FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Breed, MW Elser, SE Torben, W Jordan, APO Aye, PP Midkiff, C Schiro, F Sugimoto, C Alvarez-Hernandez, X Blair, RV Somasunderam, A Utay, NS Kuroda, MJ Pahar, B Wiseman, RW O'Connor, DH LaBranche, CC Montefiori, DC Marsh, M Li, Y Piatak, M Lifson, JD Keele, BF Fultz, PN Lackner, AA Hoxie, JA AF Breed, Matthew W. Elser, Samra E. Torben, Workineh Jordan, Andrea P. O. Aye, Pyone P. Midkiff, Cecily Schiro, Faith Sugimoto, Chie Alvarez-Hernandez, Xavier Blair, Robert V. Somasunderam, Anoma Utay, Netanya S. Kuroda, Marcelo J. Pahar, Bapi Wiseman, Roger W. O'Connor, David H. LaBranche, Celia C. Montefiori, David C. Marsh, Mark Li, Yuan Piatak, Michael, Jr. Lifson, Jeffrey D. Keele, Brandon F. Fultz, Patricia N. Lackner, Andrew A. Hoxie, James A. TI Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 ENVELOPE PROTEIN; MAJOR HISTOCOMPATIBILITY COMPLEX; ACTIVE ANTIRETROVIRAL THERAPY; NEONATAL RHESUS MACAQUES; I INTERFERON RESPONSES; ACUTE SIV INFECTION; IMMUNE ACTIVATION; PIGTAIL MACAQUES; MICROBIAL TRANSLOCATION; CYTOPLASMIC DOMAIN AB Deletion of Gly-720 and Tyr-721 from a highly conserved GYxxO trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed Delta GY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4(+) T cells and an absence of microbial translocation. Here we evaluated Delta GY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, Delta GY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4(+) T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled Delta GY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4(+) T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4(+) T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8(+) cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by Delta GY's ablation of the GYxxO trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection. IMPORTANCE The pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans and Asian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development. C1 [Breed, Matthew W.; Torben, Workineh; Aye, Pyone P.; Midkiff, Cecily; Schiro, Faith; Sugimoto, Chie; Alvarez-Hernandez, Xavier; Blair, Robert V.; Kuroda, Marcelo J.; Pahar, Bapi; Lackner, Andrew A.] Tulane Natl Primate Res Ctr, Covington, LA USA. [Elser, Samra E.; Jordan, Andrea P. O.; Hoxie, James A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Somasunderam, Anoma; Utay, Netanya S.] Baylor Coll Med, Houston, TX 77030 USA. [Wiseman, Roger W.; O'Connor, David H.] Univ Wisconsin, Natl Primate Res Ctr, Madison, WI USA. [LaBranche, Celia C.; Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC USA. [Marsh, Mark] UCL, MRC Lab Mol Cell Biol, London, England. [Li, Yuan; Piatak, Michael, Jr.; Lifson, Jeffrey D.; Keele, Brandon F.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Fultz, Patricia N.] Univ Alabama Birmingham, Birmingham, AL USA. RP Hoxie, JA (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM hoxie@mail.med.upenn.edu RI Marsh, Mark/B-4105-2009; OI Marsh, Mark/0000-0002-0213-3259; Utay, Netanya/0000-0002-6407-8670; o'connor, david/0000-0003-2139-470X; Pahar, Bapi/0000-0003-1949-973X FU Medical Research Council [MC_UU_12018/1]; NIAID NIH HHS [R01 AI097059, T32 AI007632, T32 AI070077]; NIH HHS [T32 OD011124, P51 OD011104, S10 OD019964] NR 121 TC 2 Z9 2 U1 1 U2 6 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 OCT PY 2015 VL 89 IS 20 BP 10156 EP 10175 DI 10.1128/JVI.01134-15 PG 20 WC Virology SC Virology GA CU3ZG UT WOS:000363464700003 PM 26223646 ER PT J AU Olesen, R Vigano, S Rasmussen, TA Sogaard, OS Ouyang, ZY Buzon, M Bashirova, A Carrington, M Palmer, S Brinkmann, CR Yu, XG Ostergaard, L Tolstrup, M Lichterfeld, M AF Olesen, Rikke Vigano, Selena Rasmussen, Thomas A. Sogaard, Ole S. Ouyang, Zhengyu Buzon, Maria Bashirova, Arman Carrington, Mary Palmer, Sarah Brinkmann, Christel R. Yu, Xu G. Ostergaard, Lars Tolstrup, Martin Lichterfeld, Mathias TI Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat SO JOURNAL OF VIROLOGY LA English DT Article ID HEPATITIS-C VIRUS; HISTONE DEACETYLASE INHIBITORS; IL28B GENOTYPE; LYMPHOCYTE-ACTIVATION; TYPE-1 REPLICATION; CYTOLYTIC ACTIVITY; ELITE CONTROLLERS; INTERFERON-ALPHA; I INTERFERON; SET-POINT AB The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3(-) CD56(+) total NK cells and CD16(+) CD56(dim) NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69(+) NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies. IMPORTANCE Currently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells. C1 [Olesen, Rikke; Rasmussen, Thomas A.; Sogaard, Ole S.; Brinkmann, Christel R.; Ostergaard, Lars; Tolstrup, Martin] Aarhus Univ Hosp, Div Infect Dis, DK-8000 Aarhus, Denmark. [Vigano, Selena; Ouyang, Zhengyu; Buzon, Maria; Yu, Xu G.; Lichterfeld, Mathias] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Vigano, Selena; Ouyang, Zhengyu; Buzon, Maria; Yu, Xu G.; Lichterfeld, Mathias] Harvard, Cambridge, MA USA. [Vigano, Selena; Buzon, Maria; Yu, Xu G.; Lichterfeld, Mathias] Harvard Univ, Sch Med, Boston, MA USA. [Bashirova, Arman; Carrington, Mary] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Palmer, Sarah] Univ Sydney, Westmead Millennium Inst Med Res, Sydney, NSW 2006, Australia. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lichterfeld, Mathias] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Lichterfeld, M (reprint author), MIT, Ragon Inst MGH, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mlichterfeld@mgh.harvard.edu RI Sogaard, Ole/P-6058-2016; OI Buzon, Maria Jose/0000-0003-4427-9413; Rasmussen, Thomas Aagaard/0000-0001-5354-2442; Olesen, Rikke/0000-0002-5157-080X FU Danish Strategic Research Council [0603-00521B]; American Foundation for AIDS Research [108302-51-RGRL]; Clinical Scientist Development Award from the Doris Duke Charitable Foundation [2009034]; Danish Research Council [12-133887]; Lundbeck Foundation [R126-2012-12588] FX This work was supported by The Danish Strategic Research Council (grant 0603-00521B) and the American Foundation for AIDS Research (grant 108302-51-RGRL). M.L. is a recipient of the Clinical Scientist Development Award from the Doris Duke Charitable Foundation (grant number 2009034). O.S.S. is supported by a grant from the Danish Research Council (grant 12-133887) and a grant from the Lundbeck Foundation (grant R126-2012-12588). NR 64 TC 16 Z9 16 U1 2 U2 9 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 OCT PY 2015 VL 89 IS 20 BP 10176 EP 10189 DI 10.1128/JVI.01484-15 PG 14 WC Virology SC Virology GA CU3ZG UT WOS:000363464700004 PM 26223643 ER PT J AU Mackow, N Amaro-Carambot, E Liang, B Surman, S Lingemann, M Yang, LJ Collins, PL Munir, S AF Mackow, Natalie Amaro-Carambot, Emerito Liang, Bo Surman, Sonja Lingemann, Matthias Yang, Lijuan Collins, Peter L. Munir, Shirin TI Attenuated Human Parainfluenza Virus Type 1 (HPIV1) Expressing the Fusion Glycoprotein of Human Respiratory Syncytial Virus (RSV) as a Bivalent HPIV1/RSV Vaccine SO JOURNAL OF VIROLOGY LA English DT Article ID ENHANCED PULMONARY PATHOLOGY; L-POLYMERASE PROTEIN; REVERSE GENETICS; F-GLYCOPROTEIN; COTTON RATS; EFFICIENT REPLICATION; MUCOSAL IMMUNIZATION; ANTIBODY-RESPONSE; LIVE; MUTATIONS AB Live attenuated recombinant human parainfluenza virus type 1 (rHPIV1) was investigated as a vector to express the respiratory syncytial virus (RSV) fusion (F) glycoprotein, to provide a bivalent vaccine against RSV and HPIV1. The RSV F gene was engineered to include HPIV1 transcription signals and inserted individually into three gene locations in each of the two attenuated rHPIV1 backbones. Each backbone contained a single previously described attenuating mutation that was stabilized against de-attenuation, specifically, a non-temperature-sensitive deletion mutation involving 6 nucleotides in the overlapping P/C open reading frames (ORFs) (C-Delta 170) or a temperature-sensitive missense mutation in the L ORF (L-Y942A). The insertion sites in the genome were pre-N (F1), N-P (F2), or P-M (F3) and were identical for both backbones. In vitro, the presence of the F insert reduced the rate of virus replication, but the final titers were the same as the final titer of wild-type (wt) HPIV1. High levels of RSV F expression in cultured cells were observed with rHPIV1-C-Delta 170-F1, -F2, and -F3 and rHPIV1-L-Y942A-F1. In hamsters, the rHPIV1-C-Delta 170-F1, -F2, and -F3 vectors were moderately restricted in the nasal turbinates, highly restricted in lungs, and genetically stable in vivo. Among the C-Delta 170 vectors, the F1 virus was the most immunogenic and protective against wt RSV challenge. The rHPIV1-L-Y942A vectors were highly restricted in vivo and were not detectably immunogenic or protective, indicative of over-attenuation. The C-Delta 170-F1 construct appears to be suitably attenuated and immunogenic for further development as a bivalent intranasal pediatric vaccine. IMPORTANCE There are no vaccines for the pediatric respiratory pathogens RSV and HPIV. We are developing live attenuated RSV and HPIV vaccines for use in virus-naive infants. Live attenuated RSV strains in particular are difficult to develop due to their poor growth and physical instability, but these obstacles could be avoided by the use of a vaccine vector. We describe the development and preclinical evaluation of live attenuated rHPIV1 vectors expressing the RSV F protein. Two different attenuated rHPIV1 backbones were each engineered to express RSV F from three different gene positions. The rHPIV1-C-Delta 170-F1 vector, bearing an attenuating deletion mutation (C-Delta 170) in the P/C gene and expressing RSV F from the pre-N position, was attenuated, stable, and immunogenic against the RSV F protein and HPIV1 in the hamster model and provided substantial protection against RSV challenge. This study provides a candidate rHPIV1-RSV-F vaccine virus suitable for continued development as a bivalent vaccine against two major childhood pathogens. C1 [Mackow, Natalie; Amaro-Carambot, Emerito; Liang, Bo; Surman, Sonja; Lingemann, Matthias; Yang, Lijuan; Collins, Peter L.; Munir, Shirin] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Munir, S (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM munirs@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX This study was supported by the Intramural Research Program of NIAID, NIH. NR 45 TC 2 Z9 2 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 OCT PY 2015 VL 89 IS 20 BP 10319 EP 10332 DI 10.1128/JVI.01380-15 PG 14 WC Virology SC Virology GA CU3ZG UT WOS:000363464700015 PM 26223633 ER PT J AU Dick, RA Datta, SAK Nanda, H Fang, XY Wen, Y Barros, M Wang, YX Rein, A Vogt, VM AF Dick, Robert A. Datta, Siddhartha A. K. Nanda, Hirsh Fang, Xianyang Wen, Yi Barros, Marilia Wang, Yun-Xing Rein, Alan Vogt, Volker M. TI Hydrodynamic and Membrane Binding Properties of Purified Rous Sarcoma Virus Gag Protein SO JOURNAL OF VIROLOGY LA English DT Article ID X-RAY-SCATTERING; PARTICLES IN-VITRO; HIV-1 GAG; PLASMA-MEMBRANE; MATRIX DOMAIN; TYPE-1 GAG; MODEL MEMBRANES; ASSEMBLY DOMAIN; LIPID-MEMBRANES; P10 DOMAIN AB Previously, no retroviral Gag protein has been highly purified in milligram quantities and in a biologically relevant and active form. We have purified Rous sarcoma virus (RSV) Gag protein and in parallel several truncation mutants of Gag and have studied their biophysical properties and membrane interactions in vitro. RSV Gag is unusual in that it is not naturally myristoylated. From its ability to assemble into virus-like particles in vitro, we infer that RSV Gag is biologically active. By size exclusion chromatography and small-angle X-ray scattering, Gag in solution appears extended and flexible, in contrast to previous reports on unmyristoylated HIV-1 Gag, which is compact. However, by neutron reflectometry measurements of RSV Gag bound to a supported bilayer, the protein appears to adopt a more compact, folded-over conformation. At physiological ionic strength, purified Gag binds strongly to liposomes containing acidic lipids. This interaction is stimulated by physiological levels of phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and by cholesterol. However, unlike HIV-1 Gag, RSV Gag shows no sensitivity to acyl chain saturation. In contrast with full-length RSV Gag, the purified MA domain of Gag binds to liposomes only weakly. Similarly, both an N-terminally truncated version of Gag that is missing the MA domain and a C-terminally truncated version that is missing the NC domain bind only weakly. These results imply that NC contributes to membrane interaction in vitro, either by directly contacting acidic lipids or by promoting Gag multimerization. IMPORTANCE Retroviruses like HIV assemble at and bud from the plasma membrane of cells. Assembly requires the interaction between thousands of Gag molecules to form a lattice. Previous work indicated that lattice formation at the plasma membrane is influenced by the conformation of monomeric HIV. We have extended this work to the more tractable RSV Gag. Our results show that RSV Gag is highly flexible and can adopt a folded-over conformation on a lipid bilayer, implicating both the N and C termini in membrane binding. In addition, binding of Gag to membranes is diminished when either terminal domain is truncated. RSV Gag membrane association is significantly less sensitive than HIV Gag membrane association to lipid acyl chain saturation. These findings shed light on Gag assembly and membrane binding, critical steps in the viral life cycle and an untapped target for antiretroviral drugs. C1 [Dick, Robert A.; Wen, Yi; Vogt, Volker M.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14850 USA. [Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Nanda, Hirsh] NIST, NIST Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Fang, Xianyang; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21701 USA. [Nanda, Hirsh; Barros, Marilia] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. RP Dick, RA (reprint author), Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14850 USA. EM rad82@cornell.edu; dattasi@mail.nih.gov OI Datta, Siddhartha/0000-0002-4098-7490 FU NIH [R01GM107013, RO1GM101647]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program; U.S. Department of Commerce [70NANB13H009] FX This work was supported by NIH grant R01GM107013 (to V.M.V.), NIH grant RO1GM101647 to Mathias Losche, the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, the Intramural AIDS Targeted Antiviral Program (to A.R. and Y.-X.W.), and in part by the U.S. Department of Commerce (70NANB13H009). NR 71 TC 3 Z9 3 U1 0 U2 11 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 OCT PY 2015 VL 89 IS 20 BP 10371 EP 10382 DI 10.1128/JVI.01628-15 PG 12 WC Virology SC Virology GA CU3ZG UT WOS:000363464700019 PM 26246573 ER PT J AU Okumura, A Rasmussen, AL Halfmann, P Feldmann, F Yoshimura, A Feldmann, H Kawaoka, Y Harty, RN Katze, MG AF Okumura, Atsushi Rasmussen, Angela L. Halfmann, Peter Feldmann, Friederike Yoshimura, Akihiko Feldmann, Heinz Kawaoka, Yoshihiro Harty, Ronald N. Katze, Michael G. TI Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; INNATE ANTIVIRAL RESPONSE; DENDRITIC CELLS; MATRIX PROTEIN; RECEPTOR 4; SOCS-BOX; VP40 PROTEIN; GLYCOPROTEIN; INTERACTS; MOTIF AB Ebola virus (EBOV) initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal EBOV infections. The VP40 matrix protein is a key viral structural protein that is critical for virion egress. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VP40-driven viruslike particles (VLPs) and infectious virus. Here, we show that host suppressor of cytokine signaling 3 (SOCS3) can also bind to EBOV VP40, leading to enhanced ubiquitinylation and egress of VP40. Indeed, titers of infectious EBOV derived from SOCS3 knockout mouse embryonic fibroblasts (MEFs) were significantly reduced compared to those from wild-type (WT) MEFs at 24 and 48 h postinfection. Importantly, this reduced virus yield could be rescued back to WT levels by exogenously expressing SOCS3. Lastly, we show that SOCS3 expression is induced by EBOV glycoprotein (GP) expression and that VLPs containing EBOV VP40 and GP induced production of proinflammatory cytokines, which induced SOCS3 for negative-feedback regulation. These data indicate that host innate immune protein SOCS3 may play an important role in budding and pathogenesis of EBOV. IMPORTANCE The VP40 matrix protein is a key structural protein critical for Ebola virus budding. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VLPs and infectious virus. We reported that host TLR4 is a sensor for Ebola GP on VLPs and that the resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines. Host SOCS3 regulates the innate immune response by controlling and limiting the proinflammatory response through negative-feedback inhibition of cytokine receptors. We present evidence that Ebola virus VLPs stimulate induction of SOCS3 as well as proinflammatory cytokines, and that expression of human SOCS3 enhances budding of Ebola VLPs and infectious virus via a mechanism linked to the host ubiquitinylation machinery. C1 [Okumura, Atsushi; Rasmussen, Angela L.; Katze, Michael G.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [Katze, Michael G.] Washington Natl Primate Res Ctr, Seattle, WA USA. [Halfmann, Peter; Kawaoka, Yoshihiro] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Influenza Res Inst, Madison, WI 53706 USA. [Okumura, Atsushi; Feldmann, Friederike; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Yoshimura, Akihiko] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo, Japan. [Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Virol, Tokyo, Japan. [Kawaoka, Yoshihiro] Japan Sci & Technol Agcy, ERATO Infect Induced Host Responses Project, Kawaguchi, Saitama, Japan. [Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Special Pathogens, Tokyo, Japan. [Harty, Ronald N.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Katze, MG (reprint author), Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. EM honey@uw.edu RI Yoshimura, Akihiko/K-5515-2013; Okumura, Atsushi/E-8012-2015; OI Okumura, Atsushi/0000-0002-7779-3059; Rasmussen, Angela/0000-0001-9462-3169 FU National Institute of Allergy and Infectious Diseases [R21 AI077014, R21 AI090284, U54 AI081680, U19 AI109761]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported in part by National Institute of Allergy and Infectious Diseases grants R21 AI077014 and R21 AI090284 to R.N.H., U54 AI081680 to Y.K., and U54 AI081680 and U19 AI109761 to M.G.K. and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 51 TC 4 Z9 5 U1 0 U2 9 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 OCT PY 2015 VL 89 IS 20 BP 10399 EP 10406 DI 10.1128/JVI.01736-15 PG 8 WC Virology SC Virology GA CU3ZG UT WOS:000363464700021 PM 26246577 ER PT J AU Crowell, J Hughson, A Caughey, B Bessen, RA AF Crowell, Jenna Hughson, Andrew Caughey, Byron Bessen, Richard A. TI Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSMISSIBLE MINK ENCEPHALOPATHY; CREUTZFELDT-JAKOB-DISEASE; CHRONIC WASTING DISEASE; GERSTMANN-STRAUSSLER SYNDROME; FATAL FAMILIAL INSOMNIA; TRANSGENIC MICE; ALZHEIMERS-DISEASE; SCRAPIE INCUBATION; RODENT CEREBELLUM; AMYLOID STRUCTURE AB Phenotypic diversity in prion diseases can be specified by prion strains in which biological traits are propagated through an epigenetic mechanism mediated by distinct PrPSc conformations. We investigated the role of host-dependent factors on phenotypic diversity of chronic wasting disease (CWD) in different host species that express the same prion protein gene (Prnp). Two CWD strains that have distinct biological, biochemical, and pathological features were identified in transgenic mice that express the Syrian golden hamster (SGH) Prnp. The CKY strain of CWD had a shorter incubation period than the WST strain of CWD, but after transmission to SGH, the incubation period of CKY CWD was similar to 150 days longer than WST CWD. Limited proteinase K digestion revealed strain-specific PrPSc polypeptide patterns that were maintained in both hosts, but the solubility and conformational stability of PrPSc differed for the CWD strains in a host-dependent manner. WST CWD produced PrPSc amyloid plaques in the brain of the SGH that were partially insoluble and stable at a high concentration of protein denaturant. However, in transgenic mice, PrPSc from WST CWD did not assemble into plaques, was highly soluble, and had low conformational stability. Similar studies using the HY and DY strains of transmissible mink encephalopathy resulted in minor differences in prion biological and PrPSc properties between transgenic mice and SGH. These findings indicate that host-specific pathways that are independent of Prnp can alter the PrPSc conformation of certain prion strains, leading to changes in the biophysical properties of PrPSc, neuropathology, and clinical prion disease. IMPORTANCE Prions are misfolded pathogenic proteins that cause neurodegeneration in humans and animals. Transmissible prion diseases exhibit a spectrum of disease phenotypes and the basis of this diversity is encoded in the structure of the pathogenic prion protein and propagated by an epigenetic mechanism. In the present study, we investigated prion diversity in two hosts species that express the same prion protein gene. While prior reports have demonstrated that prion strain properties are stable upon infection of the same host species and prion protein genotype, our findings indicate that certain prion strains can undergo dramatic changes in biological properties that are not dependent on the prion protein. Therefore, host factors independent of the prion protein can affect prion diversity. Understanding how host pathways can modify prion disease phenotypes may provide clues on how to alter prion formation and lead to treatments for prion, and other, human neurodegenerative diseases of protein misfolding. C1 [Crowell, Jenna; Bessen, Richard A.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Prion Res Ctr, Ft Collins, CO 80523 USA. [Hughson, Andrew; Caughey, Byron] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. RP Bessen, RA (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Prion Res Ctr, Ft Collins, CO 80523 USA. EM Richard.Bessen@colostate.edu FU Public Health Service grant from the National Institutes of Health [AI05543]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This study was supported by Public Health Service grant AI05543 from the National Institutes of Health. This study was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 74 TC 6 Z9 6 U1 2 U2 12 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 OCT PY 2015 VL 89 IS 20 BP 10427 EP 10441 DI 10.1128/JVI.01586-15 PG 15 WC Virology SC Virology GA CU3ZG UT WOS:000363464700024 PM 26246570 ER PT J AU Shunaeva, A Potashnikova, D Pichugin, A Mishina, A Filatov, A Nikolaitchik, O Hu, WS Mazurov, D AF Shunaeva, Anastasia Potashnikova, Daria Pichugin, Alexey Mishina, Alexandra Filatov, Alexander Nikolaitchik, Olga Hu, Wei-Shau Mazurov, Dmitriy TI Improvement of HIV-1 and Human T Cell Lymphotropic Virus Type 1 Replication-Dependent Vectors via Optimization of Reporter Gene Reconstitution and Modification with Intronic Short Hairpin RNA SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIROLOGICAL SYNAPSES; DOUBLE INFECTION; INDICATOR GENE; TRANSMISSION; SEQUENCES; SPREAD; RETROTRANSPOSITION; RETROVIRUSES; LYMPHOCYTES AB Cell-to-cell transmission is an efficient mechanism to disseminate human immunodeficiency virus type 1 (HIV-1) and human T cell lymphotropic virus type 1 (HTLV-1). However, it has been challenging to quantify the level of cell-to-cell transmission because the virus-producing cells cannot be easily distinguished from infected target cells. We have previously described replication-dependent vectors that can quantify infection events in cocultured cells. These vectors contain an antisense-oriented promoter and reporter gene interrupted by a sense-oriented intron from the human gamma-globin gene. This strategy prevents expression of the reporter gene in the transfected cells but permits its expression in target cells after infection. However, the gamma-globin intron is not efficiently removed by splicing in the aforementioned vectors, thereby reducing the level of reporter gene expression after transduction into target cells. Here, we used two approaches to improve the replication-dependent vectors. First, we improved the splicing events that remove the gamma-globin intron by optimizing the intron insertion site within the reporter gene. Second, we improved the packaging of the spliced RNA without the gamma-globin intron by targeting the intron-containing RNA via microRNA 30 (miR30)-based short hairpin RNAs. Using two optimized fluorescent reporter vectors and flow cytometry, we determined that multiply HIV-1-infected cells were generated at a higher frequency in coculture than in cell-free infection; furthermore, this increase was dependent upon viruses bearing HIV-1 Env. Compared with previously described vectors, these improved vectors can quantify the infection in lymphocytes and in primary cells with a higher sensitivity and allow the detection and quantitation of multiply infected cells, providing better tools to study retroviral cell-mediated infection. IMPORTANCE The human-pathogenic retroviruses HTLV-1 and HIV-1 can be transmitted more efficiently in vivo via direct contact of infected cells with healthy target cells than through cell-free virion-mediated infection. Despite its importance, cell-to-cell transmission has been difficult to quantify because the previously infected cells and the newly infected cells are mixed together in the same culture. In the current study, we generated vectors that are significantly improved over the previously described replication-dependent vectors. As a result, these improved vectors can efficiently detect and quantify cell-to-cell transmission or new infection events in cells in mixed culture. These luciferase-or fluorescence protein-based reporter vectors can be used to quantify and study HIV-1 or HTLV-1 cell-mediated infection in a simple one-step transfection/infection assay. C1 [Shunaeva, Anastasia; Pichugin, Alexey; Mishina, Alexandra; Filatov, Alexander; Mazurov, Dmitriy] Inst Immunol, Moscow, Russia. [Potashnikova, Daria] Moscow MV Lomonosov State Univ, Moscow, Russia. [Nikolaitchik, Olga; Hu, Wei-Shau] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. RP Mazurov, D (reprint author), Inst Immunol, Moscow, Russia. EM dvmazurov@yandex.ru OI Potashnikova, Daria/0000-0002-0098-827X FU Russian Foundation for Basic Research [NIH-RFBR 13-04-91449, RFBR 12-04-00415-a]; Russian Science Foundation [RSF 15-15-00135]; Lomonosov Moscow State University Program of Development; Intramural Research, Center for Cancer Research, National Cancer Institute; U.S.