TTP than women with TTP2 months (unadjusted mean difference in error: -0.40 months, 95% CI -0.71, -0.09). FORs of recent oral contraceptive use calculated from prospectively measured, retrospectively measured, and corrected TTPs were 0.82 (95% CI 0.67, 0.99), 0.74 (95% CI 0.61, 0.90), and 0.77 (95% CI 0.62, 0.96), respectively. ConclusionsRecall error was small on average among pregnancy planners who became pregnant within 12 months. Recall error biased the FOR of recent oral contraceptive use away from the null by 10%. Quantitative bias analysis of the FOR can help researchers quantify the bias from recall error. C1 [Radin, Rose G.; Rothman, Kenneth J.; Hatch, Elizabeth E.; Sorensen, Henrik T.; Fox, Matthew P.; Wise, Lauren A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Fox, Matthew P.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02118 USA. [Wise, Lauren A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02118 USA. [Radin, Rose G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, North Bethesda, MD USA. [Rothman, Kenneth J.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Mikkelsen, Ellen M.; Sorensen, Henrik T.; Riis, Anders H.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. RP Radin, RG (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St, Boston, MA 02118 USA. EM radin@bu.edu OI Riis, Anders Hammerich/0000-0002-6684-4068 FU National Institutes of Health [R21-HD050264]; Danish Medical Research Council [271-07-0338]; National Institutes of Health Intramural Research Training Award; [T32-HD052458] FX This study was supported by the National Institutes of Health (R21-HD050264) and the Danish Medical Research Council (271-07-0338). RGR was supported by training grant T32-HD052458 and by a National Institutes of Health Intramural Research Training Award. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. NR 20 TC 5 Z9 5 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2015 VL 29 IS 6 BP 576 EP 588 DI 10.1111/ppe.12245 PG 13 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA CT3RG UT WOS:000362723900014 PM 26443987 ER PT J AU Compton, WM Boyle, M Wargo, E AF Compton, Wilson M. Boyle, Maureen Wargo, Eric TI Prescription opioid abuse: Problems and responses SO PREVENTIVE MEDICINE LA English DT Editorial Material DE Prescription opioid abuse; Addiction; Overdose ID DRUG OVERDOSE DEATHS; UNITED-STATES; NALOXONE DISTRIBUTION; POLICE OFFICERS; PAIN RELIEVERS; PREVENTION; EPIDEMIC; PROGRAMS; LEVEL; MASSACHUSETTS AB Prescription opioid abuse and addiction, along with consequences such as overdose death and increasing transition to heroin use, constitute a devastating public health problem in the United States. Increasingly it is clear that overprescription of these medications over the past two decades has been a major upstream driver of the opioid abuse epidemic. This commentary considers the factors that have led to overprescription of opioids by clinicians, discusses recent evidence casting doubt on the efficacy of opioids for treating chronic pain, and describes the ongoing efforts by federal and community stakeholders to address this epidemic-for example, supporting prescription drug monitoring programs and improved clinician training in pain management to help reduce the supply of opioids, increasing dissemination of evidence-based primary prevention programs to reduce demand for opioids, and expanding access to effective opioid agonist therapies and antagonist medications for both treatment and overdose prevention. Published by Elsevier Inc. C1 [Compton, Wilson M.; Boyle, Maureen; Wargo, Eric] NIDA, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Compton, WM (reprint author), NIDA, 6001 Executive Blvd,MSC 9581, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 58 TC 14 Z9 14 U1 10 U2 42 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD NOV PY 2015 VL 80 SI SI BP 5 EP 9 DI 10.1016/j.ypmed.2015.04.003 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CT0DF UT WOS:000362463400002 PM 25871819 ER PT J AU DuMond, JF He, Y Burg, MB Ferraris, JD AF DuMond, Jenna F. He, Yi Burg, Maurice B. Ferraris, Joan D. TI Expression, fermentation and purification of a predicted intrinsically disordered region of the transcription factor, NFAT5 SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Intrinsically disordered proteins; Transcription factors; Hypertonicity; Fermentation ID ENHANCER-BINDING PROTEIN; TONICITY AB Hypertonicity stimulates Nuclear Factor of Activated T-cells 5 (NFAT5) nuclear localization and transactivating activity. Many transcription factors are known to contain intrinsically disordered regions (IDRs) which become more structured with local environmental changes such as osmolality, temperature and tonicity. The transactivating domain of NFAT5 is predicted to be intrinsically disordered under normal tonicity, and under high NaCl, the activity of this domain is increased. To study the binding of coregulatory proteins at IDRs a cDNA construct expressing the NFAT5 TAD was created and transformed into Escherichia colt cells. Transformed E. coli cells were mass produced by fermentation and extracted by cell lysis to release the NFAT5 TAD. The NFAT5 TAD was subsequently purified using a His-tag column, cation exchange chromatography as well as hydrophobic interaction chromatography and then characterized by mass spectrometry (MS). Published by Elsevier Inc. C1 [DuMond, Jenna F.; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, NIH, Syst Biol Ctr, Bethesda, MD 20892 USA. [He, Yi] NHLBI, NIH, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. RP DuMond, JF (reprint author), NHLBI, NIH, Syst Biol Ctr, Bethesda, MD 20892 USA. EM jenna.dumond@nih.gov; hey4@nhlbi.nih.gov; burgm@mail.nih.gov; ferraris@nhlbi.nih.gov FU NIH NHLBI Biochemistry Core FX We would like to thank the by the NIH NHLBI Biochemistry Core for their support of this work acquiring the HPLC-MS data and analysis. NR 14 TC 0 Z9 0 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD NOV PY 2015 VL 115 BP 141 EP 145 DI 10.1016/j.pep.2015.08.003 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA CT2HS UT WOS:000362623200019 PM 26256058 ER PT J AU Barker, TV Reeb-Sutherland, B Degnan, KA Walker, OL Chronis-Tuscano, A Henderson, HA Pine, DS Fox, NA AF Barker, Tyson V. Reeb-Sutherland, Bethany Degnan, Kathryn A. Walker, Olga L. Chronis-Tuscano, Andrea Henderson, Heather A. Pine, Daniel S. Fox, Nathan A. TI Contextual startle responses moderate the relation between behavioral inhibition and anxiety in middle childhood SO PSYCHOPHYSIOLOGY LA English DT Article DE Temperament; Risk factors; Startle; Behavioral inhibition; Anxiety ID ADOLESCENT SOCIAL ANXIETY; TEMPERAMENT; DISORDERS; CHILDREN; REPLICATION; MODULATION; REACTIVITY; RISK; FEAR; STABILITY AB Behavioral inhibition (BI), a temperament characterized in early childhood by wariness and avoidance of novelty, is a risk factor for anxiety disorders. An enhanced startle response has been observed in adolescents characterized with BI in childhood, particularly when they also manifest concurrent symptoms of anxiety. However, no prior study has examined relations among BI, startle responsivity, and anxiety in a prospective manner. Data for the present study were from a longitudinal study of infant temperament. Maternal reports and observations of BI were assessed at ages 2 and 3. At age 7, participants completed a startle procedure, while electromyography was collected, where participants viewed different colors on a screen that were associated with either the delivery of an aversive stimulus (i.e., puff of air to the larynx; threat cue) or the absence of the aversive stimulus (i.e., safety cue). Parental reports of child anxiety were collected when children were 7 and 9 years of age. Results revealed that startle responses at age 7 moderated the relation between early BI and 9-year anxiety. These findings provide insight into one potential mechanism that may place behaviorally inhibited children at risk for anxiety. C1 [Barker, Tyson V.; Degnan, Kathryn A.; Walker, Olga L.; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. [Reeb-Sutherland, Bethany] Florida Int Univ, Dept Psychol, Miami, FL 33199 USA. [Chronis-Tuscano, Andrea] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Henderson, Heather A.] Univ Waterloo, Dept Psychol, Waterloo, ON N2L 3G1, Canada. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Barker, TV (reprint author), Univ Maryland, Dept Human Dev & Quantitat Methodol, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM tvbarker@umd.edu FU Intramural NIH HHS; NICHD NIH HHS [5T32HD007542, T32 HD007542]; NIMH NIH HHS [MH093349, R01 MH074454] NR 43 TC 4 Z9 4 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD NOV PY 2015 VL 52 IS 11 BP 1544 EP 1549 DI 10.1111/psyp.12517 PG 6 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA CT0OW UT WOS:000362497000013 PM 26332665 ER PT J AU Tarasenko, TN Singh, LN Chatterji-Len, M Zerfas, PM Cusmano-Ozog, K McGuire, PJ AF Tarasenko, Tatyana N. Singh, Larry N. Chatterji-Len, Milani Zerfas, Patricia M. Cusmano-Ozog, Kristina McGuire, Peter J. TI Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE beta-oxidation; Fatty acids; Metabolism; Innate immune response; Influenza ID UREA CYCLE DISORDERS; ACUTE METABOLIC DECOMPENSATION; TUMOR-NECROSIS-FACTOR; ISOLATED RAT HEPATOCYTES; NUTRITIONAL MANAGEMENT; ADAPTIVE IMMUNITY; ENERGY-METABOLISM; NITRIC-OXIDE; FACTOR-ALPHA; LIVER AB In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57B1/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and camitine species. These metabolic adaptations coincided with a depression in hepatic long chain 3-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in 3-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection. (C) 2015 Published by Elsevier B.V. C1 [Tarasenko, Tatyana N.; Chatterji-Len, Milani; McGuire, Peter J.] NHGRI, Metab Infect & Immun Unit, NIH, Bethesda, MD 20892 USA. [Singh, Larry N.] Childrens Hosp Philadelphia, Dept Pathol, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Zerfas, Patricia M.] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Cusmano-Ozog, Kristina] Childrens Natl Med Ctr, Biochem Genet & Metab Lab, Washington, DC 20010 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A62, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU Intramural Research Program of the National Institutes of Health [HG200381-03] FX This work was supported by the Intramural Research Program of the National Institutes of Health (HG200381-03). NR 57 TC 0 Z9 0 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD NOV PY 2015 VL 1852 IS 11 BP 2391 EP 2401 DI 10.1016/j.bbadis.2015.08.021 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CS5QJ UT WOS:000362132700006 PM 26319418 ER PT J AU Blair, RJ AF Blair, R. James TI Reward Processing, Functional Connectivity, Psychopathy, and Research Domain Criteria SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DISRUPTIVE BEHAVIOR DISORDERS; EXPECTED VALUE C1 NIMH, Sect Affect & Cognit Neurosci, NIH, Bethesda, MD 20892 USA. RP Blair, RJ (reprint author), NIMH, Sect Affect & Cognit Neurosci, NIH, Bldg 15k,Room 300-E,MSC 2670,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jamesblair@mail.nih.gov FU Intramural NIH HHS [Z01 MH002860-03] NR 10 TC 0 Z9 0 U1 4 U2 18 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 NOV 1 PY 2015 VL 78 IS 9 BP 592 EP 593 DI 10.1016/j.biopsych.2015.08.014 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CS7OB UT WOS:000362271800001 PM 26434627 ER PT J AU Barrett, T Turkbey, B Choyke, PL AF Barrett, T. Turkbey, B. Choyke, P. L. TI PI-RADS version 2: what you need to know SO CLINICAL RADIOLOGY LA English DT Review ID CONTRAST-ENHANCED MRI; BENIGN PROSTATIC HYPERPLASIA; DIFFUSION-WEIGHTED MRI; RADICAL PROSTATECTOMY; CANCER-DETECTION; EXTRACAPSULAR EXTENSION; ACTIVE SURVEILLANCE; PERIPHERAL ZONE; INITIAL BIOPSY; FOCAL THERAPY AB Prostate cancer is the second most prevalent cancer in men worldwide and its incidence is expected to double by 2030. Multi-parametric magnetic resonance imaging (MRI) incorporating anatomical and functional imaging has now been validated as a means of detecting and characterising prostate tumours and can aid in risk stratification and treatment selection. The European Society of Urogenital Radiology (ESUR) in 2012 established the Prostate Imaging-Reporting and Data System (PI-RADS) guidelines aimed at standardising the acquisition, interpretation and reporting of prostate MRI. Subsequent experience and technical developments have highlighted some limitations, and a joint steering committee formed by the American College of Radiology, ESUR, and the AdMeTech Foundation have recently announced an updated version of the proposals. We summarise the main proposals of PI-RADS version 2, explore the evidence behind the recommendations, and highlight key differences for the benefit of those already familiar with the original. (C) 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Barrett, T.] Addenbrookes Hosp, Dept Radiol, Cambridge CB2 0QQ, England. [Barrett, T.] Univ Cambridge, Cambridge CB2 0QQ, England. [Turkbey, B.; Choyke, P. L.] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Barrett, T (reprint author), Addenbrookes Hosp, Dept Radiol, Cambridge CB2 0QQ, England. EM tristan.barrett@addenbrookes.nhs.uk FU Cancer Research UK; Engineering and Physical Sciences Research Council Imaging Centre in Cambridge; Engineering and Physical Sciences Research Council Imaging Centre in Manchester; NIHR Biomedical Research Centre FX Author TB is supported by the Cancer Research UK and Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the NIHR Biomedical Research Centre. NR 48 TC 25 Z9 26 U1 0 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0009-9260 EI 1365-229X J9 CLIN RADIOL JI Clin. Radiol. PD NOV PY 2015 VL 70 IS 11 BP 1165 EP 1176 DI 10.1016/j.crad.2015.06.093 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS2MF UT WOS:000361904300003 PM 26231470 ER PT J AU Pandiyan, P Zhu, JF AF Pandiyan, Pushpa Zhu, Jinfang TI Origin and functions of pro-inflammatory cytokine producing Foxp3(+) regulatory T cells SO CYTOKINE LA English DT Review DE T-reg; Th17; IL-17; Foxp3; Suppression; Inflammation; Cytokine; Reprogramming ID VERSUS-HOST-DISEASE; TRANSCRIPTION FACTOR FOXP3; TOLL-LIKE-RECEPTORS; TREG-MEDIATED SUPPRESSION; ROR-GAMMA-T; TH17 CELLS; IN-VIVO; CANDIDA-ALBICANS; CUTTING EDGE; TGF-BETA AB CD4(+)CD25(+)Foxp3(+) regulatory cells (T-regs) are a special lineage of cells central in the maintenance of immune homeostasis, and are targeted for human immunotherapy. They are conventionally associated with the production of classical anti-inflammatory cytokines such as IL-10, TGF-beta and IL-35, consistent to their anti-inflammatory functions. However, emerging evidence show that they also express effector cytokines such as IFN-gamma and IL-17A under inflammatory conditions. While some studies reveal that these pro-inflammatory cytokine producing Foxp3(+) regulatory cells retain their suppressive ability, others believe that these cells are dys-regulated and are associated with perpetuation of immunopathology. Therefore the development of these cells may challenge the efficacy of human T-reg therapy. Mechanistically, toll-like receptor (TLR) ligands and the pro-inflammatory cytokine milieu have been shown to play important roles in the induction of effector cytokines in T-regs. Here we review the mechanisms of development and the possible functions of pro-inflammatory cytokine producing Foxp3+ T-regs. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Pandiyan, Pushpa] Case Western Reserve Univ, Sch Dent Med, Dept Biol Sci, Cleveland, OH 44106 USA. [Zhu, Jinfang] NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Pandiyan, P (reprint author), Case Western Reserve Univ, Sch Dent Med, Dept Biol Sci, Cleveland, OH 44106 USA. EM pxp226@case.edu RI Zhu, Jinfang/B-7574-2012 FU Intramural NIH HHS [ZIA AI001169-03]; NIAMS NIH HHS [P30 AR039750, P30AR39750] NR 202 TC 11 Z9 15 U1 3 U2 24 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 NOV PY 2015 VL 76 IS 1 BP 13 EP 24 DI 10.1016/j.cyto.2015.07.005 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400002 PM 26165923 ER PT J AU Abdi, K Singh, NJ AF Abdi, Kaveh Singh, Nevil J. TI Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines SO CYTOKINE LA English DT Review DE IL-12; Dendritic cells; Innate activation; T cell differentiation; Hypothesis; Immunological class; Tissue immunity ID NITRIC-OXIDE SYNTHASE; P40 HOMODIMER; T-CELLS; ADAPTIVE IMMUNITY; IFN-GAMMA; MYCOBACTERIAL INFECTION; INTERLEUKIN-12 P40; HUMAN-LYMPHOCYTES; DENDRITIC CELLS; MICE AB How dendritic cells (DCs) gather information from the local milieu at a site of infection or injury and communicate this to influence adaptive immunity is not well understood. We and others have reported that soon after microbial encounter, DCs secrete the p40 subunit of IL-12, by itself, in a monomeric form. Based on recent data that this p40 monomer subsequently associates with p35 released from other cells to generate functional IL-12, we proposed that p40 can function as a DC-derived probe which samples the composition of the local milieu by looking for other binding partners. In this opinion, we discuss how such a sampling function might generate an elaborate combinatorial "code" of heterodimeric cytokines, capable of conveying location-specific information to cells downstream of DC activation, including NK and T cells. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Abdi, Kaveh] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Singh, Nevil J.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Singh, NJ (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 685 W Baltimore St,HSF1,Room 380, Baltimore, MD 21201 USA. EM nsingh@som.umaryland.edu FU NIAID NIH HHS [R01 AI110719, R01AI110719, R56 AI113313, R56AI113313] NR 66 TC 3 Z9 3 U1 2 U2 7 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 NOV PY 2015 VL 76 IS 1 BP 53 EP 57 DI 10.1016/j.cyto.2015.07.026 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400006 PM 26242928 ER PT J AU Goldbach-Mansky, R AF Goldbach-Mansky, Raphaela TI Genetically defined autoinflammatory diseases SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Goldbach-Mansky, Raphaela] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2015 VL 76 IS 1 MA 6 BP 58 EP 58 DI 10.1016/j.cyto.2015.08.010 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400009 ER PT J AU Sher, A Antonelli, L Feng, C Costa, D Andrade, B O'Garra, A Mayer-Marber, K AF Sher, Alan Antonelli, L. Feng, C. Costa, D. Andrade, B. O'Garra, A. Mayer-Marber, K. TI The probacterial activity of Type I interferons: a target for disease intervention? SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Sher, Alan; Costa, D.; Mayer-Marber, K.] NIAID, NIH, Bethesda, MD 20892 USA. [Antonelli, L.] Fiocruz MS, Belo Horizonte, MG, Brazil. [Feng, C.] Univ Sydney, Sydney, NSW 2006, Australia. [Andrade, B.] Fiocruz MS, Salvador, BA, Brazil. [O'Garra, A.] Francis Crick Inst, London, England. NR 0 TC 0 Z9 0 U1 0 U2 2 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 NOV PY 2015 VL 76 IS 1 MA 15 BP 59 EP 60 DI 10.1016/j.cyto.2015.08.019 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400018 ER PT J AU Mayer-Barber, K AF Mayer-Barber, Katrin TI Type I IFN modulation as host-directed therapy during non-viral pulmonary infections SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Mayer-Barber, Katrin] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2015 VL 76 IS 1 MA 149 BP 64 EP 64 DI 10.1016/j.cyto.2015.08.040 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400038 ER PT J AU Yoo, KH Shin, HY Oh, SM Hennighausen, L AF Yoo, Kyung Hyun Shin, Ha Youn Oh, Sumin Hennighausen, Lothar TI Fences make good neighbors: staying out of your neighbor's genetic yard SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Yoo, Kyung Hyun; Shin, Ha Youn; Oh, Sumin; Hennighausen, Lothar] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2015 VL 76 IS 1 MA 251 BP 65 EP 65 DI 10.1016/j.cyto.2015.08.043 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400041 ER PT J AU Bedsaul, J Zaritsky, L Zoon, K AF Bedsaul, Jacquelyn Zaritsky, Luna Zoon, Kathryn TI The diverse roles of type I interferon in response to EMCV and SeV infections SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Bedsaul, Jacquelyn; Zaritsky, Luna; Zoon, Kathryn] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2015 VL 76 IS 1 MA 31 BP 69 EP 69 DI 10.1016/j.cyto.2015.08.061 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400058 ER PT J AU Zaritsky, L Bedsaul, J Zoon, K AF Zaritsky, Luna Bedsaul, Jacquelyn Zoon, Kathryn TI Virus MOI affects type I IFN subtype induction profiles and ISGs SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Zaritsky, Luna; Bedsaul, Jacquelyn; Zoon, Kathryn] NIAID, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 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 NOV PY 2015 VL 76 IS 1 MA 30 BP 69 EP 69 DI 10.1016/j.cyto.2015.08.060 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400057 ER PT J AU Gibbert, K Lavender, K Peterson, ME Munch, J Piehler, J Santiago, ML Verheyen, J Hasenkrug, K Dittmer, U AF Gibbert, Kathrin Lavender, Kerry. Peterson, Mann E. Muench, Jan Piehler, Jacob Santiago, Mario L. Verheyen, Jens Hasenkrug, Kim Dittmer, Ulf TI Treatment with interferon alpha subtype 14 potently suppresses HIV infection in humanized mice SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Gibbert, Kathrin; Verheyen, Jens; Dittmer, Ulf] Univ Duisburg Essen, Essen, Germany. [Lavender, Kerry.; Peterson, Mann E.; Hasenkrug, Kim] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Muench, Jan] Univ Ulm, Med Ctr, Inst Mol Virol, D-89069 Ulm, Germany. [Piehler, Jacob] Univ Osnabruck, D-49069 Osnabruck, Germany. [Santiago, Mario L.] Univ Colorado, Denver, CO 80202 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 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 NOV PY 2015 VL 76 IS 1 MA 41 BP 71 EP 72 DI 10.1016/j.cyto.2015.08.071 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400068 ER PT J AU Donnelly, RP Sheikh, F Dickensheets, H Ramalingam, T Helming, L Gordon, S AF Donnelly, Raymond P. Sheikh, Faruk Dickensheets, Harold Ramalingam, Thirumalai Helming, Laura Gordon, Siamon TI The IL-13 receptor-alpha 1 chain is essential for induction of the alternative macrophage activation pathway by IL-13 but not IL-4 SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Donnelly, Raymond P.; Sheikh, Faruk; Dickensheets, Harold] US FDA, Rockville, MD 20857 USA. [Ramalingam, Thirumalai] NIAID, Bethesda, MD USA. [Helming, Laura] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80290 Munich, Germany. [Gordon, Siamon] Univ Oxford, Oxford OX1 2JD, England. NR 0 TC 0 Z9 0 U1 1 U2 2 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 NOV PY 2015 VL 76 IS 1 MA 43 BP 72 EP 72 DI 10.1016/j.cyto.2015.08.073 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400070 ER PT J AU Schmeisser, H Balinsky, C Singh, K Sreedhara, K Dolan, M Garboczi, D Zoon, K AF Schmeisser, Hana Balinsky, Corey Singh, Kavita Sreedhara, Karthik Dolan, Michael Garboczi, David Zoon, Kathryn TI Characterization of the antiviral properties of IFIT3 SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Schmeisser, Hana; Balinsky, Corey; Sreedhara, Karthik; Zoon, Kathryn] NIAID, NIH, Cytokine Biol Sect, Bethesda, MD 20892 USA. [Singh, Kavita; Garboczi, David] NIAID, NIH, Struct Biol Unit, Rockville, MD 20852 USA. [Dolan, Michael] NIAID, NIH, Bioinformat & Computat Biosci Branch, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 NOV PY 2015 VL 76 IS 1 MA 45 BP 72 EP 72 DI 10.1016/j.cyto.2015.08.075 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400072 ER PT J AU Young, H Valencia, J Bae, H Haines, D Lockett, S Karwan, M Hanson, C Barlow, A AF Young, Howard Valencia, Julio Bae, Heekyong Haines, Diana Lockett, Stephen Karwan, Megan Hanson, Charlotte Barlow, Alec TI Moderate chronic levels of IFN-g induced an effective anti-melanoma response with limited autoimmune effects SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Young, Howard; Valencia, Julio; Bae, Heekyong; Haines, Diana; Lockett, Stephen; Karwan, Megan; Hanson, Charlotte; Barlow, Alec] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2015 VL 76 IS 1 MA 56 BP 75 EP 75 DI 10.1016/j.cyto.2015.08.086 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400083 ER PT J AU Bae, H Valencia, JC Hodge, DL Sanford, ME Hanson, CA Back, T Karwan, M Feng, DC Gao, B Park, O Tsuneyama, K Leung, PS Gershwin, ME Young, HA AF Bae, Heekyong Valencia, Julio C. Hodge, Deborah L. Sanford, Michael E. Hanson, Charlotte A. Back, Tim Karwan, Megan Feng, Dechun Gao, Bin Park, Ogyi Tsuneyama, Koichi Leung, Patrick S. Gershwin, M. Eric Young, Howard A. TI Deletion of the IFN-gamma 3 ' UTR AU-rich element results in autoimmune cholangitis in female C57/BL6 mice SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Bae, Heekyong; Valencia, Julio C.; Hodge, Deborah L.; Sanford, Michael E.; Hanson, Charlotte A.; Back, Tim; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Karwan, Megan] NCI, Lab Anim Sci, Frederick, MD 21701 USA. [Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, Rockville, MD 20852 USA. [Park, Ogyi] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Tsuneyama, Koichi] Univ Tokushima, Dept Mol & Environm Pathol, Grad Sch, Tokushima, Japan. [Leung, Patrick S.; Gershwin, M. Eric] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. NR 0 TC 0 Z9 0 U1 0 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 NOV PY 2015 VL 76 IS 1 MA 62 BP 76 EP 76 DI 10.1016/j.cyto.2015.08.092 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400089 ER PT J AU Durum, SK Hixon, J Senkevitch, E Cramer, S Barata, J Walsh, S Li, WQ AF Durum, Scott Kenneth Hixon, Julie Senkevitch, Emilee Cramer, Sarah Barata, Joao Walsh, Scott Li, Wenqing TI Targeting the IL-7R pathway in leukemia SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Durum, Scott Kenneth; Hixon, Julie; Senkevitch, Emilee; Cramer, Sarah; Li, Wenqing] NCI, NIH, Frederick, MD 21701 USA. [Barata, Joao] Univ Lisbon, P-1699 Lisbon, Portugal. [Walsh, Scott] Univ Maryland, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 NOV PY 2015 VL 76 IS 1 MA 64 BP 76 EP 76 DI 10.1016/j.cyto.2015.08.094 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400091 ER PT J AU Fish, EN McCarthy, SDS Hoenen, T Branch, DR AF Fish, Eleanor N. McCarthy, Stephen D. S. Hoenen, Thomas Branch, Donald R. TI IFN-beta treatment for Ebola virus disease: Bench to bedside SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Fish, Eleanor N.] Univ Hlth Network, Toronto, ON, Canada. [Fish, Eleanor N.; McCarthy, Stephen D. S.; Branch, Donald R.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Hoenen, Thomas] NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 9 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 NOV PY 2015 VL 76 IS 1 MA 68 BP 77 EP 77 DI 10.1016/j.cyto.2015.08.098 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400095 ER PT J AU Green, DS Johnson, CL Zoon, KC AF Green, Daniel S. Johnson, Chase L. Zoon, Kathryn C. TI A monocyte and interferon based cell therapy for the treatment of ovarian cancer SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Green, Daniel S.; Johnson, Chase L.; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 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 NOV PY 2015 VL 76 IS 1 MA 69 BP 78 EP 78 DI 10.1016/j.cyto.2015.08.099 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400096 ER PT J AU O'Brien, T Pfeiffer, R Paquin, A Kuhs, KL Chen, S Howell, C Prokunina-Olsson, L AF O'Brien, Thomas Pfeiffer, Ruth Paquin, Ashley Kuhs, Krystle Lang Chen, Sabrina Howell, Charles Prokunina-Olsson, Ludmila TI Comparison of IFNL4-Delta G/TT and IFNL3 rs4803217 for association with hepatitis C virus clearance SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [O'Brien, Thomas; Pfeiffer, Ruth; Paquin, Ashley; Kuhs, Krystle Lang; Prokunina-Olsson, Ludmila] NCI, Bethesda, MD 20892 USA. [Chen, Sabrina] Informat Management Serv Inc, Calverton, MD USA. [Howell, Charles] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2015 VL 76 IS 1 MA 89 BP 81 EP 81 DI 10.1016/j.cyto.2015.08.116 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400113 ER PT J AU Onabajo, O Prokunina-Olsson, L AF Onabajo, Olusegun Prokunina-Olsson, Ludmila TI Anti-proliferative and cell death-inducing effects of interferon lambda-4 (IFNL4) may contribute differentially to HCV pathogenesis and cancer SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Onabajo, Olusegun; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2015 VL 76 IS 1 MA 87 BP 81 EP 81 DI 10.1016/j.cyto.2015.08.114 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400111 ER PT J AU Pavlakis, GN Bergamaschi, C Ng, SM Chen', S Bear, J Alicea, C Nagy, B Sowder, R Chertova, E Felber, BK AF Pavlakis, George N. Bergamaschi, Cristina Ng, Sin-Man Chen', Stephanie Bear, Jenifer Alicea, Candido Nagy, Bethany Sowder, Raymond Chertova, Elena Felber, Barbara K. TI Identification, function and clinical development of the heterodimeric IL-15 cytokine (hetIL-15) SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Pavlakis, George N.; Bergamaschi, Cristina; Ng, Sin-Man; Chen', Stephanie; Bear, Jenifer; Alicea, Candido; Nagy, Bethany; Felber, Barbara K.] NCI, Frederick, MD 21701 USA. [Sowder, Raymond; Chertova, Elena] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 NOV PY 2015 VL 76 IS 1 MA 99 BP 83 EP 84 DI 10.1016/j.cyto.2015.08.126 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400123 ER PT J AU Balinsky, CA Schmeisser, H Ganesan, S Jin, TC Singh, K Zoon, KC AF Balinsky, Corey A. Schmeisser, Hana Ganesan, Sundar Jin, Tengchuan Singh, Kavita Zoon, Kathryn C. TI Characterization of a novel interferon stimulated gene with antiviral activity against dengue virus SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Balinsky, Corey A.; Schmeisser, Hana; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Jin, Tengchuan] NIAID, Struct Immunobiol Unit, NIH, Bethesda, MD 20892 USA. [Singh, Kavita] NIAID, Struct Biol Unit, Res Technol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 8 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 NOV PY 2015 VL 76 IS 1 MA 112 BP 86 EP 86 DI 10.1016/j.cyto.2015.08.139 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400136 ER PT J AU Ozato, K Gupta, M Sarai, N Morse, H Platanias, L Xiong, HB Bachu, M AF Ozato, Keiko Gupta, Monica Sarai, Naoyuki Morse, Herbert Platanias, Leonidas Xiong, Huabao Bachu, Mahesh TI Chromatin exchange in macrophages and IRF8 dependent autophagy SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Ozato, Keiko; Gupta, Monica; Sarai, Naoyuki; Morse, Herbert; Bachu, Mahesh] NIH, Bethesda, MD USA. [Platanias, Leonidas] Northwestern Univ, Evanston, IL 60208 USA. [Xiong, Huabao] Mt Sinai Sch Med, Evanston, IL 60208 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2015 VL 76 IS 1 MA 211 BP 103 EP 103 DI 10.1016/j.cyto.2015.08.215 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400212 ER PT J AU De Andrea, M Lo Cigno, I Albertini, S Borgogna, C Peretti, A Johnson, K Chandran, B Landolfo, S Gariglio, M AF De Andrea, Marco Lo Cigno, Irene Albertini, Silvia Borgogna, Cinzia Peretti, Alberto Johnson, Karen Chandran, Bala Landolfo, Santo Gariglio, Marisa TI The nuclear Interferon-inducible IFI16 protein and the innate sensing to HPV18 replication SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [De Andrea, Marco; Lo Cigno, Irene; Landolfo, Santo] Turin Med Sch, Viral Pathogenesis Unit, Turin, Italy. [De Andrea, Marco; Albertini, Silvia; Borgogna, Cinzia; Gariglio, Marisa] Novara Med Sch, Virol Unit, Novara, Italy. [Peretti, Alberto] NCI, Bethesda, MD 20892 USA. [Johnson, Karen; Chandran, Bala] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, N Chicago, IL USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 NOV PY 2015 VL 76 IS 1 MA 216 BP 104 EP 104 DI 10.1016/j.cyto.2015.08.220 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400217 ER PT J AU Waldmann, TA AF Waldmann, Thomas A. TI IL-15 markedly augmented the number of circulating NK cells and enhanced ADCC mediated by tumor-directed monoclonal antibodies SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Waldmann, Thomas A.