-Russia Joint Working Group on Biomedical Research Cooperation FX This work has been supported by grants from the Russian Foundation for Basic Research (NIH-RFBR 13-04-91449, RFBR 12-04-00415-a) and the Russian Science Foundation (RSF 15-15-00135), by the Lomonosov Moscow State University Program of Development, by Intramural Research, Center for Cancer Research, National Cancer Institute, and by funding from the U.S.-Russia Joint Working Group on Biomedical Research Cooperation. NR 31 TC 3 Z9 3 U1 1 U2 5 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 OCT PY 2015 VL 89 IS 20 BP 10591 EP 10601 DI 10.1128/JVI.01940-15 PG 11 WC Virology SC Virology GA CU3ZG UT WOS:000363464700037 PM 26269177 ER PT J AU Ferrando-Martinez, S Ruiz-Mateos, E Casazza, JP de Pablo-Bernal, RS Dominguez-Molina, B Munoz-Fernandez, MA Delgado, J de la Rosa, R Solana, R Koup, RA Leal, M AF Ferrando-Martinez, Sara Ruiz-Mateos, Ezequiel Casazza, Joseph P. de Pablo-Bernal, Rebeca S. Dominguez-Molina, Beatriz Angeles Munoz-Fernandez, M. Delgado, Juan de la Rosa, Rafael Solana, Rafael Koup, Richard A. Leal, Manuel TI IFN gamma-TNF alpha(-)IL2(-)MIP1 alpha(-)CD107a(+)PRF1(+) CD8 pp65-Specific T-Cell Response Is Independently Associated With Time to Death in Elderly Humans SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE CMV-specific T-cell response; CMV; Aging; Mortality; Perforin ID LONGITUDINAL OCTO-IMMUNE; CYTOMEGALOVIRUS-INFECTION; LYMPHOCYTE SUBPOPULATIONS; VIRAL-INFECTION; RHESUS MACAQUES; IMMUNOSENESCENCE; CMV; MORTALITY; PROLIFERATION; INFLAMMATION AB Persistent cytomegalovirus (CMV) infection has been suggested to be a major driving force in the immune deterioration and an underlying source of age-related diseases in the elderly. CMV antibody titers are associated with lower responses to vaccination, cardiovascular diseases, frailty, and mortality. CMV infection is also associated with shorter T-cell telomeres and replicative senescence. Although an age-related deregulation of CMV-specific T-cell responses could be an underlying cause of the relationship between CMV and immune defects, strong and polyfunctional responses are observed in elderly individuals, casting uncertainty on their direct role in age-related immune frailty. In this study, we longitudinally followed a cohort of healthy donors aged over 50 years, assessing their mortality rates and time to death during a 2-year period. Specific T-cell responses to the immunodominant antigen pp65 (IFN gamma, TNF alpha, IL2, MIP1 alpha, CD107a, and perforin production) were analyzed at the beginning of the 2-year observation period. A cytotoxic CD8 pp65-specific T-cell response, without cytokine or chemokine coexpression, was independently associated with all-cause mortality in these elderly individuals. This pp65-specific CD8 T-cell response could be a useful tool to identify individuals with depressed immune function and a higher risk of death. C1 [Ferrando-Martinez, Sara; Angeles Munoz-Fernandez, M.] Hosp Gen Univ Gregorio Maranon, Lab InmunoBiol Mol, Madrid, Spain. [Ferrando-Martinez, Sara; Angeles Munoz-Fernandez, M.] Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain. [Ferrando-Martinez, Sara; Angeles Munoz-Fernandez, M.] Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Madrid, Spain. [Ferrando-Martinez, Sara; Ruiz-Mateos, Ezequiel; de Pablo-Bernal, Rebeca S.; Dominguez-Molina, Beatriz; Leal, Manuel] Virgen Rocio Univ Hosp, Lab Immunovirol, Clin Unit Infect Dis Microbiol & Prevent Med, Inst Biomed Seville, Seville, Spain. [Casazza, Joseph P.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Delgado, Juan; de la Rosa, Rafael] Hosp San Juan Dios Aljarafe, Internal Med Serv, Bormujos, Spain. [Solana, Rafael] Univ Cordoba, Dept Cellular Immunol, IMIBIC Reina Sofia Univ Hosp, E-14071 Cordoba, Spain. RP Ruiz-Mateos, E (reprint author), Inst Biomed Seville HUVR IbiS, Lab Immunovirol, Avda Manuel Siurot S-N 41013, Seville, Spain. EM ezequiel.ruizmateos@gmail.com RI IBIS, INMUNOVIROLOGI/O-9246-2015 FU Fondo de Investigaciones Sanitarias [CD10/00382, CP08/00172]; Proyecto de Excelencia [CTS-6313]; RETIC program; Redes Tematicas de Investigacion en SIDA [ISCIII RETIC RD12/0017/0029, RD12/0017/0037]; Consejeria de Salud [PI-0278]; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX S.F.-M. and E.R.-M. received grants from the Fondo de Investigaciones Sanitarias (CD10/00382 and CP08/00172, respectively). R.S. de P.-B. is supported by a Proyecto de Excelencia (CTS-6313) and B.D.-M. by the RETIC program. This study has been supported by Redes Tematicas de Investigacion en SIDA (ISCIII RETIC RD12/0017/0029 and RD12/0017/0037), Proyecto de Excelencia (CTS-6313), and Consejeria de Salud (PI-0278). This work was funded in part by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 37 TC 3 Z9 3 U1 0 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 OCT PY 2015 VL 70 IS 10 BP 1210 EP 1218 DI 10.1093/gerona/glu171 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CU4FD UT WOS:000363481600005 PM 25238774 ER PT J AU Miller, RR Eastlack, M Hicks, GE Alley, DE Shardell, MD Orwig, DL Goodpaster, BH Chomentowski, PJ Hawkes, WG Hochberg, MC Ferrucci, L Magaziner, J AF Miller, Ram R. Eastlack, Marty Hicks, Gregory E. Alley, Dawn E. Shardell, Michelle D. Orwig, Denise L. Goodpaster, Bret H. Chomentowski, Peter J. Hawkes, William G. Hochberg, Marc C. Ferrucci, Luigi Magaziner, Jay TI Asymmetry in CT Scan Measures of Thigh Muscle 2 Months After Hip Fracture: The Baltimore Hip Studies SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Hip fracture; Muscle composition; Computed tomography; Aged ID LOWER-EXTREMITY FUNCTION; NECROSIS-FACTOR-ALPHA; SKELETAL-MUSCLE; OLDER-ADULTS; FUNCTIONAL RECOVERY; BODY-COMPOSITION; STRENGTH; MASS; HEALTH; ATTENUATION AB Hip fracture is an important problem for older adults with significant functional consequences. After hip fracture, reduced muscle loading can result in muscle atrophy. We compared thigh muscle characteristics in the fractured leg to those in the nonfractured leg in participants from the Baltimore Hip Studies 7th cohort using computed tomography scan imaging. At 2 months postfracture, a single 10mm axial computed tomography scan was obtained at the midthigh level in 43 participants (23 men, 20 women) with a mean age of 79.9 years (range: 65-96 years), and thigh muscle cross-sectional area, cross-sectional area of intermuscular adipose tissue, and mean radiologic attenuation were measured. Total thigh muscle cross-sectional area was less on the side of the fracture by 9.46cm(2) (95% CI: 5.97cm(2), 12.95cm(2)) while the cross-sectional area of intermuscular adipose tissue was greater by 2.97cm(2) (95% CI: 1.94cm(2), 4.01cm(2)) on the fractured side. Mean muscle attenuation was lower on the side of the fracture by 3.66 Hounsfield Units (95% CI: 2.98 Hounsfield Units, 4.34 Hounsfield Units). The observed asymmetry is consistent with the effect of disuse and inflammation in the affected limb along with training effects in the unaffected limb due to the favoring of this leg with ambulation during the postfracture period. C1 [Miller, Ram R.] GlaxoSmithKline, Res Triangle Pk, NC USA. [Miller, Ram R.; Alley, Dawn E.; Orwig, Denise L.; Magaziner, Jay] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Div Gerontol, Bethesda, MD USA. [Eastlack, Marty] Arcadia Univ, Dept Phys Therapy, Glenside, PA USA. [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Shardell, Michelle D.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Div Biostat & Bioinformat, Baltimore, MD 21201 USA. [Goodpaster, Bret H.] Florida Hosp, Sanford Burnham Med Res Inst, Translat Res Inst Metab & Diabet, Orlando, FL USA. [Chomentowski, Peter J.] No Illinois Univ, Dept Kinesiol & Phys Educ, De Kalb, IL 60115 USA. [Hochberg, Marc C.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Miller, RR (reprint author), GlaxoSmithKline, Muscle Metab DPU, 5 Moore Dr N2-3213, Res Triangle Pk, NC 27709 USA. EM ram.6.miller@gsk.com FU National Institute on Aging [K23AG027746, R37 AG09901, R01 AG029315, P30 AG028747] FX This research was supported by grants from the National Institute on Aging (K23AG027746, R37 AG09901, R01 AG029315, and P30 AG028747). NR 31 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2015 VL 70 IS 10 BP 1276 EP 1280 DI 10.1093/gerona/glv053 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CU4FD UT WOS:000363481600014 PM 25969469 ER PT J AU Patridge, EV Darnell, A Kucera, K Phillips, GM Bokesch, HR Gustafson, KR Spakowicz, DJ Zhou, L Hungerford, WM Plummer, M Hoyer, D Narvaez-Trujillo, A Phillips, AJ Strobel, SA AF Patridge, Eric V. Darnell, Alicia Kucera, Kaury Phillips, Gillian M. Bokesch, Heidi R. Gustafson, Kirk R. Spakowicz, Daniel J. Zhou, Linda Hungerford, William M. Plummer, Mark Hoyer, Denton Narvaez-Trujillo, Alexandra Phillips, Andrew J. Strobel, Scott A. TI Pyrrolocin A, a 3-Decalinoyltetramic Acid with Selective Biological Activity, Isolated from Amazonian Cultures of the Novel Endophyte Diaporthales sp E6927E SO NATURAL PRODUCT COMMUNICATIONS LA English DT Article DE Diaporthales; Fungal Endophyte; Candida albicans; Tetramic Acid; Antifungal Activity ID RIBOSOMAL-RNA SEQUENCES; NATURAL-PRODUCTS; DRUG DISCOVERY; PHYLOGENETIC ANALYSIS; FUNGAL METABOLITES; DNA-SEQUENCES; TRICHOSETIN; PALLIDOROSEUM; ANTIBIOTICS; INHIBITORS AB Natural products remain an important source of new therapeutics for emerging drug-resistant pathogens like Candida albicans, which particularly affects immunocompromised patients. A bioactive 3-decalinoyltetramic acid, pyrrolocin A, was isolated from extracts of a novel Amazonian fungal endophyte, E6927E, of the Diaporthales family. The structure of the natural product was solved using NMR and CD spectroscopy and it is structurally related to the fungal setins, equisetin and phomasetin, which are well-characterized tetramic acid antibiotics specific for Gram-positive organisms. We show that the compound inhibits growth of Staphylococcus aureus and Enterococcus faecalis. It shows selective and potent bioactivity against fungal strains, with an MIC of 4 mu g/mL for C. albicans, 100 mu g/mL for Aspergillus sp. and greater than 100 mu g/mL for Saccharomyces cerevisiae. Further, the compound is less toxic to mammalian cells (IC50 = 150 mu g/mL), with an inhibitory concentration greater than forty times that for C. albicans. Pyrrolocin A retained potent activity against eight out of seventeen strains of clinical Candida sp. isolates tested. C1 [Patridge, Eric V.; Hungerford, William M.; Plummer, Mark; Hoyer, Denton] Yale Univ, Yale Ctr Mol Discovery, West Haven, CT 06516 USA. [Darnell, Alicia; Kucera, Kaury; Phillips, Gillian M.; Spakowicz, Daniel J.; Zhou, Linda; Strobel, Scott A.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Phillips, Gillian M.; Phillips, Andrew J.] Yale Univ, Dept Chem, New Haven, CT 06520 USA. [Bokesch, Heidi R.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD 21702 USA. [Bokesch, Heidi R.; Gustafson, Kirk R.] Natl Canc Inst, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. [Narvaez-Trujillo, Alexandra] Pontificia Univ Catolica Ecuador, Lab Biotecnol Vegetal, Quito, Ecuador. RP Strobel, SA (reprint author), Yale Univ, Dept Mol Biophys & Biochem, POB 6666, New Haven, CT 06520 USA. EM scott.strobel@yale.edu FU HHMI Professor's grant; NSF [OISE 853408]; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Endophytes were isolated from plants collected with permission of the Ministerio del Ambiente of Ecuador. We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCI at Frederick for assistance with CD-spectroscopy experiments. We would also like to thank Dr Kelly Caudle at the University of Cincinnati Children's Hospital for providing Candida sp. clinical isolates, and the Endophyte Collection Quito Catolica (CEQCA) for cataloguing the microorganisms that produced the extracts tested here. This project was supported by an HHMI Professor's grant and NSF grant OISE 853408 to S.A.S. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health, under contract 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 45 TC 0 Z9 0 U1 5 U2 8 PU NATURAL PRODUCTS INC PI WESTERVILLE PA 7963 ANDERSON PARK LN, WESTERVILLE, OH 43081 USA SN 1934-578X EI 1555-9475 J9 NAT PROD COMMUN JI Nat. Prod. Commun. PD OCT PY 2015 VL 10 IS 10 BP 1649 EP 1654 PG 6 WC Chemistry, Medicinal; Food Science & Technology SC Pharmacology & Pharmacy; Food Science & Technology GA CU7JZ UT WOS:000363713800006 PM 26669095 ER PT J AU Broek, RV Mohan, S Eytan, DF Chen, Z Van Waes, C AF Broek, R. Vander Mohan, S. Eytan, D. F. Chen, Z. Van Waes, C. TI The PI3K/Akt/mTOR axis in head and neck cancer: functions, aberrations, cross-talk, and therapies SO ORAL DISEASES LA English DT Review DE head and neck cancer; PI3K; Akt; mTOR; NF-kappa B; p53 ID SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; GROWTH-FACTOR-RECEPTOR; PROINFLAMMATORY CYTOKINE EXPRESSION; SERINE-THREONINE KINASE; PI3K PATHWAY; PIK3CA GENE; PHOSPHATIDYLINOSITOL 3-KINASE; PROANGIOGENIC CYTOKINES; AKT/MAMMALIAN TARGET AB Head and neck squamous cell carcinoma (HNSCC) is one of the most morbid, mortal, and genetically diverse malignancies. Although HNSCC is heterogeneous in nature, alterations in major components of the PI3K/Akt/mTOR pathway are consistently observed throughout the majority of HNSCC cases. These alterations include genetic aberrations, such as mutations or DNA copy number variations, and dysregulation of mRNA or protein expression. In normal physiology, the PI3K/Akt/mTOR axis regulates cell survival, growth, and metabolism. However, alterations in this pathway lead to the malignant phenotype which characterizes HNSCC, among many other cancers. For this reason, both pharmaceutical companies and academic institutions are actively developing and investigating inhibitors of PI3K, Akt, and mTOR in preclinical and clinical studies of HNSCC. Many of these inhibitors have shown promise, while the effects of others are tempered by the mechanisms through which HNSCC can evade therapy. As such, current research aimed at elucidating the interactions between PI3K/Akt/mTOR and other important signaling pathways which may drive resistance in HNSCC, such as p53, NF-kappa B, and MAPK, has become a prominent focus toward better understanding how to most effectively treat HNSCC. C1 [Broek, R. Vander; Mohan, S.; Eytan, D. F.; Chen, Z.; Van Waes, C.] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Broek, R. Vander; Mohan, S.; Eytan, D. F.] NIH, Med Res Scholars Program, Bethesda, MD 20892 USA. [Broek, R. Vander] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. RP Van Waes, C (reprint author), NIDCD, NIH, Bldg 10 CRC Rm 4-2732 Rm 5D55,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov OI Mohan, Suresh/0000-0002-4797-9565; Eytan, Danielle/0000-0003-1032-2276 FU National Institutes of Health (NIH) Medical Research Scholars Program; Pfizer Inc; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute; NIDCD intramural project [ZIA-DC-000016]; NIH FX R.V., S.M., and D.E. were supported through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the foundation for the NIH from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the foundation website at http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. Z.C. and C.V. were supported by NIDCD intramural project ZIA-DC-000016. NR 129 TC 5 Z9 5 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD OCT PY 2015 VL 21 IS 7 BP 815 EP 825 DI 10.1111/odi.12206 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CU7SO UT WOS:000363742000001 ER PT J AU Ohana, E AF Ohana, E. TI Transepithelial ion transport across duct cells of the salivary gland SO ORAL DISEASES LA English DT Review DE salivary gland; bicarbonate; transporters; epithelia; duct; secretion ID TRANSMEMBRANE CONDUCTANCE REGULATOR; X-RAY-STRUCTURE; CYSTIC-FIBROSIS; FLUID SECRETION; HCO3-SECRETION; ACINAR-CELLS; INTERMEDIATE CONDUCTANCE; EXPRESSION PATTERNS; SUBMANDIBULAR-GLAND; PHYSIOLOGICAL ROLES AB y Fluid and electrolyte secretions are vital for all epithelia and when aberrant lead to numerous pathophysiological conditions. Electrolyte transport across epithelia generates the osmotic force for fluid movement and is mediated by several membrane proteins expressed on both apical and basolateral poles of epithelial cells. Sodium and chloride are crucial for regulation of fluid secretion, thus regulating salivary volume. Bicarbonate (HCO3), on the other hand, is the major pH buffer; hence, aberrant HCO3- secretion is a major factor in diseases such as cystic fibrosis (CF) causing altered mucin hydration and solubilization. Here, the structure-function mechanisms of the major membrane transporters involved in salivary duct electrolyte transport are reviewed focusing on transepithelial movement of Cl- and HCO3-. C1 Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ohana, E (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM ehud.ohana@nih.gov FU National Institute of Dental and Craniofacial Research (NIDCR) FX The author's research is supported by the National Institute of Dental and Craniofacial Research (NIDCR) intramural program. NR 55 TC 2 Z9 2 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD OCT PY 2015 VL 21 IS 7 BP 826 EP 835 DI 10.1111/odi.12201 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CU7SO UT WOS:000363742000002 PM 24164806 ER PT J AU Rotman, Y AF Rotman, Yaron TI Similarity between studies of dihydromyricetin and reservatrol for NAFLD SO PHARMACOLOGICAL RESEARCH LA English DT Letter C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Rotman, Y (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM rotmany@niddk.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD OCT PY 2015 VL 100 BP 335 EP 335 DI 10.1016/j.phrs.2015.07.034 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU8VQ UT WOS:000363822600034 PM 26318761 ER PT J AU Diaz-Moreno, I Cruz-Gallardo, I Garcia-Maurino, SM Del Conte, R Karlsson, BG Ramos, A Martinez-Chantar, ML Blanco, FJ Gorospe, M Wilce, JA AF Diaz-Moreno, Irene Cruz-Gallardo, Isabel Garcia-Maurino, Sofia M. Del Conte, Rebecca Karlsson, B. Goran Ramos, Andres Martinez-Chantar, Maria L. Blanco, Francisco J. Gorospe, Myriam Wilce, Jacqueline A. TI RNA Fate is Controlled by Highly-Regulated RNA Binding Proteins SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 29th Annual Symposium of the Protein-Society CY JUL 22-25, 2015 CL Barcelona, SPAIN SP Prot Soc C1 [Diaz-Moreno, Irene; Cruz-Gallardo, Isabel; Garcia-Maurino, Sofia M.] Univ Seville, CSIC, IBVF CicCartuja, Seville, Spain. [Del Conte, Rebecca] Univ Florence, Dept Chem, CERM, I-50121 Florence, Italy. [Karlsson, B. Goran] Univ Gothenburg, Swedish NMR Ctr, Gothenburg, Sweden. [Ramos, Andres] MRC Natl Inst Med Res, Mol Struct Div, London, England. [Martinez-Chantar, Maria L.; Blanco, Francisco J.] CIC BioGUNE, Elexalde Derio, Biscay, Spain. [Gorospe, Myriam] NIA, Lab Genet, Intramural Res Program, Bethesda, MD USA. [Wilce, Jacqueline A.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. RI Diaz-Moreno, Irene/E-7181-2010; Karlsson, Goran/E-8686-2011 OI Diaz-Moreno, Irene/0000-0002-5318-7644; NR 8 TC 0 Z9 0 U1 0 U2 2 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 OCT PY 2015 VL 24 SU 1 SI SI MA PB-006 BP 5 EP 6 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU6QS UT WOS:000363658100011 ER PT J AU Gahl, R He, Y Yu, SQ Tjandra, N AF Gahl, Robert He, Yi Yu, Shiqin Tjandra, Nico TI Live-cell Measurements of the Conformational Rearrangements in Bax at the Initiation of Apoptosis SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 29th Annual Symposium of the Protein-Society CY JUL 22-25, 2015 CL Barcelona, SPAIN SP Prot Soc C1 [Gahl, Robert; He, Yi; Yu, Shiqin; Tjandra, Nico] NHLBI, Biochem & Biophys Ctr, 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 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2015 VL 24 SU 1 SI SI MA PG-001 BP 140 EP 140 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU6QS UT WOS:000363658100237 ER PT J AU Li, ZZ Xu, X Weiss, ID Jacobson, O Murphy, PM AF Li, Zhanzhuo Xu, Xin Weiss, Ido D. Jacobson, Orit Murphy, Philip M. TI Pre-treatment of allogeneic bone marrow recipients with the CXCR4 antagonist AMD3100 transiently enhances hematopoietic chimerism without promoting donor-specific skin allograft tolerance SO TRANSPLANT IMMUNOLOGY LA English DT Article DE AMD3100; CXCR4; Bone marrow mobilization; Mixed chimerism; Tolerance ID TRANSPLANTATION TOLERANCE; PREPARATIVE REGIMEN; MIXED CHIMERISM; MOBILIZATION; DEPLETION; BLOCKADE; MICE AB Hematopoietic chimerism established by allogeneic bone marrow transplantation is known to promote donor-specific organ allograft tolerance; however, clinical application is limited by the need for toxic host conditioning and "megadoses" of donor bone marrow cells. A potential solution to this problem has been suggested by the observation that recipient bone marrow mobilization by the CXCR4 antagonist AMD3100 promotes chimerism in congenic bone marrow transplantation experiments in mice. Here we report that a single subcutaneous dose of 10 mg/kg AIVID3100 in recipient C57BL/6 mice was able to enhance hematopoietic chimerism when complete MHC-mismatched BALB/c donor bone marrow cells were transplanted 1 h after drug dosing. However, levels of chimerism measured 30 days post-transplantation were not sustained when mice were reexamined on day 90 post-transplantation. Moreover, transient chimerism induced by this protocol did not support robust donor-specific skin allograft tolerance. Using the same transient immunosuppression protocol, we confirmed that "megadoses" of donor bone marrow cells could induce durable chimerism associated with donor-specific skin allograft tolerance without AMD3100 pre-treatment. We conclude that in this protocol AMD3100 pretreatment may empty bone marrow niches that become reoccupied by allogeneic donor hematopoietic progenitor cells but not by true long-lived donor hematopoietic stem cells, resulting in short-lived chimerism and failure to support durable donor-specific allograft tolerance. Published by Elsevier B.V. C1 [Li, Zhanzhuo; Xu, Xin; Weiss, Ido D.; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Jacobson, Orit] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Murphy, PM (reprint author), NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov FU Intramural NIH HHS [ZIA AI000615-19] NR 15 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 EI 2210-3384 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD OCT PY 2015 VL 33 IS 2 BP 125 EP 129 DI 10.1016/j.trim.2015.07.003 PG 5 WC Immunology; Transplantation SC Immunology; Transplantation GA CU8TY UT WOS:000363818200011 PM 26209354 ER PT J AU Yin, ZJ Chowdhury, S Mckay, C Baniel, C Wright, WS Bentley, P Kaczanowska, K Gildersleeve, JC Finn, MG BenMohamed, L Huang, XF AF Yin, Zhaojun Chowdhury, Sudipa Mckay, Craig Baniel, Claire Wright, W. Shea Bentley, Philip Kaczanowska, Katarzyna Gildersleeve, Jeffrey C. Finn, M. G. BenMohamed, Lbachir Huang, Xuefei TI Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine SO ACS CHEMICAL BIOLOGY LA English DT Article ID TUMOR-CELLS; TN ANTIGEN; MONOCLONAL-ANTIBODIES; ANTITUMOR VACCINES; SYNTHETIC VACCINES; BREAST-CANCER; MOSAIC-VIRUS; GLYCOPROTEIN; MUCIN; CARRIER AB Development of an effective vaccine targeting tumor associated carbohydrate antigens (TACAs) is an appealing approach toward tumor immunotherapy. While much emphasis has been typically placed on generating high antibody titers against the immunizing antigen, the impact of immunogen design on the diversity of TACA-specific antibodies elicited has been overlooked. Herein, we report that the immunogen structure can significantly impact the breadth and the magnitude of humoral responses. Vaccine constructs that induced diverse TACA-binding antibodies provided much stronger recognition of a variety of Tn positive tumor cells. Optimization of the breadth of the antibody response led to a vaccine construct that demonstrated long lasting efficacy in a mouse tumor model. After challenged with the highly aggressive TA3Ha cells, mice immunized with the new construct exhibited a statistically significant improvement in survival relative to controls (0% vs 50% survival; p < 0.0001). Furthermore, the surviving mice developed long-term immunity against TA3Ha. Thus, both the magnitude and the breadth of antibody reactivity should be considered when designing TACA-based antitumor vaccines. C1 [Yin, Zhaojun; Baniel, Claire; Bentley, Philip; Huang, Xuefei] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Chowdhury, Sudipa; Wright, W. Shea; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Mckay, Craig; Kaczanowska, Katarzyna; Finn, M. G.] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA. [BenMohamed, Lbachir] Univ Calif Irvine, Cellular & Mol Immunol Lab, Gavin Herbert Eye Inst, Sch Med, Irvine, CA 92697 USA. RP Huang, XF (reprint author), Michigan State Univ, Dept Chem, 578 S Shaw Lane,Room 426, E Lansing, MI 48824 USA. EM xuefei@chemistry.msu.edu OI Huang, Xuefei/0000-0002-6468-5526 FU National Cancer Institute [R01CA149451-01A1]; National Institutes of Health, NCI; Consortium for Functional Glycomics [GM62116] FX We are grateful to the National Cancer Institute (Grant R01CA149451-01A1) for financial support of our work. This work was also supported in part by the intramural research program of the National Institutes of Health, NCI. We thank the Consortium for Functional Glycomics (Grant GM62116; The Scripps Research Institute), T. Tolbert (University of Kansas), L.-X. Wang (University of Maryland), and J. Barchi (National Cancer Institute) for contributing glycans for the micro array. NR 54 TC 7 Z9 7 U1 9 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD OCT PY 2015 VL 10 IS 10 BP 2364 EP 2372 DI 10.1021/acschembio.5b00406 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CU0QZ UT WOS:000363225100021 PM 26262839 ER PT J AU Gould, RW Dencker, D Grannan, M Bubser, M Zhan, X Wess, J Xiang, Z Locuson, C Lindsley, CW Conn, PJ Jones, CK AF Gould, R. W. Dencker, D. Grannan, M. Bubser, M. Zhan, X. Wess, J. Xiang, Z. Locuson, C. Lindsley, C. W. Conn, P. J. Jones, C. K. TI Role for the M-1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Positive allosteric modulators; M-1 muscarinic acetylcholine receptors; touchscreen cognition; M-1 knockout mice; top-down processing; BQCA ID ALLOSTERIC MODULATORS; SELECTIVE ACTIVATION; PREFRONTAL CORTEX; OPERANT PLATFORM; WORKING-MEMORY; BOTTOM-UP; SCHIZOPHRENIA; DEFICITS; ATTENTION; RAT AB The M-1 muscarinic acetylcholine receptor (mAChR) subtype has been implicated in the underlying mechanisms of learning and memory and represents an important potential pharmacotherapeutic target for the cognitive impairments observed in neuropsychiatric disorders such as schizophrenia. Patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes that can be modeled in preclinical studies using touchscreen-based cognition tasks. The present studies used a touchscreen visual pairwise discrimination task in which mice discriminated between a less salient and a more salient stimulus to assess the influence of the M-1 mAChR on top-down processing. M-1 mAChR knockout (M-1 KO) mice showed a slower rate of learning, evidenced by slower increases in accuracy over 12 consecutive days, and required more days to acquire (achieve 80% accuracy) this discrimination task compared to wild-type mice. In addition, the M-1 positive allosteric modulator BQCA enhanced the rate of learning this discrimination in wild-type, but not in M-1 KO, mice when BQCA was administered daily prior to testing over 12 consecutive days. Importantly, in discriminations between stimuli of equal salience, M-1 KO mice did not show impaired acquisition and BQCA did not affect the rate of learning or acquisition in wild-type mice. These studies are the first to demonstrate performance deficits in M-1 KO mice using touchscreen cognitive assessments and enhanced rate of learning and acquisition in wild-type mice through M-1 mAChR potentiation when the touchscreen discrimination task involves top-down processing. Taken together, these findings provide further support for M, potentiation as a potential treatment for the cognitive symptoms associated with schizophrenia. C1 [Gould, R. W.; Grannan, M.; Bubser, M.; Zhan, X.; Xiang, Z.; Locuson, C.; Lindsley, C. W.; Conn, P. J.; Jones, C. K.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Gould, R. W.; Grannan, M.; Bubser, M.; Zhan, X.; Xiang, Z.; Lindsley, C. W.; Conn, P. J.; Jones, C. K.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Lindsley, C. W.] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA. [Dencker, D.] Psychiat Ctr Copenhagen, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. [Wess, J.] NIDDK, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Jones, CK (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. EM carrie.jones@vanderbilt.edu FU PhRMA Foundation postdoctoral fellowship grant in Pharmacology and Toxicology [MH086601, MH087965, MH093366, MH082867, NS065867]; Psychiatric Center Copenhagen Research Foundation; Carlsberg Foundation FX Grant nos. MH086601 (C.K.J.), MH087965 (P.J.C.), MH093366 (PJ.C.), MH082867 (C.W.L.), and NS065867 (Z.X.), a PhRMA Foundation postdoctoral fellowship grant in Pharmacology and Toxicology (RW.G.), the Psychiatric Center Copenhagen Research Foundation (D.D.), and the Carlsberg Foundation (D.D.). NR 66 TC 5 Z9 5 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD OCT PY 2015 VL 6 IS 10 BP 1683 EP 1695 DI 10.1021/aachemneuro.5b00123 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CU3OS UT WOS:000363435300003 PM 26176846 ER PT J AU Kolanos, R Saldoth, F Jain, AD Partilla, JS Baumann, MH Glennon, RA AF Kolanos, R. Saldoth, F. Jain, A. D. Partilla, J. S. Baumann, M. H. Glennon, R. A. TI Structural Modification of the Designer Stimulant alpha-Pyrrolidinovalerophenone (alpha-PVP) Influences Potency at Dopamine Transporters SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Synthetic cathinones; alpha-PVP; flakka; alpha-PPP; alpha-PBP; dopamine transporter; serotonin transporter; DAT; SERT ID PSYCHOACTIVE BATH SALTS; CENTRAL-NERVOUS-SYSTEM; METHYLENEDIOXYPYROVALERONE MDPV; 3,4-METHYLENEDIOXYPYROVALERONE MDPV; SYNTHETIC CATHINONES; MEPHEDRONE; ANALOGS; CONSTITUENT; INHIBITORS; RATS AB alpha-Pyrrolidinovalerophenone (alpha-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as "flakka" and "gravel". The potent pharmacological effects of alpha-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of alpha-PVP influences activity at DAT. Eleven analogs of alpha-PVP were synthesized and examined for their ability to inhibit uptake of [H-3]clopamine and [H-3]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [H-3]serotonin uptake when tested at 10 mu M at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the alpha-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure activity investigation on the ability of alpha-PVP analogs to act as inhibitors of DAT. C1 [Kolanos, R.; Saldoth, F.; Jain, A. D.; Glennon, R. A.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. [Partilla, J. S.; Baumann, M. H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Glennon, RA (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, 800 East Leigh St,POB 980540, Richmond, VA 23298 USA. EM glennon@vcu.edu OI Jain, Atul D/0000-0002-3281-9729 FU Public Health Service Grant [DA033930]; Intramural Program of the National Institute on Drug Abuse FX This work was supported in part by Public Health Service Grant DA033930 and by the Intramural Program of the National Institute on Drug Abuse. NR 33 TC 5 Z9 5 U1 2 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD OCT PY 2015 VL 6 IS 10 BP 1726 EP 1731 DI 10.1021/acschemneuro.5b00160 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CU3OS UT WOS:000363435300007 PM 26217965 ER PT J AU Jacobson, O Yan, XF Ma, Y Niu, G Kiesewetter, DO Chen, XY AF Jacobson, Orit Yan, Xuefeng Ma, Ying Niu, Gang Kiesewetter, Dale O. Chen, Xiaoyuan TI Novel Method for Radiolabeling and Dimerizing Thiolated Peptides Using F-18-Hexafluorobenzene SO BIOCONJUGATE CHEMISTRY LA English DT Article ID CLICK CHEMISTRY; PET; POLYFLUOROBENZENES; RADIOFLUORINATION; EXPRESSION AB Hexafluorobenzene (HFB) reacts with free thiols to produce a unique and selective perfluoroaromatic linkage between two sulfurs. We modified this chemical reaction to produce dimeric F-18-RGD-tetrafluorbenzene (TFB)-RGD, an integrin alpha(v)beta(3) receptor ligand. F-18-HFB was prepared by a fluorine exchange reaction using (KF)-F-18/K-2.2.2 at room temperature. The automated radiofluorination was optimized to minimize the amount of HFB precursor and, thus, maximize the specific activity. F-18-HFB was isolated by distillation and subsequently reacted with thiolated c(RGDfk) peptide under basic and reducing conditions. The resulting F-18-RGD-TFB-RGD demonstrated integrin receptor specific binding, cellular uptake, and in vivo tumor accumulation.F-18-HFB can be efficiently incorporated into thiol-containing peptides at room temperature to provide novel imaging agents. C1 [Jacobson, Orit; Yan, Xuefeng; Ma, Ying; Niu, Gang; Kiesewetter, Dale O.; 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 EB000073-07] NR 24 TC 3 Z9 3 U1 3 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 OCT PY 2015 VL 26 IS 10 BP 2016 EP 2020 DI 10.1021/acs.bioconjchem.5b00278 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA CU3PU UT WOS:000363438100004 PM 26086295 ER PT J AU Nash, SH Till, C Song, XL Lucia, MS Parnes, HL Thompson, IM Lippman, SM Platz, EA Schenk, J AF Nash, Sarah H. Till, Cathee Song, Xiaoling Lucia, M. Scott Parnes, Howard L. Thompson, Ian M., Jr. Lippman, Scott M. Platz, Elizabeth A. Schenk, Jeannette TI Serum Retinol and Carotenoid Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NUTRITION EXAMINATION SURVEY; QUALITY-ASSURANCE PROGRAM; VITAMIN-A; BETA-CAROTENE; PLASMA CAROTENOIDS; SCREENING TRIAL; NATIONAL-HEALTH; SUBSEQUENT RISK; EVANS COUNTY; FOLLOW-UP AB Background: Findings from epidemiologic studies examining associations of serum retinol and carotenoids with prostate cancer risk have been inconsistent. This case-control study nested in the Prostate Cancer Prevention Trial evaluated associations of serum retinol and carotenoids with total, low-, and high-grade prostate cancer risk in a highly screened study population. Methods: We used logistic regression adjusting for age, family history of prostate cancer, race, body mass index, and serum cholesterol to estimate ORs and 95% confidence intervals (CI) of prostate cancer by quartiles of serum retinol and carotenoids, separately in the placebo (975 cases/1,009 frequency-matched controls) and finasteride (708 cases/743 frequency-matched controls) arms of the trial. Results: Serum retinol concentrations were associated with increased risk of total prostate cancer [OR (95% CI) comparing the highest quartile of serum retinol with the lowest: 1.30 (1.00-1.68)] and high-grade prostate cancer [OR (95% CI), 1.74 (1.14-2.68)] in the placebo arm of the trial only. Also in the placebo arm, there was a moderate positive association of a-carotene with risk of total prostate cancer [OR (95% CI), 1.32 (1.01-1.73)]. None of the other carotenoids was associated with prostate cancer risk in the placebo arm. No associations were observed for retinol and carotenoids in the finasteride arm. Conclusion: In the placebo arm of this prospective study, high serum retinol and a-carotene concentrations were associated with increased risk of total and high-grade prostate cancers. Impact: Men with higher levels of serum retinol and a-carotene may be at increased risk for prostate cancer. (C) 2015 AACR. C1 [Nash, Sarah H.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Till, Cathee] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98109 USA. [Song, Xiaoling; Schenk, Jeannette] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Lucia, M. Scott] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. [Parnes, Howard L.] NCI, Prostate & Urol Canc Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, Sch Med, San Antonio, TX 78229 USA. [Lippman, Scott M.] Univ Calif San Diego, Off Director, Moores Canc Ctr, San Diego, CA 92103 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Platz, Elizabeth A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Schenk, J (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N, Seattle, WA 98109 USA. EM jschenk@fredhutch.org FU Public Health Service from the NCI [U10 CA37429, UM1 CA182883]; NCI [NIH P01 CA108964]; NCI's Cancer Prevention Fellowship Program FX The PCPT is funded by Public Health Service grants U10 CA37429 and UM1 CA182883 from the NCI. This study was additionally supported by the NCI, NIH P01 CA108964 (to I.M. Thompson Jr and E.A. Platz). S.H. Nash is supported by the NCI's Cancer Prevention Fellowship Program. NR 37 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2015 VL 24 IS 10 BP 1507 EP 1515 DI 10.1158/1055-9965.EPI-15-0394 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CU3CR UT WOS:000363401800008 PM 26269564 ER PT J AU Shiels, MS Kreimer, AR Coghill, AE Darragh, TM Devesa, SS AF Shiels, Meredith S. Kreimer, Aimee R. Coghill, Anna E. Darragh, Teresa M. Devesa, Susan S. TI Anal Cancer Incidence in the United States, 1977-2011: Distinct Patterns by Histology and Behavior SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-PAPILLOMAVIRUS; INTRAEPITHELIAL NEOPLASIA; HPV INFECTION; CARCINOMA; TRENDS; WOMEN; PREVALENCE; VACCINE; RATES; RISK AB Background: Although anal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are generally combined in cancer surveillance, their etiologies likely differ. Here, we describe demographic characteristics and trends in incidence rates (IR) of anal cancer by histology (SCC, ADC) and behavior (invasive, in situ) in the United States. Methods: With data from the Surveillance, Epidemiology, and End Results (SEER) Program, weestimated age-adjusted anal cancer IRs across behavior/histology by demographic and tumor characteristics for 2000-2011. Trends in IRs and annual percent changes during 1977-2011 were also estimated and compared with rectal cancer. Results: Women had higher rates of SCC [rate ratio (RR), 1.45; 95% confidence interval (CI), 1.40-1.50] and lower rates of ADC (RR, 0.68; 95% CI, 0.62-0.74) and squamous carcinoma in situ (CIS; RR, 0.36; 95% CI, 0.34-0.38) than men. Blacks had lower rates of SCC (RR, 0.82; 95% CI, 0.77-0.87) and CIS (RR, 0.90; 95% CI, 0.83-0.98) than non-Hispanic whites, but higher rates of ADC (RR, 1.48; 95% CI, 1.29-1.70). Anal cancer IRs were higher in men and blacks aged <40 years. During 1992-2011, SCC IRs increased 2.9%/year, ADC IRs declined nonsignificantly, and CIS IRs increased 14.2%/year. SCC and ADC IR patterns and trends were similar across anal and rectal cancers. Conclusions: Rates of anal SCC and CIS have increased strongly over time, in contrast to rates of anal ADC, similar to trends observed for rectal SCC and ADC. Impact: Anal SCC and ADC likely have different etiologies, but may have similar etiologies to rectal SCC and ADC, respectively. Strong increases in CIS IRs over time may reflect anal cancer screening patterns. (C) 2015 AACR. C1 [Shiels, Meredith S.; Kreimer, Aimee R.; Coghill, Anna E.; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Darragh, Teresa M.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-218,MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX This study was supported by the Intramural Research Program of the National Cancer Institute (to M.S. Shiels, A.R. Kreimer, A.E. Coghill, and S.S. Devesa). NR 32 TC 4 Z9 5 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2015 VL 24 IS 10 BP 1548 EP 1556 DI 10.1158/1055-9965.EPI-15-0044 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CU3CR UT WOS:000363401800013 PM 26224796 ER PT J AU Rohrmann, S Nimptsch, K Sinha, R Willett, WC Giovannucci, EL Platz, EA Wu, KN AF Rohrmann, Sabine Nimptsch, Katharina Sinha, Rashmi Willett, Walter C. Giovannucci, Edward L. Platz, Elizabeth A. Wu, Kana TI Intake of Meat Mutagens and Risk of Prostate Cancer in a Cohort of US Health Professionals SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HETEROCYCLIC AROMATIC-AMINES; FOOD FREQUENCY QUESTIONNAIRE; COOKING PRACTICES; MODEL SYSTEMS; COOKED FOODS; CARCINOGEN; PRODUCTS; LYCOPENE; CONSUMPTION; ENZYMES AB Background: Evidence relating heterocyclic aromatic amines (HCA), associated with high-temperature cooking methods, to prostate cancer risk is inconsistent. Methods: In a large U.S. cohort study, intakes of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline (DiMeIQx) and a meat-derived mutagenicity (MDM) index were assessed using a cooking method questionnaire administered in 1996. Until 2010, 2,770 prostate cancer cases were observed among 26,030 participants. Results: Intake of PhIP from red meat was statistically significantly associated with total prostate cancer risk (top vs. bottom quintile HR, 1.18; 95% confidence intervals; CI, 1.03-1.35), but not other HCAs (MeIQx, 1.12; 0.98-1.27, PhIP from white meat, 1.08; 0.95-1.22, DiMeIQx, 1.09; 0.97-1.21) or MDM (1.13; 1.00-1.28). For high-grade (Gleason sum 7 with pattern 4-3 and Gleason sum 8-10, n = 483 cases) and advanced cancers (n = 281), we only observed positive associations for PhIP from red meat (top vs. bottom quintile: high grade: HR, 1.44; 95% CI, 1.04-1.98, P-trend = 0.03; advanced: HR, 1.50; 95% CI, 0.99-2.26; P-trend = 0.12), but associations for advanced cancers did not reach statistical significance. Observed associations remained similar after adjustment for total, unprocessed, or processed red meat intake. Conclusion: Observed positive associations between PhIP intake from red meat and prostate cancer, particularly high-grade and possibly also advanced prostate cancer, need to be confirmed in other studies. Impact: Results do not provide strong evidence that HCAs increase risk of prostate cancers. (C) 2015 AACR. C1 [Rohrmann, Sabine] Univ Zurich, Div Chron Dis Epidemiol, EBPI, CH-8001 Zurich, Switzerland. [Nimptsch, Katharina] Max Delbruck Ctr Mol Med, Mol Epidemiol Grp, Berlin, Germany. [Nimptsch, Katharina; Willett, Walter C.; Giovannucci, Edward L.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Platz, Elizabeth A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Rohrmann, S (reprint author), Univ Zurich, Div Chron Dis Epidemiol, EBPI, Hirschengraben 84, CH-8001 Zurich, Switzerland. EM sabine.rohrmann@uzh.ch OI Nimptsch, Katharina/0000-0001-7877-205X FU NIH [UM1 CA167552, P01 CA055075, R01 CA133891] FX This work was supported by NIH grants UM1 CA167552 (to W.C. Willett), P01 CA055075 (to W.C. Willett), and R01 CA133891 (to E.L. Giovannucci). NR 38 TC 4 Z9 4 U1 2 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2015 VL 24 IS 10 BP 1557 EP 1563 DI 10.1158/1055-9965.EPI-15-0068-T PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CU3CR UT WOS:000363401800014 PM 26224797 ER PT J AU Kar, SP Tyrer, JP Li, QY Lawrenson, K Aben, KKH Anton-Culver, H Antonenkova, N Chenevix-Trench, G Baker, H Bandera, EV Bean, YT Beckmann, MW Berchuck, A Bisogna, M Bjorge, L Bogdanova, N Brinton, L Brooks-Wilson, A Butzow, R Campbell, I Carty, K Chang-Claude, J Chen, YA Chen, ZH Cook, LS Cramer, D Cunningham, JM Cybulski, C Dansonka-Mieszkowska, A Dennis, J Dicks, E Doherty, JA Dork, T du Bois, A Durst, M Eccles, D Easton, DF Edwards, RP Ekici, AB Fasching, PA Fridley, BL Gao, YT Gentry-Maharaj, A Giles, GG Glasspool, R Goode, EL Goodman, MT Grownwald, J Harrington, P Harter, P Hein, A Heitz, F Hildebrandt, MAT Hillemanns, P Hogdall, E Hogdall, CK Hosono, S Iversen, ES Jakubowska, A Paul, J Jensen, A Ji, BT Karlan, BY Kjaer, SK Kelemen, LE Kellar, M Kelley, J Kiemeney, LA Krakstad, C Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, AW Lele, S Leminen, A Lester, J Levine, DA Liang, D Lissowska, J Lu, K Lubinski, J Lundvall, L Massuger, L Matsuo, K McGuire, V McLaughlin, JR McNeish, IA Menon, U Modugno, F Moysich, KB Narod, SA Nedergaard, L Ness, RB Nevanlinna, H Odunsi, K Olson, SH Orlow, I Orsulic, S Weber, RP Pearce, CL Pejovic, T Pelttari, LM Permuth-Wey, J Phelan, CM Pike, MC Poole, EM Ramus, SJ Risch, HA Rosen, B Rossing, MA Rothstein, JH Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Schildkraut, JM Schwaab, I Shu, XO Shvetsov, YB Siddiqui, N Sieh, W Song, HL Southey, MC Sucheston-Campbell, LE Tangen, IL Teo, SH Terry, KL Thompson, PJ Timorek, A Tsai, YY Tworoger, SS van Altena, AM Van Nieuwenhuysen, E Vergote, I Vierkant, RA Wang-Gohrke, S Walsh, C Wentzensen, N Whittemore, AS Wicklund, KG Wilkens, LR Woo, YL Wu, XF Wu, AN Yang, HN Zheng, W Ziogas, A Sellers, TA Monteiro, ANA Freedman, ML Gayther, SA Pharoah, PDP AF Kar, Siddhartha P. Tyrer, Jonathan P. Li, Qiyuan Lawrenson, Kate Aben, Katja K. H. Anton-Culver, Hoda Antonenkova, Natalia Chenevix-Trench, Georgia Baker, Helen Bandera, Elisa V. Bean, Yukie T. Beckmann, Matthias W. Berchuck, Andrew Bisogna, Maria Bjorge, Line Bogdanova, Natalia Brinton, Louise Brooks-Wilson, Angela Butzow, Ralf Campbell, Ian Carty, Karen Chang-Claude, Jenny Chen, Yian Ann Chen, Zhihua Cook, Linda S. Cramer, Daniel Cunningham, Julie M. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka Dennis, Joe Dicks, Ed Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Duerst, Matthias Eccles, Diana Easton, Douglas F. Edwards, Robert P. Ekici, Arif B. Fasching, Peter A. Fridley, Brooke L. Gao, Yu-Tang Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind Goode, Ellen L. Goodman, Marc T. Grownwald, Jacek Harrington, Patricia Harter, Philipp Hein, Alexander Heitz, Florian Hildebrandt, Michelle A. T. Hillemanns, Peter Hogdall, Estrid Hogdall, Claus K. Hosono, Satoyo Iversen, Edwin S. Jakubowska, Anna Paul, James Jensen, Allan Ji, Bu-Tian Karlan, Beth Y. Kjaer, Susanne K. Kelemen, Linda E. Kellar, Melissa Kelley, Joseph Kiemeney, Lambertus A. Krakstad, Camilla Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Alice W. Lele, Shashi Leminen, Arto Lester, Jenny Levine, Douglas A. Liang, Dong Lissowska, Jolanta Lu, Karen Lubinski, Jan Lundvall, Lene Massuger, Leon Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. McNeish, Iain A. Menon, Usha Modugno, Francesmary Moysich, Kirsten B. Narod, Steven A. Nedergaard, Lotte Ness, Roberta B. Nevanlinna, Heli Odunsi, Kunle Olson, Sara H. Orlow, Irene Orsulic, Sandra Weber, Rachel Palmieri Pearce, Celeste Leigh Pejovic, Tanja Pelttari, Liisa M. Permuth-Wey, Jennifer Phelan, Catherine M. Pike, Malcolm C. Poole, Elizabeth M. Ramus, Susan J. Risch, Harvey A. Rosen, Barry Rossing, Mary Anne Rothstein, Joseph H. Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Schildkraut, Joellen M. Schwaab, Ira Shu, Xiao-Ou Shvetsov, Yurii B. Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa C. Sucheston-Campbell, Lara E. Tangen, Ingvild L. Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Timorek, Agnieszka Tsai, Ya-Yu Tworoger, Shelley S. van Altena, Anne M. Van Nieuwenhuysen, Els Vergote, Ignace Vierkant, Robert A. Wang-Gohrke, Shan Walsh, Christine Wentzensen, Nicolas Whittemore, Alice S. Wicklund, Kristine G. Wilkens, Lynne R. Woo, Yin-Ling Wu, Xifeng Wu, Anna Yang, Hannah Zheng, Wei Ziogas, Argyrios Sellers, Thomas A. Monteiro, Alvaro N. A. Freedman, Matthew L. Gayther, Simon A. Pharoah, Paul D. P. CA Australian Canc Study Australian Ovarian Canc Study Grp TI Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; TRANSCRIPTION FACTORS; SUSCEPTIBILITY LOCI; BREAST-CANCER; VARIANTS; MODELS; SET; POPULATION; CARCINOMA; PROFILES AB Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. (C) 2015 AACR. C1 [Kar, Siddhartha P.; Dennis, Joe; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Tyrer, Jonathan P.; Baker, Helen; Dicks, Ed; Easton, Douglas F.; Harrington, Patricia; Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. [Li, Qiyuan; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Lawrenson, Kate; Lee, Alice W.; Pearce, Celeste Leigh; Pike, Malcolm C.; Ramus, Susan J.; Wu, Anna; Gayther, Simon A.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K. H.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Genet Epidemiol Res Inst, Irvine, CA 92717 USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk, Byelarus. [Chenevix-Trench, Georgia; Australian Canc Study] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control, New Brunswick, NJ USA. [Bean, Yukie T.; Kellar, Melissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Bean, Yukie T.; Kellar, Melissa; Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Bjorge, Line; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Brinton, Louise; Ji, Bu-Tian; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, HUS, Helsinki, Finland. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Campbell, Ian] Peter MacCallum Canc Ctr, Canc Genet Lab, Div Res, Melbourne, Vic, Australia. [Campbell, Ian; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Campbell, Ian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Carty, Karen; Glasspool, Rosalind; Paul, James] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chen, Yian Ann; Chen, Zhihua] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Biostat, Tampa, FL 33682 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cramer, Daniel; Terry, Kathryn L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Obstet & Gynecol Ctr, Boston, MA 02115 USA. [Cramer, Daniel; Terry, Kathryn L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Inst Oncol, Warsaw, Poland. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Dept Community & Family Med, Lebanon, NH USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Duerst, Matthias; Runnebaum, Ingo B.] Univ Jena, Dept Gynecol, Jena Univ Hosp, Jena, Germany. [Eccles, Diana; Edwards, Robert P.] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Edwards, Robert P.; Modugno, Francesmary] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Biostat & Informat Shared Resource, Kansas City, KS 66103 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Elizabeth Garrett Anderson Inst Womens Hlth, Womens Canc, London, England. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Goode, Ellen L.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Dept Biomed Sci, Commun & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Cybulski, Cezary; Grownwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hillemanns, Peter] Hannover Med Sch, Dept Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Dept Gynaecol, Hannover, Germany. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc, Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Hogdall, Claus K.; Kjaer, Susanne K.; Lundvall, Lene] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Hosono, Satoyo] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Kelemen, Linda E.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Kelley, Joseph] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace] Univ Hosp Leuven, Dept Oncol, Div Gynecol Oncol, Leuven, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Lele, Shashi; Moysich, Kirsten B.; Sucheston-Campbell, Lara E.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Fukuoka 812, Japan. [McGuire, Valerie; Rothstein, Joseph H.; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Sch Med, Stanford, CA 94305 USA. [McLaughlin, John R.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [McNeish, Iain A.] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Glasgow, Lanark, Scotland. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Narod, Steven A.] Womens Coll Res Inst, Toronto, ON, Canada. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Weber, Rachel Palmieri] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Dansonka-Mieszkowska, Agnieszka; Permuth-Wey, Jennifer; Phelan, Catherine M.; Tsai, Ya-Yu; Sellers, Thomas A.; Monteiro, Alvaro N. A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Rosen, Barry] Univ Toronto, Dept Gynecol Oncol, Princess Margaret Hosp, Toronto, ON, Canada. [Rosen, Barry] Univ Toronto, Fac Med, Dept Obstet & Gynecol, Toronto, ON, Canada. [Rossing, Mary Anne; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Epidemiol Ctr, Div Epidemiol,Sch Med, Nashville, TN 37212 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Woo, Yin-Ling] Univ Malaya, Fac Med, Univ Malaya Med Ctr, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia. [Timorek, Agnieszka] Warsaw Med Univ, IInd Fac Med, Dept Obstet Gynecol & Oncol, Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, Warsaw, Poland. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89069 Ulm, Germany. [Woo, Yin-Ling] Univ Malaya, Dept Obstet & Gynaecol, Univ Malaya Med Ctr, Kuala Lumpur, Malaysia. RP Kar, SP (reprint author), Univ Cambridge, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Cambridge CB1 8RN, England. EM sk718@medschl.cam.ac.uk RI Hein, Alexander/F-6999-2010; Bandera, Elisa/M-4169-2014; Brooks-Wilson, Angela/E-9399-2012; van Altena, Anne/B-9824-2016; Teo, Soo-hwang/H-2353-2014; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Dork, Thilo/J-8620-2012; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; OI Ramus, Susan/0000-0003-0005-7798; McNeish, Iain/0000-0002-9387-7586; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Hein, Alexander/0000-0003-2601-3398; Bandera, Elisa/0000-0002-8789-2755; Brooks-Wilson, Angela/0000-0003-1009-6408; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Glasspool, Rosalind/0000-0002-5000-1680; Kjaer, Susanne/0000-0002-8347-1398 FU European Commission [223175-HEALTH-F2-2009-223175]; U.S. National Cancer Institute GAME-ON Post-GWAS Initiative [U19-CA148112]; Ovarian Cancer Research Fund [PPD/RPCI.07]; Cancer Research UK Principal Research Fellowship; National Health and Medical Research Council of Australia; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Canadian Institutes of Health Research Investigator award [MSH-87734]; U.S. National Institute of Environmental Health Sciences [T32ES013678]; U.S. National Cancer Institute [1K99CA184415-01]; Gates Cambridge Scholarship; NIH [R01-CA168758, R13-CA165638, P50-CA159981, R03-CA115195, R01-CA114343, R01-CA149429, T32-CA009001, R01-CA172404, R01-CA074850, P30-CA124435, K07-CA143047, R01-CA076016]; Cancer Research UK [C315/A2621, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre [C1312/A15589]; Norwegian Cancer Society; Norwegian Research Council; Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Ministry of Health Labour and Welfare of Japan; L&S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation; Roswell Park Cancer Institute Alliance Foundation; U.S. National Institutes of Health [R03-CA115195, R01-CA114343, R01-CA149429, R01-CA074850, K07-CA143047, R01-CA076016, K07-CA095666, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, UM1-CA186107, P01-CA87969, R01-CA49449, UM1-CA176726, R01-CA67262, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA126841, R01-CA136924, R03-CA113148, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966]; U.S. Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P. 685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; Royal Marsden Hospital; WorkSafeBC; U.K. National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme" FX Funding for the COGS infrastructure came from a European Commission's Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). The scientific development and funding for this project were, in part, supported by the U.S. National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the Ovarian Cancer Association Consortium (OCAC) GWAS infrastructure came from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). D.F. Easton is supported by a Cancer Research UK Principal Research Fellowship. G. Chenevix-Trench is supported by the National Health and Medical Research Council of Australia. B.Y. Karlan is supported by an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L.E. Keleman was supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). A.W. Lee is supported by a T32 grant from the U.S. National Institute of Environmental Health Sciences (T32ES013678). K. Lawrenson is supported by a K99/R00 grant from the U.S. National Cancer Institute (1K99CA184415-01). S.P. Kar is supported by a Gates Cambridge Scholarship.; The following authors would like to acknowledge specific grant support from the NIH: J.A. Doherty (R01-CA168758), R.P. Edwards (R13-CA165638), K. Odunsi (P50-CA159981), C.L. Pearce (R03-CA115195), J. Permuth-Wey (R01-CA114343), C.M. Phelan (R01-CA149429), E.M. Poole (T32-CA009001), S.J. Ramus (R01-CA172404), H.A. Risch (R01-CA074850), J.H. Rothstein (P30-CA124435), W. Sieh (K07-CA143047), L.E. Sucheston-Campbell (P50-CA159981), Rachel Palmieri Weber (R01-CA076016); and from Cancer Research UK: A. Gentry-Maharaj (C315/A2621) and P.D.P. Pharoah (C490/A10119). Funding of the constituent studies of the OCAC GWAS and COGS are listed by funding agency with each grant number in parentheses: American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, and C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; the L&S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the U.S. National Institutes of Health (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, UM1-CA186107, P01-CA87969, R01-CA49449, UM1-CA176726, R01-CA67262, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); the U.S. Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, and W81XWH-10-1-0280); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P. 685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the U.K.; National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; WorkSafeBC. NR 52 TC 4 Z9 4 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2015 VL 24 IS 10 BP 1574 EP 1584 DI 10.1158/1055-9965.EPI-14-1270 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CU3CR UT WOS:000363401800016 PM 26209509 ER PT J AU Pathak, A Adams, CD Loud, JT Nichols, K Stewart, DR Greene, MH AF Pathak, Anand Adams, Charleen D. Loud, Jennifer T. Nichols, Kathryn Stewart, Douglas R. Greene, Mark H. TI Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GERM-CELL TUMOR; GENOME-WIDE ASSOCIATION; SERVICES TASK-FORCE; 1ST-DEGREE RELATIVES; SUSCEPTIBILITY LOCI; POPULATION; VARIANTS; KITLG; DMRT1; MEN AB Background: Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. Methods: We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic- bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER.Stat. Results: Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR = 11.9; 95% CI, 5.1-23.4; excess absolute risk = 7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadicbilateral cases (0.15 expected; SIR = 13.4; 95% CI, 1.6-48.6). Conclusions: Our data are the first to indicate that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. Impact: Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies. (C) 2015 AACR. C1 [Pathak, Anand; Adams, Charleen D.; Loud, Jennifer T.; Stewart, Douglas R.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Nichols, Kathryn] Westat Corp, Rockville, MD USA. RP Greene, MH (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-454, Rockville, MD 20850 USA. EM greenem@mail.nih.gov FU NCI Intramural Research Program; Division of Cancer Epidemiology and Genetics; Human Genetics Program, under NIH [Z01-CP010144-16]; Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes FX All authors were supported by the NCI Intramural Research Program, Division of Cancer Epidemiology and Genetics, Human Genetics Program, under NIH Project Z01-CP010144-16, Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes. NR 53 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2015 VL 24 IS 10 BP 1614 EP 1621 DI 10.1158/1055-9965.EPI-14-1240 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CU3CR UT WOS:000363401800021 PM 26265202 ER PT J AU Santegoets, SJAM Dijkgraaf, EM Battaglia, A Beckhove, P Britten, CM Gallimore, A Godkin, A Gouttefangeas, C de Gruijl, TD Koenen, HJPM Scheffold, A Shevach, EM Staats, J Tasken, K Whiteside, TL Kroep, JR Welters, MJP van der Burg, SH AF Santegoets, Saskia J. A. M. Dijkgraaf, Eveline M. Battaglia, Alessandra Beckhove, Philipp Britten, Cedrik M. Gallimore, Awen Godkin, Andrew Gouttefangeas, Cecile de Gruijl, Tanja D. Koenen, Hans J. P. M. Scheffold, Alexander Shevach, Ethan M. Staats, Janet Tasken, Kjetil Whiteside, Theresa L. Kroep, Judith R. Welters, Marij J. P. van der Burg, Sjoerd H. TI Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Consensus; Tregs; Monitoring; Flow cytometry; Phenotyping ID HUMAN FOXP3(+) TREG; LATENCY-ASSOCIATED PEPTIDE; CANCER-PATIENTS; CERVICAL-CANCER; GARP LRRC32; EXPRESSION; SUBSETS; IMMUNOTHERAPY; RESPONSES; CD39 AB Regulatory T cell (Treg)-mediated immunosuppression is considered a major obstacle for successful cancer immunotherapy. The association between clinical outcome and Tregs is being studied extensively in clinical trials, but unfortunately, no consensus has been reached about (a) the markers and (b) the gating strategy required to define human Tregs in this context, making it difficult to draw final conclusions. Therefore, we have organized an international workshop on the detection and functional testing of Tregs with leading experts in the field, and 40 participants discussing different analyses and the importance of different markers and context in which Tregs were analyzed. This resulted in a rationally composed ranking list of "Treg markers". Subsequently, the proposed Treg markers were tested to get insight into the overlap/differences between the most frequently used Treg definitions and their utility for Treg detection in various human tissues. Here, we conclude that the CD3, CD4, CD25, CD127, and FoxP3 markers are the minimally required markers to define human Treg cells. Staining for Ki67 and CD45RA showed to provide additional information on the activation status of Tregs. The use of markers was validated in a series of PBMC from healthy donors and cancer patients, as well as in tumor-draining lymph nodes and freshly isolated tumors. In conclusion, we propose an essential marker set comprising antibodies to CD3, CD4, CD25, CD127, Foxp3, Ki67, and CD45RA and a corresponding robust gating strategy for the context-dependent analysis of Tregs by flow cytometry. C1 [Santegoets, Saskia J. A. M.; Dijkgraaf, Eveline M.; Kroep, Judith R.; Welters, Marij J. P.; van der Burg, Sjoerd H.] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. [Battaglia, Alessandra] Univ Cattolica Sacro Cuore, Dept Obstet & Gynecol, I-00168 Rome, Italy. [Beckhove, Philipp] Univ Heidelberg Hosp, German Canc Res Ctr, Dept Surg Oncol, Div Translat Immunol, Heidelberg, Germany. [Britten, Cedrik M.] Johannes Gutenberg Univ Mainz GmbH, Univ Med, TRON Translat Onkol, Mainz, Germany. [Gallimore, Awen; Godkin, Andrew] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Gouttefangeas, Cecile] Univ Tubingen, Inst Cell Biol, Dept Immunol, Tubingen, Germany. [de Gruijl, Tanja D.] Vrije Univ Amsterdam, Univ Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Koenen, Hans J. P. M.] Radboud Univ Nijmegen, Med Ctr, Lab Med Immunol, Dept Lab Med, NL-6525 ED Nijmegen, Netherlands. [Scheffold, Alexander] Charite, Dept Cellular Immunol, Clin Rheumatol & Clin Immunol, D-13353 Berlin, Germany. [Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Staats, Janet] Duke Univ, Duke Ctr AIDS Res, Durham, NC USA. [Staats, Janet] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Tasken, Kjetil] Univ Oslo, Ctr Mol Med Norway, Nordic EMBL Partnership, Oslo, Norway. [Tasken, Kjetil] Oslo Univ Hosp, Oslo, Norway. [Tasken, Kjetil] Univ Oslo, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway. [Tasken, Kjetil] Univ Oslo, Ctr Biotechnol, Oslo, Norway. [Whiteside, Theresa L.] Univ Pittsburgh, Dept Pathol, Inst Canc, Pittsburgh, PA USA. RP Santegoets, SJAM (reprint author), Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. EM s.j.a.m.santegoets@lumc.nl; shvdburg@lumc.nl OI Gallimore, Awen/0000-0001-6675-7004 FU Wallace H. Coulter Foundation (Miami, Florida, USA); Bontius stichting; Wallace Coulter Foundation; Deutsche Forschungsgemeinschaft [SFB 685/Z5, Sonderforschungsbereich 633, Sonderforschungsbereich 650]; Norwegian Cancer Society; Research Council of Norway; Kristian Gerhard Jebsen Foundation; Wellcome Trust [086983/Z/08/Z]; Cancer Research Wales; Nijmegen Institute for Infection, Inflammation, and Immunity [151692]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health (DIR/NIAID/NIH); Duke University Center for AIDS Research (CFAR), an National Institute of Health [5P30 AI064518]; Dutch Cancer Society [2009-4400]; National Institute of Health [R01-CA168628] FX We would like to acknowledge Dr. David Murdoch for his thoughtful criticisms. Saskia J.A.M. Santegoets and Sjoerd H. van der Burg were supported by a grant from the Wallace H. Coulter Foundation (Miami, Florida, USA, awarded to Sjoerd H. van der Burg, Cedrik M. Britten, and Cecile Gouttefangeas). Eveline M. Dijkgraaf and Judith R. Kroep were supported by a grant from the Bontius stichting. Cecile Gouttefangeas was supported by the Wallace Coulter Foundation and the Deutsche Forschungsgemeinschaft SFB 685/Z5. Kjetil Tasken was supported by the Norwegian Cancer Society, Research Council of Norway, and Kristian Gerhard Jebsen Foundation. Awen Gallimore was supported by the Wellcome Trust (Grant Number 086983/Z/08/Z). Andrew Godkin was supported by a grant from Cancer Research Wales. Alexander Scheffold was supported by grants from the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 633, and Sonderforschungsbereich 650. Hans J.P.M. Koenen was supported by a grant from the Nijmegen Institute for Infection, Inflammation, and Immunity (Grant Number 151692). Ethan Shevach is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health (DIR/NIAID/NIH). Janet Staats was supported by the Duke University Center for AIDS Research (CFAR), an National Institute of Health funded program (5P30 AI064518). Marij J.P Welters was supported by a grant from the Dutch Cancer Society (Grant number 2009-4400). Theresa L. Whiteside was supported by a grant from the National Institute of Health (Grant number R01-CA168628). NR 54 TC 22 Z9 23 U1 3 U2 17 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 OCT PY 2015 VL 64 IS 10 BP 1271 EP 1286 DI 10.1007/s00262-015-1729-x PG 16 WC Oncology; Immunology SC Oncology; Immunology GA CU0YZ UT WOS:000363246900006 PM 26122357 ER PT J AU Boyerinas, B Jochems, C Fantini, M Heery, CR Gulley, JL Tsang, KY Schlom, J AF Boyerinas, Benjamin Jochems, Caroline Fantini, Massimo Heery, Christopher R. Gulley, James L. Tsang, Kwong Yok Schlom, Jeffrey TI Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID NATURAL-KILLER-CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; CD8 T-CELLS; ADVANCED MELANOMA; HODGKINS-LYMPHOMA; CLINICAL-EFFICACY; CANCER-PATIENTS; BREAST-CANCER; LUNG-CANCER; THERAPY AB Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFN gamma can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab- mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. (C) 2015 AACR. C1 [Boyerinas, Benjamin; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R.; Tsang, Kwong Yok; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016; OI Gulley, James/0000-0002-6569-2912; Fantini, Massimo/0000-0002-8164-2587 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 54 TC 37 Z9 40 U1 6 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD OCT PY 2015 VL 3 IS 10 BP 1148 EP 1157 DI 10.1158/2326-6066.CIR-15-0059 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA CU3FA UT WOS:000363408400006 PM 26014098 ER PT J AU Kumar, NB Pow-Sang, J Egan, KM Spiess, PE Dickinson, S Salup, R Helal, M McLarty, J Williams, CR Schreiber, F Parnes, HL Sebti, S Kazi, A Kang, L Quinn, G Smith, T Yue, B Diaz, K Chornokur, G Crocker, T Schell, MJ AF Kumar, Nagi B. Pow-Sang, Julio Egan, Kathleen M. Spiess, Philippe E. Dickinson, Shohreh Salup, Raoul Helal, Mohamed McLarty, Jerry Williams, Christopher R. Schreiber, Fred Parnes, Howard L. Sebti, Said Kazi, Aslam Kang, Loveleen Quinn, Gwen Smith, Tiffany Yue, Binglin Diaz, Karen Chornokur, Ganna Crocker, Theresa Schell, Michael J. TI Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention SO CANCER PREVENTION RESEARCH LA English DT Article ID SMALL ACINAR PROLIFERATION; INTRAEPITHELIAL NEOPLASIA; POLYPHENON-E; CLINICAL-TRIAL; NEEDLE-BIOPSY; TRAMP MICE; EPIGALLOCATECHIN GALLATE; PRENEOPLASTIC LESIONS; RADICAL PROSTATECTOMY; HEALTHY-INDIVIDUALS AB Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [-0.87 ng/mL; 95% confidence intervals (CI), -1.66 to -0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP. (C) 2015 AACR. C1 [Kumar, Nagi B.; Egan, Kathleen M.; Spiess, Philippe E.; Smith, Tiffany; Diaz, Karen; Chornokur, Ganna] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol, Tampa, FL 33612 USA. [Pow-Sang, Julio] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Urol, Tampa, FL 33612 USA. [Dickinson, Shohreh] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Pathol, Tampa, FL 33612 USA. [Salup, Raoul] Univ S Florida, Coll Med, Dept Surg, Tampa, FL 33612 USA. [Helal, Mohamed] Tampa Urol, Dept Urol, Tampa, FL USA. [McLarty, Jerry] LSU Hlth Sci Ctr, Dept Med, Med, Tampa, FL USA. [Williams, Christopher R.] Univ Florida Jacksonville, Tampa, FL USA. [Schreiber, Fred] Watson Clin Ctr Canc Care & Res, Lakeland, FL USA. [Parnes, Howard L.] NCI, Rockville, MD USA. [Sebti, Said; Kazi, Aslam] H Lee Moffitt Canc Ctr & Res Inst Inc, Dept Drug Discovery, Tampa, FL 33612 USA. [Kang, Loveleen] James A Haley VA Med Ctr, Dept Pathol & Lab Med, Tampa, FL USA. [Quinn, Gwen] H Lee Moffitt Canc Ctr & Res Inst, Hlth Outcomes & Behav, Tampa, FL USA. [Yue, Binglin] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat, Tampa, FL 33612 USA. [Crocker, Theresa] James A Haley Vet Adm Hosp, Ctr Innovat Disabil & Rehabil Res, Tampa, FL USA. [Schell, Michael J.] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat, Tampa, FL USA. RP Kumar, NB (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Epidemiol,Canc Chemoprevent, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM nagi.kumar@moffitt.org FU NIH-National Cancer Institute [R01 CA12060-01A1] FX This research funding was awarded to N.B. Kumar by the NIH-National Cancer Institute R01 CA12060-01A1. NR 62 TC 13 Z9 13 U1 14 U2 120 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD OCT PY 2015 VL 8 IS 10 BP 879 EP 887 DI 10.1158/1940-6207.CAPR-14-0324 PG 9 WC Oncology SC Oncology GA CU3BS UT WOS:000363399200001 PM 25873370 ER PT J AU Mossoba, ME Halverson, DC Kurlander, R Schuver, BB Carpenter, A Hansen, B Steinberg, SM Ali, SA Tageja, N Hakim, FT Gea-Banacloche, J Sportes, C Hardy, NM Hickstein, DD Pavletic, SZ Khuu, H Sabatini, M Stroncek, D Levine, BL June, CH Mariotti, J Rixe, O Fojo, AT Bishop, MR Gress, RE Fowler, DH AF Mossoba, Miriam E. Halverson, David C. Kurlander, Roger Schuver, Bazetta Blacklock Carpenter, Ashley Hansen, Brenna Steinberg, Seth M. Ali, Syed Abbas Tageja, Nishant Hakim, Frances T. Gea-Banacloche, Juan Sportes, Claude Hardy, Nancy M. Hickstein, Dennis D. Pavletic, Steven Z. Khuu, Hanh Sabatini, Marianna Stroncek, David Levine, Bruce L. June, Carl H. Mariotti, Jacopo Rixe, Olivier Fojo, Antonio Tito Bishop, Michael R. Gress, Ronald E. Fowler, Daniel H. TI High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-CELL TRANSPLANTATION; ANTIGEN-PRESENTING CELLS; DONOR LEUKOCYTE INFUSIONS; REDUCED INTENSITY REGIMEN; CD4(+) T-CELLS; HOST-DISEASE; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; CLINICAL-TRIALS; ACUTE GVHD AB Purpose: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve antitumor effects while avoiding GVHD. Experimental Design: Patients (n = 10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m(2)/dose) combined with daily, dose-adjusted cyclophosphamide (C; <= 200 mg/d) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T-cell-replete peripheral blood stem cell allografts, and high-dose sirolimus (serum trough target, 20-30 ng/mL). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered days 0, 14, and 45 posttransplant), and sirolimus was discontinued early (day 60 posttransplant). Results: PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10 of 10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No antitumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed. Conclusions: Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer. (C) 2015 AACR. C1 [Mossoba, Miriam E.; Halverson, David C.; Schuver, Bazetta Blacklock; Carpenter, Ashley; Hansen, Brenna; Ali, Syed Abbas; Tageja, Nishant; Hakim, Frances T.; Gea-Banacloche, Juan; Hickstein, Dennis D.; Pavletic, Steven Z.; Gress, Ronald E.; Fowler, Daniel H.] NIH, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kurlander, Roger] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management, NIH, Bethesda, MD 20892 USA. [Sportes, Claude] Georgia Regents Univ, Ctr Canc, Augusta, GA USA. [Hardy, Nancy M.] Univ Maryland, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. [Khuu, Hanh; Sabatini, Marianna; Stroncek, David] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Levine, Bruce L.; June, Carl H.] Univ Penn, Abramson Family Canc Res Ctr, Philadelphia, PA 19104 USA. [Mariotti, Jacopo] Fdn IRCCS Inst Nazl Tumori, Milan, Italy. [Rixe, Olivier] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Fojo, Antonio Tito] NIH, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Sch Med, Chicago, IL 60637 USA. RP Fowler, DH (reprint author), NIH, 10 Ctr Dr,CRC,3-EAST Labs,3-3330, Bethesda, MD 20892 USA. EM dhfowler@helix.nih.gov FU Center for Cancer Research, NCI FX This work was supported by the Center for Cancer Research, NCI. NR 50 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2015 VL 21 IS 19 BP 4312 EP 4320 DI 10.1158/1078-0432.CCR-15-0340 PG 9 WC Oncology SC Oncology GA CU2CQ UT WOS:000363330500012 PM 26071480 ER PT J AU Draper, LM Kwong, MLM Gros, A Stevanovic, S Tran, E Kerkar, S Raffeld, M Rosenberg, SA Hinrichs, CS AF Draper, Lindsey M. Kwong, Mei Li M. Gros, Alena Stevanovic, Sanja Tran, Eric Kerkar, Sid Raffeld, Mark Rosenberg, Steven A. Hinrichs, Christian S. TI Targeting of HPV-16(+) Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6 SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL-CANCER; INTRAEPITHELIAL NEOPLASIA; ANTITUMOR IMMUNITY; NAIVE RATHER; THERAPY; IMMUNOTHERAPY; VACCINATION; RESPONSES; ANTIGEN AB Purpose: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV+ tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV+ tumor cells. ExperimentalDesign: T-cell responses against theHPV-16 oncoproteins were investigated in a patient with an ongoing 22-month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein- specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV+ epithelial tumor cells. Results: We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A* 02: 01-restric-ted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A* 02: 01-restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16+ cervical, and head and neck cancer cell lines. Conclusions: These findings demonstrate that HPV-16(+) tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV-16(+) malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers. (C) 2015 AACR. C1 [Draper, Lindsey M.; Kwong, Mei Li M.; Gros, Alena; Stevanovic, Sanja; Tran, Eric; Rosenberg, Steven A.; Hinrichs, Christian S.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kerkar, Sid; Raffeld, Mark] NCI, Pathol Lab, Clin Res Ctr, Bethesda, MD 20892 USA. RP Hinrichs, CS (reprint author), NCI, NIH, Clin Res Ctr, Room 3-3888, Bethesda, MD 20892 USA. EM Hinrichs@nih.gov FU NIH FX This work was supported by the Intramural Research Program of the NIH. NR 40 TC 13 Z9 13 U1 3 U2 12 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 OCT 1 PY 2015 VL 21 IS 19 BP 4431 EP 4439 DI 10.1158/1078-0432.CCR-14-3341 PG 9 WC Oncology SC Oncology GA CU2CQ UT WOS:000363330500025 PM 26429982 ER PT J AU Bontemps-Gallo, S Lacroix, JM AF Bontemps-Gallo, Sebastien Lacroix, Jean-Marie TI New insights into the biological role of the osmoregulated periplasmic glucans in pathogenic and symbiotic bacteria SO ENVIRONMENTAL MICROBIOLOGY REPORTS LA English DT Review ID ENTERICA SEROVAR TYPHIMURIUM; MEMBRANE-DERIVED OLIGOSACCHARIDES; PSEUDOMONAS-AERUGINOSA BIOFILM; RCSCD-RCSB PHOSPHORELAY; N-GLYCOSYLATION PATHWAY; ESCHERICHIA-COLI; DICKEYA-DADANTII; CYCLIC BETA-1,2-GLUCAN; ANTIBIOTIC-RESISTANCE; ERWINIA-CHRYSANTHEMI AB This review emphasizes the biological roles of the osmoregulated periplasmic glucans (OPGs). Osmoregulated periplasmic glucans occur in almost all -, - and -Proteobacteria. This polymer of glucose is required for full virulence. The roles of the OPGs are complex and vary depending on the species. Here, we outline the four major roles of the OPGs through four different pathogenic and one symbiotic bacterial models (Dickeya dadantii, Salmonella enterica, Pseudomonas aeruginosa, Brucella abortus and Sinorhizobium meliloti). When periplasmic, the OPGs are a part of the signal transduction pathway and indirectly regulate genes involved in virulence. The OPGs can also be secreted. When outside of the cell, they interact directly with antibiotics to protect the bacterial cell or interact with the host cell to facilitate the invasion process. When OPGs are not found, as in the epsilon-Proteobacteria, OPG-like oligosaccharides are present. Their presence strengthens the evidence that OPGs play an important role in virulence. C1 [Bontemps-Gallo, Sebastien] NIAID, Rocky Mt Labs, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. [Lacroix, Jean-Marie] Univ Lille, Struct & Funct Glycobiol Unit, Villeneuve Dascq, France. RP Lacroix, JM (reprint author), Univ Lille, Struct & Funct Glycobiol Unit, Villeneuve Dascq, France. EM jean-marie.lacroix@univ-lille1.fr FU French National Center for Scientific Research (CNRS); University of Lille; French Ministry of the Higher Education and Research; Intramural Research Program of the National Institute for Allergy and Infectious Diseases, National Institutes of Health FX We are grateful to Martha Thayer for the English corrections. We thank all the former, current and future members of our lab for their involvement and contribution in the understanding of the structure and biological role of the osmoregulated periplasmic glucans. J.-M. Lacroix is a professor at the University of Lille and the team leader of the Genetics of Bacterial Envelope in the Structural and Functional Glycobiology unit at the University of Lille. His research are supported by grants from the French National Center for Scientific Research (CNRS), the University of Lille, and the French Ministry of the Higher Education and Research. S. Bontemps-Gallo is supported by the Intramural Research Program of the National Institute for Allergy and Infectious Diseases, National Institutes of Health. NR 57 TC 3 Z9 3 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1758-2229 J9 ENV MICROBIOL REP JI Environ. Microbiol. Rep. PD OCT PY 2015 VL 7 IS 5 SI SI BP 690 EP 697 DI 10.1111/1758-2229.12325 PG 8 WC Environmental Sciences; Microbiology SC Environmental Sciences & Ecology; Microbiology GA CU3KV UT WOS:000363425000001 PM 26265506 ER PT J AU de Souza, PC Smith, N Atolagbe, O Ziegler, J Njoku, C Lerner, M Ehrenshaft, M Mason, RP Meek, B Plafker, SM Saunders, D Mamedova, N Towner, RA AF de Souza, Patricia Coutinho Smith, Nataliya Atolagbe, Oluwatomisin Ziegler, Jadith Njoku, Charity Lerner, Megan Ehrenshaft, Marilyn Mason, Ronald P. Meek, Bill Plafker, Scott M. Saunders, Debra Mamedova, Nadezda Towner, Rheal A. TI OKN-007 decreases free radical levels in a preclinical F98 rat glioma model SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Molecular magnetic resonance imaging; Glioma; Free radical; Immuno-spin-trapping; OKN-007; In vivo; F98 glioma; Nuclear factor erythroid 2-related factor 2 (NrF2); Inducible nitric oxide synthase (iNOS); 3-nitrotyrosine (3-NT); Malondialdehyde (MDA) ID NITRIC-OXIDE SYNTHASE; IN-VIVO DETECTION; SPIN TRAP AGENT; GROWTH-FACTOR; OXIDATIVE STRESS; SIGNALING PATHWAYS; LIPID-PEROXIDATION; COLORECTAL-CANCER; CEREBRAL-ISCHEMIA; NRF2 AB Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a clisulfonyl derivative of ci-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (1ST) methodologies. Free radicals are trapped with the spin-trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), to form DMPO macromolecule radical adducts, and then further tagged by immunospin trapping by an antibody against DMPO adducts.. In this study, we combined mMRI with a biotin-Gcl-DTPA-albumin-based contrast agent for signal detection with the specificity of an antibody for DMPO nitrone adducts (anti-DMPO probe), to detect in vivo free radicals in OKN-007-treated rat F98 gliomas. OKN-007 was found to significantly decrease (P < 0.05) free radical levels detected with an anti-DMPO probe in treated animals compared to untreated rats. Immunoelectron microscopy was used with gold labeled antibiotin to detect the anti-DMPO probe within the plasma membrane of F98 tumor cells from rats administered anti-DMPO in vivo. OKN-007 was also found to decrease nuclear factor eiythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotymsine, and malondialdehyde in ex vivo F98 glioma tissues via immunohistochemistry, as well as decrease 3-nitrotyrosine and malondialdehyde adducts in vitro in F98 cells via FLISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma rumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of rnacromolecular free radicals and the assessment of antioxidants. (C) 2015 Published by Elsevier Inc. C1 [de Souza, Patricia Coutinho; Smith, Nataliya; Atolagbe, Oluwatomisin; Ziegler, Jadith; Njoku, Charity; Saunders, Debra; Mamedova, Nadezda; Towner, Rheal A.] Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. [de Souza, Patricia Coutinho; Towner, Rheal A.] Oklahoma State Univ, Coll Vet Med, Dept Vet Pathobiol, Stillwater, OK 74078 USA. [Lerner, Megan] Univ Oklahoma, Hlth Sci Ctr, Dept Surg, Res Lab, Oklahoma City, OK USA. [Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Immun Inflammat & Dis Lab, Res Triangle Pk, NC 27709 USA. [Meek, Bill] Oklahoma State Univ, Ctr Hlth Sci, Tulsa, OK USA. [Plafker, Scott M.] Oklahoma Med Res Fdn, Free Rad Biol & Aging, Oklahoma City, OK 73104 USA. RP Towner, RA (reprint author), Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM Rheal-Towner@omrf.org FU National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103639]; Oklahoma Medical Research Foundation; National Institute of Environmental Health Sciences FX We gratefully acknowledge Mr. Hirst Holloway for his help during all stages of the project, We also thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, for use of their Histology and Immunohistochemistry Core for cryosectioning, funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103639. This work was also supported by the Oklahoma Medical Research Foundation (R.A.T.) and the National Institute of Environmental Health Sciences (R.P.M.). NR 59 TC 0 Z9 0 U1 2 U2 9 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 OCT PY 2015 VL 87 BP 157 EP 168 DI 10.1016/j.freeradbiomed.2015.06.026 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CU1JK UT WOS:000363277100014 ER PT J AU Serrano, OK Parrow, NL Violet, PC Yang, J Zornjak, J Basseville, A Levine, M AF Serrano, Oscar K. Parrow, Nermi L. Violet, Pierre-Christian Yang, Jacqueline Zornjak, Jennifer Basseville, Agnes Levine, Mark TI Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Melanoma; Ascorbate; Vitamin C; Hydrogen peroxide; Prooxidant; Cancer ID DACARBAZINE-BASED CHEMOTHERAPY; INHIBITOR VALPROIC ACID; I CLINICAL-TRIAL; METASTATIC MELANOMA; HYDROGEN-PEROXIDE; VITAMIN-C; PANCREATIC-CANCER; OXIDATIVE STRESS; BREAST-CANCER; CELLS AB Because 5-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on BIG-F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents clacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (P < 0.0001) and NOD-scid tumor bearing mice (P< 0.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted. (C) 2015 Published by Elsevier Inc. C1 [Serrano, Oscar K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, New York, NY USA. [Parrow, Nermi L.; Violet, Pierre-Christian; Yang, Jacqueline; Zornjak, Jennifer; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Basseville, Agnes] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Room 4D52,10 Ctr Dr, Bethesda, MD 20892 USA. EM markl@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) FX We thank Sebastian Padayatty and Yu Wang for helpful discussions during the preparation of this manuscript. We also appreciate the assistance of Dr. Jerry Collins and colleagues at the National Cancer Institute in testing ascorbate in the NCI-60 cell panel. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The opinions expressed herein are the sole responsibility of the authors and do not necessarily represent the official views of the NIH. NR 53 TC 2 Z9 2 U1 0 U2 5 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 OCT PY 2015 VL 87 BP 193 EP 203 DI 10.1016/j.freeradbiomed.2015.06.032 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CU1JK UT WOS:000363277100017 PM 26119785 ER PT J AU Thomas, DD Heinecke, JL Ridnour, LA Cheng, RY Kesarwala, AH Switzer, CH McVicar, DW Roberts, DD Glynn, S Fukuto, JM Wink, DA Miranda, KM AF Thomas, Douglas D. Heinecke, Julie L. Ridnour, Lisa A. Cheng, Robert Y. Kesarwala, Aparna H. Switzer, Christopher H. McVicar, Daniel W. Roberts, David D. Glynn, Sharon Fukuto, Jon M. Wink, David A. Miranda, Katrina M. TI Signaling and stress: The redox landscape in NOS2 biology SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Nitric oxide; Nitric oxide synthase; Breast cancer; Cell signaling; Cancer biology; Free radicals ID NITRIC-OXIDE SYNTHASE; NEGATIVE BREAST-CANCER; CYTOCHROME-C-OXIDASE; HYDROXY-L-ARGININE; PULMONARY ARTERIAL-HYPERTENSION; IRON-REGULATORY PROTEIN; NECROSIS-FACTOR-ALPHA; NEURONAL CELL-DEATH; S-NITROSYLATION; NITROSATIVE STRESS AB Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. However, deleterious as well as beneficial roles of NO have been reported. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitmsative signaling and nitrosative stress related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including processes that lead to interconversion of RNS and interactions with molecular targets. (C) 2015 Published by Elsevier B.V. C1 [Thomas, Douglas D.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Heinecke, Julie L.; Ridnour, Lisa A.; Cheng, Robert Y.; Switzer, Christopher H.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Kesarwala, Aparna H.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Roberts, David D.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon] NUI Galway, Prostate Canc Inst, Galway, Ireland. [Fukuto, Jon M.] Sonoma State Univ, Dept Chem, Rohnert Pk, CA 94928 USA. [Miranda, Katrina M.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM wink@mail.nih.gov; kmiranda@email.arizona.edu RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; Glynn, Sharon/0000-0003-1459-2580 FU National Institutes of Health [R01-GM076247, R01GM085232]; National Cancer Institute; Center for Cancer Research; National Science Foundation [CHE-0645818] FX This work was supported in part by the National Institutes of Health (R01-GM076247 to KMM; R01GM085232 to DDT), the Intramural Research Program of the National Institutes of Health, the National Cancer Institute and the Center for Cancer Research (DAW, DDR) and the National Science Foundation (CHE-0645818 to KMM). NR 294 TC 13 Z9 13 U1 1 U2 12 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 OCT PY 2015 VL 87 BP 204 EP 225 DI 10.1016/j.freeradbiomed.2015.06.002 PG 22 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CU1JK UT WOS:000363277100018 PM 26117324 ER PT J AU Miller, FW Chen, W O'Hanlon, TP Cooper, RG Vencovsky, J Rider, LG Danko, K Wedderburn, LR Lundberg, IE Pachman, LM Reed, AM Ytterberg, SR Padyukov, L Selva-O'Callaghan, A Radstake, TR Isenberg, DA Chinoy, H Ollier, WER Scheet, P Peng, B Lee, A Byun, J Lamb, JA Gregersen, PK Amos, CI AF Miller, F. W. Chen, W. O'Hanlon, T. P. Cooper, R. G. Vencovsky, J. Rider, L. G. Danko, K. Wedderburn, L. R. Lundberg, I. E. Pachman, L. M. Reed, A. M. Ytterberg, S. R. Padyukov, L. Selva-O'Callaghan, A. Radstake, T. R. Isenberg, D. A. Chinoy, H. Ollier, W. E. R. Scheet, P. Peng, B. Lee, A. Byun, J. Lamb, J. A. Gregersen, P. K. Amos, C. I. CA Myositis Genetics Consortium TI Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes SO GENES AND IMMUNITY LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; HISTOCOMPATIBILITY COMPLEX; AUTOIMMUNE-DISEASES; IMMUNE-RESPONSE; AUTOANTIBODIES; DERMATOMYOSITIS; LINKAGE; IMMUNOGENETICS; POLYMYOSITIS; PATHOGENESIS AB Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5x10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. C1 [Miller, F. W.; O'Hanlon, T. P.; Rider, L. G.] NIEHS, NIH, Bethesda, MD 20892 USA. [Chen, W.; Scheet, P.; Peng, B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Cooper, R. G.] Univ Liverpool, MRC ARUK Inst Ageing & Chron Dis, Liverpool L69 3BX, Merseyside, England. [Vencovsky, J.] Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic. [Danko, K.] Univ Debrecen, Div Immunol, Dept Internal Med 3, Debrecen, Hungary. [Wedderburn, L. R.] UCL, Inst Child Hlth, London, England. [Lundberg, I. E.; Padyukov, L.] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Pachman, L. M.] Northwestern Univ, Feinberg Sch Med, Dept Pediat Rheumatol, Chicago, IL 60611 USA. [Reed, A. M.; Ytterberg, S. R.] Mayo Clin, Rochester, MN USA. [Selva-O'Callaghan, A.] Vall dHebron Gen Hosp, Barcelona, Spain. [Radstake, T. R.] Univ Utrecht, Med Ctr, Lab Translat Immunol, Dept Rheumatol & Clin Immunol, NL-3508 TC Utrecht, Netherlands. [Radstake, T. R.] Nijmegen Ctr Mol Life Sci, Nijmegen, Netherlands. [Isenberg, D. A.] UCL, Div Med, London, England. [Chinoy, H.] Univ Manchester, Natl Inst Hlth Res, Manchester Musculoskeletal Biomed Res Unit, Ctr Musculoskeletal Res, Manchester, Lancs, England. [Ollier, W. E. R.; Lamb, J. A.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Lee, A.; Gregersen, P. K.] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA. [Byun, J.; Amos, C. I.] Dartmouth Coll, Dept Community & Family Med, Hanover, NH 03755 USA. RP Miller, FW (reprint author), NIEHS, NIH, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593; Chinoy, Hector/0000-0001-6492-1288; Padyukov, Leonid/0000-0003-2950-5670 FU Intramural Program of the NIH, National Institute of Environmental Health Sciences [NIEHS Z01ES101074]; European Community's FP6, AutoCure [LSHB CT-2006-018661]; Myositis UK; Arthritis Research UK [18474, 20164]; Cure JM Foundation; European Science Foundation; Association Francaise Contre Les Myopathies (AFM); National Institute for Health Research Biomedical Research Centre at ICH/GOSH; National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit; Wellcome Trust; Action Medical UK; Great Ormond Street Children's Charity; National Institute for Health Research Translational Research Collaboration on rare diseases; Swedish Research Council; Ministry of Health, Czech Republic [00023728] FX This study was supported in part by: the Intramural Program of the NIH, National Institute of Environmental Health Sciences (NIEHS Z01ES101074); European Community's FP6, AutoCure LSHB CT-2006-018661; Myositis UK; Arthritis Research UK (18474 and 20164); The Cure JM Foundation; the European Science Foundation in the framework of the Research Networking Programme European Myositis Network (EuMyoNet); Association Francaise Contre Les Myopathies (AFM), the National Institute for Health Research Biomedical Research Centre at ICH/GOSH; the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit; the Wellcome Trust; Action Medical UK; Great Ormond Street Children's Charity; the National Institute for Health Research Translational Research Collaboration on rare diseases; and the Swedish Research Council. The Czech cohort was partially supported by the Ministry of Health, Czech Republic (No. 00023728). NR 46 TC 9 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD OCT-NOV PY 2015 VL 16 IS 7 BP 470 EP 480 DI 10.1038/gene.2015.28 PG 11 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA CU3JS UT WOS:000363421700005 PM 26291516 ER PT J AU Chandra, G Bagh, MB Peng, SY Saha, A Sarkar, C Moralle, M Zhang, ZJ Mukherjee, AB AF Chandra, Goutam Bagh, Maria B. Peng, Shiyong Saha, Arjun Sarkar, Chinmoy Moralle, Matthew Zhang, Zhongjian Mukherjee, Anil B. TI Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders SO HUMAN MOLECULAR GENETICS LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; PALMITOYL-PROTEIN THIOESTERASE; CATHEPSIN-D DEFICIENCY; BLOOD-BRAIN-BARRIER; CELLULAR CLEARANCE; ALPHA-SYNUCLEIN; MOUSE MODEL; DISEASE; ACTIVATION; EXPRESSION AB Neurodegeneration is a devastating manifestation in the majority of >50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLNs) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S-acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1(-/-) mice that mimic INCL, we uncovered that Cln10/CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1(-/-) mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N-tert-butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link between INCL and CNCL. C1 [Chandra, Goutam; Bagh, Maria B.; Peng, Shiyong; Saha, Arjun; Sarkar, Chinmoy; Moralle, Matthew; Zhang, Zhongjian; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NIH, Bldg 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This study was supported in full by the intramural research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 53 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2015 VL 24 IS 19 BP 5416 EP 5432 DI 10.1093/hmg/ddv266 PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7TT UT WOS:000363018100005 PM 26160911 ER PT J AU Fufa, TD Harris, ML Watkins-Chow, DE Levy, D Gorkin, DU Gildea, DE Song, LY Safi, A Crawford, GE Sviderskaya, EV Bennett, DC Mccallion, AS Loftus, SK Pavan, WJ AF Fufa, Temesgen D. Harris, Melissa L. Watkins-Chow, Dawn E. Levy, Denise Gorkin, David U. Gildea, Derek E. Song, Lingyun Safi, Alexias Crawford, Gregory E. Sviderskaya, Elena V. Bennett, Dorothy C. Mccallion, Andrew S. Loftus, Stacie K. Pavan, William J. TI Genomic analysis reveals distinct mechanisms and functional classes of SOX10-regulated genes in melanocytes SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCRIPTION FACTOR SOX10; TERT PROMOTER MUTATIONS; NEURAL CREST; CHIP-SEQ; DOPACHROME-TAUTOMERASE; MOUSE MELANOCYTES; WIDE ASSOCIATION; MELANOMA-CELLS; DNA-BINDING; IN-VIVO AB SOX10 is required for melanocyte development and maintenance, and has been linked to melanoma initiation and progression. However, the molecular mechanisms by which SOX10 guides the appropriate gene expression programs necessary to promote the melanocyte lineage are not fully understood. Here we employ genetic and epigenomic analysis approaches to uncover novel genomic targets and previously unappreciated molecular roles of SOX10 in melanocytes. Through global analysis of SOX10-binding sites and epigenetic characteristics of chromatin states, we uncover an extensive catalog of SOX10 targets genome-wide. Our findings reveal that SOX10 predominantly engages 'open' chromatin regions and binds to distal regulatory elements, including novel and previously known melanocyte enhancers. Integrated chromatin occupancy and transcriptome analysis suggest a role for SOX10 in both transcriptional activation and repression to regulate functionally distinct classes of genes. We demonstrate that distinct epigenetic signatures and cis-regulatory sequence motifs predicted to bind putative co-regulatory transcription factors define SOX10-activated and SOX10-repressed target genes. Collectively, these findings uncover a central role of SOX10 as a global regulator of gene expression in the melanocyte lineage by targeting diverse regulatory pathways. C1 [Fufa, Temesgen D.; Harris, Melissa L.; Watkins-Chow, Dawn E.; Levy, Denise; Loftus, Stacie K.; Pavan, William J.] NHGRI, GDRB, NIH, Bethesda, MD 20892 USA. [Gildea, Derek E.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Gorkin, David U.; Mccallion, Andrew S.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Song, Lingyun; Safi, Alexias; Crawford, Gregory E.] Duke Univ, Ctr Genom & Computat Biol, Durham, NC 27708 USA. [Song, Lingyun; Safi, Alexias; Crawford, Gregory E.] Duke Univ, Dept Pediat, Div Mol Genet, Durham, NC 27708 USA. [Sviderskaya, Elena V.; Bennett, Dorothy C.] Univ London, Mol Cell Sci Res Ctr, London SW17 0RE, England. RP Pavan, WJ (reprint author), NHGRI, GDRB, NIH, 49 Convent Dr,Room 4A82, Bethesda, MD 20892 USA. EM bpavan@mail.nih.gov RI Bennett, Dorothy/C-2418-2008; OI Bennett, Dorothy/0000-0002-3639-7527; Watkins-Chow, Dawn/0000-0002-4355-0868 FU National Human Genome Research Institute Intramural Research Program at the National Institutes of Health; National Institutes of Health [GM071648, NS062972, 1R21NS084336, R01DA036865]; Duke Institute for Brain Sciences; Wellcome Trust [064583] FX This work was supported by the National Human Genome Research Institute Intramural Research Program at the National Institutes of Health (T.D.F., D.E.W.