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2015 VL 76 IS 1 MA 238 BP 108 EP 109 DI 10.1016/j.cyto.2015.08.241 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400238 ER PT J AU Khouri, R Decanine, D Silva-Santos, G Theys, K Li, GD Silva, AC Farre, L Bittencourt, A Mangino, M Roederer, M Van Weyenbergh, J AF Khouri, Ricardo Decanine, Daniele Silva-Santos, Gilvaneia Theys, Kristof Li, Guangdi Silva, Aline Clara Farre, Lourdes Bittencourt, Achilea Mangino, Massimo Roederer, Mario Van Weyenbergh, Johan TI A functional FAS polymorphism links CD4 T stem cell memory levels and IFN-induced apoptosis in both healthy controls and Adult T-cell Leukemia patients SO CYTOKINE LA English DT Meeting Abstract CT 3rd Annual Meeting of the International-Cytokine-and-Interferon-Society (ICIS) CY OCT 11-14, 2015 CL Bamberg, GERMANY SP Int Cytokine & Interferon Soc C1 [Khouri, Ricardo; Theys, Kristof; Li, Guangdi; Van Weyenbergh, Johan] Katholieke Univ Leuven, Dept Microbiol & Immunol, Leuven, Belgium. [Khouri, Ricardo; Decanine, Daniele; Silva-Santos, Gilvaneia; Silva, Aline Clara; Farre, Lourdes; Van Weyenbergh, Johan] CPqGM FIOCRUZ, Salvador, BA, Brazil. [Bittencourt, Achilea] HUPES UFBA, Salvador, BA, Brazil. [Mangino, Massimo] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RI Van Weyenbergh, Johan/B-4187-2009; mangino, massimo/F-5134-2011 OI Van Weyenbergh, Johan/0000-0003-3234-8426; mangino, massimo/0000-0002-2167-7470 NR 0 TC 0 Z9 0 U1 0 U2 3 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 NOV PY 2015 VL 76 IS 1 MA 239 BP 109 EP 109 DI 10.1016/j.cyto.2015.08.242 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS1XO UT WOS:000361862400239 ER PT J AU Sabanayagam, C Lye, WK Klein, R Klein, BEK Cotch, MF Wang, JJ Mitchell, P Shaw, JE Selvin, E Sharrett, AR Wong, TY AF Sabanayagam, Charumathi Lye, Weng Kit Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Wang, Jie Jin Mitchell, Paul Shaw, Jonathan E. Selvin, Elizabeth Sharrett, A. Richey Wong, Tien Y. TI Retinal microvascular calibre and risk of diabetes mellitus: a systematic review and participant-level meta-analysis SO DIABETOLOGIA LA English DT Review DE Cohort studies; Diabetes; Meta-analysis; Retinal vessels; Systematic review ID IMPAIRED FASTING GLUCOSE; LIFE-STYLE AUSDIAB; BEAVER DAM EYE; VASCULAR CALIBER; INSULIN-RESISTANCE; ENDOTHELIAL DYSFUNCTION; ATHEROSCLEROSIS RISK; VESSEL DIAMETERS; ARTERIOLAR; MUSCLE AB Aims/hypothesis The calibre of the retinal vessels has been linked to diabetes mellitus but studies have not shown consistent results. We conducted a participant-level meta-analysis to evaluate the association between retinal arteriolar and venular calibre and diabetes. Methods We performed a systematic review on MEDLINE and EMBASE for articles published up to December 2014. We identified five population-based prospective cohort studies that provided individual-level data on 18,771 diabetes-free participants. We used discrete time proportional hazards models to estimate pooled HRs of diabetes associated with 1 SD (20 mu m) change in retinal vascular calibre. Results We identified 2,581 incident cases of diabetes over a median follow-up period of 10 years (interquartile interval of 3.4-15.8 years). After adjustment for demographic, lifestyle and clinical factors, retinal venular calibre was significantly associated with incident diabetes (pooled HR 1.09 [95% CI 1.02, 1.15] per SD increase in venular calibre). This association persisted in analyses excluding individuals with < 5 years of follow-up (1.07 [1.0, 1.12]) or those with impaired fasting glucose at baseline (1.10 [1.03, 1.17]); in subgroup analyses, the association was stronger in men than in women but was consistent across subgroups of race/ethnicity, smoking status, hypertension and BMI categories. Retinal arteriolar calibre was not associated with diabetes (0.95 [0.86, 1.06] per SD decrease in arteriolar calibre). Conclusions/interpretation Wider retinal venules but not narrower retinal arterioles were associated with a modestly increased risk for diabetes. Knowledge of pathological mechanisms underlying wider retinal venule may provide further insights concerning microvascular alterations in diabetes. C1 [Sabanayagam, Charumathi; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Sabanayagam, Charumathi; Wong, Tien Y.] Duke NUS Grad Med Sch, Ophthalmol & Visual Sci Acad Clin Program, Singapore, Singapore. [Sabanayagam, Charumathi; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Lye, Weng Kit] Duke NUS Grad Med Sch, Ctr Quantitat Med, Singapore, Singapore. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2006, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Shaw, Jonathan E.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Selvin, Elizabeth; Sharrett, A. Richey] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Wong, TY (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, 11 Third Hosp Ave, Singapore 168751, Singapore. EM ophwty@nus.edu.sg OI Sabanayagam, Charumathi/0000-0002-4042-4719; Cotch, Mary Frances/0000-0002-2046-4350 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01-HC-95159, N01-HC-95165]; NIH Intramural Research award from the National Eye Institute, USA [ZIAEY000403]; National Health and Medical Research Council [350448, 233200]; Sylvia and Charles Viertel Charitable Foundation; National Eye Institute, National Institutes of Health Grant [EY-06594]; Research to Prevent Blindness, New York, NY, USA; Australian National Health & Medical Research Council; National Medical Research Council, Singapore [STaR/0003/2008, CG/SERI/2010] FX We used restricted access datasets of the ARIC study and MESA. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). MESA was supported by contracts N01-HC-95159 through N01-HC-95165 from the National Heart, Lung and Blood Institute and NIH Intramural Research award ZIAEY000403 from the National Eye Institute, USA. This article does not necessarily convey the opinions or views of the ARIC study, MESA or the National Heart, Lung and Blood Institute. The AusDiab study was supported by National Health and Medical Research Council Grants 350448 and 233200, and a Sylvia and Charles Viertel Charitable Foundation grant. BDES was supported by the National Eye Institute, National Institutes of Health Grant EY-06594, and by Research to Prevent Blindness, New York, NY, USA. The BMES was supported by the Australian National Health & Medical Research Council. The study was funded by grants from the National Medical Research Council, Singapore (STaR/0003/2008 and CG/SERI/2010), which had no role in study design, data analysis or interpretation of results. NR 41 TC 2 Z9 2 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2015 VL 58 IS 11 BP 2476 EP 2485 DI 10.1007/s00125-015-3717-2 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS3RR UT WOS:000361993000003 PM 26232097 ER PT J AU Li, GN Huang, K Nikolic, D van Breemen, RB AF Li, Guannan Huang, Ke Nikolic, Dejan van Breemen, Richard B. TI High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID TANDEM MASS-SPECTROMETRY; HUMAN LIVER-MICROSOMES; IN-VITRO COCKTAIL; ENZYMES; METABOLISM; ISOFORMS; P450S; GOLDENSEAL; RUN AB Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry-based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography-tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example. C1 [Li, Guannan; Huang, Ke; Nikolic, Dejan; van Breemen, Richard B.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP van Breemen, RB (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, 833 S Wood St, Chicago, IL 60612 USA. EM breemen@uic.edu OI Li, Guannan/0000-0002-9533-7524 FU National Institutes of Health Office of Dietary Supplements [P50 AT000155]; National Center for Complementary and Integrative Health [P50 AT000155, R01 AT007659] FX This work was supported by the National Institutes of Health Office of Dietary Supplements [Grant P50 AT000155] and the National Center for Complementary and Integrative Health [Grants P50 AT000155 and R01 AT007659]. NR 41 TC 4 Z9 4 U1 1 U2 16 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 NOV PY 2015 VL 43 IS 11 BP 1670 EP 1678 DI 10.1124/dmd.115.065987 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CS5JC UT WOS:000362113300004 PM 26285764 ER PT J AU Starling, AP Engel, LS Calafat, AM Koutros, S Satagopan, JM Yang, G Matthews, CE Cai, QY Buckley, JP Ji, BT Cai, H Chow, WH Zheng, W Gao, YT Rothman, N Xiang, YB Shu, XO AF Starling, Anne P. Engel, Lawrence S. Calafat, Antonia M. Koutros, Stella Satagopan, Jaya M. Yang, Gong Matthews, Charles E. Cai, Qiuyin Buckley, Jessie P. Ji, Bu-Tian Cai, Hui Chow, Wong-Ho Zheng, Wei Gao, Yu-Tang Rothman, Nathaniel Xiang, Yong-Bing Shu, Xiao-Ou TI Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Phthalates; Reproducibility; Predictors; Food contaminants; Personal care products ID NUTRITION EXAMINATION SURVEY; HUMAN EXPOSURE; BISPHENOL-A; TEMPORAL VARIABILITY; NATIONAL-HEALTH; US POPULATION; UNITED-STATES; CHINA; ESTERS; MEDICATIONS AB Phthalate esters are man-made chemicals commonly used as plasticizers and solvents, and humans may be exposed through ingestion, inhalation, and dermal absorption. Little is known about predictors of phthalate exposure, particularly in Asian countries. Because phthalates are rapidly metabolized and excreted from the body following exposure, it is important to evaluate whether phthalate metabolites measured at a single point in time can reliably rank exposures to phthalates over a period of time. We examined the concentrations and predictors of phthalate metabolite concentrations among 50 middle-aged women and 50 men from two Shanghai cohorts, enrolled in 1997-2000 and 2002-2006, respectively. We assessed the reproducibility of urinary concentrations of phthalate metabolites in three spot samples per participant taken several years apart (mean interval between first and third sample was 7.5 years [women] or 2.9 years [men]), using Spearman's rank correlation coefficients and intra-class correlation coefficients. We detected ten phthalate metabolites in at least 50% of individuals for two or more samples. Participant sex, age, menopausal status, education, income, body mass index, consumption of bottled water, recent intake of medication, and time of day of collection of the urine sample were associated with concentrations of certain phthalate metabolites. The reproducibility of an individual's urinary concentration of phthalate metabolites across several years was low, with all intra-class correlation coefficients and most Spearman rank correlation coefficients <= 03. Only mono(2-ethylhexyl) phthalate, a metabolite of di(2-ethylhexyl) phthalate, had a Spearman rank correlation coefficient >= 0.4 among men, suggesting moderate reproducibility. These findings suggest that a single spot urine sample is not sufficient to rank exposures to phthalates over several years in an adult urban Chinese population. Published by Elsevier Ltd. C1 [Starling, Anne P.; Engel, Lawrence S.; Buckley, Jessie P.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Koutros, Stella; Matthews, Charles E.; Ji, Bu-Tian; Chow, Wong-Ho; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Satagopan, Jaya M.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Yang, Gong; Cai, Qiuyin; Cai, Hui; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Gao, Yu-Tang] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Dept Epidemiol, Shanghai 200030, Peoples R China. [Xiang, Yong-Bing] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst, Shanghai 200030, Peoples R China. RP Starling, AP (reprint author), Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Anschutz Med Campus,Campus Box F426,12474 E 19th, Aurora, CO 80045 USA. EM Anne.Starling@ucdenver.edu OI Satagopan, Jaya/0000-0001-7102-5633; Engel, Lawrence/0000-0001-9268-4830 FU National Institutes of Health; National Cancer Institute Division of Cancer Epidemiology and Genetics; National Cancer Institute [R37 CA070867, UM1182910, UM1 CA173640, NO2-CP11010-66]; National Institutes of Health from National Cancer Institute [R01CA137420]; Cancer Center Core Grant from the National Cancer Institute [P30CA008748]; Clinical and Translational Science Center at Weill Cornell Medical College, New York, USA [UL1RR024996] FX Funding sources: The study was funded in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute Division of Cancer Epidemiology and Genetics. Support for the Shanghai Women's Health Study (R37 CA070867, UM1182910, PI: Zheng), the Shanghai Men's Health Study (UM1 CA173640, PI: Shu) and the physical activity substudy (NO2-CP11010-66, PI: Shu) was provided by grants from the National Cancer Institute. Dr. Satagopan was supported by the following grants from the National Institutes of Health: R01CA137420, Cancer Center Core Grant P30CA008748 from the National Cancer Institute, and UL1RR024996 from the Clinical and Translational Science Center at Weill Cornell Medical College, New York, USA NR 46 TC 4 Z9 4 U1 5 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD NOV PY 2015 VL 84 BP 94 EP 106 DI 10.1016/j.envint.2015.07.003 PG 13 WC Environmental Sciences SC Environmental Sciences & Ecology GA CS5UK UT WOS:000362143600011 PM 26255822 ER PT J AU Giesel, FL Fiedler, H Stefanova, M Sterzing, F Rius, M Kopka, K Moltz, JH Afshar-Oromieh, A Choyke, PL Haberkorn, U Kratochwil, C AF Giesel, Frederik L. Fiedler, H. Stefanova, M. Sterzing, F. Rius, M. Kopka, K. Moltz, J. H. Afshar-Oromieh, A. Choyke, P. L. Haberkorn, U. Kratochwil, C. TI PSMA PET/CT with Glu-urea-Lys-(Ahx)-[Ga-68(HBED-CC)] versus 3D CT volumetric lymph node assessment in recurrent prostate cancer SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Ga-68-PSMA-11 PET/CT; Recurrent prostate cancer; Lymph node evaluation; Lymph node metastasis ID MEMBRANE ANTIGEN; COMPUTERIZED-TOMOGRAPHY; ANDROGEN RECEPTOR; METASTASES; DISSECTION; DIAGNOSIS; THERAPY; LIGAND; MRI AB Purpose PET/CT with the PSMA ligand is a powerful new method for the early detection of nodal metastases in patients with biochemical relapse. The purpose of this retrospective investigation was to evaluate the volume and dimensions of nodes identified by Glu-urea-Lys-(Ahx)-[Ga-68(HBED-CC)] (Ga-68-PSMA-11) in the setting of recurrent prostate cancer. Methods All PET/CT images were acquired 60 +/- 10 min after intravenous injection of Ga-68-PSMA-11 (mean dose 176 MBq). In 21 patients with recurrent prostate cancer and rising PSA, 49 PSMA-positive lymph nodes were identified. Using semiautomated lymph node segmentation software, node volume and short-axis and long-axis dimensions were measured and compared with the maximum standardized uptake values (SUVmax). Round nodes greater than or equal to 8 mm were considered positive by morphological criteria alone. The percentage of nodes identified by elevated SUVmax but not by conventional morphological criteria was determined. Results The mean volume of Ga-68-PSMA-11-positive nodes was 0.5 ml (range 0.2 - 2.3 ml), and the mean short-axis diameter was 5.8 mm (range 2.4 - 13.3 mm). In 7 patients (33.3 %) with 31 PSMA-positive nodes only 11 (36 %) were morphologically positive based on diameters > 8 mm on CT. In the remaining 14 patients (66.7 %), 18 (37 %) of PSMA positive lymph nodes had short-axis diameters < 8 mm with a mean short-axis diameter of 5.0 mm (range 2.4 - 7.9 mm). Thus, in this population, Ga-68-PSMA-11 PET/CT detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. Conclusion Ga-68-PSMA-11 PET/CT is more sensitive than CT based 3D volumetric lymph node evaluation in determining the node status of patients with recurrent prostate cancer, and is a promising method of restaging prostate cancers in this setting. C1 [Giesel, Frederik L.; Fiedler, H.; Stefanova, M.; Afshar-Oromieh, A.; Haberkorn, U.; Kratochwil, C.] Heidelberg Univ, Dept Nucl Med, Univ Heidelberg Hosp, INF 400, D-69120 Heidelberg, Germany. [Sterzing, F.] Heidelberg Univ, Dept RadioOncol, D-69120 Heidelberg, Germany. [Rius, M.] European Commiss, Inst Transuranium Elements ITU, Karlsruhe, Germany. [Kopka, K.; Moltz, J. H.] German Canc Res Ctr, Radiopharmaceut Chem, Heidelberg, Germany. [Choyke, P. L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Giesel, Frederik L.; Rius, M.; Haberkorn, U.] DKFZ, Cooperat Unit Nucl Med, Heidelberg, Germany. RP Giesel, FL (reprint author), Heidelberg Univ, Dept Nucl Med, Univ Heidelberg Hosp, INF 400, D-69120 Heidelberg, Germany. EM frederik@egiesel.com FU Klaus-Tschira-Stiftung [00.198.2012] FX This research was supported by the Klaus-Tschira-Stiftung (project no. 00.198.2012). NR 26 TC 25 Z9 25 U1 2 U2 11 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 NOV PY 2015 VL 42 IS 12 BP 1794 EP 1800 DI 10.1007/s00259-015-3106-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS3TJ UT WOS:000361997600003 PM 26162799 ER PT J AU Saporito, RA Norton, RA Garraffo, MH Spande, TF AF Saporito, Ralph A. Norton, Roy A. Garraffo, Martin H. Spande, Thomas F. TI Taxonomic distribution of defensive alkaloids in Nearctic oribatid mites (Acari, Oribatida) SO EXPERIMENTAL AND APPLIED ACAROLOGY LA English DT Article DE Chemical defense; Dendrobatids; Opisthonotal (oil) gland; Poison frogs; Soil mites; Scheloribates; Protokalumma ID POISON FROGS; CHEMICAL DEFENSE; SKIN ALKALOIDS; ANURA; DIET; MECHANISMS; BUFONIDAE; EVOLUTION; TOXICITY AB The opisthonotal (oil) glands of oribatid mites are the source of a wide diversity of taxon-specific defensive chemicals, and are likely the location for the more than 90 alkaloids recently identified in oribatids. Although originally recognized in temperate oribatid species, alkaloids have also been detected in related lineages of tropical oribatids. Many of these alkaloids are also present in a worldwide radiation of poison frogs, which are known to sequester these defensive chemicals from dietary arthropods, including oribatid mites. To date, most alkaloid records involve members of the superfamily Oripodoidea (Brachypylina), although few species have been examined and sampling of other taxonomic groups has been highly limited. Herein, we examined adults of more than 60 species of Nearctic oribatid mites, representing 46 genera and 33 families, for the presence of alkaloids. GC-MS analyses of whole body extracts led to the detection of 15 alkaloids, but collectively they occur only in members of the genera Scheloribates (Scheloribatidae) and Protokalumma (Parakalummidae). Most of these alkaloids have also been detected previously in the skin of poison frogs. All examined members of the oripodoid families Haplozetidae and Oribatulidae were alkaloid-free, and no mites outside the Oripodoidea contained alkaloids. Including previous studies, all sampled species of the cosmopolitan oripodoid families Scheloribatidae and Parakalummidae, and the related, mostly tropical families Mochlozetidae and Drymobatidae contain alkaloids. Our findings are consistent with a generalization that alkaloid presence is widespread, but not universal in Oripodoidea. Alkaloid presence in tropical, but not temperate members of some non-oripodoid taxa (in particular Galumnidae) deserves further study. C1 [Saporito, Ralph A.] John Carroll Univ, Dept Biol, University Hts, OH 44118 USA. [Norton, Roy A.] SUNY Coll Environm Sci & Forestry, Syracuse, NY 13210 USA. [Garraffo, Martin H.] NIDDK, DHHS, Clin Mass Spectrometry Core, NIH, Bethesda, MD 20892 USA. [Spande, Thomas F.] NIDA, DHHS, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Saporito, RA (reprint author), John Carroll Univ, Dept Biol, University Hts, OH 44118 USA. EM rsaporito@jcu.edu FU NIDDK; John Carroll University (JCU); Kresge Challenge Grant FX This study was supported by intramural funds of NIDDK, John Carroll University (JCU), and a Kresge Challenge Grant awarded to JCU. We thank Dr. Michael A. Nichols for his assistance in maintaining the GC-MS, and Dr. Valerie Behan-Pelletier for taxonomic advice on the identity of Ceratozetes species. NR 46 TC 4 Z9 4 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0168-8162 EI 1572-9702 J9 EXP APPL ACAROL JI Exp. Appl. Acarol. PD NOV PY 2015 VL 67 IS 3 BP 317 EP 333 DI 10.1007/s10493-015-9962-8 PG 17 WC Entomology SC Entomology GA CS8FI UT WOS:000362321000001 PM 26264156 ER PT J AU Gooskens, SL Gadd, S Auvil, JG Gerhard, DS Khan, J Patidar, R Meerzaman, D Chen, QR Hsu, CH Yan, C Nguyen, C Hu, Y Mullighan, CG Ma, J de Krijger, R van den Heuvel-Eibrink, MM Smith, MA Ross, N Gastier-Foster, JM Perlman, EJ AF Gooskens, S. L. Gadd, S. Auvil, J. Guidry Gerhard, D. S. Khan, J. Patidar, R. Meerzaman, D. Chen, Q. R. Hsu, C. H. Yan, C. Nguyen, C. Hu, Y. Mullighan, C. G. Ma, J. de Krijger, R. van den Heuvel-Eibrink, M. M. Smith, M. A. Ross, N. Gastier-Foster, J. M. Perlman, E. J. TI TCF21 IS HYPERMETHYLATED IN CLEAR CELL SARCOMA OF THE KIDNEY: A GENOME-WIDE TARGET STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Gooskens, S. L.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Hematol & Oncol, Rotterdam, Netherlands. [Gadd, S.; Perlman, E. J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gadd, S.; Perlman, E. J.] Robert H Lurie Canc Ctr, Dept Pathol, Chicago, IL USA. [Auvil, J. Guidry; Gerhard, D. S.] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Khan, J.; Patidar, R.] Oncogen Sect, Genet Branch, Bethesda, MD USA. [Meerzaman, D.; Chen, Q. R.; Hsu, C. H.; Yan, C.; Nguyen, C.; Hu, Y.] NCI, NIH, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Mullighan, C. G.; Ma, J.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [de Krijger, R.] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands. [van den Heuvel-Eibrink, M. M.] Princess Maxima Ctr Pediat Oncol, Dept Pediat Oncol, Utrecht, Netherlands. [Smith, M. A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Ross, N.; Gastier-Foster, J. M.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-117 BP S176 EP S176 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200118 ER PT J AU Gupta, S Aitken, J Bartels, U Brierley, J Dolendo, M Friedrich, P Fuentes, S Garcia, C Gatta, G Gospodarowicz, M Gross, T Howard, S Molyneaux, E Moreno, F Pritchard-Jones, K Pole, J Ramirez, O Ries, L Rodriguez-Galindo, C Shin, HY Steliarova-Foucher, E Sung, L Supriyadi, E Swaminathan, R Torode, J Vora, T Kutluk, T Frazier, AL AF Gupta, S. Aitken, J. Bartels, U. Brierley, J. Dolendo, M. Friedrich, P. Fuentes, S. Garcia, C. Gatta, G. Gospodarowicz, M. Gross, T. Howard, S. Molyneaux, E. Moreno, F. Pritchard-Jones, K. Pole, J. Ramirez, O. Ries, L. Rodriguez-Galindo, C. Shin, H. Y. Steliarova-Foucher, E. Sung, L. Supriyadi, E. Swaminathan, R. Torode, J. Vora, T. Kutluk, T. Frazier, A. L. TI CONSENSUS-BASED PRINCIPLES AND CLASSIFICATION SYSTEMS FOR COLLECTING PAEDIATRIC CANCER STAGE IN POPULATION-BASED CANCER REGISTRIES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Gupta, S.; Bartels, U.; Sung, L.] Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Aitken, J.] Canc Care Queensland, Dept Res, Brisbane, Qld, Australia. [Brierley, J.; Gospodarowicz, M.] Princess Margaret Hosp, Div Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Dolendo, M.] Davao Med Ctr, Pediat Oncol, Davao, Philippines. [Friedrich, P.; Rodriguez-Galindo, C.; Frazier, A. L.] Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02115 USA. [Fuentes, S.] Hostpital Nacl Ninos Benjamin Bloom, Oncol Serv, San Salvador, El Salvador. [Garcia, C.] Unidad Nacl Oncol Pediat, Pediat Oncol, Guatemala City, Guatemala. [Gatta, G.] Ist Nazl Studio & Cura Tumori, Epidemiol Unit, I-20133 Milan, Italy. [Gross, T.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Howard, S.] Univ Tennessee, Coll Med, Memphis, TN USA. [Molyneaux, E.] Queen Elizabeth Cent Hosp, Dept Pediat, Blantyre, Malawi. [Moreno, F.] Natl Canc Inst, Paediat Canc Registry, Buenos Aires, DF, Argentina. [Pritchard-Jones, K.] Kings Coll London, Inst Child Hlth, London WC2R 2LS, England. [Pole, J.] Pediat Oncol Grp Ontario, POGO Res Unit, Toronto, ON, Canada. [Ramirez, O.] Univ Valle, Registro Poblac Canc Cali, Cali, Colombia. [Ries, L.] NCI, SEER Program, Bethesda, MD 20892 USA. [Shin, H. Y.] Seoul Natl Univ, Childrens Hosp, Pediat Oncol, Seoul, South Korea. [Steliarova-Foucher, E.] IARC, Canc Informat Sect, Lyon, France. [Supriyadi, E.] Univ Gadjah Mada, Div Pediat Hematol Oncol, Yogyakarta, Indonesia. [Swaminathan, R.] Canc Inst WIA, Canc Registry, Madras, Tamil Nadu, India. [Torode, J.] UICC, Geneva, Switzerland. [Vora, T.] Tata Mem Hosp, Pediat Med Oncol, Bombay, Maharashtra, India. [Kutluk, T.] Hacettepe Univ, Sch Med, Pediat Oncol, Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA O-094 BP S169 EP S170 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200095 ER PT J AU Jindal, B Naredi, BK Vuriti, M Rijhwani, A Chakkalakkoombil, SV Badhe, BA Han, JC Reyes-Capo, D AF Jindal, B. Naredi, B. K. Vuriti, M. Rijhwani, A. Chakkalakkoombil, S. V. Badhe, B. A. Han, J. C. Reyes-Capo, D. TI BILATERAL WILMS' TUMOR (WT) IN A HORSE SHOE KIDNEY WITH WAGR SYNDROME: A RARE ASSOCIATION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Jindal, B.; Naredi, B. K.; Vuriti, M.; Rijhwani, A.] Jawaharlal Inst Postgrad Med Educ & Res, Dept Pediat Surg, Pondicherry, India. [Chakkalakkoombil, S. V.] Jawaharlal Inst Postgrad Med Educ & Res, Dept Radiol, Pondicherry, India. [Badhe, B. A.] Jawaharlal Inst Postgrad Med Educ & Res, Dept Pathol, Pondicherry, India. [Han, J. C.; Reyes-Capo, D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA P-658 BP S397 EP S397 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247201490 ER PT J AU Lock, R Houghton, P Smith, M AF Lock, R. Houghton, P. Smith, M. TI A REVIEW OF NEW AGENTS TESTED BY THE PEDIATRIC PRECLINICAL TESTING PROGRAM AGAINST ACUTE LYMPHOBLASTIC LEUKEMIA XENOGRAFTS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Lock, R.] UNSW Australia, Childrens Canc Inst, Randwick, NSW, Australia. [Houghton, P.] UT Hlth Sci Ctr, Greehey Childrens Canc Res Inst, San Antonio, TX USA. [Smith, M.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 4 MA PD-004 BP S211 EP S211 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3QE UT WOS:000361247200258 ER PT J AU Raznahan, A Lue, Y Probst, F Greenstein, D Giedd, J Wang, C Lerch, J Swerdloff, R AF Raznahan, Armin Lue, YanHe Probst, Frank Greenstein, Deanna Giedd, Jay Wang, Christina Lerch, Jason Swerdloff, Ronald TI Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Brain anatomy; Sexual dimorphism; XO; XXY ID ORIGIN ALLELIC EXPRESSION; KLINEFELTER-SYNDROME; PERIAQUEDUCTAL GRAY; TURNER-SYNDROME; X-CHROMOSOME; MOUSE-BRAIN; NEUROPSYCHIATRIC DISORDERS; STRIA TERMINALIS; SOCIAL-BEHAVIOR; XXY MICE AB Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study-XO, XX, XY and XXY-to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ("forebrain cholinergic" and "cerebelo-pontine-thalamo-cortical"), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA. C1 [Raznahan, Armin; Greenstein, Deanna; Giedd, Jay] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20815 USA. [Lue, YanHe; Wang, Christina; Swerdloff, Ronald] Harbor UCLA Med Ctr, Los Angele Biomed Res Inst, Dept Med, Div Endocrinol, Torrance, CA USA. [Probst, Frank] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lerch, Jason] Hosp Sick Children Hosp, Mouse Imaging Ctr, Toronto, ON, Canada. [Lerch, Jason] Hosp Sick Children Hosp, Program Neurosci & Mental, Toronto, ON, Canada. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Rm 4C108,Bldg 20,10 Ctr Dr, Bethesda, MD 20815 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z99 MH999999] NR 66 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD NOV PY 2015 VL 220 IS 6 BP 3581 EP 3593 DI 10.1007/s00429-014-0875-9 PG 13 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CR7XS UT WOS:000361566000031 PM 25146308 ER PT J AU Chetty, IJ Martel, MK Jaffray, DA Benedict, SH Hahn, SM Berbeco, R Deye, J Jeraj, R Kavanagh, B Krishnan, S Lee, N Low, DA Mankoff, D Marks, LB Ollendorf, D Paganetti, H Ross, B Siochi, RAC Timmerman, RD Wong, JW AF Chetty, Indrin J. Martel, Mary K. Jaffray, David A. Benedict, Stanley H. Hahn, Stephen M. Berbeco, Ross Deye, James Jeraj, Robert Kavanagh, Brian Krishnan, Sunil Lee, Nancy Low, Daniel A. Mankoff, David Marks, Lawrence B. Ollendorf, Daniel Paganetti, Harald Ross, Brian Siochi, Ramon Alfredo C. Timmerman, Robert D. Wong, John W. TI Technology for Innovation in Radiation Oncology SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CELL LUNG-CANCER; FUTURE PERSPECTIVES; GOLD NANOPARTICLES; ION RADIOTHERAPY; CLINICAL-TRIALS; PROTON-BEAM; THERAPY; RISK; MRI; IRRADIATION AB Radiation therapy is an effective, personalized cancer treatment that has benefited from technological advances associated with the growing ability to identify and target tumors with accuracy and precision. Given that these advances have played a central role in the success of radiation therapy as a major component of comprehensive cancer care, the American Society for Radiation Oncology (ASTRO), the American Association of Physicists in Medicine (AAPM), and the National Cancer Institute (NCI) sponsored a workshop entitled "Technology for Innovation in Radiation Oncology," which took place at the National Institutes of Health (NIH) in Bethesda, Maryland, on June 13 and 14, 2013. The purpose of this workshop was to discuss emerging technology for the field and to recognize areas for greater research investment. Expert clinicians and scientists discussed innovative technology in radiation oncology, in particular as to how these technologies are being developed and translated to clinical practice in the face of current and future challenges and opportunities. Technologies encompassed topics in functional imaging, treatment devices, nanotechnology, and information technology. The technical, quality, and safety performance of these technologies were also considered. A major theme of the workshop was the growing importance of innovation in the domain of process automation and oncology informatics. The technologically advanced nature of radiation therapy treatments predisposes radiation oncology research teams to take on informatics research initiatives. In addition, the discussion on technology development was balanced with a parallel conversation regarding the need for evidence of efficacy and effectiveness. The linkage between the need for evidence and the efforts in informatics research was clearly identified as synergistic. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chetty, Indrin J.] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [Martel, Mary K.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Jaffray, David A.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Jaffray, David A.] Princess Margaret Hosp, Dept Med Biophys, Toronto, ON M4X 1K9, Canada. [Benedict, Stanley H.] Univ Calif Davis, Ctr Canc, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Hahn, Stephen M.; Krishnan, Sunil] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Berbeco, Ross] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Deye, James] Natl Canc Inst, Radiat Res Programs, Bethesda, MD USA. [Jeraj, Robert] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Kavanagh, Brian] Univ Colorado, Dept Radiat Oncol, Aurora, CO USA. [Lee, Nancy] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Low, Daniel A.] Univ Calif Los Angeles, Dept Radiat Oncol, Los Angeles, CA 90024 USA. [Mankoff, David] Univ Washington, Sch Med, Dept Radiol, Seattle, WA USA. [Marks, Lawrence B.] Univ North Carolina Hosp, Dept Radiat Oncol, Chapel Hill, NC USA. [Ollendorf, Daniel] Inst Clin & Econ Review, Boston, MA USA. [Paganetti, Harald] Proton Therapy Ctr, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA USA. [Ross, Brian] Univ Michigan Hlth Syst, Dept Radiol, Ann Arbor, MI USA. [Siochi, Ramon Alfredo C.] W Virginia Univ, Dept Radiat Oncol, Morgantown, WV 26506 USA. [Timmerman, Robert D.] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Wong, John W.] Johns Hopkins Univ, Dept Radiat Oncol, Baltimore, MD USA. RP Martel, MK (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. EM mmartel@mdanderson.org FU American Society for Radiation Oncology; American Association of Physicists in Medicine FX The authors thank the National Cancer Institute for their support of the meeting in providing resources and hosting the meeting at the National Institutes of Health. They also thank the American Society for Radiation Oncology and the American Association of Physicists in Medicine for their financial assistance, without which this meeting would not have been possible. NR 54 TC 7 Z9 7 U1 3 U2 40 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2015 VL 93 IS 3 BP 485 EP 492 DI 10.1016/j.ijrobp.2015.07.007 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS2ED UT WOS:000361879700003 PM 26460989 ER PT J AU Palmer, NRA Weaver, KE Hauser, SP Lawrence, JA Talton, J Case, LD Geiger, AM AF Palmer, Nynikka R. A. Weaver, Kathryn E. Hauser, Sally P. Lawrence, Julia A. Talton, Jennifer Case, L. Douglas Geiger, Ann M. TI Disparities in barriers to follow-up care between African American and White breast cancer survivors SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Barriers; Follow-up care; Health disparities; Cancer survivor; Breast cancer ID UNITED-STATES; NONCANCER CONTROLS; MEDICAL-CARE; PATIENT; SURVEILLANCE; METAANALYSIS; DIAGNOSIS; SUPPORT; ACCESS; SYSTEM AB Despite recommendations for breast cancer survivorship care, African American women are less likely to receive appropriate follow-up care, which is concerning due to their higher mortality rates. This study describes differences in barriers to follow-up care between African American and White breast cancer survivors. We conducted a mailed survey of women treated for non-metastatic breast cancer in 2009-2011, 6-24 months post-treatment (N = 203). Survivors were asked about 14 potential barriers to follow-up care. We used logistic regression to explore associations between barriers and race, adjusting for covariates. Our participants included 31 African American and 160 White survivors. At least one barrier to follow-up care was reported by 62 %. Compared to White survivors, African Americans were more likely to identify barriers related to out-of-pocket costs (28 vs. 51.6 %, p = 0.01), other health care costs (21.3 vs. 45.2 %, p = 0.01), anxiety/worry (29.4 vs. 51.6 %, p = 0.02), and transportation (4.4 vs. 16.1 %, p = 0.03). After adjustment for covariates, African Americans were three times as likely to report at least one barrier to care (odds ratio (OR) = 3.3, 95 % confidence interval (CI) = 1.1-10.1). Barriers to care are common among breast cancer survivors, especially African American women. Financial barriers to care may prevent minority and underserved survivors from accessing follow-up care. Enhancing insurance coverage or addressing out-of-pocket costs may help address financial barriers to follow-up care among breast cancer survivors. Psychosocial care aimed at reducing fear of recurrence may also be important to improve access among African American breast cancer survivors. C1 [Palmer, Nynikka R. A.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94143 USA. [Weaver, Kathryn E.] Wake Forest Sch Med, Div Publ Hlth Sci, Social Sci & Hlth Policy, Winston Salem, NC USA. [Hauser, Sally P.; Lawrence, Julia A.] Wake Forest Comprehens Canc Ctr, Gen Surg, Winston Salem, NC USA. [Talton, Jennifer; Case, L. Douglas] Wake Forest Sch Med, Div Publ Hlth Sci, Biostat Sci, Winston Salem, NC USA. [Geiger, Ann M.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Palmer, NRA (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94143 USA. EM palmern@medsfgh.ucsf.edu OI Palmer, Nynikka/0000-0002-5311-447X FU National Cancer Institute at the National Institutes of Health [5R21CA155932-02, R25CA122061] FX This work was supported by the National Cancer Institute at the National Institutes of Health, grant numbers 5R21CA155932-02 (AM Geiger, PI) and R25CA122061 (NE Avis, PI). We thank Kim Derzen for her contribution to this study. NR 42 TC 6 Z9 6 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2015 VL 23 IS 11 BP 3201 EP 3209 DI 10.1007/s00520-015-2706-9 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA CS1PC UT WOS:000361838000010 PM 25821145 ER PT J AU Blood, JD Wu, J Chaplin, TM Hommer, R Vazquez, L Rutherford, HJV Mayes, LC Crowley, MJ AF Blood, Julia D. Wu, Jia Chaplin, Tara M. Hommer, Rebecca Vazquez, Lauren Rutherford, Helena J. V. Mayes, Linda C. Crowley, Michael J. TI The variable heart: High frequency and very low frequency correlates of depressive symptoms in children and adolescents SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Adolescence; depression; heart rate variability; time-frequency analysis ID CARDIAC VAGAL TONE; RATE-VARIABILITY; MAJOR DEPRESSION; NEUROVISCERAL INTEGRATION; AUTONOMIC FUNCTION; ANXIETY DISORDERS; STRESS-RESPONSE; MODEL; ASSOCIATION; MECHANISMS AB Background: Work examining the link between lower heart rate variability (HRV) and depression in children and adolescents is lacking, especially in light of the physiological changes that occur during pubertal development. Method: We investigated the association between spectral measures of resting HRV and depressive symptoms among 127 children and adolescents, ages 10-17. Using spectral analysis, we evaluated (1) the association between relative high frequency (HF) HRV and depressive symptoms; (2) the predictive power of relative HF HRV for depressive symptoms in the context of relative low frequency (LF) and relative very low frequency (VLF) HRV; and (3) the relationship between relative HF, LF, and VLF band activity, age and pubertal maturation. Results: Consistent with previous work, results revealed that relative HF HRV was negatively associated with self-reported depressive symptoms. As well, relative VLF HRV was positively associated with depressive symptoms. Regression analyses revealed that relative HF HRV and relative VLF HRV significantly predicted self-report depressive symptoms while controlling for age, sex and pubertal maturation, with relative VLF HRV emerging as the strongest indicator of depressive symptoms. Developmental findings also emerged. Age and pubertal maturation were negatively associated with relative HF HRV and positively correlated with relative VLF HRV. Conclusions: Results provide support for the relationship between HRV and depression and suggest that both HF and VLF HRV are relevant to depression symptom severity. Findings also reinforce the importance of considering pubertal development when investigating HRV-depression associations in children and adolescents. Limitations: Influences on cardiac control including physical activity levels and exercise patterns could be controlled in future work. Our data speak to a depressive symptom dimension and relative spectral power HRV. Thus, we cannot make strong claims about relative spectral power HRV and clinical depression. (C) 2015 Elsevier B.V. All rights reserved. C1 [Blood, Julia D.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, San Antonio, TX 78229 USA. [Wu, Jia; Vazquez, Lauren; Rutherford, Helena J. V.; Mayes, Linda C.; Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Chaplin, Tara M.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Hommer, Rebecca] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. [Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, Program Anxiety Disorders, New Haven, CT USA. [Wu, Jia; Rutherford, Helena J. V.; Mayes, Linda C.; Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, Dev Electrophysiol Lab, New Haven, CT USA. [Crowley, Michael J.] Yale Univ, Sch Med, Yale Child Study Ctr, Ctr Translat Dev Neurosci, New Haven, CT USA. RP Crowley, MJ (reprint author), Yale Child Study Ctr, 230 South Frontage Rd, New Haven, CT 06520 USA. EM michael.crowley@yale.edu FU NARSAD Young Investigator Award; Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot project funding [1UL1RR024925-01]; NIDA [K01 DA034125, RO1-DA-06025, DA-017863, KO5]; Gustavus and Louise Pfeiffer Research Foundation; CTSA Grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR024139]; NIH Roadmap for Medical Research FX This research was supported by NARSAD Young Investigator Award (MJC), Yale Interdisciplinary Research Consortium on Stress, Self-Control and Addiction Pilot project funding (MJC) through 1UL1RR024925-01 (R. Sinha); NIDA grants K01 DA034125 (MJC), RO1-DA-06025 (LCM), DA-017863 (LCM) and KO5 (LCM), and a grant from the Gustavus and Louise Pfeiffer Research Foundation (LCM). This publication was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 73 TC 5 Z9 5 U1 3 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD NOV 1 PY 2015 VL 186 BP 119 EP 126 DI 10.1016/j.jad.2015.06.057 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9WR UT WOS:000360966400018 PM 26233322 ER PT J AU Durham, B Diamond, E Yao, Z Ma, J Choi, J Kim, E Lee, S Gao, YJ Micol, JB Campbell, P Walsh, M Nakitandwe, J Estrada-Veras, J Lacouture, M Chung, YR Rampal, R Pichardo, J Briggs, S Hyman, D Baselga Janku, F Taylor, B Park, C Emile, JF Haroche, J Rosen, N Gruber, T Abdel-Wahab, O AF Durham, Benjamin Diamond, Eli Yao, Zhan Ma, Jing Choi, John Kim, Eunhee Lee, Stanley Gao, Yijun Micol, Jean-Baptiste Campbell, Patrick Walsh, Michael Nakitandwe, Joy Estrada-Veras, Juvianee Lacouture, Mario Chung, Young Rock Rampal, Raajit Pichardo, Janine Briggs, Samuel Hyman, David Baselga Janku, Filip Taylor, Barry Park, Christopher Emile, Jean-Francois Haroche, Julien Rosen, Neal Gruber, Tanja Abdel-Wahab, Omar TI DIVERSE KINASE MUTATIONS AND FUSIONS DRIVE NON-LANGERHANS CELL HISTIOCYTOSES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Durham, Benjamin; Pichardo, Janine; Park, Christopher] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Diamond, Eli; Briggs, Samuel] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Yao, Zhan; Gao, Yijun; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10021 USA. [Ma, Jing; Choi, John; Nakitandwe, Joy; Gruber, Tanja] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Kim, Eunhee; Lee, Stanley; Micol, Jean-Baptiste; Chung, Young Rock; Taylor, Barry; Park, Christopher; Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Campbell, Patrick; Walsh, Michael; Gruber, Tanja] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Estrada-Veras, Juvianee] NHGRI, NIH, Bethesda, MD 20892 USA. [Lacouture, Mario] Mem Sloan Kettering Canc Ctr, Dept Med, Serv Dermatol, New York, NY 10021 USA. [Rampal, Raajit; Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Hyman, David; Baselga] Mem Sloan Kettering Canc Ctr, Dept Med, Dev Therapeut, New York, NY 10021 USA. [Janku, Filip] Univ Texas Houston, MD Anderson Canc Ctr, Dept Med, Houston, TX 77030 USA. [Emile, Jean-Francois] Hop Univ Ambroise Pare, Pathol Serv, Paris, France. [Haroche, Julien] Hop La Pitie Salpetriere, Internal Med Serv, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 3 BP S125 EP S126 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3JW UT WOS:000361229700021 ER PT J AU Estrada-Veras, J O'Brien, K Gahl, W AF Estrada-Veras, Juvianee O'Brien, Kevin Gahl, William TI WHEN TWO CONDITIONS WITH SIMILAR FEATURES MEET: A CASE OF ERDHEIM CHESTER DISEASE IN A PATIENT WITH A COMMON GENETIC DISORDER SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Estrada-Veras, Juvianee; O'Brien, Kevin; Gahl, William] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 3 BP S127 EP S127 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3JW UT WOS:000361229700026 ER PT J AU Estrada-Veras, J O'Brien, K Toro, C Gahl, W AF Estrada-Veras, Juvianee O'Brien, Kevin Toro, Camilo Gahl, William TI CEREBELLAR SYNDROME AND COGNITIVE DEFICITS IN ERDHEIM CHESTER DISEASE: JUST ACCUMULATION OF HISTIOCYTES OR SECONDARY METABOLIC/ENDOCRINE DEFICIT? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Estrada-Veras, Juvianee; O'Brien, Kevin; Toro, Camilo; Gahl, William] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 3 BP S126 EP S126 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3JW UT WOS:000361229700024 ER PT J AU Estrada-Veras, JI Gardner, PJ AF Estrada-Veras, Juvianee I. Gardner, Pamela J. TI ORAL MANIFESTATIONS OF ERDHEIM CHESTER DISEASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Estrada-Veras, Juvianee I.] NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. [Gardner, Pamela J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 3 BP S126 EP S126 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3JW UT WOS:000361229700025 ER PT J AU Nichols, KE Ruffo, E Malacarne, V Larsen, S Das, R Patrussi, L Wulfing, C Biskup, C Schwartzberg, P Baldari, C Rubio, I Snow, A Baldanzi, G Graziani, A AF Nichols, Kim E. Ruffo, Elisa Malacarne, Valeria Larsen, Sasha Das, Rupali Patrussi, Laura Wuelfing, Christoph Biskup, Christoph Schwartzberg, Pamela Baldari, Cosima Rubio, Ignacio Snow, Andrew Baldanzi, Gianluca Graziani, Andrea TI INHIBITION OF DIACYLGLYCEROL KINASE ALPHA RESTORES SENSITIVITY TO TCR-INDUCED CELL DEATH AND LESSENS IMMUNOPATHOLOGY IN A MURINE MODEL OF XLP-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Nichols, Kim E.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Ruffo, Elisa; Malacarne, Valeria; Baldanzi, Gianluca; Graziani, Andrea] Univ Piemonte Orientale, Dept Translat Med, Novara, Italy. [Ruffo, Elisa; Malacarne, Valeria; Baldanzi, Gianluca; Graziani, Andrea] Univ Piemonte Orientale, Inst Res & Cure Autoimmune Dis, Novara, Italy. [Ruffo, Elisa; Malacarne, Valeria; Graziani, Andrea] Univ Vita & Salute San Raffaele, Sch Med, Milan, Italy. [Larsen, Sasha; Snow, Andrew] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD USA. [Das, Rupali] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Patrussi, Laura; Baldari, Cosima] Univ Siena, Dept Life Sci, I-53100 Siena, Italy. [Wuelfing, Christoph] Univ Bristol, Sch Cellular & Mol Med, Bristol, Avon, England. [Biskup, Christoph] Jena Univ Hosp, Biomol Photon Grp, Jena, Germany. [Schwartzberg, Pamela] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Rubio, Ignacio] Univ Jena, Ctr Sepsis Control & Care, Integrated Res & Treatment Ctr, Jena, Germany. [Rubio, Ignacio] Univ Jena, Ctr Mol Biomed, Inst Mol Cell Biol, Jena, Germany. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2015 VL 62 SU 3 BP S134 EP S134 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CR3JW UT WOS:000361229700056 ER PT J AU Guselnikov, SV Grayfer, L Andino, FD Rogozin, IB Robert, J Taranin, AV AF Guselnikov, S. V. Grayfer, L. Andino, F. De Jesus Rogozin, I. B. Robert, J. Taranin, A. V. TI Retention of duplicated ITAM-containing transmembrane signaling subunits in the tetraploid amphibian species Xenopus laevis SO DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY LA English DT Article DE Xenopus; Genome mining; Activating receptor complexes; TCR; Tetraploidization; Protein dosage effect; Immunogenetics ID LEUKOCYTE RECEPTOR COMPLEX; T-CELL DEVELOPMENT; ANTIGEN-RECEPTOR; GENE DUPLICATION; FCR-GAMMA; IMMUNE-SYSTEM; EVOLUTION; FAMILY; TROPICALIS; ALPHA AB The ITAM-bearing transmembrane signaling subunits (TSS) are indispensable components of activating leukocyte receptor complexes. The TSS-encoding genes map to paralogous chromosomal regions, which are thought to arise from ancient genome tetraploidization(s). To assess a possible role of tetraploidization in the TSS evolution, we studied TSS and other functionally linked genes in the amphibian species Xenopus laevis whose genome was duplicated about 40 MYR ago. We found that X. laevis has retained a duplicated set of sixteen TSS genes, all except one being transcribed. Furthermore, duplicated TCR alpha loci and genes encoding TSS-coupling protein kinases have also been retained. No clear evidence for functional divergence of the TSS paralogs was obtained from gene expression and sequence analyses. We suggest that the main factor of maintenance of duplicated TSS genes in X. laevis was a protein dosage effect and that this effect might have facilitated the TSS set expansion in early vertebrates. Published by Elsevier Ltd. C1 [Guselnikov, S. V.; Taranin, A. V.] Russian Acad Sci, Siberian Branch, Inst Mol & Cellular Biol, Novosibirsk 630090, Russia. [Guselnikov, S. V.; Taranin, A. V.] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Grayfer, L.; Andino, F. De Jesus; Robert, J.] Univ Rochester, Med Ctr, MRBX, Rochester, NY 14642 USA. [Rogozin, I. B.] NIH, Natl Ctr Biotechnol Informat NLM, Bethesda, MD 20892 USA. RP Taranin, AV (reprint author), IMCB SB RAS, 8-2 Lavrentiev Ave, Novosibirsk 630090, Russia. EM sguselnikov@mcb.nsc.ru; Leon_Grayfer@urmc.rochester.edu; f_dejesus7@yahoo.com; rogozin@ncbi.nlm.nih.gov; Jacques_Robert@urmc.rochester.edu; taranin@mcb.nsc.ru RI Guselnikov, Sergey/N-2525-2015; Taranin, Alexander/N-5136-2015 OI Taranin, Alexander/0000-0002-9184-4238 FU Intramural Research Program of the National Library of Medicine at National Institutes of Health (US Department Health and Human Services); National Institutes of Health [R24-AI-059830]; National Sciences Foundation [IOB-074271]; Howard Hughes Medical Institute; Russian Basic Research Fund [11-04-01165-a]; Russian Academy of Sciences program "Molecular and Cellular Biology" [6.23] FX IBR was supported by the Intramural Research Program of the National Library of Medicine at National Institutes of Health (US Department Health and Human Services).; JR and FDA were supported by grants from the National Institutes of Health (R24-AI-059830) and National Sciences Foundation (IOB-074271).; LG was supported by a LSRF PDF from the Howard Hughes Medical Institute.; AVT was supported by the Russian Basic Research Fund program 11-04-01165-a and by the Russian Academy of Sciences program "Molecular and Cellular Biology", grant number 6.23. NR 57 TC 0 Z9 0 U1 2 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0145-305X EI 1879-0089 J9 DEV COMP IMMUNOL JI Dev. Comp. Immunol. PD NOV PY 2015 VL 53 IS 1 BP 158 EP 168 DI 10.1016/j.dci.2015.07.002 PG 11 WC Immunology; Zoology SC Immunology; Zoology GA CQ7HF UT WOS:000360772900018 PM 26170006 ER PT J AU Holmes, A AF Holmes, Andrew TI Neural mechanisms of glucocorticoid effects on the extinction of traumatic memories SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Society-of-Psychoneuroendocrinology (ISPNE) on Stress and the Brain - From Fertility to Senility CY SEP 08-11, 2015 CL Edinburgh, SCOTLAND SP Int Soc Psychoneuroendocrinol C1 [Holmes, Andrew] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD NOV PY 2015 VL 61 MA PS4.3.3 BP 20 EP 20 DI 10.1016/j.psyneuen.2015.07.443 PG 1 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA CP9XY UT WOS:000360250400059 PM 26383331 ER PT J AU Meyer, J Grant, K Burbacher, T Worlein, J Kenney, C Dettmer, A Suomi, S Hamell, A Rosenberg, K Novak, M AF Meyer, Jerrold Grant, Kimberly Burbacher, Tom Worlein, Julie Kenney, Caroline Dettmer, Amanda Suomi, Stephen Hamell, Amanda Rosenberg, Kendra Novak, Melinda TI Relationship between prenatal cortisol exposure and behavioral development in macaque monkeys SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Society-of-Psychoneuroendocrinology (ISPNE) on Stress and the Brain - From Fertility to Senility CY SEP 08-11, 2015 CL Edinburgh, SCOTLAND SP Int Soc Psychoneuroendocrinol C1 [Meyer, Jerrold; Hamell, Amanda; Rosenberg, Kendra; Novak, Melinda] Univ Massachusetts, Amherst, MA 01003 USA. [Grant, Kimberly; Burbacher, Tom; Worlein, Julie; Kenney, Caroline] Washington Natl Primate Res Ctr, Seattle, WA USA. [Hamell, Amanda; Rosenberg, Kendra] NIH, Comparat Ethol Lab, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD NOV PY 2015 VL 61 MA PO25 BP 30 EP 31 DI 10.1016/j.psyneuen.2015.07.473 PG 2 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA CP9XY UT WOS:000360250400089 PM 26383357 ER PT J AU Hardy, T McCarthy, D Fourie, N Henderson, W AF Hardy, Theresa McCarthy, Donnalee Fourie, Nicolaas Henderson, Wendy TI The relationship of anti-Mullerian hormone levels and urine cortisol in women with chronic abdominal pain SO PSYCHONEUROENDOCRINOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Society-of-Psychoneuroendocrinology (ISPNE) on Stress and the Brain - From Fertility to Senility CY SEP 08-11, 2015 CL Edinburgh, SCOTLAND SP Int Soc Psychoneuroendocrinol C1 [Hardy, Theresa; McCarthy, Donnalee] Marquette Univ, Milwaukee, WI 53233 USA. [Hardy, Theresa; Fourie, Nicolaas; Henderson, Wendy] NIH, Bethesda, MD 20892 USA. OI Henderson, Wendy/0000-0003-3924-7118 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD NOV PY 2015 VL 61 MA PO136 BP 70 EP 70 DI 10.1016/j.psyneuen.2015.07.584 PG 1 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA CP9XY UT WOS:000360250400200 PM 26383470 ER PT J AU Mondul, AM Moore, SC Weinstein, SJ Karoly, ED Sampson, JN Albanes, D AF Mondul, Alison M. Moore, Steven C. Weinstein, Stephanie J. Karoly, Edward D. Sampson, Joshua N. Albanes, Demetrius TI Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE metabolomics; prostate cancer; serology; energy metabolism; lipid metabolism; biomarkers; thyroxine; TMAO; TCA cycle; Warburg ID INTERMEDIARY METABOLISM; LIPID-METABOLISM; STATIN USE; CELLS; REQUIREMENTS; EPIDEMIOLOGY; METAANALYSIS; OXIDATION; PATHWAYS; SYSTEMS AB Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome-wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, broad-spectrum approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort based on 200 cases (100 aggressive) and 200 controls (age- and blood collection date-matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men and the odds ratio per 1-standard deviation increase in log-metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p=0.018 and p=0.041, respectively, for chemical class over-representation). Inositol-1-phosphate showed the strongest association (OR=0.56, 95% CI=0.39-0.81, p=0.002) and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl-linoleoyl-glycerophosphoinositol (OR=0.64, p=0.004), 1-stearoylglycerophosphoglycerol (OR=0.65, p=0.025), stearate (OR=0.65, p=0.010) and docosadienoate (OR=0.66, p=0.014). Both alpha-ketoglutarate and citrate were associated with aggressive disease risk (OR=0.69, 95% CI=0.51-0.94, p=0.02; OR=0.69, 95% CI=0.50-0.95, p=0.02), as were elevated thyroxine and trimethylamine oxide (OR=1.65, 95% CI=1.08-2.54, p=0.021; and OR=1.36, 95% CI=1.02-1.81, p=0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research. What's new? Prostate cancer is the second most common cancer in men, yet few modifiable risk factors are known. A window to the study of modifiable risk factors is the metabolome, with prospective metabolomic serum profiling being a promising new investigative approach. In prostate cancer, use of this approach had resulted in the identification of numerous circulating lipids associated with risk of aggressive disease. Here, the authors report inverse associations between aggressive disease and energy and lipid metabolites, including alpha-ketoglutarate, citrate, inositol-1-phosphate and several glycerophospholipids and fatty acids. Some of the metabolites may be relevant to prostate cancer development and progression. C1 [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Moore, Steven C.; Weinstein, Stephanie J.; Sampson, Joshua N.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Karoly, Edward D.] Metabolon, Morrisville, NC USA. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr 6E342, Bethesda, MD 20892 USA. EM daa@nih.gov RI Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Mondul, Alison/0000-0002-8843-1416 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; DHHS; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS FX Grant sponsor: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS NR 42 TC 15 Z9 15 U1 6 U2 48 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 NOV 1 PY 2015 VL 137 IS 9 BP 2124 EP 2132 DI 10.1002/ijc.29576 PG 9 WC Oncology SC Oncology GA CP3ME UT WOS:000359782700010 PM 25904191 ER PT J AU Campa, D Rizzato, C Stolzenberg-Solomon, R Pacetti, P Vodicka, P Cleary, SP Capurso, G Bueno-de-Mesquita, HB Werner, J Gazouli, M Butterbach, K Ivanauskas, A Giese, N Petersen, GM Fogar, P Wang, ZM Bassi, C Ryska, M Theodoropoulos, GE Kooperberg, C Li, DH Greenhalf, W Pasquali, C Hackert, T Fuchs, CS Mohelnikova-Duchonova, B Sperti, C Funel, N Dieffenbach, AK Wareham, NJ Buring, J Holcatova, I Costello, E Zambon, CF Kupcinskas, J Risch, HA Kraft, P Bracci, PM Pezzilli, R Olson, SH Sesso, HD Hartge, P Strobel, O Malecka-Panas, E Visvanathan, K Arslan, AA Pedrazzoli, S Soucek, P Gioffreda, D Key, TJ Talar-Wojnarowska, R Scarpa, A Mambrini, A Jacobs, EJ Jamroziak, K Klein, A Tavano, F Bambi, F Landi, S Austin, MA Vodickova, L Brenner, H Chanock, SJ Delle Fave, G Piepoli, A Cantore, M Zheng, W Wolpin, BM Amundadottir, LT Canzian, F AF Campa, Daniele Rizzato, Cosmeri Stolzenberg-Solomon, Rachael Pacetti, Paola Vodicka, Pavel Cleary, Sean P. Capurso, Gabriele Bueno-de-Mesquita, H. B(as) Werner, Jens Gazouli, Maria Butterbach, Katja Ivanauskas, Audrius Giese, Nathalia Petersen, Gloria M. Fogar, Paola Wang, Zhaoming Bassi, Claudio Ryska, Miroslav Theodoropoulos, George E. Kooperberg, Charles Li, Donghui Greenhalf, William Pasquali, Claudio Hackert, Thilo Fuchs, Charles S. Mohelnikova-Duchonova, Beatrice Sperti, Cosimo Funel, Niccola Dieffenbach, Aida Karina Wareham, Nicholas J. Buring, Julie Holcatova, Ivana Costello, Eithne Zambon, Carlo-Federico Kupcinskas, Juozas Risch, Harvey A. Kraft, Peter Bracci, Paige M. Pezzilli, Raffaele Olson, Sara H. Sesso, Howard D. Hartge, Patricia Strobel, Oliver Malecka-Panas, Ewa Visvanathan, Kala Arslan, Alan A. Pedrazzoli, Sergio Soucek, Pavel Gioffreda, Domenica Key, Timothy J. Talar-Wojnarowska, Renata Scarpa, Aldo Mambrini, Andrea Jacobs, Eric J. Jamroziak, Krzysztof Klein, Alison Tavano, Francesca Bambi, Franco Landi, Stefano Austin, Melissa A. Vodickova, Ludmila Brenner, Hermann Chanock, Stephen J. Delle Fave, Gianfranco Piepoli, Ada Cantore, Maurizio Zheng, Wei Wolpin, Brian M. Amundadottir, Laufey T. Canzian, Federico TI TERT gene harbors multiple variants associated with pancreatic cancer susceptibility SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; polymorphisms; telomerase; susceptibility ID GENOME-WIDE ASSOCIATION; TELOMERE LENGTH; RISK; LOCI; 5P15.33; POLYMORPHISMS; METAANALYSIS; POPULATION; DISEASE; IDENTIFICATION AB A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 x 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 x 10(-5)), rs4583925 (p = 4.0 x 10(-5)) and rs2735948 (p = 5.0 x 10(-5)). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools. C1 [Campa, Daniele] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Rizzato, Cosmeri; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany. [Stolzenberg-Solomon, Rachael; Wang, Zhaoming; Hartge, Patricia; Chanock, Stephen J.; Amundadottir, Laufey T.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pacetti, Paola; Mambrini, Andrea; Cantore, Maurizio] ASL1 Massa Carrara, Dept Oncol, Massa Carrara, Italy. [Vodicka, Pavel; Vodickova, Ludmila] Acad Sci Czech Republic, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic. [Cleary, Sean P.] Univ Toronto, Dept Surg, Univ Hlth Network, Toronto, ON, Canada. [Capurso, Gabriele; Delle Fave, Gianfranco] Univ Roma La Sapienza, S Andrea Hosp, Digest & Liver Dis Unit, I-00185 Rome, Italy. [Bueno-de-Mesquita, H. B(as)] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B(as)] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B(as)] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. B(as)] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Werner, Jens; Giese, Nathalia; Hackert, Thilo; Strobel, Oliver] Univ Heidelberg Hosp, Dept Gen Surg, Heidelberg, Germany. [Gazouli, Maria] Univ Athens, Sch Med, Dept Basic Med Sci, Biol Lab, GR-11527 Athens, Greece. [Butterbach, Katja; Dieffenbach, Aida Karina; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Ivanauskas, Audrius; Kupcinskas, Juozas] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania. [Petersen, Gloria M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Fogar, Paola] Univ Hosp Padua, Dept Lab Med, Padua, Italy. [Bassi, Claudio] Univ & Hosp Trust Verona, Surg & Oncol Dept, Pancreas Inst, Verona, Italy. [Ryska, Miroslav] Charles Univ Prague, Fac Med 2, Dept Surg, Prague, Czech Republic. [Ryska, Miroslav] Cent Mil Hosp, Prague, Czech Republic. [Theodoropoulos, George E.] Univ Athens, Sch Med, Dept Propaedeut Surg 1, GR-11527 Athens, Greece. [Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Greenhalf, William; Costello, Eithne] Univ Liverpool, Natl Inst Hlth Res, Liverpool Pancreas Biomed Res Unit, Liverpool L69 3BX, Merseyside, England. [Pasquali, Claudio; Sperti, Cosimo] Univ Padua, Dept Surg Gastroenterol & Oncol DISCOG, Padua, Italy. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mohelnikova-Duchonova, Beatrice] Palacky Univ, Sch Med, Dept Oncol, CR-77147 Olomouc, Czech Republic. [Mohelnikova-Duchonova, Beatrice] Teaching Hosp Olomouc, Olomouc, Czech Republic. [Funel, Niccola] Univ Hosp Pisa, Dept Surg, Unit Expt Surg Pathol, Pisa, Italy. [Dieffenbach, Aida Karina; Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Wareham, Nicholas J.] Univ Cambridge, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Buring, Julie; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Buring, Julie; Sesso, Howard D.] Harvard Univ, Sch Med, Boston, MA USA. [Holcatova, Ivana] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Zambon, Carlo-Federico] Univ Padua, Dept Med DIMED, Padua, Italy. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Epidemiol & Publ Hlth, New Haven, CT USA. [Kraft, Peter; Sesso, Howard D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Pezzilli, Raffaele] St Orsola Malpighi Hosp, Pancreas Unit, Dept Digest Dis & Internal Med, Bologna, Italy. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Malecka-Panas, Ewa; Talar-Wojnarowska, Renata] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, Div Epidemiol, New York, NY USA. [Arslan, Alan A.] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Arslan, Alan A.] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Pedrazzoli, Sergio] Univ Padua, Surg Clin 4, Padua, Italy. [Soucek, Pavel] Natl Inst Publ Hlth, Dept Toxicogen, Prague, Czech Republic. [Gioffreda, Domenica; Tavano, Francesca; Piepoli, Ada] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Della, Div Gastroenterol, San Giovanni Rotondo, Italy. [Gioffreda, Domenica; Tavano, Francesca; Piepoli, Ada] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Della, Res Lab, San Giovanni Rotondo, Italy. [Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Scarpa, Aldo] Univ & Hosp Trust Verona, ARC NET Ctr Appl Res Canc, Verona, Italy. [Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Jamroziak, Krzysztof] Inst Hematol & Transfus Med, Dept Hematol, Warsaw, Poland. [Klein, Alison] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Bambi, Franco] Azienda Osped Univ Meyer, Blood Transfus Serv, Florence, Italy. [Landi, Stefano] Univ Pisa, Dept Biol, Pisa, Italy. [Austin, Melissa A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Canzian, F (reprint author), German Canc Res Ctr, Genom Epidemiol Grp, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM f.canzian@dkfz.de RI Zambon, Carlo Federico/J-8187-2016; Campa, Daniele/K-1617-2016; Tavano, Francesca/K-2203-2016; Piepoli, Ada/K-9299-2016; scarpa, aldo/K-6832-2016; Talar-Wojnarowska, Renata/T-1009-2016; Brenner, Hermann/B-4627-2017; OI Landi, Stefano/0000-0001-8364-6357; Zambon, Carlo Federico/0000-0002-4244-879X; Campa, Daniele/0000-0003-3220-9944; Tavano, Francesca/0000-0002-8831-7349; Piepoli, Ada/0000-0001-7487-8754; scarpa, aldo/0000-0003-1678-739X; Brenner, Hermann/0000-0002-6129-1572; Soucek, Pavel/0000-0002-4294-6799 FU Czech Science Foundation [P301/12/1734]; Internal Grant Agency of the Czech Ministry of Health [IGA NT 13 263]; NIH [5R01 CA098870, R01 CA102765, R21 CA115878, R37 CA70867, P01 CA87969, P01 CA55075, U54 CA155626, P50 CA127003, R01 CA124908, R01 CA49449, 1UM1 CA167552, CA 97193, CA 34944, CA 40360, HL 26490, HL 34595, CA 047988, HL 043851, HL 080467]; Baden-Wurttemberg State Ministry of Research, Science and Arts; Italian Ministry of Health [RC1203GA57, RC1303GA53, RC1303GA54, RC1303GA50]; National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK FX Grant sponsor: Czech Science Foundation; Grant number: P301/12/1734; Grant sponsor: Internal Grant Agency of the Czech Ministry of Health; Grant number: IGA NT 13 263 (to M.R.); Grant sponsor: NIH; Grant numbers: 5R01 CA098870 (to H.A.R.), R01 CA102765 and R21 CA115878 (to M.A.A.), R37 CA70867 (to the Shanghai Women's Health Study), P01 CA87969, P01 CA55075, U54 CA155626, P50 CA127003, R01 CA124908, R01 CA49449 and 1UM1 CA167552 (to the Nurses Health Study and the Health Professionals Follow-Up Study), CA 97193, CA 34944, CA 40360, HL 26490 and HL 34595 (to the Physicians' Health Study), CA 047988, HL 043851 and HL 080467 (to the Women's Health Study); Grant sponsor: Baden-Wurttemberg State Ministry of Research, Science and Arts (to the ESTHER study); Grant number: "5 x 1000" voluntary contribution; Grant sponsor: Italian Ministry of Health; Grant numbers: RC1203GA57, RC1303GA53, RC1303GA54 and RC1303GA50; Grant sponsor: National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK NR 50 TC 8 Z9 8 U1 2 U2 34 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 NOV 1 PY 2015 VL 137 IS 9 BP 2175 EP 2183 DI 10.1002/ijc.29590 PG 9 WC Oncology SC Oncology GA CP3ME UT WOS:000359782700016 PM 25940397 ER PT J AU Linet, MS Yin, SN Gilbert, ES Dores, GM Hayes, RB Vermeulen, R Tian, HY Lan, Q Portengen, L Ji, BT Li, GL Rothman, N AF Linet, Martha S. Yin, Song-Nian Gilbert, Ethel S. Dores, Graca M. Hayes, Richard B. Vermeulen, Roel Tian, Hao-Yuan Lan, Qing Portengen, Lutzen Ji, Bu-Tian Li, Gui-Lan Rothman, Nathaniel CA Chinese Ctr Dis Control Prevention US Natl Canc Inst Benzene Study Grp TI A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE benzene; leukemia; lymphoma; lung cancer; mortality ID EPIDEMIOLOGIC RISK ASSESSMENT; ACUTE MYELOID-LEUKEMIA; NON-HODGKIN-LYMPHOMA; MULTIPLE-MYELOMA; OCCUPATIONAL-EXPOSURE; PETROLEUM WORKERS; CANCER-MORTALITY; APLASTIC-ANEMIA; METAANALYSIS; NEOPLASMS AB Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI=1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI=1.2, 2.3) and diseases of blood forming organs (RR = infinity, 95% CI = 3.4, ). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95% CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95% CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders. What's new? More than two million workers worldwide are exposed to benzene each year. In this long-term study of Chinese workers, the authors found that chronic benzene exposure was associated with a substantial increase in the risk of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases. The results also suggest possible associations with other malignant and non-malignant disorders. C1 [Linet, Martha S.; Gilbert, Ethel S.; Dores, Graca M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20850 USA. [Yin, Song-Nian; Tian, Hao-Yuan; Li, Gui-Lan] Chinese Ctr Dis Control & Prevent, Natl Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Utrecht, Netherlands. [Lan, Qing; Ji, Bu-Tian; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20850 USA. [Portengen, Lutzen] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Linet, MS (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM linetm@mail.nih.gov RI Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; Hayes, Richard/0000-0002-0918-661X FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; US Public Health Service of the Department of Health and Human Services FX Grant sponsor: Intramural Research Program of the National Institutes of Health; National Cancer Institute; US Public Health Service of the Department of Health and Human Services NR 59 TC 4 Z9 4 U1 2 U2 34 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 NOV 1 PY 2015 VL 137 IS 9 BP 2184 EP 2197 DI 10.1002/ijc.29591 PG 14 WC Oncology SC Oncology GA CP3ME UT WOS:000359782700017 PM 25944549 ER PT J AU Zhao, Q Tran, H Dimitrov, DS Cheung, NKV AF Zhao, Qi Tran, Hoa Dimitrov, Dimiter S. Cheung, Nai-Kong V. TI A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IGF-1; IGF-2; temsirolimus; chemotherapy; neuroblastoma ID GROWTH-FACTOR-RECEPTOR; MTOR INHIBITOR TEMSIROLIMUS; BREAST-CANCER; IN-VITRO; SIGNAL-TRANSDUCTION; PEDIATRIC-PATIENTS; INSULIN-RECEPTOR; SOLID TUMORS; CELL-LINES; IGF SYSTEM AB The insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors. What's new? Insulin-like growth factors (IGF) 1 and 2 promote the biogenesis of neuroblastoma, a frequent neuroendocrine tumor in early childhood. Here the authors show that targeting IGF-1 and 2 with a specific antibody (m708.5) has anti-tumor activity in neuroblastoma cell lines as well as in cell culture models of the Ewing family of tumors, rhabdomyosarcoma, and osteosarcoma. Similarly, in xenograft mouse models of neuroblastoma, m798.5 together with an inhibitor of mammalian target of rapamycin (mTOR) suppressed tumor growth and increased survival, supporting a potential clinical application of antibodies targeting IGF-1/2 in children afflicted with solid tumors. C1 [Zhao, Qi; Tran, Hoa; Cheung, Nai-Kong V.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Zhao, Qi] Chinese Acad Sci, Shenzhen Inst Adv Technol, Lab Fully Human Antibody Engn, Beijing 100864, Guangdong, Peoples R China. [Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Cheung, NKV (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. EM cheungn@mskcc.org FU Commonwealth Foundation for Cancer Research; Experimental Therapeutics Center of MSK; Cookies for Kids' Cancer; Robert Steel Foundation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsors: Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center of MSK, Cookies for Kids' Cancer, the Robert Steel Foundation and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 42 TC 2 Z9 2 U1 0 U2 27 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 NOV 1 PY 2015 VL 137 IS 9 BP 2243 EP 2252 DI 10.1002/ijc.29588 PG 10 WC Oncology SC Oncology GA CP3ME UT WOS:000359782700023 PM 25924852 ER PT J AU Moss, HB Goldstein, RB Chen, CM Yi, HY AF Moss, Howard B. Goldstein, Rise B. Chen, Chiung M. Yi, Hsiao-Ye TI Patterns of use of other drugs among those with alcohol dependence: Associations with drinking behavior and psychopathology SO ADDICTIVE BEHAVIORS LA English DT Article DE Alcohol dependence; Polysubstance use; Drug use; Alcohol use; Psychopathology ID NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; INTERVIEW SCHEDULE AUDADIS; UNITED-STATES; USE-DISORDER; REPRESENTATIVE SAMPLE; TERM OUTCOMES; POLYDRUG USE; IV AB Introduction: Alcohol dependence (AD) presents with substantial clinical heterogeneity, induding concurrent use of non-alcohol drugs. Here, we examine specific patterns of concurrent non-alcohol substance use during the previous year among a nationally representative sample of adults with DSM-IV AD, and estimate their population prevalence in the U.S. We then evaluate alcohol use behavior and comorbid psychopathology among respondents with AD according to their patterns of concurrent non-alcohol substance use. Methods: These analyses utilized data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Latent class analyses classified respondents with AD into four clinically meaningful patterns of concurrent substance use: (1) use of alcohol only; (2) use of alcohol and tobacco only; (3) use of alcohol, tobacco and cannabis; and (4) use of alcohol, tobacco, cannabis, cocaine, and other illicit drug(s). Results: Among AD respondents, the most prevalent pattern was the use of alcohol and tobacco only (weighted percentage, 32.4%), followed by the use of alcohol only (weighted percentage, 27.5%). AD respondents who used alcohol, tobacco, cannabis, cocaine, and other illicit drug(s) (weighted percentage, 253%) manifested the most severe pattern of alcohol consumption, and had significant overrepresentations of major depression, panic, and other anxiety disorders as well as paranoid, schizotypal, borderline, antisocial, and histrionic personality disorders compared with those who used alcohol alone. Conclusions: Specific patterns of concurrent substance use convey important information regarding the clinical presentation and prognosis for AD. In particular, concurrent use of illicit drugs over the past year by AD individuals was associated with greater severity and comorbid psychopathology. These data suggest the need for pragmatic trials of AD interventions that take into account patterns of substance use behavior in addition to an AD diagnosis. Published by Elsevier Ltd. C1 [Moss, Howard B.; Goldstein, Rise B.] NIAAA, Bethesda, MD 20892 USA. [Chen, Chiung M.; Yi, Hsiao-Ye] CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA 22201 USA. RP Moss, HB (reprint author), Medicat Assisted Therapy, 1150 Silverado St, La Jolla, CA 92037 USA. OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism FX Funding for this study was provided by National Institute on Alcohol Abuse and Alcoholism using internal funds. At the institutional level, NIAAA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. However, the first author, Dr. Moss was Associate Director of NIAAA at the time this work was conducted. NR 47 TC 7 Z9 7 U1 1 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD NOV PY 2015 VL 50 BP 192 EP 198 DI 10.1016/j.addbeh.2015.06.041 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CO4YO UT WOS:000359167000034 PM 26151585 ER PT J AU Liu, HW Ren, W Zhao, JY Zhao, HF Wu, XQ Shi, P Zhou, QF Shung, KK AF Liu, Hongwei Ren, Wei Zhao, Jinyan Zhao, Huifeng Wu, Xiaoqing Shi, Peng Zhou, Qifa Shung, K. Kirk TI Design and fabrication of high frequency BNT film based linear array transducer SO CERAMICS INTERNATIONAL LA English DT Article DE Lead-free BNT film; Micro-machining technologies; High frequency ultrasound array transducer ID THICK-FILMS; ULTRASONIC TRANSDUCERS; ELECTRICAL-PROPERTIES; COMPOSITE; ELEMENTS AB Intravascular ultrasound (IVUS) has been used for diagnosis of coronary diseases. According to the outstanding transducer performance, Ba0.5Na0.5TiO3 (BNT)-based piezoelectric materials are good candidates for the IVUS applications. In this paper, lead-free BNT piezoelectric thick film has been used to fabricate a linear array transducer. The BNT based transducer array has a 2 x 16-element pattern. In the fabrication process of transducers, micro-machining technologies have been adopted. Wet etching was used to pattern the silicon substrate. The thin layers of Si3N4 and SiO2, are used as etching masks, and patterned by reactive etching and buffered oxide etch (BOE), respectively. After that, the part of Si not covered by the patterned masks is etched by 30% KOH solution. BNT slurry prepared by mixing BNT solution and BNT powder has been deposited on the substrate by spin coating and then thermally treated to obtain the thick film. The PiezoCAD software has been employed to analyze the performance of the array, and the simulation results show that the BNT film array has a center frequency of 82.84 MHz and a -6 dB bandwidth of 46.77%. (C) 2015 Elsevier Ltd and Techna Group S.r.l. All rights reserved. C1 [Liu, Hongwei; Ren, Wei; Zhao, Jinyan; Zhao, Huifeng; Wu, Xiaoqing; Shi, Peng] Xi An Jiao Tong Univ, Minist Educ, Key Lab, Elect Mat Res Lab, Xian 710049, Peoples R China. [Liu, Hongwei; Ren, Wei; Zhao, Jinyan; Zhao, Huifeng; Wu, Xiaoqing; Shi, Peng] Xi An Jiao Tong Univ, Int Ctr Dielect Res, Xian 710049, Peoples R China. [Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Ren, W (reprint author), Xi An Jiao Tong Univ, Minist Educ, Key Lab, Elect Mat Res Lab, Xian 710049, Peoples R China. EM wren@mail.xjtu.edu.cn RI shi, peng/C-8551-2011 OI shi, peng/0000-0003-2217-8486 FU National Natural Science Foundation of China [51332003, 51202184]; International Science & Technology Cooperation Program of China [2010DFB13640, 2011DFA51880] FX The authors would like to thank the National Natural Science Foundation of China, under Grant nos. 51332003 and 51202184, and the International Science & Technology Cooperation Program of China under Grant nos. 2010DFB13640 and 2011DFA51880 for their financial support. NR 25 TC 0 Z9 0 U1 6 U2 34 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0272-8842 EI 1873-3956 J9 CERAM INT JI Ceram. Int. PD NOV PY 2015 VL 41 SU 1 BP S631 EP S637 DI 10.1016/j.ceramint.2015.03.256 PG 7 WC Materials Science, Ceramics SC Materials Science GA CO2EF UT WOS:000358968100111 ER PT J AU Sun, YY Birnbaumer, L Singh, BB AF Sun, Yuyang Birnbaumer, Lutz Singh, Brij B. TI TRPC1 regulates calcium-activated chloride channels in salivary gland cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID FLUID SECRETION; ACINAR-CELLS; CL-CHANNELS; CA2+ INFLUX; TMEM16A; PROTEIN; MODULATION; EXPRESSION; MICE AB Calcium-activated chloride channel (CaCC) plays an important role in modulating epithelial secretion. It has been suggested that in salivary tissues, sustained fluid secretion is dependent on Ca2+ influx that activates ion channels such as CaCC to initiate Cl- efflux. However direct evidence as well as the molecular identity of the Ca2+ channel responsible for activating CaCC in salivary tissues is not yet identified. Here we provide evidence that in human salivary cells, an outward rectifying Cl- current was activated by increasing [Ca2+](i), which was inhibited by the addition of pharmacological agents niflumic acid (NFA), an antagonist of CaCC, or T16Ainh-A01, a specific TMEM16a inhibitor. Addition of thapsigargin (Tg), that induces store-depletion and activates TRPC1-mediated Ca2+ entry, potentiated the Cl- current, which was inhibited by the addition of a non-specific TRPC channel blocker SKF96365 or removal of external Ca2+. Stimulation with Tg also increased plasma membrane expression of TMEM16a protein, which was also dependent on Ca2+ entry. Importantly, in salivary cells, TRPC1 silencing, but not that of TRPC3, inhibited CaCC especially upon store depletion. Moreover, primary acinar cells isolated from submandibular gland also showed outward rectifying Cl- currents upon increasing [Ca2+](i). These Cl- currents were again potentiated with the addition of Tg, but inhibited in the presence of T16Ainh-A01. Finally, acinar cells isolated from the submandibular glands of TRPC1 knockout mice showed significant inhibition of the outward Cl- currents without decreasing TMEM16a expression. Together the data suggests that Ca2+ entry via the TRPC1 channels is essential for the activation of CaCC. J. Cell. Physiol. 9999: 2848-2856, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Sun, Yuyang; Singh, Brij B.] Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58201 USA. [Birnbaumer, Lutz] NIHES, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. RP Singh, BB (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58201 USA. EM brij.singh@med.und.edu FU National Institutes of Health [DE017102]; Intramural Research Program of the NIH [Z01-ES-101684] FX Contract grant sponsor: National Institutes of Health;; Contract grant number: DE017102.; Contract grant sponsor: Intramural Research Program of the NIH;; Contract grant number: Z01-ES-101684. NR 34 TC 4 Z9 4 U1 3 U2 11 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 NOV PY 2015 VL 230 IS 11 BP 2848 EP 2856 DI 10.1002/jcp.25017 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CN8LS UT WOS:000358692700028 PM 25899321 ER PT J AU Naeem, MA Gottsch, ADH Ullah, I Khan, SN Husnain, T Butt, NH Qazi, ZA Akram, J Riazuddin, S Ayyagari, R Hejtmancik, JF Riazuddin, SA AF Naeem, Muhammad Asif Gottsch, Alexander D. H. Ullah, Inayat Khan, Shaheen N. Husnain, Tayyab Butt, Nadeem H. Qazi, Zaheeruddin A. Akram, Javed Riazuddin, Sheikh Ayyagari, Radha Hejtmancik, J. Fielding Riazuddin, S. Amer TI Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness SO MOLECULAR VISION LA English DT Article ID MISSENSE MUTATION; COMPLETE FORM; GENE; RICH; ELECTRORETINOGRAM; RESPONSES; SEQUENCE; PROTEIN; GPR179; NYX AB Purpose: This study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families. Methods: Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon-intron boundaries of GRM6, were sequenced bidirectionally. Results: According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively. Conclusions: We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent. C1 [Naeem, Muhammad Asif; Ullah, Inayat; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Gottsch, Alexander D. H.; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe St,Maumenee 840, Baltimore, MD 21287 USA. [Butt, Nadeem H.; Akram, Javed; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore, Pakistan. [Qazi, Zaheeruddin A.] Layton Rahmatulla Benevolent Trust Hosp, Lahore, Pakistan. [Akram, Javed; Riazuddin, Sheikh] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad, Pakistan. [Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA. [Hejtmancik, J. Fielding] NEI, NIH, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. RP Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe St,Maumenee 840, Baltimore, MD 21287 USA. EM riazuddin@jhmi.edu FU Higher Education Commission (HEC), Islamabad, Pakistan; Ministry of Science and Technology, Islamabad, Pakistan; National Eye Institute [R01EY021237] FX We are thankful to all family members for their participation in this study. We are also thankful to the staff of Layton Rehmatulla Benevolent Trust (LRBT) hospital for clinical evaluation of affected individuals. This study was supported in part by Higher Education Commission (HEC), Islamabad, Pakistan, Ministry of Science and Technology, Islamabad, Pakistan, and National Eye Institute Grant R01EY021237 (RA & SAR). NR 30 TC 2 Z9 2 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD OCT 31 PY 2015 VL 21 BP 1261 EP 1271 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA DC4FC UT WOS:000369174900001 PM 26628857 ER PT J AU Gara, SK Wang, YH Patel, D Liu-Chittenden, Y Jain, M Boufraqech, M Zhang, LS Meltzer, PS Kebebew, E AF Gara, Sudheer Kumar Wang, Yonghong Patel, Dhaval Liu-Chittenden, Yi Jain, Meenu Boufraqech, Myriem Zhang, Lisa Meltzer, Paul S. Kebebew, Electron TI Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PANCREATIC DUCTAL ADENOCARCINOMA; TUMOR-SUPPRESSOR GENE; BREAST-CANCER CELLS; P53 MUTATIONS; MOLECULAR CLASSIFICATION; BETA-CATENIN; ONCOSTATIN M; CARCINOMA; EXPRESSION; TUMORIGENESIS AB To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics. C1 [Gara, Sudheer Kumar; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Yonghong; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov RI Gara, Sudheer Kumar/E-8084-2016; Boufraqech, Myriem/E-4823-2016; OI Liu-Chittenden, Yi/0000-0001-6357-5360; Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research; National Cancer Institute; National Institutes of Health [1 ZIA BC011275 05] FX Intramural research program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health [1 ZIA BC011275 05]. Funding for open access charge: Intramural research program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health [1 ZIA BC011275 05]. NR 49 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 30 PY 2015 VL 43 IS 19 BP 9327 EP 9339 DI 10.1093/nar/gkv908 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CY4VA UT WOS:000366405600024 PM 26446994 ER PT J AU Sambuughin, N Goldfarb, LG Sivtseva, TM Davydova, TK Vladimirtsev, VA Osakovskiy, VL Danilova, AP Nikitina, RS Ylakhova, AN Diachkovskaya, MP Sundborger, AC Renwick, NM Platonov, FA Hinshaw, JE Toro, C AF Sambuughin, Nyamkhishig Goldfarb, Lev G. Sivtseva, Tatiana M. Davydova, Tatiana K. Vladimirtsev, Vsevolod A. Osakovskiy, Vladimir L. Danilova, Al'bina P. Nikitina, Raisa S. Ylakhova, Anastasia N. Diachkovskaya, Margarita P. Sundborger, Anna C. Renwick, Neil M. Platonov, Fyodor A. Hinshaw, Jenny E. Toro, Camilo TI Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2 SO BMC NEUROLOGY LA English DT Article DE Paraplegia; HSP; Dynamin; DNM2; Neuropathy; Exome sequencing; Endocytosis ID MARIE-TOOTH NEUROPATHY; CENTRONUCLEAR MYOPATHY; MUSCLE INVOLVEMENT; I-TASSER; VARIANTS; PREDICTION; SPECTRUM; DISEASE; MODEL; SPG3A AB Background: Hereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity. Methods: Whole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative. Results: Nine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c. 2155C > T, p. R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p. R719W potentially disrupts dynamin 2 assembly. Conclusion: This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c. 2155C > T, p. R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes. C1 [Sambuughin, Nyamkhishig] Uniformed Serv Univ Hlth Sci, Consortium Hlth & Mil Performance, Bethesda, MD 20814 USA. [Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. [Sivtseva, Tatiana M.; Davydova, Tatiana K.; Vladimirtsev, Vsevolod A.; Osakovskiy, Vladimir L.; Danilova, Al'bina P.; Nikitina, Raisa S.; Ylakhova, Anastasia N.; Diachkovskaya, Margarita P.; Platonov, Fyodor A.] MK Ammosov North Eastern Fed Univ, Inst Hlth, Yakutsk 677010, Russia. [Sundborger, Anna C.; Hinshaw, Jenny E.] NIDDK, NIH, Bethesda, MD 20892 USA. [Renwick, Neil M.] Queens Univ, Kingston Gen Hosp, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada. [Toro, Camilo] NHGRI, NIH, Bethesda, MD 20892 USA. RP Goldfarb, LG (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov RI Sundborger, Anna/J-6590-2014 OI Sundborger, Anna/0000-0003-4696-7543 FU Ministry of Education and Science of the Russian Federation [3095]; Uniformed Services University (USU) [R080148613]; National Institute of Neurological Disorders and Stroke, NIH; National Institute of Diabetes, Digestive and Kidney Diseases, NIH; National Human Genome Research Institute, NIH FX We wish to thank Dr. C. Merrifield for providing the cloned wild-type human DNM2 and Dr. W. Gall for helpful comments and suggestions. The study was funded in part by the Ministry of Education and Science of the Russian Federation (project No. 3095). Research was supported by the Uniformed Services University (USU) R080148613 grant to N.S., Intramural Research Programs of the National Institute of Neurological Disorders and Stroke, the National Institute of Diabetes, Digestive and Kidney Diseases, and the National Human Genome Research Institute, NIH. Technical support was provided by the NIH Intramural Sequencing Center (NISC), Bioinformatics core of the NIH Undiagnosed Diseases Program, and the Biomedical Instrumentation Center of USU. NR 43 TC 1 Z9 1 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD OCT 30 PY 2015 VL 15 AR 223 DI 10.1186/s12883-015-0481-3 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA CW9CN UT WOS:000365296100002 PM 26517984 ER PT J AU Appella, E Jenkins, LMM Guengerich, FP AF Appella, Ettore Jenkins, Lisa M. Miller Guengerich, F. Peter TI Introduction to Thematic Series: Protein Interactions, Structures, and Networks SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Editorial Material AB Protein interactions are fundamental to the proper functioning of cells, and aberrant formation or regulation of protein interactions is at the heart of many diseases, including cancer. The advancement of methods to study the identity, function, and regulation of protein complexes makes possible the understanding of how those complexes malfunction in human diseases. New methodologies in mass spectrometry, microscopy, and protein structural analysis are rapidly advancing the amount and quality of the data, as well as the level of detail that can be obtained from experiments. With this progress, the questions that can be addressed and the biological landscape are changing. This series of minireviews highlights methodological advances and how they have been applied in novel ways to explore the function and regulation of pathways and dynamic networks in cells. C1 [Appella, Ettore; Jenkins, Lisa M. Miller] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Guengerich, F. Peter] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM appellae@mail.nih.gov NR 6 TC 0 Z9 0 U1 3 U2 5 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 OCT 30 PY 2015 VL 290 IS 44 BP 26393 EP 26394 DI 10.1074/jbc.R115.690370 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AO UT WOS:000364793600005 PM 26354433 ER PT J AU Balagopalan, L Kortum, RL Coussens, NP Barr, VA Samelson, LE AF Balagopalan, Lakshmi Kortum, Robert L. Coussens, Nathan P. Barr, Valarie A. Samelson, Lawrence E. TI The Linker for Activation of T Cells (LAT) Signaling Hub: From Signaling Complexes to Microclusters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ANTIGEN RECEPTOR; MULTIPOINT BINDING; TYROSINE RESIDUES; PROTEIN COMPLEXES; LIPID RAFTS; GRB2; DOMAINS; SLP-76; PLC-GAMMA-1; RECRUITMENT AB Since the cloning of the critical adapter, LAT (linker for activation of T cells), more than 15 years ago, a combination of multiple scientific approaches and techniques continues to provide valuable insights into the formation, composition, regulation, dynamics, and function of LAT-based signaling complexes. In this review, we will summarize current views on the assembly of signaling complexes nucleated by LAT. LAT forms numerous interactions with other signaling molecules, leading to cooperativity in the system. Furthermore, oligomerization of LAT by adapter complexes enhances intracellular signaling and is physiologically relevant. These results will be related to data from super-resolution microscopy studies that have revealed the smallest LAT-based signaling units and nanostructure. C1 [Balagopalan, Lakshmi] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kortum, Robert L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Coussens, Nathan P.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM samelsonl@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research (CCR) FX This work was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research (CCR). This is the fourth article in the Thematic Minireview series "Protein Interactions, Structures, and Networks." The authors declare that they have no conflicts of interest with the contents of this article. NR 64 TC 7 Z9 7 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 30 PY 2015 VL 290 IS 44 BP 26422 EP 26429 DI 10.1074/jbc.R115.665869 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AO UT WOS:000364793600009 PM 26354432 ER PT J AU Blasic, JR Worcester, DL Gawrisch, K Gurnev, P Mihailescu, M AF Blasic, Joseph R. Worcester, David L. Gawrisch, Klaus Gurnev, Philip Mihailescu, Mihaela TI Pore Hydration States of KcsA Potassium Channels in Membranes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BILAYER STRUCTURE DETERMINATION; NEUTRON-DIFFRACTION DATA; INFLUENZA-A VIRUS; K+ CHANNEL; X-RAY; CRYSTAL-STRUCTURE; CYTOCHROME P450CAM; JOINT REFINEMENT; VOLUME CHANGES; ION-CHANNEL AB Water-filled hydrophobic cavities in channel proteins serve as gateways for transfer of ions across membranes, but their properties are largely unknown. We determined water distributions along the conduction pores in two tetrameric channels embedded in lipid bilayers using neutron diffraction: potassium channel KcsA and the transmembrane domain of M2 protein of influenza A virus. For the KcsA channel in the closed state, the distribution of water is peaked in the middle of the membrane, showing water in the central cavity adjacent to the selectivity filter. This water is displaced by the channel blocker tetrabutylammonium. The amount of water associated with the channel was quantified, using neutron diffraction and solid state NMR. In contrast, the M2 proton channel shows a V-shaped water profile across the membrane, with a narrow constriction at the center, like the hourglass shape of its internal surface. These two types of water distribution are therefore very different in their connectivity to the bulk water. The water and protein profiles determined here provide important evidence concerning conformation and hydration of channels in membranes and the potential role of pore hydration in channel gating. C1 [Blasic, Joseph R.; Mihailescu, Mihaela] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Worcester, David L.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92697 USA. [Worcester, David L.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Gurnev, Philip] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Gurnev, Philip] NICHHD, NIH, Bethesda, MD 20892 USA. RP Mihailescu, M (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM emihailescu@ibbr.umd.edu FU National Research Council; NIST Biomanufacturing Initiative FX We thank Crina Nimigean for providing the KcsA plasmid and Jun Wang and William F. DeGrado for the M2 peptide. We also thank Kenton Swartz, Dmitriy Krepkiy (NINDS, National Institutes of Health), and Stephen H. White (University of California, Irvine) for helpful discussions. We acknowledge the National Research Council for the postdoctoral fellowship awarded to J. B. We acknowledge the National Institute of Standards and Technology, U.S. Department of Commerce, in providing the neutron research facilities and the support provided by NIST Biomanufacturing Initiative. The identification of any commercial product or trade name does not imply endorsement or recommendation by the National Institute of Standards and Technology. NR 43 TC 1 Z9 1 U1 4 U2 13 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 OCT 30 PY 2015 VL 290 IS 44 BP 26765 EP U472 DI 10.1074/jbc.M115.661819 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AO UT WOS:000364793600038 PM 26370089 ER PT J AU Sheldon, KL Gurnev, PA Bezrukov, SM Sackett, DL AF Sheldon, Kely L. Gurnev, Philip A. Bezrukov, Sergey M. Sackett, Dan L. TI Tubulin Tail Sequences and Post-translational Modifications Regulate Closure of Mitochondrial Voltage-dependent Anion Channel (VDAC) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-HEMOLYSIN; MEMBRANE; POLYMERIZATION; TERMINI; CELLS; PORE AB It was previously shown that tubulin dimer interaction with the mitochondrial outer membrane protein voltage-dependent anion channel (VDAC) blocks traffic through the channel and reduces oxidative metabolism and that this requires the unstructured anionic C-terminal tail peptides found on both alpha- and beta-tubulin subunits. It was unclear whether the alpha- and beta-tubulin tails contribute equally to VDAC blockade and what effects might be due to sequence variations in these tail peptides or to tubulin post-translational modifications, which mostly occur on the tails. The nature of the contribution of the tubulin body beyond acting as an anchor for the tails had not been clarified either. Here we present peptide-protein chimeras to address these questions. These constructs allow us to easily combine a tail peptide with different proteins or combine different tail peptides with a particular protein. The results show that a single tail grafted to an inert protein is sufficient to produce channel closure similar to that observed with tubulin. We show that the beta-tail is more than an order of magnitude more potent than the alpha-tail and that the lower alpha-tail activity is largely due to the presence of a terminal tyrosine. Detyrosination activates the alpha-tail, and activation is reversed by the removal of the glutamic acid penultimate to the tyrosine. Nitration of tyrosine reverses the tyrosine inhibition of binding and even induces prolonged VDAC closures. Our results demonstrate that small changes in sequence or post-translational modification of the unstructured tails of tubulin result in substantial changes in VDAC closure. C1 [Sheldon, Kely L.; Gurnev, Philip A.; Bezrukov, Sergey M.; Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Sheldon, KL (reprint author), Emory Univ, Div Cardiol, Dept Med, Sch Med, 307 Woodruff Mem Bldg,1639 Pierce Dr, Atlanta, GA 30322 USA. EM ksheldo@emory.edu; sackettd@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. The authors declare that they have no conflicts of interest with the contents of this article. NR 25 TC 2 Z9 2 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 30 PY 2015 VL 290 IS 44 BP 26784 EP 26789 DI 10.1074/jbc.M115.678854 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CW2AO UT WOS:000364793600040 PM 26306046 ER PT J AU Oh, J Chun, JW Jo, HJ Kim, E Park, HJ Lee, B Kim, JJ AF Oh, Jooyoung Chun, Ji-Won Jo, Hang Joon Kim, Eunseong Park, Hae-Jeong Lee, Boreom Kim, Jae-Jin TI The neural basis of a deficit in abstract thinking in patients with schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Abstract thinking; Theme identification; Schizophrenia; Frontopolar cortex; Orbitofrontal cortex; FMRI ID NEAR-INFRARED SPECTROSCOPY; REDUCED FRONTOPOLAR ACTIVATION; DORSOLATERAL PREFRONTAL CORTEX; VERBAL FLUENCY TASK; WORKING-MEMORY; NEURODEVELOPMENTAL HYPOTHESIS; PHYSIOLOGICAL DYSFUNCTION; COGNITIVE CONTROL; SOCIAL COGNITION; CONCRETE AB Abnormal abstract thinking is a major cause of social dysfunction in patients with schizophrenia, but little is known about its neural basis. In this study, we aimed to determine the characteristic abstract thinking-related brain responses in patients using a task reflecting social situations. We conducted functional magnetic resonance imaging while 16 patients with schizophrenia and 16 healthy controls performed a theme-identification task, in which various emotional pictures depicting social situations were presented. Compared with healthy controls, the patients showed significantly decreased activity in the left frontopolar and right orbitofrontal cortices during theme identification. Activity in these two regions correlated well in the controls, but not in patients. Instead, the patients exhibited a close correlation between activity in both sides of the frontopolar cortex, and a positive correlation between the right orbitofrontal cortex activity and degrees of theme identification. Reduced activity in the left frontopolar and right orbitofrontal cortices and the underlying aberrant connectivity may be implicated in the patients' deficits in abstract thinking. These newly identified features of the neural basis of abnormal abstract thinking are important as they have implications for the impaired social behavior of patients with schizophrenia during real-life situations. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Oh, Jooyoung; Lee, Boreom] Gwangju Inst Sci & Technol, DMSE, Gwangju 500712, South Korea. [Chun, Ji-Won; Kim, Eunseong; Kim, Jae-Jin] Yonsei Univ, Coll Med, Inst Behav Sci Med, Seoul, South Korea. [Jo, Hang Joon] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Park, Hae-Jeong] Yonsei Univ, Coll Med, Dept Nucl Med, Seoul, South Korea. [Lee, Boreom] Gwangju Inst Sci & Technol, Sch Mechatron, Gwangju 500712, South Korea. [Kim, Jae-Jin] Yonsei Univ, Coll Med, Dept Psychiat, Seoul, South Korea. RP Lee, B (reprint author), Gwangju Inst Sci & Technol, DMSE, 123 Cheomdangwagi Ro, Gwangju 500712, South Korea. EM leebr@gist.ac.kr; jaekim@yonsei.ac.kr OI Jo, Hang Joon/0000-0002-9180-3831 FU Institute of Medical System Engineering (iMSE) in the GIST, Korea; National Research Foundation of Korea (NRF) - Korea government (MEST) [NRF-2013R1A2A2A03068342] FX The research was supported by a grant from the Institute of Medical System Engineering (iMSE) in the GIST, Korea, and was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. NRF-2013R1A2A2A03068342). NR 57 TC 1 Z9 2 U1 4 U2 10 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 OCT 30 PY 2015 VL 234 IS 1 BP 66 EP 73 DI 10.1016/j.pscychresns.2015.08.007 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CW8AT UT WOS:000365221500009 PM 26329118 ER PT J AU Ruszkowski, M Nocek, B Forlani, G Dauter, Z AF Ruszkowski, Milosz Nocek, Boguslaw Forlani, Giuseppe Dauter, Zbigniew TI The structure of Medicago truncatula delta(1)-pyrroline-5-carboxylate reductase provides new insights into regulation of proline biosynthesis in plants SO FRONTIERS IN PLANT SCIENCE LA English DT Article DE protein structure; decamer; coenzyme preference; salt stress; abiotic stress; P5C reductase; P5CR ID OSMOTIC-STRESS; PYRROLINE-5-CARBOXYLATE REDUCTASE; STREPTOCOCCUS-PYOGENES; ARABIDOPSIS-THALIANA; ENHANCED TOLERANCE; CRYSTAL-STRUCTURES; SYNTHETASE GENE; P5C REDUCTASE; ROOT-NODULES; ACCUMULATION AB The two pathways for proline biosynthesis in higher plants share the last step, the conversion of delta(1)-pyrroline-5-carboxylate (P5C) to L-proline, which is catalyzed by P5C reductase (P5OR, EC 1.5.1.2) with the use of NAD(P)H as a coenzyme. There is increasing amount of evidence to suggest a complex regulation of P5CR activity at the post-translational level, yet the molecular basis of these mechanisms is unknown. Here we report the three-dimensional structure of the P5CR enzyme from the model legume Medicago truncatula (Mt). The crystal structures of unliganded MtP5CR decamer, and its complexes with the products NAD+, NADP, and L-proline were refined using x-ray diffraction data (at 1.7, 1.85, 1.95, and 2.1 angstrom resolution, respectively). Based on the presented structural data, the coenzyme preference for NADPH over NADH was explained, and NADPH is suggested to be the only coenzyme used by MtP5CR in vivo. Furthermore, the insensitivity of MtP5CR to feed-back inhibition by proline, revealed by enzymatic analysis, was correlated with structural features. Additionally, a mechanism for the modulation of enzyme activity by chloride anions is discussed, as well as the rationale for the possible development of effective enzyme inhibitors. C1 [Ruszkowski, Milosz; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. [Nocek, Boguslaw] Argonne Natl Lab, Biosci Div, Struct Biol Ctr, Argonne, IL 60439 USA. [Forlani, Giuseppe] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy. RP Ruszkowski, M (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. EM mruszkowski@anl.gov RI Forlani, Giuseppe/B-7869-2009 OI Forlani, Giuseppe/0000-0003-2598-5718 FU NCI, Center for Cancer Research; U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX This project was supported in part by the Intramural Research Program of the NCI, Center for Cancer Research. Structural results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. NR 70 TC 3 Z9 3 U1 3 U2 15 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-462X J9 FRONT PLANT SCI JI Front. Plant Sci. PD OCT 30 PY 2015 VL 6 AR 869 DI 10.3389/fpls.2015.00869 PG 17 WC Plant Sciences SC Plant Sciences GA CV8ZD UT WOS:000364576000001 PM 26579138 ER PT J AU Dasarathy, D Ito, Y AF Dasarathy, Dhweeja Ito, Yoichiro TI An improved design of spiral tube assembly for separation of proteins by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Spiral tube assembly; Flat-twisted tubing; High-speed countercurrent chromatography; Protein separation; Polymer phase system ID SUPPORT AB A new spiral tube assembly was designed to improve the column capacity and partition efficiency for protein separation. This spiral tube assembly has greater column capacity than the original tubing because of an increase in radial grooves from 4 to 12 to accommodate more spiral layers and 12 narrow spots instead of 4 in each circular loop to interrupt the laminar flow that causes sample band broadening. Standard PTFE tubing (1.6 mm ID) and the modified flat-twisted tubing were used as the separation column. The performances of both assemblies were compared for separating three stable test proteins including cytochrome c, myoglobin, and lysozyme using a two phase aqueous aqueous solvent system composed of polyethylene glycol 1000 (12.5% w/w) and dibasic potassium phosphate (12.5% w/w). All samples were run at 1, 2, 3, and 5 mL/min at both 800 rpm and 1000 rpm. The separation of these three protein samples produced high stationary phase retentions at 1, 2, and 3 mL/min, yet separated efficiently at 5 mL/min in 40 min. After comparing the separation efficiency in terms of the peak resolutions, theoretical plate numbers, and separation times, it was determined that the flat-twisted tubing was more effective in separating these protein samples. In order to validate the efficacy of this novel assembly, a mixture of five protein samples (cytochrome c, myoglobin, ovalbumin, lysozyme, and hemoglobin) were separated, under the optimal conditions established with these three protein samples, at I mL/min with a revolution speed of 1000 rpm. There were high stationary phase retentions of around 60%, with effective separations, demonstrating the efficiency of the flat-twisted spiral tube assembly. The separation time of 6 h was a limitation but can potentially be shortened by improving the strength of the column that will permit an increase in revolution speed and flow rate. This novel spiral separation column will allow rapid and efficient separation of mixtures with high yield of the constituent components. Published by Elsevier B.V. C1 [Dasarathy, Dhweeja; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Dasarathy, Dhweeja] Hawken Sch, Gates Mills, OH 44040 USA. RP Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Rm 8N230, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov FU NHLBI summer internship program FX The authors thank Dr. Xiaofeng Ma for technical instruction and Dr. Martha Knight of CCBiotech for preparation and use of the standard spiral tube assembly. This study is supported by the NHLBI summer internship program. NR 17 TC 2 Z9 2 U1 4 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD OCT 30 PY 2015 VL 1418 BP 77 EP 82 DI 10.1016/j.chroma.2015.09.033 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CV4WW UT WOS:000364268200008 PM 26427324 ER PT J AU Bis, JC Sitlani, C Irvin, R Avery, CL Smith, AV Sun, FG Evans, DS Musani, SK Li, XH Trompet, S Krijthe, BP Harris, TB Quibrera, PM Brody, JA Demissie, S Davis, BR Wiggins, KL Tranah, GJ Lange, LA Sotoodehnia, N Stott, DJ Franco, OH Launer, LJ Sturmer, T Taylor, KD Cupples, LA Eckfeldt, JH Smith, NL Liu, YM Wilson, JG Heckbert, SR Buckley, BM Ikram, MA Boerwinkle, E Chen, YDI de Craen, AJM Uitterlinden, AG Rotter, JI Ford, I Hofman, A Sattar, N Slagboom, PE Westendorp, RGJ Gudnason, V Vasan, RS Lumley, T Cummings, SR Taylor, HA Post, W Jukema, JW Stricker, BH Whitsel, EA Psaty, BM Arnett, D AF Bis, Joshua C. Sitlani, Colleen Irvin, Ryan Avery, Christy L. Smith, Albert Vernon Sun, Fangui Evans, Daniel S. Musani, Solomon K. Li, Xiaohui Trompet, Stella Krijthe, Bouwe P. Harris, Tamara B. Quibrera, P. Miguel Brody, Jennifer A. Demissie, Serkalem Davis, Barry R. Wiggins, Kerri L. Tranah, Gregory J. Lange, Leslie A. Sotoodehnia, Nona Stott, David J. Franco, Oscar H. Launer, Lenore J. Stuermer, Til Taylor, Kent D. Cupples, L. Adrienne Eckfeldt, John H. Smith, Nicholas L. Liu, Yongmei Wilson, James G. Heckbert, Susan R. Buckley, Brendan M. Ikram, M. Arfan Boerwinkle, Eric Chen, Yii-Der Ida de Craen, Anton J. M. Uitterlinden, Andre G. Rotter, Jerome I. Ford, Ian Hofman, Albert Sattar, Naveed Slagboom, P. Eline Westendorp, Rudi G. J. Gudnason, Vilmundur Vasan, Ramachandran S. Lumley, Thomas Cummings, Steven R. Taylor, Herman A., Jr. Post, Wendy Jukema, J. Wouter Stricker, Bruno H. Whitsel, Eric A. Psaty, Bruce M. Arnett, Donna TI Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium SO PLOS ONE LA English DT Article ID GENOMIC ASSOCIATION ANALYSIS; BLOOD-PRESSURE; ENVIRONMENT INTERACTION; WIDE ASSOCIATION; HYPERTENSION; OUTCOMES; VARIANTS; HEART; LOCI AB Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regressionmodels to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (P-interaction > 5.0x10(-8)). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (P-interaction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD. C1 [Bis, Joshua C.; Sitlani, Colleen; Brody, Jennifer A.; Wiggins, Kerri L.; Sotoodehnia, Nona; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Irvin, Ryan; Arnett, Donna] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Avery, Christy L.; Stuermer, Til; Whitsel, Eric A.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sun, Fangui; Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Evans, Daniel S.; Tranah, Gregory J.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Musani, Solomon K.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RA Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RA Leiden, Netherlands. [Krijthe, Bouwe P.; Franco, Oscar H.; Ikram, M. Arfan; Uitterlinden, Andre G.; Hofman, Albert; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Harris, Tamara B.; Launer, Lenore J.] Natl Inst Aging, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD USA. [Quibrera, P. Miguel] Univ N Carolina, Gillings Sch Global Publ Hlth, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Davis, Barry R.] Univ Texas Houston, Sch Publ Hlth, Dept Biostat, Houston, TX USA. [Tranah, Gregory J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Stuermer, Til] Univ N Carolina, GSK Ctr Excellence Pharmacoepidemiol, Chapel Hill, NC USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Cupples, L. Adrienne; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs Off Res & Dev, Seattle, WA USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Sattar, Naveed] BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Westendorp, Rudi G. J.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Taylor, Herman A., Jr.] Morehouse Sch Med, Dept Med, Atlanta, GA 30310 USA. [Post, Wendy] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. [Whitsel, Eric A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. RP Psaty, BM (reprint author), Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. EM psaty@uw.edu RI Slagboom, P. Eline/R-4790-2016; Smith, Albert Vernon/K-5150-2015; OI Slagboom, P. Eline/0000-0002-2875-4723; Smith, Albert Vernon/0000-0003-1942-5845; Ramachandran, Vasan/0000-0001-7357-5970; Sattar, Naveed/0000-0002-1604-2593 FU National Institutes of Health (NIH) [N01-AG-1-2100]; National Institutes on Aging (NIA) Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIH Roadmap for Medical Research; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, N02-HL-6-4278HL085251, HL073410, HL085251, HL068986]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Heart, Lung and Blood Institute [N01-HC-25195, HHSN268201500001I]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; NIH Heart, Lung and Blood Institute [5 R01 HL-63082]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung, and Blood Institute on Minority Health and Health Disparities [HSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Heart, Lung, and Blood Institute (NHLBI) [N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, RR-024156]; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases; Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810] FX The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AGES: This study has been funded by National Institutes of Health (NIH) contract N01-AG-1-2100, the National Institutes on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. FHS: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and an NHLBI contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Additional support for these analyses was provided by R01HL103612 (PI Psaty, subcontract PI, Vasan). GenHAT: This work was supported by NIH Heart, Lung and Blood Institute grant 5 R01 HL-63082, Genetics of Hypertension Associated Treatment. The ALLHAT study was supported by a contract with the National Heart, Lung and Blood Institute.; Health ABC: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HVH: The Heart and Vascular Health Study research reported in this article were supported by National Heart, Lung, and Blood Institute grants NHLBI grants, HL085251, HL073410, HL085251, and HL068986. JHS: The authors thank the Jackson Heart Study team (University of Mississippi Medical Center, Jackson State University and Tougaloo College) and participants for their long-term commitment that continues to improve our understanding of the risk factors of cardiovascular diseases. The Jackson Heart Study is supported by contracts HSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute on Minority Health and Health Disparities. MESA: MESA and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). Rotterdam Study (RS): The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research; The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by The Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project nr. 050-060-810. NR 31 TC 3 Z9 3 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 30 PY 2015 VL 10 IS 10 AR e0140496 DI 10.1371/journal.pone.0140496 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0EH UT WOS:000363920800007 PM 26516778 ER PT J AU McCormick, DL Horn, TL Johnson, WD Peng, XJ Lubet, RA Steele, VE AF McCormick, David L. Horn, Thomas L. Johnson, William D. Peng, Xinjian Lubet, Ronald A. Steele, Vernon E. TI Suppression of Rat Oral Carcinogenesis by Agonists of Peroxisome Proliferator Activated Receptor gamma SO PLOS ONE LA English DT Article ID CANCER EPIDEMIOLOGY CONSORTIUM; PPAR-GAMMA; HUMAN-PAPILLOMAVIRUS; INTERNATIONAL HEAD; POOLED ANALYSIS; RISK; ROSIGLITAZONE; EXPRESSION; ALCOHOL; SMOKING AB Peroxisome-proliferator-activated receptor. (PPAR.) is a ligand-activated transcription factor that regulates cell proliferation, differentiation, and apoptosis. In vivo studies were performed to evaluate the activities of two thiazolidinedione PPAR. agonists, rosiglitazone and pioglitazone, as inhibitors of oral carcinogenesis in rats. Oral squamous cell carcinomas (OSCC) were induced in male F344 rats by 4-nitroquinoline-1-oxide (NQO; 20 ppm in the drinking water for 10 weeks). In each study, groups of 30 NQO-treated rats were exposed to a PPAR. agonist beginning at week 10 (one day after completion of NQO administration) or at week 17 (7 weeks post-NQO); chemopreventive agent exposure was continued until study termination at week 22 (rosiglitazone study) or week 24 (pioglitazone study). Administration of rosiglitazone (800 mg/kg diet) beginning at week 10 increased survival, reduced oral cancer incidence, and reduced oral cancer invasion score in comparison to dietary controls; however, chemopreventive activity was largely lost when rosiglitazone administration was delayed until week 17. Administration of pioglitazone (500 mg/kg diet beginning at week 10 or 1000 mg/kg diet beginning at week 17) induced significant reductions in oral cancer incidence without significant effects on OSCC invasion scores. Transcript levels of PPAR. and its three transcriptional variants (PPAR.v1, PPAR.v2, and PPAR.v3) were not significantly different in OSCC versus age-and site-matched phenotypically normal oral tissues from rats treated with NQO. These data suggest that PPAR. provides a useful molecular target for oral cancer chemoprevention, and that overexpression of PPAR. at the transcriptional level in neoplastic lesions is not essential for chemopreventive efficacy. C1 [McCormick, David L.; Horn, Thomas L.; Johnson, William D.; Peng, Xinjian] IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Lubet, Ronald A.; Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20852 USA. RP McCormick, DL (reprint author), IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. EM dmccormick@iitri.org FU U.S. National Cancer Institute [N01-CN-85175, HHSN261200433003C (N01-CN-43303)] FX Grants N01-CN-85175 and HHSN261200433003C (N01-CN-43303) were awarded to DLM by the U.S. National Cancer Institute (www.nci.nih.gov). National Cancer Institute scientists (RAL and VES) participated in study design and preparation of the manuscript. NR 40 TC 2 Z9 2 U1 1 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 OCT 30 PY 2015 VL 10 IS 10 AR e0141849 DI 10.1371/journal.pone.0141849 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0EH UT WOS:000363920800087 PM 26516762 ER PT J AU Prince, TL Kijima, T Tatokoro, M Lee, S Tsutsumi, S Yim, K Rivas, C Alarcon, S Schwartz, H Khamit-Kush, K Scroggins, BT Beebe, K Trepel, JB Neckers, L AF Prince, Thomas L. Kijima, Toshiki Tatokoro, Manabu Lee, Sunmin Tsutsumi, Shinji Yim, Kendrick Rivas, Candy Alarcon, Sylvia Schwartz, Harvey Khamit-Kush, Kofi Scroggins, Bradley T. Beebe, Kristin Trepel, Jane B. Neckers, Len TI Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants SO PLOS ONE LA English DT Article ID HEAT-SHOCK PROTEINS; IN-VIVO; ATP HYDROLYSIS; TRANSCRIPTION FACTOR; CHAPERONE MACHINERY; COMPLEX; GELDANAMYCIN; CELLS; ACTIVATION; MECHANISM AB The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90 alpha and constitutively expressed HSP90 beta, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90 alpha and HSP90 beta with the transcription factors HSF1 and HIF1 alpha, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90 alpha binding each client protein with greater apparent affinity compared to HSP90 beta, while HSP90 beta bound each inhibitor with greater relative interaction strength compared to HSP90 alpha. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states. C1 [Prince, Thomas L.; Kijima, Toshiki; Tatokoro, Manabu; Tsutsumi, Shinji; Yim, Kendrick; Rivas, Candy; Schwartz, Harvey; Khamit-Kush, Kofi; Beebe, Kristin; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Sunmin; Alarcon, Sylvia; Trepel, Jane B.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Scroggins, Bradley T.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prince, TL (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM thomas.prince@nih.gov; neckers@nih.gov FU Intramural Research Program, NCI [Z01 BC011032-01, Z01 SC010074-12]; JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH FX This work was supported by funds to L.N. from the Intramural Research Program, NCI (project #s Z01 BC011032-01 and Z01 SC010074-12). Biotinylated ganetespib (STA-7346) was provided by Weiwen Ying (Synta Pharmaceuticals, Lexington, MA). T.K. is supported by a JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH. NR 55 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 30 PY 2015 VL 10 IS 10 AR e0141786 DI 10.1371/journal.pone.0141786 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0EH UT WOS:000363920800077 PM 26517842 ER PT J AU Bodelon, C Heaphy, CM Meeker, AK Geller, B Vacek, PM Weaver, DL Chicoine, RE Shepherd, JA Mahmoudzadeh, AP Patel, DA Brinton, LA Sherman, ME Gierach, GL AF Bodelon, Clara Heaphy, Christopher M. Meeker, Alan K. Geller, Berta Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Shepherd, John A. Mahmoudzadeh, Amir Pasha Patel, Deesha A. Brinton, Louise A. Sherman, Mark E. Gierach, Gretchen L. TI Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy SO BMC CANCER LA English DT Article DE Telomere; Mammographic density; Breast pathology; Hyperplasia; Breast diseases; Breast neoplasms ID CANCER RISK; SHORTENING OCCURS; PATERNAL AGE; BLOOD-CELLS; METAANALYSIS; HORMONES; HEALTH; EPITHELIUM; MENOPAUSE; OBESITY AB Background: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis. Methods: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses). Results: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non-proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95 % CI: 1.47, 4.42). Conclusions: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging. C1 [Heaphy, Christopher M.; Meeker, Alan K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. [Meeker, Alan K.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD USA. [Meeker, Alan K.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD USA. [Geller, Berta] Univ Vermont, Coll Med, Dept Hlth Promot Res, Burlington, VT USA. [Geller, Berta; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Vermont Canc Ctr, Burlington, VT USA. [Vacek, Pamela M.] Univ Vermont, Coll Med, Dept Biostat, Burlington, VT USA. [Weaver, Donald L.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT USA. [Chicoine, Rachael E.] Univ Vermont, Coll Med, Off Hlth Promot Res, Burlington, VT USA. [Shepherd, John A.; Mahmoudzadeh, Amir Pasha] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sherman, Mark E.] Natl Canc Inst, Breast & Gynecol Canc Res Grp, Canc Prevent Div, Rockville, MD USA. [Bodelon, Clara] Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM clara.bodelon@nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU National Center for Research Resources - blood processing at the University of Vermont's General Clinical Research Center [M01 RR000109]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; National Cancer Institute federal funds [HHSN261200800001E]; National Cancer Institute [U01CA70013, 1R21CA157254] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Cancer Institute federal funds awarded under Contract No. HHSN261200800001E to SAIC-Frederick, Inc. Breast Cancer Research Stamp Funds and cooperative agreement U01CA70013 (B. Geller, P. Vacek, D. Weaver, R. Chicoine) and 1R21CA157254 (J. Shepherd, A. Mahmoudzadeh) from the National Cancer Institute funded some of the data collection and image analysis for this study. Grant number M01 RR000109 from the National Center for Research Resources funded the blood processing at the University of Vermont's General Clinical Research Center. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors are indebted to the participants in the BREAST Stamp Project for their outstanding cooperation and to the physicians, pathologists, nurses, technologists, and interviewers for their efforts in the field. The authors thank Clair Bove, Patricia Lutton, Ellen Young, Aileen Burke, Laura Linville, Daphne Papathomas, and Jeff Wang for research assistance. We also thank Bo Fan from the University of California at San Francisco for providing the area measures of mammographic density, Bharathi Anekella from SeraCare Life Sciences for assistance with DNA extraction, Sally Larson from the Cancer Genomics Research Laboratory for assistance with DNA quantitation, Janet Lawler-Heaver and Kerry Grace Morrissey from Westat for study management support, and Franklin Demuth at Information Management Services for data support and analysis. NR 50 TC 1 Z9 1 U1 1 U2 7 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 OCT 30 PY 2015 VL 15 AR 823 DI 10.1186/s12885-015-1860-2 PG 12 WC Oncology SC Oncology GA CU9BD UT WOS:000363836900004 PM 26519084 ER PT J AU Xi, S Inchauste, S Guo, H Shan, J Xiao, Z Xu, H Miettenen, M Zhang, MR Hong, JA Raiji, MT Altorki, NK Casson, AG Beer, DG Robles, AI Bowman, ED Harris, CC Steinberg, SM Schrump, DS AF Xi, S. Inchauste, S. Guo, H. Shan, J. Xiao, Z. Xu, H. Miettenen, M. Zhang, M. R. Hong, J. A. Raiji, M. T. Altorki, N. K. Casson, A. G. Beer, D. G. Robles, A. I. Bowman, E. D. Harris, C. C. Steinberg, S. M. Schrump, D. S. TI Cigarette smoke mediates epigenetic repression of miR-217 during esophageal adenocarcinogenesis SO ONCOGENE LA English DT Article ID PANCREATIC DUCTAL ADENOCARCINOMA; SQUAMOUS-CELL CARCINOMA; LINEAGE PROGRESSION; MICRORNA EXPRESSION; BARRETTS-ESOPHAGUS; CANCER CELLS; E-CADHERIN; CARCINOGENESIS; INVASION; OVEREXPRESSION AB Although microRNAs (miRs) have been implicated in the pathogenesis of various human malignancies, limited information is available regarding mechanisms by which these noncoding RNAs contribute to initiation and progression of tobacco-induced esophageal cancers. In this study, array and quantitative reverse transcriptase-PCR techniques were used to examine miR expression in immortalized esophageal epithelia (IEE) and esophageal adenocarcinoma (EAC) cells cultured in normal media with or without cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly decreased miR-217 expression in these cells. Endogenous levels of miR-217 expression in cultured EAC cells (EACC)/primary EACs were significantly lower than those observed in IEE/paired normal esophageal tissues. RNA crosslink immunoprecipitation, quantitative reverse transcriptase-PCR (qRT-PCR) and immunoblot experiments demonstrated direct interaction of miR-217 with kallikrein 7 (KLK7), encoding a putative oncogene not previously implicated in EAC. Repression of miR-217 correlated with increased levels of KLK7 in primary EACs, particularly those from smokers. Chromatin and methylated DNA immunoprecipitation experiments demonstrated that CSC-mediated repression of miR-217 coincided with DNMT3b-dependent hypermethylation and decreased occupancy of nuclear factor 1 within the miR-217 genomic locus. Deoxyazacytidine induced miR-217 expression and downregulated KLK7 in EACC; deoxyazacytidine also attenuated CSC-mediated miR-217 repression and upregulation of KLK7 in IEE and EACC. Overexpression of miR-217 significantly decreased, whereas overexpression of KLK7 increased proliferation, invasion and tumorigenicity of EACC. Collectively, these data demonstrate that epigenetic repression of miR-217 contributes to the pathogenesis of EAC via upregulation of KLK7 and suggest that restoration of miR-217 expression may be a novel treatment strategy for these malignancies. C1 [Xi, S.; Inchauste, S.; Zhang, M. R.; Hong, J. A.; Raiji, M. T.; Schrump, D. S.] NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Guo, H.] Shandong Tumor Hosp & Inst, Gastrointestinal Surg, Jinan, Shandong, Peoples R China. [Shan, J.] NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21701 USA. [Xiao, Z.] NCI, Canc & Inflammat Lab, Frederick, MD 21701 USA. [Xu, H.] NCI, Lab Canc Prevent, Frederick, MD 21701 USA. [Miettenen, M.] NCI, Pathol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Altorki, N. K.] Weill Cornell Univ, Med Ctr, Dept Thorac Surg, New York, NY USA. [Casson, A. G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Beer, D. G.] Univ Michigan, Sect Thorac Surg, Ann Arbor, MI 48109 USA. [Robles, A. I.; Bowman, E. D.; Harris, C. C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, Ctr Canc Res, Bldg 10,Room 4-3942,10 Ctr Dr, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov FU NIH intramural funding; Stephen J. Solarz Memorial Fund FX We thank Ms Jan Pappas for assistance with manuscript preparation. This study was supported by NIH intramural funding and the Stephen J. Solarz Memorial Fund. NR 43 TC 4 Z9 4 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD OCT 29 PY 2015 VL 34 IS 44 BP 5548 EP 5559 DI 10.1038/onc.2015.10 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CV9FX UT WOS:000364594000004 PM 25703328 ER PT J AU Krupovic, M Cvirkaite-Krupovic, V Prangishvili, D Koonin, EV AF Krupovic, Mart Cvirkaite-Krupovic, Virginija Prangishvili, David Koonin, Eugene V. TI Evolution of an archaeal virus nucleocapsid protein from the CRISPR-associated Cas4 nuclease SO BIOLOGY DIRECT LA English DT Article DE Virus evolution; Capsid proteins; Nucleocapsid; Virus origin; Archaea viruses ID STRANDED DNA VIRUSES; THERMOPROTEUS-TENAX; ADAPTIVE IMMUNITY; VIRAL UNIVERSE; SYSTEMS; TTV1; CLASSIFICATION; TRANSPOSONS; UNIFICATION; POLYMERASE AB Many proteins of viruses infecting hyperthermophilic Crenarchaeota have no detectable homologs in current databases, hampering our understanding of viral evolution. We used sensitive database search methods and structural modeling to show that a nucleocapsid protein (TP1) of Thermoproteus tenax virus 1 (TTV1) is a derivative of the Cas4 nuclease, a component of the CRISPR-Cas adaptive immunity system that is encoded also by several archaeal viruses. In TTV1, the Cas4 gene was split into two, with the N-terminal portion becoming TP1, and lost some of the catalytic amino acid residues, apparently resulting in the inactivation of the nuclease. To our knowledge, this is the first described case of exaptation of an enzyme for a virus capsid protein function. C1 [Krupovic, Mart; Cvirkaite-Krupovic, Virginija; Prangishvili, David] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Krupovic, M (reprint author), Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. EM krupovic@pasteur.fr RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU Agence nationale de la recherche (ANR) program BLANC, project EXAVIR; US Department of Health and Human Services FX This work was supported by the Agence nationale de la recherche (ANR) program BLANC, project EXAVIR. EVK is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 40 TC 3 Z9 3 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 29 PY 2015 VL 10 AR 65 DI 10.1186/s13062-015-0093-2 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CV1GQ UT WOS:000364002100001 PM 26514828 ER PT J AU Kliment, CR Araki, T Doyle, TJ Gao, W Dupuis, J Latourelle, JC Zazueta, OE Fernandez, IE Nishino, M Okajima, Y Ross, JC Estepar, RSJ Diaz, AA Lederer, DJ Schwartz, DA Silverman, EK Rosas, IO Washko, GR O'Connor, GT Hatabu, H Hunninghake, GM AF Kliment, Corrine R. Araki, Tetsuro Doyle, Tracy J. Gao, Wei Dupuis, Josee Latourelle, Jeanne C. Zazueta, Oscar E. Fernandez, Isis E. Nishino, Mizuki Okajima, Yuka Ross, James C. Estepar, Raul San Jose Diaz, Alejandro A. Lederer, David J. Schwartz, David A. Silverman, Edwin K. Rosas, Ivan O. Washko, George R. O'Connor, George T. Hatabu, Hiroto Hunninghake, Gary M. TI A comparison of visual and quantitative methods to identify interstitial lung abnormalities SO BMC PULMONARY MEDICINE LA English DT Article DE High attenuation areas; Idiopathic pulmonary fibrosis; Interstitial lung disease; Interstitial lung abnormalities (ILA); MUC5B ID IDIOPATHIC PULMONARY-FIBROSIS; MUC5B PROMOTER POLYMORPHISM; GENOME-WIDE ASSOCIATION; AUTOMATED QUANTIFICATION; CT METRICS; DISEASE; EMPHYSEMA; SYSTEM; SUSCEPTIBILITY; DIAGNOSIS AB Background: Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA. Methods: To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between -600 and -250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses. Results: Increased measures of HAAs (in >= 10 % of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 % in COPDGene and 13 % in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS. Conclusion: Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype. C1 [Kliment, Corrine R.; Doyle, Tracy J.; Zazueta, Oscar E.; Fernandez, Isis E.; Diaz, Alejandro A.; Silverman, Edwin K.; Rosas, Ivan O.; Washko, George R.; Hunninghake, Gary M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Pulm & Crit Care Div, Boston, MA 02115 USA. [Araki, Tetsuro; Nishino, Mizuki; Okajima, Yuka; Hatabu, Hiroto] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Latourelle, Jeanne C.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Latourelle, Jeanne C.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Nishino, Mizuki; Estepar, Raul San Jose; Washko, George R.; Hatabu, Hiroto; Hunninghake, Gary M.] Brigham & Womens Hosp, Ctr Pulm Funct Imaging, Boston, MA 02115 USA. [Ross, James C.; Silverman, Edwin K.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ross, James C.; Estepar, Raul San Jose] Brigham & Womens Hosp, Dept Radiol, Surg Planning Lab, Boston, MA 02115 USA. [Diaz, Alejandro A.] Pontificia Univ Catolica Chile, Dept Pulm Dis, Santiago, Chile. [Lederer, David J.] Columbia Univ, Coll Phys & Surg, Div Pulm & Crit Care, New York, NY USA. [Lederer, David J.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Schwartz, David A.] Univ Colorado, Dept Med, Denver, CO USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. RP Hunninghake, GM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Pulm & Crit Care Div, Boston, MA 02115 USA. EM ghunninghake@partners.org FU NIH [K23 CA157631, K25 HL104085, R01 HL116931, R01 HL116473, R01 HL103676, R01 HL114626, R01 HL089856, P01 HL105339, P01 HL114501, U01 HL105371, R01 HL107246, R01 HL111024]; National Heart, Lung and Blood Institute [R01-HL095393, R01-HL097163, P01-HL092870, RC2-HL101715]; Veterans Administration [1I01BX001534]; NHLBI's Framingham Heart Study [N01-HC-25195]; [R01 HL089897] FX Dr. Nishino is supported by NIH Grant Number: K23 CA157631. Dr. San Jose Estepar is supported by NIH Grant Numbers: K25 HL104085, R01 HL116931 and R01 HL116473. Dr. Lederer is supported by NIH Grant Numbers: R01 HL103676 and R01 HL114626. Dr. Schwartz is supported by the National Heart, Lung and Blood Institute (R01-HL095393, R01-HL097163, P01-HL092870, and RC2-HL101715) and the Veterans Administration (1I01BX001534). Dr. Silverman is supported by NIH Grant Numbers: R01 HL089856, P01 HL105339, and P01 HL114501. Dr. Rosas is supported by NIH Grant Number: U01 HL105371 and P01 HL114501. Dr. Washko is supported by NIH Grant Number: R01 HL116473, R01 HL107246 and P01 HL114501. Dr. Hunninghake is supported by NIH Grant Number: U01 HL105371, P01 HL114501, and R01 HL111024. This work was partially supported by the NHLBI's Framingham Heart Study contract: N01-HC-25195 (FHS) and by R01 HL089897 and R01 HL089856 (COPDGene) and R01 HL111024. This paper is subject to the NIH public access policy: http://publicaccess.nih.gov. NR 35 TC 2 Z9 2 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2466 J9 BMC PULM MED JI BMC Pulm. Med. PD OCT 29 PY 2015 VL 15 AR 134 DI 10.1186/s12890-015-0124-x PG 9 WC Respiratory System SC Respiratory System GA CU7RP UT WOS:000363739400001 PM 26514822 ER PT J AU Polackwich, RJ Koch, D McAllister, R Geller, HM Urbach, JS AF Polackwich, Robert J. Koch, Daniel McAllister, Ryan Geller, Herbert M. Urbach, Jeffrey S. TI Traction force and tension fluctuations in growing axons SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE growth cone; stress; mechanical; traction force; axon outgrowth; DRG neurons ID FOCAL ADHESIONS; MIGRATING CELLS; NEURONS; MICROSCOPY; GROWTH; INHIBITION; MECHANICS; OUTGROWTH; DYNAMICS AB Actively generated mechanical forces play a central role in axon growth and guidance, but the mechanisms that underly force generation and regulation in growing axons remain poorly understood. We report measurements of the dynamics of traction stresses from growth cones of actively advancing axons from postnatal rat DRG neurons. By tracking the movement of the growth cone and analyzing the traction stress field from a reference frame that moves with it, we are able to show that there is a clear and consistent average stress field that underlies the complex spatial stresses present at any one time. The average stress field has strong maxima on the sides of the growth cone, directed inward toward the growth cone neck. This pattern represents a contractile stress contained within the growth cone, and a net force that is balanced by the axon tension. Using high time-resolution measurements of the growth cone traction stresses, we show that the stress field is composed of fluctuating local stress peaks, with a large number peaks that live for a short time, a population of peaks whose lifetime distribution follows an exponential decay, and a small number of very long-lived peaks. We show that the high time-resolution data also reveal that the tension appears to vary randomly over short time scales, roughly consistent with the lifetime of the stress peaks, suggesting that the tension fluctuations originate from stochastic adhesion dynamics. C1 [Polackwich, Robert J.; Koch, Daniel; McAllister, Ryan; Urbach, Jeffrey S.] Georgetown Univ, Dept Phys, Washington, DC 20057 USA. [Polackwich, Robert J.; Koch, Daniel; McAllister, Ryan; Urbach, Jeffrey S.] Georgetown Univ, Inst Soft Matter Synth & Metrol, Washington, DC USA. [Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Polackwich, RJ (reprint author), Georgetown Univ, Dept Phys, Washington, DC 20057 USA. EM rjp73@georgetown.edu OI Urbach, Jeffrey/0000-0002-1593-520X FU National Institute of Neurological Disorders and Stroke [1R01NS064250-01]; National Heart, Lung, and Blood Institute Intramural Research Program FX This work was supported by National Institute of Neurological Disorders and Stroke grant 1R01NS064250-01 (JU) and the National Heart, Lung, and Blood Institute Intramural Research Program (HG). NR 29 TC 0 Z9 0 U1 5 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD OCT 29 PY 2015 VL 9 AR 417 DI 10.3389/fncel.2015.00417 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CU8PK UT WOS:000363805000001 PM 26578882 ER PT J AU Peifer, M Hertwig, F Roels, F Dreidax, D Gartlgruber, M Menon, R Kramer, A Roncaioli, JL Sand, F Heuckmann, JM Ikram, F Schmidt, R Ackermann, S Engesser, A Kahlert, Y Vogel, W Altmuller, J Nurnberg, P Thierry-Mieg, J Thierry-Mieg, D Mariappan, A Heynck, S Mariotti, E Henrich, KO Gloeckner, C Bosco, G Leuschner, I Schweiger, MR Savelyeva, L Watkins, SC Shao, CX Bell, E Hofer, T Achter, V Lang, U Theissen, J Volland, R Saadati, M Eggert, A de Wilde, B Berthold, F Peng, ZY Zhao, C Shi, LM Ortmann, M Buttner, R Perner, S Hero, B Schramm, A Schulte, JH Herrmann, C O'Sullivan, RJ Westermann, F Thomas, RK Fischer, M AF Peifer, Martin Hertwig, Falk Roels, Frederik Dreidax, Daniel Gartlgruber, Moritz Menon, Roopika Kraemer, Andrea Roncaioli, Justin L. Sand, Frederik Heuckmann, Johannes M. Ikram, Fakhera Schmidt, Rene Ackermann, Sandra Engesser, Anne Kahlert, Yvonne Vogel, Wenzel Altmueller, Janine Nuernberg, Peter Thierry-Mieg, Jean Thierry-Mieg, Danielle Mariappan, Aruljothi Heynck, Stefanie Mariotti, Erika Henrich, Kai-Oliver Gloeckner, Christian Bosco, Graziella Leuschner, Ivo Schweiger, Michal R. Savelyeva, Larissa Watkins, Simon C. Shao, Chunxuan Bell, Emma Hoefer, Thomas Achter, Viktor Lang, Ulrich Theissen, Jessica Volland, Ruth Saadati, Maral Eggert, Angelika de Wilde, Bram Berthold, Frank Peng, Zhiyu Zhao, Chen Shi, Leming Ortmann, Monika Buettner, Reinhard Perner, Sven Hero, Barbara Schramm, Alexander Schulte, Johannes H. Herrmann, Carl O'Sullivan, Roderick J. Westermann, Frank Thomas, Roman K. Fischer, Matthias TI Telomerase activation by genomic rearrangements in high-risk neuroblastoma SO NATURE LA English DT Article ID TERT PROMOTER MUTATIONS; GENE; LANDSCAPE; ENHANCERS; MELANOMA AB Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system(1). Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive(2-4). Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type(1,2,5). In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours. C1 [Peifer, Martin; Bosco, Graziella; Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol Cologne Bonn, Fac Med, Dept Translat Genom, D-50931 Cologne, Germany. [Peifer, Martin; Hertwig, Falk; Roels, Frederik; Kraemer, Andrea; Sand, Frederik; Ikram, Fakhera; Ackermann, Sandra; Nuernberg, Peter; Mariappan, Aruljothi; Fischer, Matthias] Univ Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany. [Hertwig, Falk; Roels, Frederik; Kraemer, Andrea; Ikram, Fakhera; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Theissen, Jessica; Volland, Ruth; Berthold, Frank; Hero, Barbara; Fischer, Matthias] Univ Cologne, Univ Childrens Hosp Cologne, Fac Med, Dept Pediat Oncol & Hematol, D-50937 Cologne, Germany. [Dreidax, Daniel; Gartlgruber, Moritz; Henrich, Kai-Oliver; Savelyeva, Larissa; Bell, Emma; Westermann, Frank] German Canc Res Ctr, Div Neuroblastoma Genom B087, D-69120 Heidelberg, Germany. [Menon, Roopika; Vogel, Wenzel; Perner, Sven] Univ Hosp Bonn, Ctr Integrated Oncol Cologne Bonn, Inst Pathol, Dept Prostate Canc Res, D-53127 Bonn, Germany. [Menon, Roopika; Heuckmann, Johannes M.; Heynck, Stefanie; Mariotti, Erika; Gloeckner, Christian] NEO New Oncol AG, D-51105 Cologne, Germany. [Roncaioli, Justin L.; O'Sullivan, Roderick J.] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Ikram, Fakhera; Altmueller, Janine; Nuernberg, Peter] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany. [Schmidt, Rene] Univ Munster, Inst Biostat & Clin Res, D-48149 Munster, Germany. [Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [Thierry-Mieg, Jean; Thierry-Mieg, Danielle] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Leuschner, Ivo] Univ Kiel, Dept Pathol, D-24118 Kiel, Germany. [Schweiger, Michal R.] Univ Cologne, Funct Epigen, D-50931 Cologne, Germany. [Watkins, Simon C.] Univ Pittsburgh, Ctr Biol Imaging, Dept Cell Biol, Pittsburgh, PA 15261 USA. [Shao, Chunxuan; Hoefer, Thomas] German Canc Res Ctr, Div Theoret Syst Biol, D-69120 Heidelberg, Germany. [Achter, Viktor; Lang, Ulrich] Univ Cologne, Comp Ctr, D-50931 Cologne, Germany. [Lang, Ulrich] Univ Cologne, Dept Informat, D-50931 Cologne, Germany. [Saadati, Maral] German Canc Res Ctr, Div Biostat, D-69120 Heidelberg, Germany. [Eggert, Angelika; Schulte, Johannes H.] Charite Univ Med Ctr Berlin, Dept Pediat Oncol & Hematol, D-10117 Berlin, Germany. [de Wilde, Bram] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Peng, Zhiyu] BGI Shenzhen, Shenzhen 518083, Guangdong, Peoples R China. [Zhao, Chen; Shi, Leming] Fudan Univ, Ctr Pharmacogen, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Zhao, Chen; Shi, Leming] Fudan Univ, Fudan Zhangjiang Ctr Clin Genom, State Key Lab Genet Engn, Shanghai 201203, Peoples R China. [Zhao, Chen; Shi, Leming] Fudan Univ, Sch Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 201203, Peoples R China. [Zhao, Chen; Shi, Leming] Fudan Univ, Sch Life Sci, Shanghai 201203, Peoples R China. [Ortmann, Monika; Buettner, Reinhard; Thomas, Roman K.] Univ Cologne, Dept Pathol, D-50937 Cologne, Germany. [Schramm, Alexander] Univ Childrens Hosp, Dept Pediat Oncol & Hematol, D-45147 Essen, Germany. [Schulte, Johannes H.] German Canc Consortium DKTK, D-10117 Berlin, Germany. [Schulte, Johannes H.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Herrmann, Carl] Heidelberg Univ, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. [Herrmann, Carl] Heidelberg Univ, Bioquant Ctr, D-69120 Heidelberg, Germany. [Herrmann, Carl] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany. [Fischer, Matthias] Max Planck Inst Metab Res, D-50931 Cologne, Germany. RP Fischer, M (reprint author), Univ Cologne, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany. EM mpeifer@uni-koeln.de; frank.westermann@dkfz-heidelberg.de; roman.thomas@uni-koeln.de; matthias.fischer@uk-koeln.de RI Herrmann, Carl/H-5859-2011; Hofer, Thomas/G-5665-2013; Ikram, Fakhera/E-3162-2017; THIERRY-MIEG, Jean/F-1975-2017; OI Hofer, Thomas/0000-0003-3560-8780; THIERRY-MIEG, Jean/0000-0002-0396-6789; Hertwig, Falk/0000-0003-4784-6516 FU German Cancer Aid [110122]; German Ministry of Science and Education (BMBF) as part of the e:Med initiative [01ZX1303A, 01ZX1406, 01ZX1307D]; BMBF [0316076A]; European Union [259348]; Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V.; German-Israeli Helmholtz Research School in Cancer Biology; Volkswagenstiftung (Lichtenberg Program); Center for Molecular Medicine Cologne FX We are indebted to the patients and their parents for making available the tumour specimens analysed in this study. We thank the German Neuroblastoma Biobank for providing samples from patients. The Institutional Review Board approved collection and use of all specimens in this study. We also thank our colleagues N. Hemstedt, H. Duren, E. Hess, J. Kreth, and J. Gopalakrishnan; and our collaboration partners I. Amit and F. Paul at the Weizmann Institute of Science for technical assistance. We further acknowledge the Center for Molecular Medicine Cologne light microscope facility for helping us to obtain high-quality data of FISH analyses, and S. Wolf and the Next Generation Sequencing Unit at the German Cancer Research Center (DKFZ) for sequencing. This work was supported by the German Cancer Aid (grant 110122) to M.F., F.W., J.H.S., A.S., and S.A.; the German Ministry of Science and Education (BMBF) as part of the e:Med initiative (grant 01ZX1303A to M.P., M.F.,J.H.S., R.B., U.L., and R.K.T., grant 01ZX1406 to M.P., and grant01ZX1307D to M.F. and F.W.); the BMBF (grant 0316076A to F.W.); the European Union (grant 259348 to F.W); the Fordergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V. (to M.F); the German-Israeli Helmholtz Research School in Cancer Biology (to M.G. and F.W.); the Volkswagenstiftung (Lichtenberg Program) (to M.R.S.); and the Center for Molecular Medicine Cologne. NR 24 TC 39 Z9 42 U1 8 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 29 PY 2015 VL 526 IS 7575 BP 700 EP 704 DI 10.1038/nature14980 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8ZH UT WOS:000363832100048 PM 26466568 ER PT J AU Pavletic, AJ AF Pavletic, Adriana J. TI An Integrated View of Potassium Homeostasis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HYPERKALEMIA C1 NIMH, Bethesda, MD 20892 USA. RP Pavletic, AJ (reprint author), NIMH, Bethesda, MD 20892 USA. EM pavletia@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 3 TC 0 Z9 0 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 29 PY 2015 VL 373 IS 18 BP 1786 EP 1787 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CU4QH UT WOS:000363514100029 PM 26510041 ER PT J AU Berezhkovskii, AM Dagdug, L Bezrukov, SM AF Berezhkovskii, Alexander M. Dagdug, Leonardo Bezrukov, Sergey M. TI Range of applicability of modified Fick-Jacobs equation in two dimensions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DIFFUSION AB Axial diffusion in a two-dimensional channel of smoothly varying geometry can be approximately described as one-dimensional diffusion in the entropy potential with position-dependent effective diffusivity by means of the modified Fick-Jacobs equation. In this paper, Brownian dynamics simulations are used to study the range of applicability of such a description, as well as the accuracy of the expressions for the effective diffusivity proposed by different researchers. (C) 2015 AIP Publishing LLC. C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Phys, Mexico City 09340, DF, Mexico. RP Berezhkovskii, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. OI Bezrukov, Sergey/0000-0002-8209-8050 FU Consejo Nacional de Ciencia y Tecnologia (CONACyT) [176452]; Division of Basic Science and Engineering (CBI); Intramural Research Program of the NIH; Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology, and Eunice Kennedy Shriver National Institute of Child Health and Human Development. L.D. thanks Consejo Nacional de Ciencia y Tecnologia (CONACyT) (under Grant No. 176452) and the Division of Basic Science and Engineering (CBI), for partial support. NR 19 TC 4 Z9 4 U1 2 U2 5 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 28 PY 2015 VL 143 IS 16 AR 164102 DI 10.1063/1.4934223 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA CV4KN UT WOS:000364235800002 PM 26520493 ER PT J AU Abrams, LR McBride, CM Hooker, GW Cappella, JN Koehly, LM AF Abrams, Leah R. McBride, Colleen M. Hooker, Gillian W. Cappella, Joseph N. Koehly, Laura M. TI The Many Facets of Genetic Literacy: Assessing the Scalability of Multiple Measures for Broad Use in Survey Research SO PLOS ONE LA English DT Article ID PUBLIC KNOWLEDGE; SCALE ANALYSIS; DECISION AID; HEALTH; FORMAT; IMPACT; COMMUNICATION; PREFERENCES; INFORMATION; PERCEPTIONS AB Objectives To determine how three dimensions of genetic literacy (familiarity, skills, and factual knowledge) fit the hierarchy of knowledge outlined in E.M. Rogers' Diffusion of Innovations to better conceptualize lay understandings of genomics. Methods A consumer panel representing the US adult population (N = 1016) completed an electronic survey in November 2013. Adjusting for education, we used correlations, principle components analysis, Mokken Scale tests, and linear regressions to assess how scores on the three genetic literacy sub-dimensions fit an ordered scale. Results The three scores significantly loaded onto one factor, even when adjusting for education. Analyses revealed moderate strength in scaling (0.416, p<0.001) and a difficulty ordering that matched Rogers' hierarchy (knowledge more difficult than skills, followed by familiarity). Skills scores partially mediated the association between familiarity and knowledge with a significant indirect effect (0.241, p<0.001). Conclusion We established an ordering in genetic literacy sub-dimensions such that familiarity with terminology precedes skills using information, which in turn precedes factual knowledge. This ordering is important to contextualizing previous findings, guiding measurement in future research, and identifying gaps in the understanding of genomics relevant to the demands of differing applications. C1 [Abrams, Leah R.; Koehly, Laura M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [McBride, Colleen M.