-C., D.L., S.K.L., D.E.G. and W.J.P.), by the National Institutes of Health (K99/R00 Pathway to Independence Award to M.L.H., GM071648 and NS062972 to A.S.M and D.U.G., 1R21NS084336 and R01DA036865 to L.S., A.S. and G.E.C.); by the Duke Institute for Brain Sciences (L.S., A.S. and G.E.C.) and by the Wellcome Trust (064583 to D.C.B. and E.V.S.). NR 66 TC 2 Z9 2 U1 0 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 OCT 1 PY 2015 VL 24 IS 19 BP 5433 EP 5450 DI 10.1093/hmg/ddv267 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7TT UT WOS:000363018100006 PM 26206884 ER PT J AU Han, Y Hazelett, DJ Wiklund, F Schumacher, FR Stram, DO Berndt, SI Wang, ZM Rand, KA Hoover, RN Machiela, MJ Yeager, M Burdette, L Chung, CC Hutchinson, A Yu, K Xu, JF Travis, RC Key, TJ Siddiq, A Canzian, F Takahashi, A Kubo, M Stanford, JL Kolb, S Gapstur, SM Diver, WR Stevens, VL Strom, SS Pettaway, CA Al Olama, AA Kote-Jarai, Z Eeles, RA Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Chokkalingam, AP Isaacs, WB Chen, C Lindstrom, S Le Marchand, L Giovannucci, EL Pomerantz, M Long, H Li, FG Ma, J Stampfer, M John, EM Ingles, SA Kittles, RA Murphy, AB Blot, WJ Signorello, LB Zheng, W Albanes, D Virtamo, J Weinstein, S Nemesure, B Carpten, J Leske, MC Wu, SY Hennis, AJM Rybicki, BA Neslund-Dudas, C Hsing, AW Chu, LS Goodman, PJ Klein, EA Zheng, SL Witte, JS Casey, G Riboli, E Li, QY Freedman, ML Hunter, DJ Gronberg, H Cook, MB Nakagawa, H Kraft, P Chanock, SJ Easton, DF Henderson, BE Coetzee, GA Conti, DV Haiman, CA AF Han, Ying Hazelett, Dennis J. Wiklund, Fredrik Schumacher, Fredrick R. Stram, Daniel O. Berndt, Sonja I. Wang, Zhaoming Rand, Kristin A. Hoover, Robert N. Machiela, Mitchell J. Yeager, Merideth Burdette, Laurie Chung, Charles C. Hutchinson, Amy Yu, Kai Xu, Jianfeng Travis, Ruth C. Key, Timothy J. Siddiq, Afshan Canzian, Federico Takahashi, Atsushi Kubo, Michiaki Stanford, Janet L. Kolb, Suzanne Gapstur, Susan M. Diver, W. Ryan Stevens, Victoria L. Strom, Sara S. Pettaway, Curtis A. Al Olama, Ali Amin Kote-Jarai, Zsofia Eeles, Rosalind A. Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Chokkalingam, Anand P. Isaacs, William B. Chen, Constance Lindstrom, Sara Le Marchand, Loic Giovannucci, Edward L. Pomerantz, Mark Long, Henry Li, Fugen Ma, Jing Stampfer, Meir John, Esther M. Ingles, Sue A. Kittles, Rick A. Murphy, Adam B. Blot, William J. Signorello, Lisa B. Zheng, Wei Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Nemesure, Barbara Carpten, John Leske, M. Cristina Wu, Suh-Yuh Hennis, Anselm J. M. Rybicki, Benjamin A. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Zheng, S. Lilly Witte, John S. Casey, Graham Riboli, Elio Li, Qiyuan Freedman, Matthew L. Hunter, David J. Gronberg, Henrik Cook, Michael B. Nakagawa, Hidewaki Kraft, Peter Chanock, Stephen J. Easton, Douglas F. Henderson, Brian E. Coetzee, Gerhard A. Conti, David V. Haiman, Christopher A. TI Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions SO HUMAN MOLECULAR GENETICS LA English DT Article ID RISK-ASSOCIATED LOCI; WIDE ASSOCIATION; CAUSAL VARIANTS; TRANSETHNIC METAANALYSIS; SEQUENCE VARIANTS; GENE-EXPRESSION; ANALYSES REVEAL; COMMON VARIANT; MULTIPLE; IDENTIFICATION AB Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 x 10(-4)-5.6 x 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 x 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation. C1 [Han, Ying; Hazelett, Dennis J.; Schumacher, Fredrick R.; Stram, Daniel O.; Rand, Kristin A.; Ingles, Sue A.; Casey, Graham; Henderson, Brian E.; Coetzee, Gerhard A.; Conti, David V.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Schumacher, Fredrick R.; Stram, Daniel O.; Ingles, Sue A.; Casey, Graham; Henderson, Brian E.; Coetzee, Gerhard A.; Conti, David V.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Coetzee, Gerhard A.] Univ So Calif, Keck Sch Med, Dept Urol, Los Angeles, CA 90033 USA. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Berndt, Sonja I.; Wang, Zhaoming; Hoover, Robert N.; Machiela, Mitchell J.; Burdette, Laurie; Chung, Charles C.; Hutchinson, Amy; Yu, Kai; Albanes, Demetrius; Weinstein, Stephanie; Cook, Michael B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Yeager, Merideth; Burdette, Laurie; Hutchinson, Amy] SAIC Frederick Inc, NCI DCEG, Canc Genom Res Lab, Frederick, MD USA. [Xu, Jianfeng] NorthShore Univ HealthSyst, Program Personalized Canc Care, Evanston, IL USA. [Xu, Jianfeng] NorthShore Univ HealthSyst, Dept Surg, Evanston, IL USA. [Travis, Ruth C.; Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Takahashi, Atsushi] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Tokyo, Japan. [Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Tokyo, Japan. [Nakagawa, Hidewaki] RIKEN Ctr Integrat Med Sci, Lab Genome Sequencing Anal, Tokyo, Japan. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Gapstur, Susan M.; Diver, W. Ryan; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Pettaway, Curtis A.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Al Olama, Ali Amin; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, London SW3 6JB, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Korle Bu Teaching Hosp, Accra, Ghana. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Univ Ghana, Sch Med, Accra, Ghana. [Truelove, Ann; Niwa, Shelley] WESTAT Corp, Rockville, MD 20850 USA. [Chokkalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Isaacs, William B.] Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. [Isaacs, William B.] Inst Med, Baltimore, MD USA. [Chen, Constance; Lindstrom, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir; Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Pomerantz, Mark; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Long, Henry; Li, Fugen] Dana Farber Canc Inst, Dept Med Oncol, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Ma, Jing] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA. [Kittles, Rick A.] Univ Arizona, Coll Med, Tucson, AZ USA. [Kittles, Rick A.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Nemesure, Barbara; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anselm J. M.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Hennis, Anselm J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Rybicki, Benjamin A.; Neslund-Dudas, Christine] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. [Zheng, S. Lilly] Wake Forest Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen 361102, Peoples R China. RP Haiman, CA (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM haiman@usc.edu RI Cook, Michael/A-5641-2009; Kubo, Michiaki/N-7947-2015 OI Eeles, Rosalind/0000-0002-3698-6241; Machiela, Mitchell/0000-0001-6538-9705; Cook, Michael/0000-0002-0533-7302; FU National Institutes of Health (NIH), National Cancer Institute (NCI) GAME-ON U19 initiative for prostate cancer (ELLIPSE) [CA148537]; NIH/NCI [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics; NIH; NCI; U.S. Public Health Service from the NCI, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; Cancer Risk Prediction Center (CRisP); Linneus Centre - Swedish Research Council [70867902, K2010-70X-20430-04-3]; Swedish Cancer Foundation [09-0677]; Hedlund Foundation; Soderberg Foundation; Enqvist Foundation; Stockholm County Council; Stiftelsen Johanna Hagstrand och Sigfrid Linner's Minne; Karlsson's Fund for urological and surgical research; NIH [CA63464, CA54281, CA1326792, CA148085, HG004726, CA056678, CA082664, CA092579, ES011126, S06GM08016, CA092447, CA098758]; Division of Cancer Epidemiology and Genetics, NCI, NIH; Cancer Research Fund [99-00524V-10258]; Department of Health Services Cancer Research Program [97-12013, 98-00924V]; NCI, NIH, Department of Health and Human Services [N01-PC-35139]; California Department of Health Services [103885]; Centers for Disease Control and Prevention [1U58DP000807-3]; Fred Hutchinson Cancer Research Center; National Human Genome Research Institute; DOD [W81XWH-07-1-0122, DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066, W81XWH-10-1-0532]; American Cancer Society; Public Health Service from the National Cancer Institute [CA37429, 5UM1CA182883]; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); NIH/National Human Genome Research Institute [U01 HG004726-01]; Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government; Princess Takamatsu Cancer Research Fund; Takeda Science Foundation; [CA136924]; [CA68578]; [ES007784]; [DAMD W81XWH-07-1-0645]; [CA140388]; [U01 HG004446]; [R01 CA136924]; [R01 GM107427] FX This work was supported by the National Institutes of Health (NIH), National Cancer Institute (NCI) GAME-ON U19 initiative for prostate cancer (ELLIPSE, CA148537). The BPC3 was supported by NIH/NCI cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). ATBC, PEGASUS/PLCO and the Ghana Prostate Study were supported in part by the Intramural Research Program of the NIH and NCI. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the NCI, Department of Health and Human Services. CAPS was supported by the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council (grant no. K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no. 09-0677), the Hedlund Foundation, the Soderberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linner's Minne, Karlsson's Fund for urological and surgical research. The AAPC studies were supported as follows: The MEC and the genotyping in AAPC were supported by NIH grants CA63464, CA54281, CA1326792, CA148085 and HG004726. Functional annotation was supported by grant CA136924. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract # 98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health and Human Services, under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664 and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. MDA was support by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. GECAP was supported by NIH grant ES011126. CaP Genes was supported by CA88164 and CA127298. IPCG was support by DOD grant W81XWH-07-1-0122. DCPC was supported by NIH grant S06GM08016 and DOD grants DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066 and DOD W81XWH-10-1-0532. CPS-II is supported by the American Cancer Society. SELECT is funded by Public Health Service grants CA37429 and 5UM1CA182883 from the National Cancer Institute. SCCS is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt Ingram Cancer Center (CA68485).; Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. JAPC and LAPC were supported by NIH grants CA63464, CA54281 and CA098758, the NIH/National Human Genome Research Institute by U01 HG004726-01 and the Genome Coordinating Center was supported by U01 HG004446. BBJ was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government, and this study was supported in part by the Princess Takamatsu Cancer Research Fund and Takeda Science Foundation Award (to H.N.). G.A. Coetzee was supported by grant R01 CA136924 and M.L. Freedman was supported by grant R01 GM107427. We should like to thank all of the men who took part in these studies. NR 78 TC 7 Z9 7 U1 1 U2 8 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 OCT 1 PY 2015 VL 24 IS 19 BP 5603 EP 5618 DI 10.1093/hmg/ddv269 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CT7TT UT WOS:000363018100018 PM 26162851 ER PT J AU Schliep, KC Mumford, SL Peterson, CM Chen, Z Johnstone, EB Sharp, HT Stanford, JB Hammoud, AO Sun, L Louis, GMB AF Schliep, K. C. Mumford, S. L. Peterson, C. M. Chen, Z. Johnstone, E. B. Sharp, H. T. Stanford, J. B. Hammoud, A. O. Sun, L. Louis, G. M. Buck TI Pain typology and incident endometriosis SO HUMAN REPRODUCTION LA English DT Article DE endometriosis; epidemiology; laparoscopy; dysmenorrhea; dyspareunia ID CHRONIC PELVIC PAIN; DEEP INFILTRATING ENDOMETRIOSIS; DIAGNOSTIC LAPAROSCOPY; AMERICAN SOCIETY; INFERTILE WOMEN; SYMPTOMS; STAGE; CLASSIFICATION; LOCALIZATION; DYSMENORRHEA AB STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Mullerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomyatone of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (>= 30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. C1 [Schliep, K. C.; Mumford, S. L.; Chen, Z.; Sun, L.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Schliep, K. C.; Stanford, J. B.] Univ Utah, Sch Med, Dept Family & Prevent Med, Div Publ Hlth, Salt Lake City, UT 84108 USA. [Peterson, C. M.; Johnstone, E. B.; Sharp, H. T.; Hammoud, A. O.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Salt Lake City, UT 84108 USA. RP Schliep, KC (reprint author), 6100 Executive Blvd Room 7B05,MSC 7510, Rockville, MD 20852 USA. EM schliepkc2@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health [N01-DK-6-3428, N01-DK-6-3427, 10001406-02] FX This work was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (contract numbers N01-DK-6-3428, N01-DK-6-3427, and 10001406-02). Ethicon Endo-Surgery kindly donated the Harmonic Ace 36P shears and scalpel blades for use in the study through a signed materials transfer agreement with the University of Utah and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 5 Z9 5 U1 2 U2 4 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 OCT PY 2015 VL 30 IS 10 BP 2427 EP 2438 DI 10.1093/humrep/dev147 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CT8GG UT WOS:000363052400023 PM 26269529 ER PT J AU Bonow, RO Castelvecchio, S Panza, JA Berman, DS Velazquez, EJ Michler, RE She, LL Holly, TA Desvigne-Nickens, P Kosevic, D Rajda, M Chrzanowski, L Deja, M Lee, KL White, H Oh, JK Doenst, T Hill, JA Rouleau, JL Menicanti, L AF Bonow, Robert O. Castelvecchio, Serenella Panza, Julio A. Berman, Daniel S. Velazquez, Eric J. Michler, Robert E. She, Lilin Holly, Thomas A. Desvigne-Nickens, Patrice Kosevic, Dragana Rajda, Miroslaw Chrzanowski, Lukasz Deja, Marek Lee, Kerry L. White, Harvey Oh, Jae K. Doenst, Torsten Hill, James A. Rouleau, Jean L. Menicanti, Lorenzo CA STICH Trial Investigators TI Severity of Remodeling, Myocardial Viability, and Survival in Ischemic LV Dysfunction After Surgical Revascularization SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE coronary artery bypass surgery; coronary artery disease; heart failure; myocardial viability ID LEFT-VENTRICULAR DYSFUNCTION; CORONARY-ARTERY-DISEASE; CHRONIC HEART-FAILURE; CARDIAC RESYNCHRONIZATION THERAPY; BETA-BLOCKER THERAPY; HIBERNATING MYOCARDIUM; SYSTOLIC DYSFUNCTION; EJECTION FRACTION; VIABLE MYOCARDIUM; CONTROLLED-TRIAL AB OBJECTIVES This study sought to test the hypothesis that end-systolic volume (ESV), as a marker of severity of Left ventricular (LV) remodeling, influences the relationship between myocardial viability and survival in patients with coronary artery disease and LV systolic dysfunction. BACKGROUND Retrospective studies of ischemic LV dysfunction suggest that the severity of LV remodeling determines whether myocardial viability predicts improved survival with surgical compared with medical therapy, with coronary artery bypass grafting (CABG) only benefitting patients with viable myocardium who have smaller ESV. However, this has not been tested prospectively. METHODS Interactions of end-systolic volume index (ESVI), myocardial viability, and treatment with respect to survival were assessed in patients in the prospective randomized STICH (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease) trial of CABG versus medical therapy who underwent viability assessment (n = 601; age 61 +/- 9 years; ejection fraction <= 35%), with a median follow-up of 5.1 years. Median ESVI was 84 ml/m(2). Viability was assessed by single-photon emission computed tomography or dobutamine echocardiography using pre-specified criteria. RESULTS Mortality was highest among patients with Larger ESVI and nonviability (p < 0.001), but no interaction was observed between ESVI, viability status, and treatment assignment (p = 0.491). Specifically, the effect of CABG versus medical therapy in patients with viable myocardium and ESVI <= 84 ml/m(2) (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.56 to 1.29) was no different than in patients with viability and ESVI >84 ml/m(2) (HR: 0.87; 95% CI: 0.57 to 1.31). Other ESVI thresholds yielded similar results, including ESVI <= 60 ml/m(2) (HR: 0.87; 95% CI: 0.44 to 1.74). ESVI and viability assessed as continuous rather than dichotomous variables yielded similar results (p = 0.562). CONCLUSIONS Among patients with ischemic cardiomyopathy, those with greater LV ESVI and no substantial viability had worse prognosis. However, the effect of CABG relative to medical therapy was not differentially influenced by the combination of these 2 factors. Lower ESVI did not identify patients in whom myocardial viability predicted better outcome with CABG relative to medical therapy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595) (C) 2015 by the American College of Cardiology Foundation. C1 [Bonow, Robert O.; Holly, Thomas A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Castelvecchio, Serenella; Menicanti, Lorenzo] IRCCS, Policlin San Donato, Milan, Italy. [Panza, Julio A.] Westchester Med Ctr, Valhalla, NY USA. [Berman, Daniel S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Velazquez, Eric J.; She, Lilin; Lee, Kerry L.] Duke Univ, Durham, NC USA. [Michler, Robert E.] Montefiore Med Ctr, New York, NY USA. [Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 USA. [Kosevic, Dragana] Dedinje Cardiovasc Inst, Belgrade, Serbia. [Rajda, Miroslaw] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Chrzanowski, Lukasz] Med Univ Lodz, Lodz, Poland. [Deja, Marek] Med Univ Silesia, Katowice, Poland. [White, Harvey] Auckland City Hosp, Auckland, New Zealand. [Oh, Jae K.] Mayo Clin, Rochester, MN USA. [Doenst, Torsten] Univ Jena, Jena, Germany. [Hill, James A.] Univ Florida, Gainesville, FL USA. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. RP Bonow, RO (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, 251 East Huron St,Galter 3-150, Chicago, IL 60611 USA. EM r-bonow@northwestern.edu OI castelvecchio, serenella/0000-0001-5365-7063 FU National Heart, Lung, and Blood Institute (NHLBI) [U01 HL-069009, HL-069010, HL-069011, HL-069012, HL-069012-03, HL-069013, HL-069015, HL-070011, HL-072683]; Sanofi Aventis; Eli Lilly; National Institutes of Health; Merck Sharp Dohme; AstraZeneca; Daiichi-Sankyo; GlaxoSmithKline FX The STICH trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) through cooperative agreement mechanisms: U01 HL-069009, HL-069010, HL-069011, HL-069012, HL-069012-03, HL-069013, HL-069015, HL-070011, and HL-072683. The views expressed in this manuscript do not necessarily reflect those of the NHLBI or the National Institutes of Health. Dr. Berman has received royalties from Cedars-Sinai Medical Center for computer software. Dr. White has received research grants from Sanofi Aventis, Eli Lilly, National Institutes of Health, Merck Sharp & Dohme, AstraZeneca, Daiichi-Sankyo, and GlaxoSmithKline; and has served as a consultant for Astrazeneca. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 39 TC 10 Z9 10 U1 4 U2 9 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 OCT PY 2015 VL 8 IS 10 BP 1121 EP 1129 DI 10.1016/j.jcmg.2015.03.013 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CT8VX UT WOS:000363096100001 PM 26363840 ER PT J AU Murphy, CC Harlan, LC Lund, JL Lynch, CF Geiger, AM AF Murphy, Caitlin C. Harlan, Linda C. Lund, Jennifer L. Lynch, Charles F. Geiger, Ann M. TI Patterns of Colorectal Cancer Care in the United States: 1990-2010 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID III COLON-CANCER; ADJUVANT CHEMOTHERAPY USE; CLINICAL-PRACTICE GUIDELINES; RESECTABLE RECTAL-CANCER; STAGE-III; PREOPERATIVE RADIOTHERAPY; PHASE-III; POSTOPERATIVE CHEMORADIOTHERAPY; RADIATION-THERAPY; IMPROVED SURVIVAL AB Background: Colorectal cancer (CRC) mortality has declined in the United States, in part because of advances in treatment. Few studies have evaluated the adoption of therapies and temporal changes in patterns of care. Methods: Patients age 20 years and older diagnosed with stages II/III CRC were randomly sampled from the population-based Surveillance, Epidemiology, and End Results (SEER) program in 1990-1991, 1995, 2000, 2005, and 2010 (n = 7057). Therapy was obtained from medical records and physician verification. We described the receipt of chemotherapy and radiation therapy. Log-binomial regression was used to examine factors associated with therapy. All statistical tests were two-sided. Results: Chemotherapy receipt among colon cancer patients increased from 1990 (stage II: 22.5%; stage III: 56.3%) to 2005 (stage II: 32.1%; stage III: 72.4%) and declined slightly in 2010 (stage II: 29.3%; stage III: 66.4%). Stage III colon cancer patients who were older (vs <55 years, 75-79 years: risk ratio [RR] 0.81, 95% confidence interval [CI] = 0.71 to 0.91; >= 80 years: RR = 0.37, 95% CI = 0.28 to 0.47) or had a comorbidity score of 2 or higher (vs 0, RR = 0.56, 95% CI = 0.35 to 0.87) received chemotherapy less often. Receipt of radiation therapy by rectal cancer patients increased across all years from 45.5% to 66.1%. Increasing age (vs <55 years, 75-79 years: RR = 0.59, 95% CI = 0.47 to 0.74; >= 80 years: RR = 0.33, 95% CI = 0.25 to 0.45) was associated with lower chemoradiation use among stage II/III rectal cancer patients. Conclusion: Our findings demonstrate increased adoption of chemotherapy and radiation therapy for colon and rectal cancer patients and differences in therapy by age, comorbidity, and diagnosis year. Increased receipt of these therapies in the community may further reduce CRC mortality. C1 [Murphy, Caitlin C.; Lund, Jennifer L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Harlan, Linda C.; Geiger, Ann M.] NCI, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Murphy, CC (reprint author), Univ N Carolina, Gillings Sch Publ Hlth, Dept Epidemiol, 135 Dauer Dr,2101 McGavran Greenberg Hall,CB 7435, Chapel Hill, NC 27599 USA. EM caitlin_murphy@med.unc.edu FU National Institutes of Health [T32 DK07634]; National Cancer Institute [HHSN261201300019I, HHSN261201300005I, HHSN261201300011I, HHSN261201300015I, HHSN261201300014I, HHSN261201300009I, HHSN261201300020I, HHSN261201300013I, HHSN261201300004I, HHSN261201300016I, HHSN261201300021I, HHSN261201300010I, HHSN261201300012I, HHSN261201300017I] FX Grant Support: National Institutes of Health Grant T32 DK07634 (C. C. Murphy).; National Cancer Institute Contracts: HHSN261201300019I, HHSN261201300005I, HHSN261201300011I, HHSN261201300015I, HHSN261201300014I, HHSN261201300009I, HHSN261201300020I, HHSN261201300013I, HHSN261201300004I, HHSN261201300016I, HHSN261201300021I, HHSN261201300010I, HHSN261201300012I, HHSN261201300017I. NR 67 TC 7 Z9 7 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2015 VL 107 IS 10 AR djv198 DI 10.1093/jnci/djv198 PG 11 WC Oncology SC Oncology GA CU0KK UT WOS:000363204900007 ER PT J AU Shiels, MS Katki, HA Hildesheim, A Pfeiffer, RM Engels, EA Williams, M Kemp, TJ Caporaso, NE Pinto, LA Chaturvedi, AK AF Shiels, Meredith S. Katki, Hormuzd A. Hildesheim, Allan Pfeiffer, Ruth M. Engels, Eric A. Williams, Marcus Kemp, Troy J. Caporaso, Neil E. Pinto, Ligia A. Chaturvedi, Anil K. TI Circulating Inflammation Markers, Risk of Lung Cancer, and Utility for Risk Stratification SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; C-REACTIVE PROTEIN; RECEPTOR 2; DISEASE; BENEFITS; PATHWAY; CELLS AB Background: We conducted two independent nested case-control studies to identify circulating inflammation markers reproducibly associated with lung cancer risk and to investigate the utility of replicated markers for lung cancer risk stratification. Methods: Nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the previously published discovery study included 526 lung cancer patients and 592 control subjects and the replication study included 526 lung cancer case patients and 625 control subjects. Control subjects were matched by sex, age, smoking, study visit, and years of blood draw and exit. Serum levels of 51 inflammation markers were measured. Odds ratios (ORs) were estimated with conditional logistic regression. All statistical tests were two-sided. Results: Of 11 markers identified in the discovery study, C-reactive protein (CRP) (odds ratio [OR] [highest vs. lowest category] = 1.77, 95% confidence interval [CI] = 1.23 to 2.54), serum amyloid A (SAA) (OR = 1.88, 95% CI = 1.28 to 2.76), soluble tumor necrosis factor receptor-2 (sTNFRII) (OR = 1.70, 95% CI = 1.18 to 2.45), and monokine induced by gamma interferon (CXCL9/MIG) (OR = 2.09, 95% CI = 1.41 to 3.00) were associated with lung cancer risk in the replication study (P-trend < .01). In pooled analyses, CRP, SAA, and CXCL9/MIG remained associated with lung cancer more than six years before diagnosis (P-trend < .05). The incorporation of an inflammation score combining these four markers did not improve the sensitivity (77.6% vs 75.8%, P = .33) or specificity (56.1% vs 56.1%, P = .98) of risk-based lung cancer models. Conclusions: Circulating levels of CRP, SAA, sTNFRII, and CXCL9/MIG were reproducibly associated with lung cancer risk in two independent studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, underscoring an etiologic role for inflammation in lung carcinogenesis, though replication is needed in other populations. Markers did not improve lung cancer risk stratification beyond standard demographic and behavioral characteristics. C1 [Shiels, Meredith S.; Katki, Hormuzd A.; Hildesheim, Allan; Pfeiffer, Ruth M.; Engels, Eric A.; Caporaso, Neil E.; Chaturvedi, Anil K.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Williams, Marcus; Kemp, Troy J.