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Hooker, Gillian W.] NextGxDx, Franklin, TN USA. [Cappella, Joseph N.] Univ Penn, Annenberg Sch Commun, Philadelphia, PA 19104 USA. RP Koehly, LM (reprint author), NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute; NextGxDx FX This work was funded by the Intramural Research Program of the National Human Genome Research Institute. NextGxDx provided support in the form of salaries for authors [GWH], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the "author contributions" section. NR 36 TC 1 Z9 1 U1 2 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 OCT 28 PY 2015 VL 10 IS 10 AR e0141532 DI 10.1371/journal.pone.0141532 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0DL UT WOS:000363918100099 PM 26510161 ER PT J AU Alonso, WJ Rabaa, MA Giglio, R Miller, MA Schuck-Paim, C AF Alonso, Wladimir J. Rabaa, Maia A. Giglio, Ricardo Miller, Mark A. Schuck-Paim, Cynthia TI Modeling the Impact of Alternative Immunization Strategies: Using Matrices as Memory Lanes SO PLOS ONE LA English DT Article ID MEASLES EPIDEMICS; DYNAMICS; VACCINATION AB Existing modeling approaches are divided between a focus on the constitutive (micro) elements of systems or on higher (macro) organization levels. Micro-level models enable consideration of individual histories and interactions, but can be unstable and subject to cumulative errors. Macro-level models focus on average population properties, but may hide relevant heterogeneity at the micro-scale. We present a framework that integrates both approaches through the use of temporally structured matrices that can take large numbers of variables into account. Matrices are composed of several bidimensional (timexage) grids, each representing a state (e.g. physiological, immunological, socio-demographic). Time and age are primary indices linking grids. These matrices preserve the entire history of all population strata and enable the use of historical events, parameters and states dynamically in the modeling process. This framework is applicable across fields, but particularly suitable to simulate the impact of alternative immunization policies. We demonstrate the framework by examining alternative strategies to accelerate measles elimination in 15 developing countries. The model recaptured long-endorsed policies in measles control, showing that where a single routine measles-containing vaccine is employed with low coverage, any improvement in coverage is more effective than a second dose. It also identified an opportunity to save thousands of lives in India at attractively low costs through the implementation of supplementary immunization campaigns. The flexibility of the approach presented enables estimating the effectiveness of different immunization policies in highly complex contexts involving multiple and historical influences from different hierarchical levels. C1 [Alonso, Wladimir J.; Rabaa, Maia A.; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Alonso, Wladimir J.; Schuck-Paim, Cynthia] Origem Sci Epidemiol & Modeling, Sao Paulo, SP, Brazil. [Rabaa, Maia A.] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Giglio, Ricardo] Univ Fed Santa Catarina, Dept Econ, Florianopolis, SC, Brazil. RP Alonso, WJ (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM Wladimir.Alonso@nih.gov OI Rabaa, Maia/0000-0003-0529-2228 FU Fogarty International Center, National Institutes of Health; Origem Scientifica (Sao Paulo, Brazil) FX This work was supported by intramural funds from Fogarty International Center, National Institutes of Health. CSP and WJA were also funded by Origem Scientifica (Sao Paulo, Brazil), a company specializing in the analyses of global health data. The funder provided support in the form of salaries for authors [CSP, WJA], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 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 OCT 28 PY 2015 VL 10 IS 10 AR e0141147 DI 10.1371/journal.pone.0141147 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0DL UT WOS:000363918100057 PM 26509976 ER PT J AU Jaekl, P Seidlitz, J Harris, LR Tadin, D AF Jaekl, Philip Seidlitz, Jakob Harris, Laurence R. Tadin, Duje TI Audiovisual Delay as a Novel Cue to Visual Distance SO PLOS ONE LA English DT Article ID MULTISENSORY INTEGRATION; PERCEPTION; SOUND; MOTION; CAPTURE; SIMULTANEITY; PERSPECTIVE; CONGRUENCY; ATTENTION; OCCLUSION AB For audiovisual sensory events, sound arrives with a delay relative to light that increases with event distance. It is unknown, however, whether humans can use these ubiquitous sound delays as an information source for distance computation. Here, we tested the hypothesis that audiovisual delays can both bias and improve human perceptual distance discrimination, such that visual stimuli paired with auditory delays are perceived as more distant and are thereby an ordinal distance cue. In two experiments, participants judged the relative distance of two repetitively displayed three-dimensional dot clusters, both presented with sounds of varying delays. In the first experiment, dot clusters presented with a sound delay were judged to be more distant than dot clusters paired with equivalent sound leads. In the second experiment, we confirmed that the presence of a sound delay was sufficient to cause stimuli to appear as more distant. Additionally, we found that ecologically congruent pairing of more distant events with a sound delay resulted in an increase in the precision of distance judgments. A control experiment determined that the sound delay duration influencing these distance judgments was not detectable, thereby eliminating decision-level influence. In sum, we present evidence that audiovisual delays can be an ordinal cue to visual distance. C1 [Jaekl, Philip; Seidlitz, Jakob; Tadin, Duje] Univ Rochester, Ctr Visual Sci, Rochester, NY 14627 USA. [Jaekl, Philip; Seidlitz, Jakob; Tadin, Duje] Univ Rochester, Dept Brain & Cognit Sci, Rochester, NY USA. [Seidlitz, Jakob] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Harris, Laurence R.] York Univ, Ctr Vis Res, Toronto, ON M3J 2R7, Canada. [Harris, Laurence R.] York Univ, Dept Psychol, Toronto, ON M3J 2R7, Canada. [Harris, Laurence R.] York Univ, Dept Biol & Kinesiol, Toronto, ON M3J 2R7, Canada. [Tadin, Duje] Univ Rochester, Sch Med, Dept Ophthalmol, Rochester, NY USA. RP Jaekl, P (reprint author), Univ Rochester, Ctr Visual Sci, Rochester, NY 14627 USA. EM pjaekl@cvs.rochester.edu FU National Institutes of Health; Center for Visual Science (University of Rochester) [NEI P30 EY001319] FX Support was provided by the National Institutes of Health and the Center for Visual Science (University of Rochester) core grant: NEI P30 EY001319. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 1 Z9 1 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2015 VL 10 IS 10 AR e0141125 DI 10.1371/journal.pone.0141125 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CV0DL UT WOS:000363918100055 PM 26509795 ER PT J AU Xiong, LH Cui, R Zhang, ZL Tu, JW Shi, YB Pang, DW AF Xiong, Ling-Hong Cui, Ran Zhang, Zhi-Ling Tu, Jia-Wei Shi, Yun-Bo Pang, Dai-Wen TI Harnessing Intracellular Biochemical Pathways for In Vitro Synthesis of Designer Tellurium Nanorods SO SMALL LA English DT Article DE designer nanomaterials; intracellular biochemical pathways; in vitro synthesis; nanorods; Staphylococcus aureus ID QUANTUM DOTS; SACCHAROMYCES-CEREVISIAE; CDSE NANOCRYSTALS; YEAST-CELLS; NANOPARTICLES; GROWTH; GOLD AB Synthesizing nanomaterials of desired properties is a big challenge, which requires extremely harsh conditions and/or use of toxic materials. More recently developed in vivo methods have brought a different set of problems such as separation and purification of nanomaterials made in vivo. Here, a novel approach that harnesses cellular pathways for in vitro synthesis of high-quality tellurium nanorods with tunable lengths and optical properties is reported. It is first demonstrated that in vivo biochemical pathways could be used to synthesize Te nanorods via the intracellular reduction of TeO3 (2-) in living Staphylococcus aureus cells. The pathways to set up a quasi-biological system for Te precursor formation are then utilized, which could further synthesize Te nanorods in vitro. This allows to successfully synthesize in vitro, under routine laboratory conditions, Te nanorods with uniform and tunable lengths, ranging from about 10 to 200 nm, and controllable optical properties with high molar extinction coefficients. The approach here should open new avenues for controllable, facile, and efficient synthesis of designer nanomaterials for diverse industrial and biomedical applications. C1 [Xiong, Ling-Hong; Cui, Ran; Zhang, Zhi-Ling; Tu, Jia-Wei; Pang, Dai-Wen] Wuhan Univ, Inst Adv Studies, State Key Lab Virol,Coll Chem & Mol Sci, Key Lab Analyt Chem Biol & Med,Minist Educ, Wuhan 430072, Peoples R China. [Xiong, Ling-Hong; Cui, Ran; Zhang, Zhi-Ling; Tu, Jia-Wei; Pang, Dai-Wen] Wuhan Univ, Wuhan Inst Biotechnol, Wuhan 430072, Peoples R China. [Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. RP Pang, DW (reprint author), Wuhan Univ, Inst Adv Studies, State Key Lab Virol,Coll Chem & Mol Sci, Key Lab Analyt Chem Biol & Med,Minist Educ, Wuhan 430072, Peoples R China. EM dwpang@whu.edu.cn RI Zhang, Zhi-Ling/B-3135-2010 OI Zhang, Zhi-Ling/0000-0001-7807-2264 FU National Basic Research Program of China (973 Program) [2011CB933600]; 111 Project [111-2-10]; Collaborative Innovation Center for Chemistry and Molecular Medicine; Intramural Research Program of NICHD, NIH, USA FX This work was supported by the National Basic Research Program of China (973 Program, No. 2011CB933600) and the 111 Project (111-2-10), and Collaborative Innovation Center for Chemistry and Molecular Medicine. Y.-B.S. was supported by the Intramural Research Program of NICHD, NIH, USA. NR 25 TC 2 Z9 3 U1 11 U2 35 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD OCT 28 PY 2015 VL 11 IS 40 BP 5416 EP 5422 DI 10.1002/smll.201500816 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CU4CP UT WOS:000363474200010 PM 26313741 ER PT J AU Narayanan, SP Singh, S Gupta, A Yadav, S Singh, SR Shukla, S AF Narayanan, Sathiya Pandi Singh, Smriti Gupta, Amit Yadav, Sandhya Singh, Shree Ram Shukla, Sanjeev TI Integrated genomic analyses identify KDM1A's role in cell proliferation via modulating E2F signaling activity and associate with poor clinical outcome in oral cancer SO CANCER LETTERS LA English DT Article DE Oral cancer; Histone demethylase; KDM1A; E2F1 signaling; Cell proliferation ID PROTEIN LYSINE METHYLATION; EPITHELIAL OVARIAN-CANCER; BREAST-CANCER; EPIGENETIC MODIFICATIONS; HISTONE DEMETHYLASES; GENE-EXPRESSION; PROSTATE-CANCER; STEM-CELLS; LSD1; TRANSCRIPTION AB The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silica pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Narayanan, Sathiya Pandi; Singh, Smriti; Gupta, Amit; Yadav, Sandhya; Shukla, Sanjeev] IISERB, ERPL, Bhopal, Madhya Pradesh, India. [Singh, Shree Ram] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Shukla, S (reprint author), IISERB, ERPL, Bhopal, Madhya Pradesh, India. EM singhshr@mail.nih.gov; sanjeevs@iiserb.ac.in RI Singh, Shree Ram/B-7614-2008; OI Singh, Shree Ram/0000-0001-6545-583X; Shukla, Sanjeev/0000-0003-3361-0588 FU IISER Bhopal; Ministry of Human Resource Development; Council of Scientific & Industrial Research FX We thank IISER Bhopal for Intramural research funds. We thank Ministry of Human Resource Development for fellowships to Dr. Sathiya Pandi, Ms. Smriti Singh and Mr. Amit Gupta. We thank Council of Scientific & Industrial Research for fellowship to Ms. Sandhya Yadav. NR 55 TC 1 Z9 1 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD OCT 28 PY 2015 VL 367 IS 2 BP 162 EP 172 DI 10.1016/j.canlet.2015.07.022 PG 11 WC Oncology SC Oncology GA CQ9QJ UT WOS:000360949600011 PM 26225839 ER PT J AU Abraham, TM Pedley, A Massaro, JM Hoffmann, U Fox, CS AF Abraham, Tobin M. Pedley, Alison Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors SO CIRCULATION LA English DT Article DE adipose tissue; epidemiology; population; risk factors ID INSULIN-RESISTANCE; JAPANESE-AMERICANS; TISSUE VOLUMES; HEART; FAT; FRAMINGHAM; INFLAMMATION; OBESITY; HYPERTENSION; ADIPOKINES AB Background-Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes. Methods and Results-Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm(3)) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm(3) increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.712.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97-2.28) in women (P<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05-0.12; P=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment. Conclusions-VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk. C1 [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Abraham, Tobin M.; Fox, Caroline S.] NHLBI, Bethesda, MD USA. [Abraham, Tobin M.; Pedley, Alison; Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, Boston, MA USA. [Abraham, Tobin M.; Pedley, Alison; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Fox, CS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Institutes of Health; [N01-HC-25195] FX The FHS of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. Dr Abraham is supported by an National Institutes of Health-sponsored T32 training grant. NR 27 TC 16 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 27 PY 2015 VL 132 IS 17 BP 1639 EP 1647 DI 10.1161/CIRCULATIONAHA.114.015000 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500013 PM 26294660 ER PT J AU Roth, GA Huffman, MD Moran, AE Feigin, V Mensah, GA Naghavi, M Murray, CJL AF Roth, Gregory A. Huffman, Mark D. Moran, Andrew E. Feigin, Valery Mensah, George A. Naghavi, Mohsen Murray, Christopher J. L. TI Global and Regional Patterns in Cardiovascular Mortality From 1990 to 2013 SO CIRCULATION LA English DT Article DE cardiovascular diseases; epidemiology; global health; mortality ID CORONARY-HEART-DISEASE; SUB-SAHARAN AFRICA; RISK-FACTORS; EPIDEMIOLOGIC TRANSITION; MYOCARDIAL-INFARCTION; NONCOMMUNICABLE DISEASES; INTERNATIONAL TRENDS; DEVELOPING-COUNTRIES; SYSTEMATIC ANALYSIS; INCOME COUNTRIES AB There is a global commitment to reduce premature cardiovascular diseases (CVDs) 25% by 2025. CVD mortality rates have declined dramatically over the past 2 decades, yet the number of life years lost to premature CVD deaths is increasing in low-and middle-income regions. Ischemic heart disease and stroke remain the leading causes of premature death in the world; however, there is wide regional variation in these patterns. Some regions, led by Central Asia, face particularly high rates of premature death from ischemic heart disease. Sub-Saharan Africa and Asia suffer disproportionately from death from stroke. The purpose of the present report is to (1) describe global trends and regional variation in premature mortality attributable to CVD, (2) review past and current approaches to the measurement of these trends, and (3) describe the limitations of existing models of epidemiological transitions for explaining the observed distribution and trends of CVD mortality. We describe extensive variation both between and within regions even while CVD remains a dominant cause of death. Policies and health interventions will need to be tailored and scaled for a broad range of local conditions to achieve global goals for the improvement of cardiovascular health. C1 [Roth, Gregory A.; Naghavi, Mohsen; Murray, Christopher J. L.] Univ Washington, Seattle, WA 98121 USA. [Huffman, Mark D.] Northwestern Univ, Chicago, IL 60611 USA. [Moran, Andrew E.] Columbia Univ, Dept Med, Div Gen Med, New York, NY USA. [Feigin, Valery] Auckland Univ Technol, Fac Hlth & Environm Sci, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bethesda, MD USA. RP Roth, GA (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Div Cardiol, Dept Med, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM rothg@uw.edu OI Huffman, Mark/0000-0001-7412-2519 FU Bill and Melinda Gates Foundation; American Heart Association Western States Postdoctoral Fellowship; National Heart, Lung, and Blood Institute [4R00HL107749-03, K08 HL089675-01A1]; Columbia University Irving Scholarship FX This work was supported by the Bill and Melinda Gates Foundation, an American Heart Association Western States Postdoctoral Fellowship (to Dr Roth), the National Heart, Lung, and Blood Institute (4R00HL107749-03; to Dr Huffman), a National Heart, Lung, and Blood Institute award (K08 HL089675-01A1) and a Columbia University Irving Scholarship (to Dr. Moran). NR 56 TC 32 Z9 33 U1 3 U2 14 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 OCT 27 PY 2015 VL 132 IS 17 BP 1667 EP 1678 DI 10.1161/CIRCULATIONAHA.114.008720 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IU UT WOS:000369255500015 PM 26503749 ER PT J AU Ziats, MN Grosvenor, LP Rennert, OM AF Ziats, M. N. Grosvenor, L. P. Rennert, O. M. TI Functional genomics of human brain development and implications for autism spectrum disorders SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID LONG NONCODING RNAS; LYMPHOBLASTOID CELL-LINES; GENE REGULATORY NETWORKS; STEM-CELLS; OLIGODENDROCYTE DIFFERENTIATION; COEXPRESSION NETWORKS; CORTICAL DEVELOPMENT; PREFRONTAL CORTEX; HUMAN TISSUES; EXPRESSION AB Transcription of the inherited DNA sequence into copies of messenger RNA is the most fundamental process by which the genome functions to guide development. Encoded sequence information, inherited epigenetic marks and environmental influences all converge at the level of mRNA gene expression to allow for cell-type-specific, tissue-specific, spatial and temporal patterns of expression. Thus, the transcriptome represents a complex interplay between inherited genomic structure, dynamic experiential demands and external signals. This property makes transcriptome studies uniquely positioned to provide insight into complex genetic-epigenetic-environmental processes such as human brain development, and disorders with non-Mendelian genetic etiologies such as autism spectrum disorders. In this review, we describe recent studies exploring the unique functional genomics profile of the human brain during neurodevelopment. We then highlight two emerging areas of research with great potential to increase our understanding of functional neurogenomics-non-coding RNA expression and gene interaction networks. Finally, we review previous functional genomics studies of autism spectrum disorder in this context, and discuss how investigations at the level of functional genomics are beginning to identify convergent molecular mechanisms underlying this genetically heterogeneous disorder. C1 [Ziats, M. N.; Rennert, O. M.] NICHHD, Lab Clin & Dev Genom, NIH, Bethesda, MD 20814 USA. [Ziats, M. N.] Univ Cambridge, Robinson Coll, Cambridge CB2 1TN, Cambs, England. [Ziats, M. N.] Baylor Coll Med MSTP, Houston, TX USA. [Grosvenor, L. P.] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Ziats, MN (reprint author), NICHHD, Lab Clin & Dev Genom, NIH, 49 Convent Dr,Bldg 49,Room 2C08, Bethesda, MD 20814 USA. EM ziats@bcm.edu FU Intramural Research Program at the National Institute of Child Health and Human Development; Baylor College of Medicine MSTP; NIH-University of Cambridge Biomedical Scholars Program; National Institute of Mental Health FX The Intramural Research Program at the National Institute of Child Health and Human Development supported this work. MNZ was also supported by Baylor College of Medicine MSTP and the NIH-University of Cambridge Biomedical Scholars Program. LPG was funded by the National Institute of Mental Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We apologize for unintentionally omitting other relevant work because of space limitations. We would like to thank Jeremy Swan for help with figure generation. NR 123 TC 4 Z9 4 U1 3 U2 9 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 OCT 27 PY 2015 VL 5 AR e665 DI 10.1038/tp.2015.153 PG 10 WC Psychiatry SC Psychiatry GA DA2ZF UT WOS:000367665000002 PM 26506051 ER PT J AU Hausmann, C Temme, A Cordes, N Eke, I AF Hausmann, Christina Temme, Achim Cordes, Nils Eke, Iris TI ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation SO ONCOTARGET LA English DT Article DE ILKAP; DNA repair; radioresistance; ILK; PINCH1 ID INTEGRIN-LINKED KINASE; DOUBLE-STRAND BREAKS; IONIZING-RADIATION; CARCINOMA-CELLS; PROTEIN PHOSPHATASE; DNA-PKCS; IN-VITRO; DOWN-REGULATION; CANCER CELLS; P53 AB The prognosis is generally poor for patients suffering from glioblastoma multiforme (GBM) due to radiation and drug resistance. Prosurvival signaling originating from focal adhesion hubs essentially contributes to therapy resistance and tumor aggressiveness. As the underlying molecular mechanisms remain largely elusive, we addressed whether targeting of the focal adhesion proteins particularly interesting new cysteine-histidine-rich 1 (PINCH1), integrin-linked kinase (ILK) and ILK associated phosphatase (ILKAP) modulates GBM cell radioresistance. Intriguingly, PINCH1, ILK and ILKAP depletion sensitized p53-wildtype, but not p53-mutant, GBM cells to radiotherapy. Concomitantly, these cells showed inactivated Glycogen synthase kinase-3 beta (GSK3 beta) and reduced proliferation. For PINCH1 and ILKAP knockdown, elevated levels of radiation-induced gamma H2AX/53BP1-positive foci, as a marker for DNA double strand breaks, were observed. Mechanistically, we identified radiation-induced phosphorylation of DNA protein kinase (DNAPK), an important DNA repair protein, to be dependent on ILKAP. This interaction was fundamental to radiation survival of p53-wildtype GBM cells. Conclusively, our data suggest an essential role of PINCH1, ILK and ILKAP for the radioresistance of p53-wildtype GBM cells and provide evidence for DNAPK functioning as a central mediator of ILKAP signaling. Strategies for targeting focal adhesion proteins in combination with radiotherapy might be a promising approach for patients with GBM. C1 [Hausmann, Christina; Cordes, Nils; Eke, Iris] Tech Univ Dresden, Med Fac Carl Gustav Carus, OncoRay Natl Ctr Radiat Res Oncol, D-01307 Dresden, Germany. [Temme, Achim] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Neurosurg, Sect Expt Neurosurg Tumor Immunol, D-01307 Dresden, Germany. [Cordes, Nils] Tech Univ Dresden, Univ Hosp, Dept Radiat Oncol, D-01307 Dresden, Germany. [Cordes, Nils] Tech Univ Dresden, Med Fac Carl Gustav Carus, D-01307 Dresden, Germany. [Cordes, Nils] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol, D-01328 Dresden, Germany. [Cordes, Nils] German Canc Consortium DKTK, D-01307 Dresden, Germany. [Cordes, Nils] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Eke, Iris] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cordes, N (reprint author), Tech Univ Dresden, Med Fac Carl Gustav Carus, OncoRay Natl Ctr Radiat Res Oncol, D-01307 Dresden, Germany. EM Nils.Cordes@OncoRay.de; Iris.Eke@nih.gov OI Cordes, Nils/0000-0001-5684-629X FU Bundesministerium fur Bildung und Forschung (BMBF) [03ZIK041, BMBF-02NUK006B]; Deutsche Forschungsgemeinschaft [CO668/4-1]; Deutsche Krebshilfe [108976]; EFRE Europaische Fonds fur regionale Entwicklung; Europa fordert Sachsen [100066308]; NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX The authors were in part supported by a grant from the Bundesministerium fur Bildung und Forschung (BMBF Contracts 03ZIK041 and BMBF-02NUK006B to N.C.), the Deutsche Forschungsgemeinschaft (CO668/4-1 to N.C.), the Deutsche Krebshilfe (108976 to N.C.), the EFRE Europaische Fonds fur regionale Entwicklung, Europa fordert Sachsen (100066308) and by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (to I.E.). NR 64 TC 1 Z9 1 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 27 PY 2015 VL 6 IS 33 BP 34592 EP 34605 DI 10.18632/oncotarget.5423 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CY0PE UT WOS:000366107200055 PM 26460618 ER PT J AU Miquelajauregui, A Sandoval-Schaefer, T Martinez-Armenta, M Perez-Martinez, L Carabez, A Zhao, YG Heide, M Alvarez-Bolado, G Varela-Echavarria, A AF Miquelajauregui, Amaya Sandoval-Schaefer, Teresa Martinez-Armenta, Miriam Perez-Martinez, Leonor Carabez, Alfonso Zhao, Yangu Heide, Michael Alvarez-Bolado, Gonzalo Varela-Echavarria, Alfredo TI LIM homeobox protein 5 (Lhx5) is essential for mamillary body development SO FRONTIERS IN NEUROANATOMY LA English DT Article DE transcription factor; diencephalon; hypothalamus; mouse; embryonic development ID MAMMILLARY BODY; SONIC-HEDGEHOG; SPINAL-CORD; HYPOTHALAMIC DEVELOPMENT; NEURON SUBPOPULATIONS; BRAIN-STEM; GENE LHX5; MOUSE; EXPRESSION; FOREBRAIN AB The mamillary body (MM) is a group of hypothalamic nuclei related to memory and spatial navigation that interconnects hippocampal, thalamic, and tegmental regions. Here we demonstrate that Lhx5, a LIM-HD domain transcription factor expressed early in the developing posterior hypothalamus, is required for the generation of the MM and its derived tracts. The MM markers Foxb1, Sim2, and Lhx1 are absent in Lhx5 knock out mice from early embryonic stages, suggesting abnormal specification of this region. This was supported by the absence of Nkx2,1 and expansion of Shh in the prospective mamillary area. Interestingly, we also found an ectopic domain expressing Lhx2 and Lhx9 along the anterio-posterior hypothalamic axis. Our results suggest that Lhx5 controls early aspects of hypothalamic development by regulating gene expression and cellular specification in the prospective MM. C1 [Miquelajauregui, Amaya; Sandoval-Schaefer, Teresa; Carabez, Alfonso; Varela-Echavarria, Alfredo] Univ Nacl Autonoma Mexico, Inst Neurobiol, Dept Neurobiol Desarrollo & Neurofisiol, Queretaro, Mexico. [Martinez-Armenta, Miriam; Perez-Martinez, Leonor] Univ Nacl Autonoma Mexico, Inst Biotechnol, Dept Med Mol & Bioproc, Lab Neuroinmunobiol, Cuernavaca 62191, Morelos, Mexico. [Zhao, Yangu] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Heide, Michael; Alvarez-Bolado, Gonzalo] Heidelberg Univ, Inst Anat & Cell Biol, Heidelberg, Germany. RP Miquelajauregui, A (reprint author), Univ Calif Los Angeles, Semel Inst, Ctr Autism Res & Treatment, 760 Westwood Plaza,Room A7-461, Los Angeles, CA 90095 USA. EM amayam@ucla.edu; avarela@unam.mx FU NICHD/NIH; Consejo Nacional de Ciencia y Tecnologia [CONACYT-232722, 249744]; DGAPA-UNAM [IN203713]; DGAPA-UNAM FX The work was supported by funds from the intramural research program of NICHD/NIH, Consejo Nacional de Ciencia y Tecnologia (CONACYT-232722 and 249744), and DGAPA-UNAM IN203713. AM was supported by a postdoctoral fellowship from DGAPA-UNAM. Technical support was provided by Anaid Antaramian Salas, Adriana Gonzalez Gallant, Pilar Galarza, Martin Garcia Servin, Nydia Hernandez, Alberto Lara, and Omar Gonzalez. We thank Prof. Jacques Michaud for kindly providing probes and Dorothy Pless for editing of the manuscript. NR 57 TC 0 Z9 0 U1 1 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD OCT 27 PY 2015 VL 9 AR 136 DI 10.3389/fnana.2015.00136 PG 10 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CX6XM UT WOS:000365845000001 PM 26578897 ER PT J AU Wang, HC Nair, VS Holland, AA Capolicchio, S Jessen, HJ Johnson, MK Shears, SB AF Wang, Huanchen Nair, Vasudha S. Holland, Ashley A. Capolicchio, Sarnanta Jessen, Henning J. Johnson, Michael K. Shears, Stephen B. TI Asp1 from Schizosaccharomyces pombe Binds a [2Fe-2S](2+) Cluster Which Inhibits Inositol Pyrophosphate 1-Phosphatase Activity SO BIOCHEMISTRY LA English DT Article ID IRON-SULFUR CLUSTER; CONSERVED CYSTEINE RESIDUES; SITE-DIRECTED MUTAGENESIS; RESONANCE RAMAN; DIPHOSPHOINOSITOL POLYPHOSPHATES; CLOSTRIDIAL FERREDOXIN; 2FE-2S CLUSTERS; PROTEIN; ENZYMES; IDENTIFICATION AB Iron-sulfur (Fe-S) clusters are widely distributed protein cofactors that are vital to cellular biochemistry and the maintenance of bioenergetic homeostasis, but to our knowledge, they have never been identified in any phosphatase. Here, we describe an iron-sulfur cluster in Asp1, a dual-function kinase/phosphatase that regulates cell morphogenesis in Schizosaccharomyces pombe. Full-length Asp1, and its phosphatase domain (Asp1(371-920)), were each heterologously expressed in Escherichia coli. The phosphatase activity is exquisitely specific: it hydrolyzes the 1-diphosphate from just two members of the inositol pyrophosphate (PP-InsP) signaling family, namely, 1-InsP(7) and 1,5-InsP(8). We demonstrate that Asp1 does not hydrolyze either InsP(6), 2-InsP(7), 3-InsP(7), 4-InsP(7), 5-InsP(7), 6-InsP(7), or 3,5-InsP(8). We also recorded 1-phosphatase activity in a human homologue of Asp1, hPPIP5K1, which was heterologously expressed in Drosophila S3 cells with a biotinylated N-terminal tag, and then isolated from cell lysates with avidin beads. Purified, recombinant Asp1(371-920) contained iron and acid-labile sulfide, but the stoichiometry (0.8 atoms of each per protein molecule) indicates incomplete iron sulfur cluster assembly. We reconstituted the Fe-S cluster in vitro under anaerobic conditions, which increased the stoichiometry to approximately 2 atoms of iron and acid-labile sulfide per Asp1 molecule. The presence of a [2Fe-2S](2+) cluster in Asp1(371-920). was demonstrated by UV-visible absorption, resonance Raman spectroscopy, and electron paramagnetic resonance spectroscopy. We determined that this [2Fe-2S](2+) cluster is unlikely to participate in redox chemistry, since it rapidly degraded upon reduction by dithionite. Biochemical and mutagenic studies demonstrated that the [2Fe-2S](2+) cluster substantially inhibits the phosphatase activity of Asp1, thereby increasing its net kinase activity. C1 [Wang, Huanchen; Nair, Vasudha S.; Shears, Stephen B.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Holland, Ashley A.; Johnson, Michael K.] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Holland, Ashley A.; Johnson, Michael K.] Univ Georgia, Ctr Metalloenzyme Studies, Athens, GA 30602 USA. [Capolicchio, Sarnanta; Jessen, Henning J.] Univ Zurich UZH, Dept Chem, CH-8057 Zurich, Switzerland. RP Shears, SB (reprint author), NIEHS, Lab Signal Transduct, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov RI Jessen, Henning/F-5108-2014 OI Jessen, Henning/0000-0002-1025-9484 FU NIH/National Institute of Environmental Health Sciences; National Institutes of Health [GM62524] FX This research was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences, and by a grant from the National Institutes of Health (GM62524 to M.K.J.). NR 69 TC 3 Z9 3 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 27 PY 2015 VL 54 IS 42 BP 6462 EP 6474 DI 10.1021/acs.biochem.5b00532 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CV0CY UT WOS:000363916200006 PM 26422458 ER PT J AU Le, KY Otto, M AF Le, Katherine Y. Otto, Michael TI Quorum-sensing regulation in staphylococci-an overview SO FRONTIERS IN MICROBIOLOGY LA English DT Review DE Staphylococcus aureus; Staphylococcus epidermidis; quorum-sensing; toxins; biofilm; Agr; LuxS ID PHENOL-SOLUBLE MODULINS; AUREUS ALPHA-HEMOLYSIN; TO-CELL COMMUNICATION; PROTEIN-A; VIRULENCE FACTORS; AUTOINDUCING PEPTIDE; BIOFILM MATURATION; IN-VIVO; INFLAMMATORY RESPONSES; TRANSMEMBRANE TOPOLOGY AB Staphylococci are frequent human commensals and some species can cause disease. Staphylococcus aureus in particular is a dangerous human pathogen. In staphylococci, the ability to sense the bacterial cell density, or quorum, and to respond with genetic adaptations is due to one main system, which is called accessory gene regulator (Agr). The extracellular signal of Agr is a post-translationally modified peptide containing a thiolactone structure. Under conditions of high cell density, Agr is responsible for the increased expression of many toxins and degradative exoenzymes, and decreased expression of several colonization factors. This regulation is important for the timing of virulence factor expression during infection and the development of acute disease, while low activity of Agr is associated with chronic staphylococcal infections, such as those involving biofilm formation. Accordingly, drugs inhibiting Agr are being evaluated for their capacity to control acute forms of S. aureus infection. C1 [Le, Katherine Y.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Bactenol, NIH, Bethesda, MD 20892 USA. [Le, Katherine Y.] Mayo Clin, Coll Med, Dept Med, Div Hosp Internal Med, Rochester, MN USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Bactenol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of health [ZIA AI000904-14] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of health (grant ZIA AI000904-14). NR 100 TC 10 Z9 10 U1 13 U2 63 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD OCT 27 PY 2015 VL 6 AR 1174 DI 10.3389/fmicb.2015.01174 PG 8 WC Microbiology SC Microbiology GA CV3OL UT WOS:000364168400001 PM 26579084 ER PT J AU Parra, M Liu, X Derrick, SC Yang, A Molina-Cruz, A Barillas-Mury, C Zheng, H Pham, PT Sedegah, M Belmonte, A Litilit, DD Waldmann, TA Kumar, S Morris, SL Perera, LP AF Parra, Marcela Liu, Xia Derrick, Steven C. Yang, Amy Molina-Cruz, Alvaro Barillas-Mury, Carolina Zheng, Hong Phuong Thao Pham Sedegah, Martha Belmonte, Arnel Litilit, Dianne D. Waldmann, Thomas A. Kumar, Sanjai Morris, Sheldon L. Perera, Liyanage P. TI Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein SO PLOS ONE LA English DT Article AB Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS, S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naive controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL-15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. C1 [Parra, Marcela; Liu, Xia; Derrick, Steven C.; Yang, Amy; Zheng, Hong; Kumar, Sanjai; Morris, Sheldon L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Phuong Thao Pham; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D.] Naval Med Res Ctr, Silver Spring, MD 20910 USA. [Waldmann, Thomas A.; Perera, Liyanage P.] NCI, Bethesda, MD 20892 USA. RP Perera, LP (reprint author), NCI, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov FU Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, NIH; Food and Drug Administration FX Funding was provided by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, NIH (T.A.W and L.P.P) and the Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 0 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2015 VL 10 IS 10 AR e0141141 DI 10.1371/journal.pone.0141141 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8PC UT WOS:000363804200032 PM 26505634 ER PT J AU Ocampo, J Clark, DJ AF Ocampo, Josefina Clark, David J. TI A Positive Twist to the Centromeric Nucleosome SO CELL REPORTS LA English DT Editorial Material ID BUDDING YEAST; CHROMATIN; DNA; ORGANIZATION; SCM3 C1 [Ocampo, Josefina; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 27 PY 2015 VL 13 IS 4 BP 645 EP 646 DI 10.1016/j.celrep.2015.10.007 PG 2 WC Cell Biology SC Cell Biology GA CU8GY UT WOS:000363780900001 PM 26510160 ER PT J AU Bhattacharyya, S Gesteland, PH Korgenski, K Bjornstad, ON Adler, FR AF Bhattacharyya, Samit Gesteland, Per H. Korgenski, Kent Bjornstad, Ottar N. Adler, Frederick R. TI Cross-immunity between strains explains the dynamical pattern of paramyxoviruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE paramyxoviruses; respiratory syncytial viruses; human parainfluenza; pathogen interactions; cross-immunity ID RESPIRATORY SYNCYTIAL VIRUS; PARAINFLUENZA VIRUS; TRANSMISSION DYNAMICS; HOSPITAL ADMISSIONS; INFECTIOUS-DISEASES; CHILDHOOD DISEASES; VIRAL-INFECTIONS; YOUNG-CHILDREN; AIR-POLLUTION; RSV INFECTION AB Viral respiratory tract diseases pose serious public health problems. Our ability to predict and thus, be able to prepare for outbreaks is strained by the complex factors driving the prevalence and severity of these diseases. The abundance of diseases and transmission dynamics of strains are not only affected by external factors, such as weather, but also driven by interactions among viruses mediated by human behavior and immunity. To untangle the complex out-of-phase annual and biennial pattern of three common paramyxoviruses, Respiratory Syncytial Virus (RSV), Human Parainfluenza Virus (HPIV), and Human Metapneumovirus (hMPV), we adopt a theoretical approach that integrates ecological and immunological mechanisms of disease interactions. By estimating parameters from multiyear time series of laboratory-confirmed cases from the intermountain west region of the United States and using statistical inference, we show that models of immune-mediated interactions better explain the data than those based on ecological competition by convalescence. The strength of cross-protective immunity among viruses is correlated with their genetic distance in the phylogenetic tree of the paramyxovirus family. C1 [Bhattacharyya, Samit; Bjornstad, Ottar N.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bhattacharyya, Samit; Adler, Frederick R.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Gesteland, Per H.; Korgenski, Kent] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84112 USA. [Gesteland, Per H.] Univ Utah, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Korgenski, Kent] Intermt Healthcare, Pediat Clin Program, Salt Lake City, UT 84111 USA. [Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Adler, Frederick R.] Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. RP Bhattacharyya, S (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM szb16@psu.edu FU University of Utah Funding Incentive SEED Grant; Agency for Healthcare Research and Quality Grant [K08 HS018538]; Bill and Melinda Gates Foundation; Research and Policy for Infectious Disease Dynamics (RAPIDD) Program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; James S. McDonnell Foundation 21st Century Science Initiative Grant FX We thank Pejman Rohani and Sourya Shrestha (University of Michigan) for fruitful discussion about the work and two anonymous reviewers for useful comments to improve the analysis in the paper. This work was supported by a University of Utah Funding Incentive SEED Grant; Agency for Healthcare Research and Quality Grant K08 HS018538 (to P.H.G.); the Bill and Melinda Gates Foundation (O.N.B.); the Research and Policy for Infectious Disease Dynamics (RAPIDD) Program of the Science and Technology Directorate; the Department of Homeland Security; the Fogarty International Center, National Institutes of Health (O.N.B.); and James S. McDonnell Foundation 21st Century Science Initiative Grant (to F.R.A.). NR 56 TC 2 Z9 2 U1 0 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 OCT 27 PY 2015 VL 112 IS 43 BP 13396 EP 13400 DI 10.1073/pnas.1516698112 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU3WY UT WOS:000363458100073 PM 26460003 ER PT J AU Doyle, JJ Doyle, AJ Wilson, NK Habashi, JP Bedja, D Whitworth, RE Lindsay, ME Schoenhoff, F Myers, L Huso, N Bachir, S Squires, O Rusholme, B Ehsan, H Huso, D Thomas, CJ Caulfield, MJ Van Eyk, JE Judge, DP Dietz, HC AF Doyle, Jefferson J. Doyle, Alexander J. Wilson, Nicole K. Habashi, Jennifer P. Bedja, Djahida Whitworth, Ryan E. Lindsay, Mark E. Schoenhoff, Florian Myers, Loretha Huso, Nick Bachir, Suha Squires, Oliver Rusholme, Benjamin Ehsan, Hamid Huso, David Thomas, Craig J. Caulfield, Mark J. Van Eyk, Jennifer E. Judge, Daniel P. Dietz, Harry C. CA GenTAC Registry Consortium MIBAVA Leducq Consortium TI A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome SO ELIFE LA English DT Article ID KINASE-C-DELTA; AORTIC-ANEURYSM PROGRESSION; ANGIOTENSIN-II; MOUSE MODEL; BETA; GROWTH; ACTIVATION; BLOCKADE; PATHWAY; CELLS AB Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKC beta and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. C1 [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Doyle, Jefferson J.; Ehsan, Hamid] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Doyle, Alexander J.; Caulfield, Mark J.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, London, England. [Habashi, Jennifer P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. [Bedja, Djahida] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Bedja, Djahida] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW, Australia. [Whitworth, Ryan E.] Res Triangle Inst Int, Durham, NC USA. [Lindsay, Mark E.] Harvard Med Sch, Thorac Aort Ctr, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Lindsay, Mark E.] Harvard Med Sch, Thorac Aort Ctr, Massachusetts Gen Hosp, Dept Pediat, Boston, MA USA. [Schoenhoff, Florian] Inselspital Bern, Dept Cardiovasc Surg, Bern, Switzerland. [Schoenhoff, Florian; Van Eyk, Jennifer E.] Johns Hopkins Univ, Sch Med, Prote Innovat Ctr Heart Failure, Baltimore, MD USA. [Huso, David] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Bethesda, MD USA. [Judge, Daniel P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Doyle, JJ (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. EM doyle@jhmi.edu; hdietz@jhmi.edu FU National Institutes of Health [AR041135, AR049698]; Howard Hughes Medical Institute; National Marfan Foundation Bloomberg Fund; National Marfan Foundation Smilow Center for Marfan Syndrome Research; Fondation Leducq MIBAVA Leducq Consortium; National Heart, Lung, and Blood Institute GenTAC Consortium FX National Institutes of Health AR041135 Jennifer P Habashi, Harry C Dietz; Howard Hughes Medical Institute Alexander J Doyle, Harry C Dietz; National Marfan Foundation Bloomberg Fund Jefferson J Doyle, Jennifer P Habashi, Harry C Dietz; National Marfan Foundation Smilow Center for Marfan Syndrome Research Harry C Dietz; Fondation Leducq MIBAVA Leducq Consortium MIBAVA Members; National Heart, Lung, and Blood Institute GenTAC Consortium GenTAC Members; National Institute of Health AR049698 Jennifer P Habashi, Harry C Dietz NR 36 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 27 PY 2015 VL 4 AR e08648 DI 10.7554/eLife.08648 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7RE UT WOS:000393419100001 ER PT J AU Doyle, JJ Doyle, AJ Wilson, NK Habashi, JP Bedja, D Whitworth, RE Lindsay, ME Schoenhoff, F Myers, L Huso, N Bachir, S Squires, O Rusholme, B Ehsan, H Huso, D Thomas, CJ Caulfield, MJ Van Eyk, JE Judge, DP Dietz, HC AF Doyle, Jefferson J. Doyle, Alexander J. Wilson, Nicole K. Habashi, Jennifer P. Bedja, Djahida Whitworth, Ryan E. Lindsay, Mark E. Schoenhoff, Florian Myers, Loretha Huso, Nick Bachir, Suha Squires, Oliver Rusholme, Benjamin Ehsan, Hamid Huso, David Thomas, Craig J. Caulfield, Mark J. Van Eyk, Jennifer E. Judge, Daniel P. Dietz, Harry C. CA GenTAC Registry Consortium MIBAVA Leducq Consortium TI A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome SO ELIFE LA English DT Article ID KINASE-C-DELTA; AORTIC-ANEURYSM PROGRESSION; ANGIOTENSIN-II; MOUSE MODEL; GROWTH; ACTIVATION; BLOCKADE; PATHWAY; CELLS; MICE AB Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCa and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. C1 [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Doyle, Jefferson J.; Doyle, Alexander J.; Wilson, Nicole K.; Habashi, Jennifer P.; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Doyle, Jefferson J.; Ehsan, Hamid] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Doyle, Alexander J.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England. [Habashi, Jennifer P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. [Bedja, Djahida] Johns Hopkins Univ, Sch Med, Dept Cardiol, Baltimore, MD USA. [Bedja, Djahida] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Whitworth, Ryan E.] Res Triangle Inst Int, Durham, NC USA. [Lindsay, Mark E.] Harvard Univ, Sch Med, Dept Med, Thorac Aort Ctr,Massachusetts Gen Hosp, Boston, MA USA. [Lindsay, Mark E.] Harvard Univ, Sch Med, Dept Pediat, Thorac Aort Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schoenhoff, Florian] Univ Bern, Inselspital, Dept Cardiovasc Surg, CH-3010 Bern, Switzerland. [Schoenhoff, Florian; Van Eyk, Jennifer E.] Johns Hopkins Univ, Sch Med, Prote Innovat Ctr Heart Failure, Baltimore, MD USA. [Huso, David] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Thomas, Craig J.] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Bethesda, MD USA. [Judge, Daniel P.; Dietz, Harry C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Doyle, JJ (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. EM jefferson.doyle@jhmi.edu; hdietz@jhmi.edu FU National Institutes of Health [AR041135, AR049698]; Howard Hughes Medical Institute; National Marfan Foundation; Fondation Leducq MIBAVA Leducq Consortium; National Heart, Lung, and Blood Institute GenTAC Consortium FX National Institutes of Health AR041135 Jennifer P Habashi, Harry C Dietz; Howard Hughes Medical Institute Alexander J Doyle, Harry C Dietz; National Marfan Foundation Bloomberg Fund Jefferson J Doyle, Jennifer P Habashi, Harry C Dietz; National Marfan Foundation Smilow Center for Marfan Syndrome Research Harry C Dietz; Fondation Leducq MIBAVA Leducq Consortium MIBAVA Members; National Heart, Lung, and Blood Institute GenTAC Consortium GenTAC Members; National Institute of Health AR049698 Jennifer P Habashi, Harry C Dietz NR 36 TC 10 Z9 10 U1 0 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 27 PY 2015 VL 4 AR e08648 DI 10.7554/eLife.08648 PG 18 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CU8MS UT WOS:000363797700001 ER PT J AU Chen, G Saad, ZS Adleman, NE Leibenluft, E Cox, RW AF Chen, Gang Saad, Ziad S. Adleman, Nancy E. Leibenluft, Ellen Cox, Robert W. TI Detecting the subtle shape differences in hemodynamic responses at the group level SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE hemodynamic response; basis function; multivariate general linear model; linear mixed-effects model; FMRI group analysis; AFNI ID GENERAL LINEAR-MODEL; FMRI GROUP-ANALYSIS; MULTI-SUBJECT FMRI; EVENT-RELATED FMRI; STATISTICAL-ANALYSIS; BOLD SIGNAL; BRAIN; ACTIVATION; INFERENCE; HIPPOCAMPAL AB The nature of the hemodynamic response (HDR) is still not fully understood due to the multifaceted processes involved. Aside from the overall amplitude, the response may vary across cognitive states, tasks, brain regions, and subjects with respect to characteristics such as rise and fall speed, peak duration, undershoot shape, and overall duration. Here we demonstrate that the fixed-shape (FSM) or adjusted-shape (ASM) methods may fail to detect some shape subtleties (e.g., speed of rise or recovery, or undershoot). In contrast, the estimated-shape method (ESM) through multiple basis functions can provide the opportunity to identify some subtle shape differences and achieve higher statistical power at both individual and group levels. Previously, some dimension reduction approaches focused on the peak magnitude, or made inferences based on the area under the curve (AUC) or interaction, which can lead to potential misidentifications. By adopting a generic framework of multivariate modeling (MVM), we showcase a hybrid approach that is validated by simulations and real data. With the whole HDR shape integrity maintained as input at the group level, the approach allows the investigator to substantiate these more nuanced effects through the unique HDR shape features. Unlike the few analyses that were limited to main effect, two- or three-way interactions, we extend the modeling approach to an inclusive platform that is more adaptable than the conventional GLM. With multiple effect estimates from ESM for each condition, linear mixed-effects (LME) modeling should be used at the group level when there is only one group of subjects without any other explanatory variables. Under other situations, an approximate approach through dimension reduction within the MVM framework can be adopted to achieve a practical equipoise among representation, false positive control, statistical power, and modeling flexibility. The associated program 3 dMVM is publicly available as part of the AFNI suite. C1 [Chen, Gang; Saad, Ziad S.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Adleman, Nancy E.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM gangchen@mail.nih.gov FU NIMH; NINDS intramural Research Programs of the NIH/HHS, USA FX Our work benefited significantly from the statistical computational language and environment R, its many packages, and the great support of the R community. All the plots were created in R with the base graphics library. Special thanks are due to Helios de Rosario for his help in technical details of using the R package phia. The research and writing of the paper were supported by the NIMH and NINDS intramural Research Programs of the NIH/HHS, USA. NR 63 TC 1 Z9 1 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD OCT 26 PY 2015 VL 9 AR 375 DI 10.3389/fnins.2015.00375 PG 18 WC Neurosciences SC Neurosciences & Neurology GA CY9EV UT WOS:000366711100001 PM 26578853 ER PT J AU Taraska, JW AF Taraska, Justin W. TI Cell biology of the future: Nanometer-scale cellular cartography SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID ELECTRON-MICROSCOPY; SUPERRESOLUTION FLUORESCENCE; LOCALIZATION; ENDOCYTOSIS; TOMOGRAPHY; PROTEINS; DYNAMICS; YEAST AB Understanding cellular structure is key to understanding cellular regulation. New developments in super-resolution fluorescence imaging, electron microscopy, and quantitative image analysis methods are now providing some of the first three-dimensional dynamic maps of biomolecules at the nanometer scale. These new maps-comprehensive nanometer-scale cellular cartographies-will reveal how the molecular organization of cells influences their diverse and changeable activities. C1 NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural NIH HHS NR 24 TC 0 Z9 0 U1 1 U2 13 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD OCT 26 PY 2015 VL 211 IS 2 BP 211 EP 214 DI 10.1083/jcb.201508021 PG 4 WC Cell Biology SC Cell Biology GA CV4XN UT WOS:000364269900003 PM 26483557 ER PT J AU Choudhary, V Ojha, N Golden, A Prinz, WA AF Choudhary, Vineet Ojha, Namrata Golden, Andy Prinz, William A. TI A conserved family of proteins facilitates nascent lipid droplet budding from the ER SO JOURNAL OF CELL BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; PRESSURE FROZEN SAMPLES; ENDOPLASMIC-RETICULUM; FAT STORAGE; CAENORHABDITIS-ELEGANS; TRANSMEMBRANE PROTEIN-2; ELECTRON-MICROSCOPY; BODY FORMATION; BIOGENESIS; SEIPIN AB Lipid droplets (LDs) are found in all cells and play critical roles in lipid metabolism. De novo LD biogenesis occurs in the endoplasmic reticulum (ER) but is not well understood. We imaged early stages of LD biogenesis using electron microscopy and found that nascent LDs form lens-like structures that are in the ER membrane, raising the question of how these nascent LDs bud from the ER as they grow. We found that a conserved family of proteins, fat storage-inducing transmembrane (FIT) proteins, is required for proper budding of LDs from the ER. Elimination or reduction of FIT proteins in yeast and higher eukaryotes causes LDs to remain in the ER membrane. Deletion of the single FIT protein in Caenorhabditis elegans is lethal, suggesting that LD budding is an essential process in this organism. Our findings indicated that FIT proteins are necessary to promote budding of nascent LDs from the ER. C1 [Choudhary, Vineet; Ojha, Namrata; Prinz, William A.] NIDDK, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Golden, Andy] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDK, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Swiss National Science Foundation [PA00P3_145358, P300P3_158454] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. V. Choudhary is supported by fellowship from Swiss National Science Foundation (grants PA00P3_145358 and P300P3_158454). NR 67 TC 13 Z9 13 U1 7 U2 17 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD OCT 26 PY 2015 VL 211 IS 2 BP 261 EP 271 DI 10.1083/jcb.201505067 PG 11 WC Cell Biology SC Cell Biology GA CV4XN UT WOS:000364269900009 PM 26504167 ER PT J AU Colineau, L Rouers, A Yamamoto, T Xu, Y Urrutia, A Pham, HP Cardinaud, S Samri, A Dorgham, K Coulon, PG Cheynier, R Hosmalin, A Oksenhendler, E Six, A Kelleher, AD Zaunders, J Koup, RA Autran, B Moris, A Graff-Dubois, S AF Colineau, Lucie Rouers, Angeline Yamamoto, Takuya Xu, Yin Urrutia, Alejandra Hang-Phuong Pham Cardinaud, Sylvain Samri, Assia Dorgham, Karim Coulon, Pierre-Gregoire Cheynier, Remi Hosmalin, Anne Oksenhendler, Eric Six, Adrien Kelleher, Anthony D. Zaunders, John Koup, Richard A. Autran, Brigitte Moris, Arnaud Graff-Dubois, Stephanie TI HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation SO PLOS ONE LA English DT Article ID GERMINAL CENTER REACTIONS; IMMUNE THROMBOCYTOPENIA; UP-REGULATION; REGULATORY CELLS; DENDRITIC CELLS; CENTER RESPONSE; LYMPH-NODES; CD40 LIGAND; WHITE PULPS; IN-VIVO AB Follicular helper T (Tfh) cells within secondary lymphoid organs control multiple steps of B cell maturation and antibody (Ab) production. HIV-1 infection is associated with an altered B cell differentiation and Tfh isolated from lymph nodes of HIV-infected (HIV+) individuals provide inadequate B cell help in vitro. However, the mechanisms underlying this impairment of Tfh function are not fully defined. Using a unique collection of splenocytes, we compared the frequency, phenotype and transcriptome of Tfh subsets in spleens from HIV negative (HIV-) and HIV+ subjects. We observed an increase of CXCR5(+)PD-1(high)CD57-Tfh and germinal center (GC) CD57+ Tfh in HIV+ spleens. Both subsets showed a reduced mRNA expression of the transcription factor STAT-3, co-stimulatory, regulatory and signal transduction molecules as compared to HIV-spleens. Similarly, Foxp3 expressing follicular regulatory T (Tfr) cells were increased, suggesting sustained GC reactions in chronically HIV+ spleens. As a consequence, GC B cell populations were expanded, however, complete maturation into memory B cells was reduced in HIV+ spleens where we evidenced a compromised production of B cell-activating cytokines such as IL-4 and IL-10. Collectively our data indicate that, although Tfh proliferation and GC reactions seem to be ongoing in HIV-infected spleens, Tfh "differentiation" and expression of costimulatory molecules is skewed with a profound effect on B cell maturation. C1 [Colineau, Lucie; Rouers, Angeline; Urrutia, Alejandra; Cardinaud, Sylvain; Samri, Assia; Dorgham, Karim; Coulon, Pierre-Gregoire; Autran, Brigitte; Moris, Arnaud; Graff-Dubois, Stephanie] Univ Paris 06, Sorbonne Univ, Ctr Immunol & Microbial Infect CIMI Paris, Paris, France. [Colineau, Lucie; Rouers, Angeline; Urrutia, Alejandra; Cardinaud, Sylvain; Samri, Assia; Dorgham, Karim; Coulon, Pierre-Gregoire; Autran, Brigitte; Moris, Arnaud; Graff-Dubois, Stephanie] INSERM, U1135, Ctr Immunol & Microbial Infect CIMI Paris, Paris, France. [Colineau, Lucie; Rouers, Angeline; Urrutia, Alejandra; Cardinaud, Sylvain; Coulon, Pierre-Gregoire; Moris, Arnaud; Graff-Dubois, Stephanie] CNRS, ERL 8255, Ctr Immunol & Microbial Infect CIMI Paris, Paris, France. [Yamamoto, Takuya; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Xu, Yin; Kelleher, Anthony D.] Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW, Australia. [Hang-Phuong Pham; Six, Adrien] Univ Paris 06, Sorbonne Univ, UMRS 959, Immunol Immunopathol Imunotherapy I3, Paris, France. [Hang-Phuong Pham; Six, Adrien] INSERM, UMRS 959, Immunol Immunopathol Immunotherapy I3, Paris, France. [Hang-Phuong Pham; Six, Adrien] CNRS, FRE3632, Immunol Immunopathol Immunotherapy I3, Paris, France. [Cheynier, Remi; Hosmalin, Anne] Inst Cochin, INSERM, U1016, Paris, France. [Cheynier, Remi; Hosmalin, Anne] CNRS, UMR8104, Paris, France. [Cheynier, Remi; Hosmalin, Anne] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Hosmalin, Anne] Hop Cochin, AP HP, F-75674 Paris, France. [Oksenhendler, Eric] Univ Paris Diderot, Hop St Louis, AP HP, Dept Clin Immunol, Paris, France. [Zaunders, John] St Vincents Hosp, St Vincents Ctr Appl Med Res, Sydney, NSW 2010, Australia. [Samri, Assia; Dorgham, Karim; Autran, Brigitte; Moris, Arnaud] Hop La Pitie Salpetriere, AP HP, Dept Immunol, Paris, France. RP Graff-Dubois, S (reprint author), Univ Paris 06, Sorbonne Univ, Ctr Immunol & Microbial Infect CIMI Paris, Paris, France. EM stephanie.graff-dubois@upmc.fr RI Cheynier, Remi/E-9921-2010; OI Cheynier, Remi/0000-0003-1146-660X; dorgham, karim/0000-0001-9539-3203; Moris, Arnaud/0000-0002-5052-1678; Yamamoto, Takuya/0000-0003-3753-1211 FU Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS); INSERMFrench government's [ANR-10-LABX-62-IBEID]; French government; CutHIVac European consortium EU-FP7; LabEx Transimmunom [ANR-11-IDEX-0004-02]; ANRS; Sidaction FX This work was supported by the Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS) and INSERM, by the French government's "Investissement d'Avenir" Program, Laboratoire d'excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID) and by the CutHIVac European consortium EU-FP7. A. Six and HPP contribution was partially sponsored by the LabEx Transimmunom (ANR-11-IDEX-0004-02). S. Cardinaud was supported by ANRS and Sidaction. A. Urrutia was supported by Sidaction. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 7 Z9 7 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 26 PY 2015 VL 10 IS 10 AR e0140978 DI 10.1371/journal.pone.0140978 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CU8NN UT WOS:000363799900019 PM 26501424 ER EF