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E-218,MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 33 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2015 VL 107 IS 10 AR djv199 DI 10.1093/jnci/djv199 PG 9 WC Oncology SC Oncology GA CU0KK UT WOS:000363204900008 ER PT J AU Weinberg, CR Zaykin, D AF Weinberg, Clarice R. Zaykin, Dmitri TI Clarice R. Weinberg, Dmitri Zaykin SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Weinberg, Clarice R.; Zaykin, Dmitri] NIEHS, Biostat & Computat Biol Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat & Computat Biol Branch, MD A3-03,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT PY 2015 VL 107 IS 10 AR djv228 DI 10.1093/jnci/djv228 PG 1 WC Oncology SC Oncology GA CU0KK UT WOS:000363204900018 ER PT J AU Lee, D Bergamaschi, MM Milman, G Barnes, AJ Queiroz, RHC Vandrey, R Huestis, MA AF Lee, Dayong Bergamaschi, Mateus M. Milman, Garry Barnes, Allan J. Queiroz, Regina H. C. Vandrey, Ryan Huestis, Marilyn A. TI Plasma Cannabinoid Pharmacokinetics After Controlled Smoking and Ad libitum Cannabis Smoking in Chronic Frequent Users SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID CONTROLLED SMOKED CANNABIS; MARIJUANA USERS; WHOLE-BLOOD; THC; DRUGS; DRIVERS; HEAVY; DELTA-9-TETRAHYDROCANNABINOL; PERFORMANCE; CRASHES AB More Americans are dependent on cannabis than any other illicit drug. The main analytes for cannabis testing include the primary psychoactive constituent, Delta(9) -tetrahydrocannabinol (THC), equipotent 11-hydroxy-THC (11-OH-THC) and inactive 11-nor-9-carboxy-THC (THCCOOH). Eleven adult chronic frequent cannabis smokers resided on a closed research unit with unlimited access to 5.9% THC cannabis cigarettes from 12: 00 to 23: 00 during two ad libitum smoking phases, followed by a 5-day abstinence period in seven participants. A single cigarette was smoked under controlled topography on the last day of the smoking and abstinence phases. Plasma cannabinoids were quantified by two-dimensional gas chromatography-mass spectrometry. Median plasma maximum concentrations (C-max) were 28.3 (THC), 3.9 (11-OH-THC) and 47.0 mu g/L (THCCOOH) 0.5 h after controlled single cannabis smoking. Median C-max 0.2-0.5 h after ad libitum smoking was higher for all analytes: 83.5 (THC), 14.2 (11-OH-THC) and 155 mu g/L (THCCOOH). All 11 participants' plasma samples were THC and THCCOOH-positive, 58.3% had THC >= 5 mu g/L and 79.2% were 11-OH-THC-positive 8.1-14 h after last cannabis smoking. Cannabinoid detection rates in seven participants 106-112 h (4-5 days) after last smoking were 92.9 (THC), 35.7 (11-OH-THC) and 100% (THCCOOH), with limits of quantification of 0.5 mg/L for THC and THCCOOH, and 1.0 mu g/L for 11-OH-THC. These data greatly expand prior research findings on cannabinoid excretion profiles in chronic frequent cannabis smokers during ad libitum smoking. Smoking multiple cannabis cigarettes led to higher C-max and AUC compared with smoking a single cigarette. The chronic frequent cannabis smokers exhibited extended detection windows for plasma cannabinoids, reflecting a large cannabinoid body burden. C1 [Lee, Dayong; Bergamaschi, Mateus M.; Milman, Garry; Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, Biomed Res Ctr,NIH, Baltimore, MD 21224 USA. [Bergamaschi, Mateus M.; Queiroz, Regina H. C.] Univ Sao Paulo, Sch Pharmaceut Sci, BR-14040903 Ribeirao Preto, SP, Brazil. [Vandrey, Ryan] Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, Biomed Res Ctr,NIH, 251 Bayview Blvd Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA) [R01 DA025044] FX This research was funded by the Intramural Research Program of the National Institute on Drug Abuse (the internal funding of NIDA for NIDA employees) and NIDA grant R01 DA025044 to R.V. NR 45 TC 1 Z9 1 U1 4 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-4760 EI 1945-2403 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD OCT PY 2015 VL 39 IS 8 SI SI BP 580 EP 587 DI 10.1093/jat/bkv082 PG 8 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA CU1AS UT WOS:000363252000001 PM 26378131 ER PT J AU Green, KA Werner, MD Franasiak, JM Juneau, CR Hong, KH Scott, RT AF Green, Katherine A. Werner, Marie D. Franasiak, Jason M. Juneau, Caroline R. Hong, Kathleen H. Scott, Richard T., Jr. TI Investigating the optimal preconception TSH range for patients undergoing IVF when controlling for embryo quality SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article DE Thyroid-stimulating hormone; Infertility; In vitro fertilization; Implantation; Live birth; Miscarriage ID THYROID-STIMULATING HORMONE; IN-VITRO FERTILIZATION; CONGENITAL UTERINE ANOMALIES; SUBCLINICAL HYPOTHYROIDISM; INFERTILE WOMEN; PREGNANCY; OUTCOMES; ASSOCIATION; DYSFUNCTION; MISCARRIAGE AB The ideal thyroid-stimulating hormone (TSH) range for infertile women attempting conception has not been determined. Current recommendations include optimizing the preconception TSH value to a parts per thousand currency sign2.5 mIU/L, which is the established goal for pregnant women. The aim of this study was to determine if there is a distinct range of TSH a parts per thousand currency sign2.5 mIU/L for infertile women undergoing in vitro fertilization (IVF) that improves reproductive outcomes. One thousand five hundred ninety-nine euploid blastocyst transfer cycles were evaluated in which TSH measurements were obtained 8 days after embryo transfer. Only euploid embryo transfers were included in an effort to control for embryo quality. Patients were separated into TSH groups utilizing 0.5 mIU/L increments. Implantation, live birth, and miscarriage rates among the TSH groups were compared. Outcomes for individuals on thyroid hormone supplementation and those not requiring supplementation were evaluated. There was no difference in implantation (p = 0.56), live birth (p = 0.36), or miscarriage rates (p = 0.10) between TSH groups. Receiver operating characteristic (ROC) curves for implantation, live birth, and miscarriage approached the line of no discrimination, signifying that there is no value of TSH within the recommended range for pregnancy (a parts per thousand currency sign2.5 mIU/L) that predicts IVF outcomes better than other values in this range. Live birth rates for patients requiring thyroid hormone supplementation and those not on medication were similar (p = 0.86). The recommended TSH range for pregnancy (a parts per thousand currency sign2.5 mIU/L) may be applied to infertile patients attempting conception without a need for further adjustment. C1 [Green, Katherine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Werner, Marie D.; Hong, Kathleen H.; Scott, Richard T., Jr.] Reprod Med Associates New Jersey, Basking Ridge, NJ 07920 USA. [Werner, Marie D.; Franasiak, Jason M.; Juneau, Caroline R.; Hong, Kathleen H.; Scott, Richard T., Jr.] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Obstet Gynecol & Reprod Sci, Div Reprod Endocrinol, New Brunswick, NJ 08901 USA. RP Green, KA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC,Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM katherine.green@nih.gov NR 23 TC 2 Z9 3 U1 1 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD OCT PY 2015 VL 32 IS 10 BP 1469 EP 1476 DI 10.1007/s10815-015-0549-4 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA CU1HZ UT WOS:000363272800006 PM 26280527 ER PT J AU Leaman, R Khare, R Lu, ZY AF Leaman, Robert Khare, Ritu Lu, Zhiyong TI Challenges in clinical natural language processing for automated disorder normalization SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Natural language processing; Electronic health records; Information extraction ID ELECTRONIC HEALTH RECORDS; TEXT; METAMAP; UMLS; FEASIBILITY; RECOGNITION AB Background: Identifying key variables such as disorders within the clinical narratives in electronic health records has wide-ranging applications within clinical practice and biomedical research. Previous research has demonstrated reduced performance of disorder named entity recognition (NER) and normalization (or grounding) in clinical narratives than in biomedical publications. In this work, we aim to identify the cause for this performance difference and introduce general solutions. Methods: We use closure properties to compare the richness of the vocabulary in clinical narrative text to biomedical publications. We approach both disorder NER and normalization using machine learning methodologies. Our NER methodology is based on linear-chain conditional random fields with a rich feature approach, and we introduce several improvements to enhance the lexical knowledge of the NER system. Our normalization method - never previously applied to clinical data - uses pairwise learning to rank to automatically learn term variation directly from the training data. Results: We find that while the size of the overall vocabulary is similar between clinical narrative and biomedical publications, clinical narrative uses a richer terminology to describe disorders than publications. We apply our system, DNorm-C, to locate disorder mentions and in the clinical narratives from the recent ShARe/CLEF eHealth Task. For NER (strict span-only), our system achieves precision = 0.797, recall = 0.713, f-score = 0.753. For the normalization task (strict span + concept) it achieves precision = 0.712, recall = 0.637, f-score = 0.672. The improvements described in this article increase the NER f-score by 0.039 and the normalization f-score by 0.036. We also describe a high recall version of the NER, which increases the normalization recall to as high as 0.744, albeit with reduced precision. Discussion: We perform an error analysis, demonstrating that NER errors outnumber normalization errors by more than 4-to-1. Abbreviations and acronyms are found to be frequent causes of error, in addition to the mentions the annotators were not able to identify within the scope of the controlled vocabulary. Conclusion: Disorder mentions in text from clinical narratives use a rich vocabulary that results in high term variation, which we believe to be one of the primary causes of reduced performance in clinical narrative. We show that pairwise learning to rank offers high performance in this context, and introduce several lexical enhancements - generalizable to other clinical NER tasks - that improve the ability of the NER system to handle this variation. DNorm-C is a high performing, open source system for disorders in clinical text, and a promising step toward NER and normalization methods that are trainable to a wide variety of domains and entities. (DNorm-C is open source software, and is available with a trained model at the DNorm demonstration website: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/tmTools/ #DNorm.) Published by Elsevier Inc. C1 [Leaman, Robert; Khare, Ritu; Lu, Zhiyong] NIH, NCBI, NLM, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), NIH, NCBI, NLM, MSC3825,Bldg 38A,Rm 1003A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM robert.leaman@nih.gov; ritu.khare@nih.gov; zhiyong.lu@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX The authors are grateful to the authors of the eHealth corpus, thank Dr. Chih-Hsuan Wei for his help preparing the demonstration website, and the anonymous reviewers for their insightful observations. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 44 TC 6 Z9 6 U1 3 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2015 VL 57 BP 28 EP 37 DI 10.1016/j.jbi.2015.07.010 PG 10 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA CU3PO UT WOS:000363437500004 PM 26187250 ER PT J AU Huser, V Sastry, C Breymaier, M Idriss, A Cimino, JJ AF Huser, Vojtech Sastry, Chandan Breymaier, Matthew Idriss, Asma Cimino, James J. TI Standardizing data exchange for clinical research protocols and case report forms: An assessment of the suitability of the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM) SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Clinical research informatics; Clinical protocol; Standards; Clinical trial; electronic Case Report Forms ID REPRESENTATION; CHALLENGES; TRIAL AB Efficient communication of a clinical study protocol and case report forms during all stages of a human clinical study is important for many stakeholders. An electronic and structured study representation format that can be used throughout the whole study life-span can improve such communication and potentially lower total study costs. The most relevant standard for representing clinical study data, applicable to unregulated as well as regulated studies, is the Operational Data Model (ODM) in development since 1999 by the Clinical Data Interchange Standards Consortium (CDISC). ODM's initial objective was exchange of case report forms data but it is increasingly utilized in other contexts. An ODM extension called Study Design Model, introduced in 2011, provides additional protocol representation elements. Using a case study approach, we evaluated ODM's ability to capture all necessary protocol elements during a complete clinical study lifecycle in the Intramural Research Program of the National Institutes of Health. ODM offers the advantage of a single format for institutions that deal with hundreds or thousands of concurrent clinical studies and maintain a data warehouse for these studies. For each study stage, we present a list of gaps in the ODM standard and identify necessary vendor or institutional extensions that can compensate for such gaps. The current version of ODM (1.3.2) has only partial support for study protocol and study registration data mainly because it is outside the original development goal. ODM provides comprehensive support for representation of case report forms (in both the design stage and with patient level data). Inclusion of requirements of observational, non-regulated or investigator-initiated studies (outside Food and Drug Administration (FDA) regulation) can further improve future revisions of the standard. Published by Elsevier Inc. C1 [Huser, Vojtech; Cimino, James J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [Sastry, Chandan] NIDDK, NIH, Bethesda, MD 20892 USA. [Breymaier, Matthew; Idriss, Asma] NICHHD, NIH, Bethesda, MD 20892 USA. [Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. RP Huser, V (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Ctr Clin, 10 Ctr Dr,Room 6-5561, Bethesda, MD 20892 USA. EM vojtech.huser@nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center; National Library of Medicine; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Diseases FX We would like to thank Dr. Lynnette Nieman and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) for support and permission to use the Raloxifene protocol document as a case study to illustrate protocol element representation in ODM. We would like to thank Robert Annechiarico, Thomas Caruso and the CTDB electronic data capture system team for their help with protocol case report forms. We would like to thank the BTRIS team for contributing relevant information regarding the NIH clinical research data repository. We would like to thank Sam Hume and Wayne Kubick for providing helpful comments on earlier drafts of the manuscript. VH and BC are supported by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Library of Medicine. MG and AI are supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. SC is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. NR 35 TC 5 Z9 5 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2015 VL 57 BP 88 EP 99 DI 10.1016/j.jbi.2015.06.023 PG 12 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA CU3PO UT WOS:000363437500010 PM 26188274 ER PT J AU Winnenburg, R Sorbello, A Ripple, A Harpaz, R Tonning, J Szarfman, A Francis, H Bodenreider, O AF Winnenburg, Rainer Sorbello, Alfred Ripple, Anna Harpaz, Rave Tonning, Joseph Szarfman, Ana Francis, Henry Bodenreider, Olivier TI Leveraging MEDLINE indexing for pharmacovigilance - Inherent limitations and mitigation strategies SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE MEDLINE indexing; Pharmacovigilance; Adverse drug events ID ADVERSE DRUG EVENTS; SAFETY; RECORDS; DESIGN; ADULTS AB Background: Traditional approaches to pharmacovigilance center on the signal detection from spontaneous reports, e.g., the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS). In order to enrich the scientific evidence and enhance the detection of emerging adverse drug events that can lead to unintended harmful outcomes, pharmacovigilance activities need to evolve to encompass novel complementary data streams, for example the biomedical literature available through MEDLINE. Objectives: (1) To review how the characteristics of MEDLINE indexing influence the identification of adverse drug events (ADEs); (2) to leverage this knowledge to inform the design of a system for extracting ADEs from MEDLINE indexing; and (3) to assess the specific contribution of some characteristics of MEDLINE indexing to the performance of this system. Methods: We analyze the characteristics of MEDLINE indexing. We integrate three specific characteristics into the design of a system for extracting ADEs from MEDLINE indexing. We experimentally assess the specific contribution of these characteristics over a baseline system based on co-occurrence between drug descriptors qualified by adverse effects and disease descriptors qualified by chemically induced. Results: Our system extracted 405,300 ADEs from 366,120 MEDLINE articles. The baseline system accounts for 297,093 ADEs (73%). 85,318 ADEs (21%) can be extracted only after integrating specific pre-coordinated MeSH descriptors and additional qualifiers. 22,889 ADEs (6%) can be extracted only after considering indirect links between the drug of interest and the descriptor that bears the ADE context. Conclusions: In this paper, we demonstrate significant improvement over a baseline approach to identifying ADEs from MEDLINE indexing, which mitigates some of the inherent limitations of MEDLINE indexing for pharmacovigilance. ADEs extracted from MEDLINE indexing are complementary to, not a replacement for, other sources. Published by Elsevier Inc. C1 [Winnenburg, Rainer; Ripple, Anna; Bodenreider, Olivier] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. [Sorbello, Alfred; Tonning, Joseph; Szarfman, Ana; Francis, Henry] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Silver Spring, MD 20993 USA. [Harpaz, Rave] Oracle Hlth Sci GBU, Bedford, MA 01730 USA. RP Bodenreider, O (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM olivier.bodenreider@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine (NLM); US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [XLM12011 001]; Office of Translational Sciences at CDER; U.S. Department of Energy; National Library of Medicine; NIH [U54-HG004028]; NIGMS [GM101430- 01A1] FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine (NLM). This work also received support from the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) Critical Path Program [interagency agreement with NLM (XLM12011 001)] and from the Office of Translational Sciences at CDER. RW was supported by an appointment to the NLM Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the National Library of Medicine. RH was employed by Stanford University while conducting this research, and acknowledges support by NIH grant U54-HG004028 for the National Center for Biomedical Ontology and by NIGMS grant GM101430- 01A1. NR 31 TC 4 Z9 4 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD OCT PY 2015 VL 57 BP 425 EP 435 DI 10.1016/j.jbi.2015.08.022 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA CU3PO UT WOS:000363437500036 PM 26342964 ER PT J AU Chan, JJ Cupples, LA Kiel, DP O'Donnell, CJ Hoffmann, U Samelson, EJ AF Chan, Jimmy J. Cupples, L. Adrienne Kiel, Douglas P. O'Donnell, Christopher J. Hoffmann, Udo Samelson, Elizabeth J. TI QCT Volumetric Bone Mineral Density and Vascular and Valvular Calcification: The Framingham Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE BONE; AGING; QCT; OSTEOPOROSIS; VASCULAR CALCIFICATION; VALVULAR CALCIFICATION; EPIDEMIOLOGY ID CORONARY-ARTERY CALCIUM; ABDOMINAL AORTIC CALCIFICATION; CARDIOVASCULAR-DISEASE; VALVE CALCIFICATION; COMPUTED-TOMOGRAPHY; TRABECULAR BONE; DEFICIENT MICE; RISK-FACTORS; GLA PROTEIN; LONG-TERM AB There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex-specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS > 0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events. (C) 2015 American Society for Bone and Mineral Research. C1 [Chan, Jimmy J.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kiel, Douglas P.; O'Donnell, Christopher J.; Hoffmann, Udo; Samelson, Elizabeth J.] Harvard Univ, Sch Med, Boston, MA USA. [Kiel, Douglas P.; Samelson, Elizabeth J.] Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA. [Kiel, Douglas P.; Samelson, Elizabeth J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [O'Donnell, Christopher J.; Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Samelson, EJ (reprint author), Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM samelson@hsl.harvard.edu OI Kiel, Douglas/0000-0001-8474-0310 FU National Institutes of Health [K01 AR053118]; Medical Student Training in Aging Research Grants [1T35AG038027-03, R01 AR053986, R01 AR41398]; National Heart, Lung, and Blood Institute [N01-HC-25195] FX This work was supported by National Institutes of Health Grant K01 AR053118; Medical Student Training in Aging Research Grants 1T35AG038027-03, R01 AR053986, and R01 AR41398; and National Heart, Lung, and Blood Institute's Framingham Heart Study Grant N01-HC-25195. NR 59 TC 7 Z9 7 U1 0 U2 2 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 OCT PY 2015 VL 30 IS 10 BP 1767 EP 1774 DI 10.1002/jbmr.2530 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU1MR UT WOS:000363286500004 PM 25871790 ER PT J AU Koide, H Holmbeck, K Lui, JC Guo, XXC Driggers, P Chu, T Tatsuno, I Quaglieri, C Kino, T Baron, J Young, MF Robey, PG Segars, JH AF Koide, Hisashi Holmbeck, Kenn Lui, Julian C. Guo, Xiaoxiao C. Driggers, Paul Chu, Tiffany Tatsuno, Ichiro Quaglieri, Caroline Kino, Tomoshige Baron, Jeffrey Young, Marian F. Robey, Pamela G. Segars, James H. TI Mice Deficient in AKAP13 (BRX) Are Osteoporotic and Have Impaired Osteogenesis SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOPOROSIS; BRX; RHO-GEF; OSTEOGENESIS; RUNX2 ID NUCLEOTIDE-EXCHANGE FACTORS; MARROW STROMAL CELLS; OSTEOBLAST DIFFERENTIATION; GENE-EXPRESSION; RHO-GTPASES; PROTEIN; ACTIVATION; KINASE; LBC; CBFA1 AB Mechanical stimulation is crucial to bone growth and triggers osteogenic differentiation through a process involving Rho and protein kinase A. We previously cloned a gene (AKAP13, aka BRX) encoding a protein kinase A-anchoring protein in the N-terminus, a guanine nucleotide-exchange factor for RhoA in the mid-section, coupled to a carboxyl region that binds to estrogen and glucocorticoid nuclear receptors. Because of the critical role of Rho, estrogen, and glucocorticoids in bone remodeling, we examined the multifunctional role of Akap13. Akap13 was expressed in bone, and mice haploinsufficient for Akap13 (Akap13(+/-)) displayed reduced bone mineral density, reduced bone volume/total volume, and trabecular number, and increased trabecular spacing; resembling the changes observed in osteoporotic bone. Consistent with the osteoporotic phenotype, Colony forming unit-fibroblast numbers were diminished in Akap13(+/-) mice, as were osteoblast numbers and extracellular matrix production when compared to control littermates. Transcripts of Runx2, an essential transcription factor for the osteogenic lineage, and alkaline phosphatase (Alp), an indicator of osteogenic commitment, were both reduced in femora of Akap13(+/-) mice. Knockdown of Akap13 reduced levels of Runx2 and Alp transcripts in immortalized bone marrow stem cells. These findings suggest that Akap13 haploinsufficient mice have a deficiency in early osteogenesis with a corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity. (C) 2015 American Society for Bone and Mineral Research. C1 [Koide, Hisashi; Guo, Xiaoxiao C.; Driggers, Paul; Chu, Tiffany; Quaglieri, Caroline; Kino, Tomoshige; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Reprod Endocrinol, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Holmbeck, Kenn; Young, Marian F.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Lui, Julian C.; Baron, Jeffrey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Tatsuno, Ichiro] Toho Univ, Sakura Med Ctr, Ctr Diabet Metab & Endocrinol, Chiba 2748510, Japan. RP Segars, JH (reprint author), Dept Gynecol & Obstet, Div Reprod Sci & Womens Hlth Res, 720 Rutland Ave,Room 624 Ross Bldg, Baltimore, MD 21205 USA. EM jsegars2@jhmi.edu RI Lui, Chun Kin Julian/E-2253-2012; Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Koide, Hisashi/0000-0002-8545-7530 FU Intramural NIH HHS [ZIA HD008737-09] NR 53 TC 1 Z9 2 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2015 VL 30 IS 10 BP 1887 EP 1895 DI 10.1002/jbmr.2534 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CU1MR UT WOS:000363286500017 PM 25892096 ER PT J AU Kaltman, JR Berul, CI AF Kaltman, Jonathan R. Berul, Charles I. TI Attention-Deficit Hyperactivity Disorder and Long-QT Syndrome: Risky Business SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE adrenergic side effect; attention-deficit hyperactivity disorder; congenital arrhythmia; long-QT syndrome; stimulants ID SUDDEN CARDIAC DEATH; DEFICIT/HYPERACTIVITY DISORDER; CARDIOVASCULAR EVENTS; STIMULANT MEDICATIONS; YOUNG-ADULTS; ADHD DRUGS; CHILDREN; ADOLESCENTS; STATEMENT; YOUTH C1 [Kaltman, Jonathan R.; Berul, Charles I.] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. [Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Berul, CI (reprint author), Childrens Natl Med Ctr, Div Cardiol, 111 Michigan Ave,NW, Washington, DC 20010 USA. EM cberul@childrensnational.org FU National Heart, Lung, and Blood Institute FX Dr. Kaltman is a full- time employee of the National Heart, Lung, and Blood Institute, which provided partial funding support for the article that is the subject of this editorial. The views expressed in this editorial are those of the author and do not necessarily reflect those of the NHLBI, the National Institutes of Health, or the U.S. Department of Health and Human Services. Dr. Berul: No disclosures. NR 25 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD OCT PY 2015 VL 26 IS 10 BP 1045 EP 1047 DI 10.1111/jce.12744 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CU0MR UT WOS:000363211600007 PM 26102514 ER PT J AU Leibovitch, EC Jacobson, S AF Leibovitch, Emily C. Jacobson, Steven TI Human Herpesvirus 6 as a Viral Trigger in Mesial Temporal Lobe Epilepsy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE human herpesvirus 6; viral trigger; epilepsy; MTLE; CNS infection; MTS; HHV-6B ID MULTIPLE-SCLEROSIS LESIONS; POLYMERASE-CHAIN-REACTION; HUMAN-HERPESVIRUS-6; ASTROCYTES; INFECTION; SEIZURE; VIRUS; EXPRESSION; CHILDREN; FEBSTAT C1 [Leibovitch, Emily C.; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Leibovitch, Emily C.] George Washington Univ, Sch Med & Hlth Sci, Inst Biomed Sci, Washington, DC 20052 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 28 TC 2 Z9 2 U1 0 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 OCT 1 PY 2015 VL 212 IS 7 BP 1011 EP 1013 DI 10.1093/infdis/jiv162 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0FK UT WOS:000363191300001 PM 25840442 ER PT J AU Cross, RW Fenton, KA Geisbert, JB Ebihara, H Mire, CE Geisbert, TW AF Cross, Robert W. Fenton, Karla A. Geisbert, Joan B. Ebihara, Hideki Mire, Chad E. Geisbert, Thomas W. TI Comparison of the Pathogenesis of the Angola and Ravn Strains of Marburg Virus in the Outbred Guinea Pig Model SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE filovirus; Marburg virus; Angola; Ravn; guinea pig; animal model; pathogenesis; coagulation ID EBOLA HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; SEPTIC SHOCK; INFECTION; DISEASE; SEPSIS; LETHAL; PROTECTION; PARTICLES; VACCINE AB Background. Phylogenetic comparisons of known Marburg virus (MARV) strains reveal 2 distinct genetic lineages: Ravn and the Lake Victoria Marburg complex (eg, Musoke, Popp, and Angola strains). Nucleotide variances of >20% between Ravn and other MARV genomes suggest that differing virulence between lineages may accompany this genetic divergence. To date, there exists limited systematic experimental evidence of pathogenic differences between MARV strains. Methods. Uniformly lethal outbred guinea pig models of MARV-Angola (MARV-Ang) and MARV-Ravn (MARV-Rav) were developed by serial adaptation. Changes in genomic sequence, weight, temperature, histopathologic findings, immunohistochemical findings, hematologic profiles, circulating biochemical enzyme levels, coagulation parameters, viremia levels, cytokine levels, eicanosoid levels, and nitric oxide production were compared between strains. Results. MARV-Rav infection resulted in delayed increases in circulating inflammatory and prothrombotic elements, notably lower viremia levels, less severe histologic alterations, and a delay in mean time to death, compared with MARV-Ang infection. Both strains produced more marked coagulation abnormalities than previously seen in MARV-infected mice or inbred guinea pigs. Conclusions. Although both strains exhibit great similarity to pathogenic markers of human and nonhuman primate MARV infection, these data highlight several key differences in pathogenicity that may serve to guide the choice of strain and model used for development of vaccines or therapeutics for Marburg hemorrhagic fever. C1 [Cross, Robert W.; Fenton, Karla A.; Geisbert, Joan B.; Mire, Chad E.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Cross, Robert W.; Fenton, Karla A.; Geisbert, Joan B.; Mire, Chad E.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Ebihara, Hideki] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, 301 Univ Blvd, Galveston, TX 77550 USA. EM twgeisbe@utmb.edu FU Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston; Intramural Research Program of the NIAID, NIH FX This work was supported by the Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston (to T. W. G.); and the Intramural Research Program of the NIAID, NIH (to H. E.). NR 31 TC 9 Z9 9 U1 0 U2 4 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 OCT 1 PY 2015 VL 212 SU 2 BP S258 EP S270 DI 10.1093/infdis/jiv182 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100025 PM 26092858 ER PT J AU Gabriel, G Feldmann, F Reimer, R Thiele, S Fischer, M Hartmann, E Bader, M Ebihara, H Hoenen, T Feldmann, H AF Gabriel, Guelsah Feldmann, Friederike Reimer, Rudolph Thiele, Swantje Fischer, Meike Hartmann, Enno Bader, Michael Ebihara, Hideki Hoenen, Thomas Feldmann, Heinz TI Importin-alpha 7 Is Involved in the Formation of Ebola Virus Inclusion Bodies but Is Not Essential for Pathogenicity in Mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; importin-alpha; inclusion bodies; pathogenicity; VP24; interferon; STAT1 ID HEMORRHAGIC-FEVER; NUCLEAR IMPORT; KARYOPHERIN ALPHA-1; PATHOGENESIS; STAT1; GLYCOPROTEINS; ACTIVATION; MODELS; SITE AB Ebola virus (EBOV) protein 24 antagonizes the host interferon (IFN) response by hijacking select nuclear importin-alpha isoforms. Thereby, it blocks STAT1-mediated IFN-alpha/beta and IFN-gamma synthesis. However, owing to the lack of importin-alpha knockout animal models in the past, their role in EBOV pathogenesis remained largely unknown. Here, we demonstrate that importin-alpha 7 is involved in the formation of EBOV inclusion bodies and replication. However, deletion of the gene encoding importin-alpha 7 was not sufficient to increase survival rates among mice infected with EBOV. C1 [Gabriel, Guelsah; Reimer, Rudolph; Thiele, Swantje; Fischer, Meike] Heinrich Pette Inst, Leibniz Inst Expt Virol, Viral Zoonoses & Adaptat, D-20251 Hamburg, Germany. [Gabriel, Guelsah; Hartmann, Enno; Bader, Michael] Univ Lubeck, Inst Biol, Ctr Struct & Cellular Biol Med, Lubeck, Germany. [Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Bader, Michael] Max Delbruck Ctr Mol Med, Berlin, Germany. [Ebihara, Hideki; Hoenen, Thomas; Feldmann, Heinz] NIAID, Virol Lab, NIH, Hamilton, MT USA. RP Gabriel, G (reprint author), Heinrich Pette Inst, Leibniz Inst Expt Virol, Martinistr 52, D-20251 Hamburg, Germany. EM guesah.gabriel@hpi.uni-hamburg.de FU Emmy-Noether Research Programme of the German Research Foundation [GA 1575/1-1]; Free and Hanseatic City of Hamburg; German Federal Ministry of Health; Intramural Research Program of NIAID, NIH FX This work was supported by the Emmy-Noether Research Programme of the German Research Foundation (grant GA 1575/1-1 to G. G.), the Free and Hanseatic City of Hamburg, the German Federal Ministry of Health, and the Intramural Research Program of NIAID, NIH. NR 26 TC 2 Z9 2 U1 0 U2 5 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 OCT 1 PY 2015 VL 212 SU 2 BP S316 EP S321 DI 10.1093/infdis/jiv240 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100031 PM 26185094 ER PT J AU Geisbert, TW Strong, JE Feldmann, H AF Geisbert, Thomas W. Strong, James E. Feldmann, Heinz TI Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; Marburg virus; filovirus; nonhuman primate; animal model; vaccine; treatment ID HEMORRHAGIC-FEVER; GUINEA-PIGS; AEROSOL EXPOSURE; MOUSE MODEL; DISEASE; ZAIRE; PATHOGENESIS; MONKEYS; LETHAL; PATHOLOGY AB The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions. C1 [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Feldmann, Heinz] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Strong, James E.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Strong, James E.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Strong, James E.] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, 301 Univ Blvd, Galveston, TX 77550 USA. EM twgeisbe@utmb.edu FU Department of Defense; University of Texas Medical Branch at Galveston; Canadian Center for Security Science; NIAID, NIH FX This work was supported by the Extramural Research Program (to T. W. G.) and Intramural Research Program (to H. F.), NIAID, NIH; the Department of Defense (to T. W. G.); the University of Texas Medical Branch at Galveston (to T. W. G.); the Canadian Center for Security Science (to J. E. S.). NR 41 TC 17 Z9 17 U1 1 U2 14 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 OCT 1 PY 2015 VL 212 SU 2 BP S91 EP S97 DI 10.1093/infdis/jiv284 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100003 PM 26063223 ER PT J AU Hernandez, H Marceau, C Halliday, H Callison, J Borisevich, V Escaffre, O Creech, J Feldmann, H Rockx, B AF Hernandez, Humberto Marceau, Caleb Halliday, Hailey Callison, Julie Borisevich, Viktoriya Escaffre, Olivier Creech, Jeffrey Feldmann, Heinz Rockx, Barry TI Development and Characterization of Broadly Cross-reactive Monoclonal Antibodies Against All Known Ebolavirus Species SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebolavirus; cross-reactive; antibody ID MEDIATED PROTECTION; VIRUS; CHALLENGE; EPITOPES; LEVEL AB As of 25 March 2015, the largest recorded outbreak of Ebola virus infection is ongoing, with almost 25 000 cases and >10 000 deaths. There are 5 genetically and antigenically distinct species within the genus Ebolavirus. Limited cross-reactivity and protection is observed between these 5 Ebolavirus species, which complicates vaccine development. However, on the basis of sequence homology between the 5 Ebolavirus species, we hypothesize that conserved epitopes are present on the viral glycoprotein (GP), which can be targeted by antibodies. In the current study, a panel of mouse monoclonal antibodies was isolated and characterized using an enzyme-linked immunosorbent assay (ELISA) to determine cross-reactivity, avidity, and competition for epitope binding; Western blot analysis was also performed. Four monoclonal antibodies were identified by ELISA as crossreacting with the GPs of all 5 Ebolavirus species. The identification of cross-reactive antibodies that bind the GPs of all known Ebolavirus species will give us important insight into the presence of conserved epitopes on the viral GP. These data will be crucial for the development of novel therapeutics and diagnostic assays. C1 [Hernandez, Humberto; Halliday, Hailey; Borisevich, Viktoriya; Escaffre, Olivier; Creech, Jeffrey; Rockx, Barry] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Marceau, Caleb; Callison, Julie; Feldmann, Heinz; Rockx, Barry] NIAID, Virol Lab, Div Intramural Res, Hamilton, MT USA. [Rockx, Barry] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, Dept Rare & Emerging Viral Infect & Response, NL-3720 BA Bilthoven, Netherlands. RP Rockx, B (reprint author), Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, Dept Rare & Emerging Viral Infect & Response, POB 1, NL-3720 BA Bilthoven, Netherlands. EM barry.rockx@rivm.nl FU University of Texas Medical Branch; Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the University of Texas Medical Branch and the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 12 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2015 VL 212 SU 2 BP S410 EP S413 DI 10.1093/infdis/jiv209 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100045 PM 25999057 ER PT J AU Hill-Batorski, L Halfmann, P Marzi, A Lopes, TJS Neumann, G Feldmann, H Kawaoka, Y AF Hill-Batorski, Lindsay Halfmann, Peter Marzi, Andrea Lopes, Tiago J. S. Neumann, Gabriele Feldmann, Heinz Kawaoka, Yoshihiro TI Loss of Interleukin 1 Receptor Antagonist Enhances Susceptibility to Ebola Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; interleukin 1 receptor antagonist; Il1rn; IL-1Ra ID COLONY-STIMULATING FACTOR; HEMORRHAGIC-FEVER; NEUTROPHIL RECRUITMENT; INFLAMMATORY RESPONSE; MOUSE MODEL; GENE; MICE; PATHOGENESIS; EXPRESSION; IL-1-BETA AB The current outbreak of Ebola virus (EBOV) infection in West Africa is unprecedented, with nearly 26 000 confirmed cases and >10 000 deaths. Comprehensive data on the pathogenesis of EBOV infection are lacking; however, recent studies suggested that fatal EBOV infections are characterized by dysregulation of the innate immune response and a subsequent cytokine storm. Specifically, several studies suggested that hypersecretion of interleukin 1 receptor antagonist (IL-1Ra) correlates with lethal EBOV infections. To examine the significance of IL-1Ra in EBOV infections, we infected mice that lack the gene encoding IL-1Ra, Il1rn (IL-1RNKO), and mice with wild-type Il1rn (IL-1RN-WT) with a mouse-adapted EBOV (MA-EBOV). Infected IL-1RN-KO mice lost more weight and had a lower survival rate than IL-1RN-WT mice infected with MA-EBOV. In addition, IL-1RN-KO mice infected with wild-type EBOV, which does not cause lethal infection in adult immunocompetent mice, such as C57BL/6 mice, experienced greater weight loss than IL-1RN-WT mice infected with wild-type EBOV. Further studies revealed that the levels of 6 cytokines in spleens-IL-1 alpha, IL-1 beta, interleukin 12p40, interleukin 17, granulocyte colony-stimulating factor, and regulated on activation, normal T-cell expressed and secreted-were significantly different between IL-1RN-KO mice and IL-1RN-WT mice infected with MA-EBOV. Collectively, our data suggest that IL-1Ra may have a protective effect upon EBOV infection, likely by damping an overactive proinflammatory immune response. C1 [Hill-Batorski, Lindsay; Halfmann, Peter; Lopes, Tiago J. S.; Neumann, Gabriele; Kawaoka, Yoshihiro] Univ Wisconsin, Influenza Res Inst, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Marzi, Andrea; Feldmann, Heinz] NIAID, Div Intramural Res, Virol Lab, NIH, Hamilton, MT USA. [Lopes, Tiago J. S.; Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Microbiol & Immunol,Div Virol, Tokyo 1138654, Japan. [Kawaoka, Yoshihiro] Japan Sci & Technol Agcy, ERATO Infect Induced Host Responses Project, Saitama, Japan. RP Kawaoka, Y (reprint author), 575 Sci Dr, Madison, WI 53711 USA. EM kawaokay@svm.vetmed.wisc.edu FU National Institutes of Health (NIH) [5 U19 AI106772-02]; National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the National Institutes of Health (NIH; project5 U19 AI106772-02) and by the intramural research program of the National Institute of Allergy and Infectious Diseases, NIH. NR 48 TC 2 Z9 2 U1 0 U2 6 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 OCT 1 PY 2015 VL 212 SU 2 BP S329 EP S335 DI 10.1093/infdis/jiv335 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100033 PM 26209680 ER PT J AU Hoenen, T Marzi, A Scott, DP Feldmann, F Callison, J Safronetz, D Ebihara, H Feldmann, H AF Hoenen, Thomas Marzi, Andrea Scott, Dana P. Feldmann, Friederike Callison, Julie Safronetz, David Ebihara, Hideki Feldmann, Heinz TI Soluble Glycoprotein Is Not Required for Ebola Virus Virulence in Guinea Pigs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE ebola virus; soluble glycoprotein; sGP; virulence; guinea pigs; recombinant virus; reverse genetics; mRNA editing ID RNA; GP AB Ebola virus (EBOV) uses transcriptional editing to express several glycoproteins (GPs), including secreted soluble GP (sGP) and structural GP(1,2), from a single gene. Recombinant viruses predominantly expressing GP1,2 are known to rapidly mutate and acquire an editing site predominantly expressing sGP in vivo, suggesting an important role of this protein during infection. Therefore, we generated a recombinant virus that is no longer able to express sGP and assessed its virulence in the EBOV guinea pig model. Surprisingly, although this virus remained genetically stable, it did not show any significant attenuation in vivo, showing that sGP is not required for virulence in this model. C1 [Hoenen, Thomas; Marzi, Andrea; Callison, Julie; Safronetz, David; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, NIH, Hamilton, MT USA. [Scott, Dana P.; Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. RP Hoenen, T (reprint author), Rocky Mt Labs, Virol Lab, 903 S 4th St Hamilton, Hamilton, MT 59840 USA. EM thomas.hoenen@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural Research Program of National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 17 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2015 VL 212 SU 2 BP S242 EP S246 DI 10.1093/infdis/jiv111 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100023 PM 25957965 ER PT J AU Jahrling, PB Hensley, LE Barrett, K Lane, HC Davey, RT AF Jahrling, Peter B. Hensley, Lisa E. Barrett, Kevin Lane, Henry Clifford Davey, Richard T. TI State-of-the-Art Workshops on Medical Countermeasures Potentially Available for Human Use Following Accidental Exposures to Ebola Virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE antisense; Ebola virus; medical countermeasures; monoclonal antibody; randomized clinical trial; siRNA ID NONHUMAN-PRIMATES; HEMORRHAGIC-FEVER; POSTEXPOSURE PROTECTION; INFECTION; INHIBITOR; THERAPIES; MONKEYS; DISEASE AB The ongoing outbreak of Ebola in West Africa has raised a general awareness that at present there are no Ebola-specific medical countermeasures (MCMs) with proven effectiveness. This paper recapitulates discussions held at the 6th International Filovirus Symposium in March 2014 as well as the subsequent design of a randomized clinical trial design for treating Ebola virus-infected patients evacuated from West Africa to the United States. A number of different drugs or biologics were critically reviewed and 3 different postexposure strategies were identified as being farthest along in development; passive immunotherapy with monoclonal antibodies, postexposure vaccination with constructs involving viral vectors (such as vesicular stomatitis virus), and antisense compounds directly targeting the viral genome such as modified phosphorodiamidate morpholino oligomer-based compounds and small interfering RNA products. At the time of the meetings, there were no investigational new drugs (INDs) in place for the candidate MCMs. Developers and sponsors of these candidate products were strongly encouraged to prepare pre-IND packets and submit pre-IND meeting requests to the Food and Drug Administration. Some of these investigational products have already been used under emergency authorizations to treat patients in Africa as well as patients evacuated to the United States or Western Europe. C1 [Jahrling, Peter B.; Hensley, Lisa E.] NIAID, Integrated Res Facil, Bethesda, MD 20892 USA. [Barrett, Kevin; Lane, Henry Clifford; Davey, Richard T.] NIAID, Div Clin Res, Bethesda, MD 20892 USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil, 8200 Res Plaza, Frederick, MD 21702 USA. EM jahrlingp@niaid.nih.gov FU program of National Institutes of Health, National Institute of Allergy and Infectious Disease, Division of Clinical Research FX This work was supported by the intramural program of National Institutes of Health, National Institute of Allergy and Infectious Disease, Division of Clinical Research. NR 26 TC 6 Z9 6 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 OCT 1 PY 2015 VL 212 SU 2 BP S84 EP S90 DI 10.1093/infdis/jiv115 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100002 PM 25957962 ER PT J AU Marzi, A Kercher, L Marceau, J York, A Callsion, J Gardner, DJ Geisbert, TW Feldmann, H AF Marzi, Andrea Kercher, Lisa Marceau, Joshua York, Anthony Callsion, Julie Gardner, Donald J. Geisbert, Thomas W. Feldmann, Heinz TI Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Vesicular stomatitis virus; Ebolavirus; Marburgvirus; vaccine; Stat1-deficient mice ID EBOLA; INFECTION AB Stat1(-/-) mice lack a response to interferon alpha, beta, and gamma, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. C1 [Marzi, Andrea; Marceau, Joshua; York, Anthony; Callsion, Julie; Feldmann, Heinz] NIAID, Rocky Mt Labs, Virol Lab, NIH, Hamilton, MT 59840 USA. [Kercher, Lisa; Gardner, Donald J.] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, Hamilton, MT 59840 USA. [Marceau, Joshua] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Marzi, A (reprint author), NIAID, Rocky Mt Labs, Virol Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM marzia@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was funded by the Division of Intramural Research, NIAID, NIH. NR 14 TC 3 Z9 3 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 OCT 1 PY 2015 VL 212 SU 2 BP S404 EP S409 DI 10.1093/infdis/jiv188 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100044 PM 26022440 ER PT J AU Matassov, D Marzi, A Latham, T Xu, R Ota-Setlik, A Feldmann, F Geisbert, JB Mire, CE Hamm, S Nowak, B Egan, MA Geisbert, TW Eldridge, JH Feldmann, H Clarke, DK AF Matassov, Demetrius Marzi, Andrea Latham, Terri Xu, Rong Ota-Setlik, Ayuko Feldmann, Friederike Geisbert, Joan B. Mire, Chad E. Hamm, Stefan Nowak, Becky Egan, Michael A. Geisbert, Thomas W. Eldridge, John H. Feldmann, Heinz Clarke, David K. TI Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE attenuation; rVSV vector; Ebola vaccine; glycoprotein; challenge; nonhuman primates ID NONHUMAN-PRIMATES; PHLEBOTOMINE SANDFLIES; GENE TRANSLOCATIONS; SINGLE IMMUNIZATION; ANTIVIRAL DEFENSE; INDIANA SEROTYPE; MARBURG VIRUSES; GUINEA-PIGS; INFECTION; VACCINES AB Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7-9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines. C1 [Matassov, Demetrius; Latham, Terri; Hamm, Stefan; Nowak, Becky; Eldridge, John H.; Clarke, David K.] Profectus BioSci, Dept Virol & Vaccine Vectors, Tarrytown, NY 10591 USA. [Xu, Rong; Ota-Setlik, Ayuko; Egan, Michael A.; Eldridge, John H.] Profectus BioSci, Dept Immunol, Tarrytown, NY 10591 USA. [Marzi, Andrea; Feldmann, Heinz] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Feldmann, Friederike] NIAID, Rocky Mt Labs, Rocky Mt Vet Branch, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Geisbert, Joan B.; Mire, Chad E.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Geisbert, Joan B.; Mire, Chad E.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Matassov, D (reprint author), Profectus BioSci, Dept Virol & Vaccine Vectors, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. EM dmatassov@profectusbiosciences.com FU Profectus BioSciences and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by Profectus BioSciences and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 50 TC 6 Z9 7 U1 4 U2 20 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 OCT 1 PY 2015 VL 212 SU 2 BP S443 EP S451 DI 10.1093/infdis/jiv316 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100049 PM 26109675 ER PT J AU Ogawa, H Miyamoto, H Nakayama, E Yoshida, R Nakamura, I Sawa, H Ishii, A Thomas, Y Nakagawa, E Matsuno, K Kajihara, M Maruyama, J Nao, N Muramatsu, M Kuroda, M Simulundu, E Changula, K Hang'ombe, B Namangala, B Nambota, A Katampi, J Igarashi, M Ito, K Feldmann, H Sugimoto, C Moonga, L Mweene, A Takada, A AF Ogawa, Hirohito Miyamoto, Hiroko Nakayama, Eri Yoshida, Reiko Nakamura, Ichiro Sawa, Hirofumi Ishii, Akihiro Thomas, Yuka Nakagawa, Emiko Matsuno, Keita Kajihara, Masahiro Maruyama, Junki Nao, Naganori Muramatsu, Mieko Kuroda, Makoto Simulundu, Edgar Changula, Katendi Hang'ombe, Bernard Namangala, Boniface Nambota, Andrew Katampi, Jackson Igarashi, Manabu Ito, Kimihito Feldmann, Heinz Sugimoto, Chihiro Moonga, Ladslav Mweene, Aaron Takada, Ayato TI Seroepidemiological Prevalence of Multiple Species of Filoviruses in Fruit Bats (Eidolon helvum) Migrating in Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; Marburg virus; filovirus; specific antibody; fruit bat; Zambia ID EBOLA-VIRUS; ANTIBODY PREVALENCE; GLYCOPROTEIN AB Fruit bats are suspected to be a natural reservoir of filoviruses, including Ebola and Marburg viruses. Using an enzyme-linked immunosorbent assay based on the viral glycoprotein antigens, we detected filovirus-specific immunoglobulin G antibodies in 71 of 748 serum samples collected from migratory fruit bats (Eidolon helvum) in Zambia during 2006-2013. Although antibodies to African filoviruses (eg, Zaire ebolavirus) were most prevalent, some serum samples showed distinct specificity for Reston ebolavirus, which that has thus far been found only in Asia. Interestingly, the transition of filovirus species causing outbreaks in Central and West Africa during 2005-2014 seemed to be synchronized with the change of the serologically dominant virus species in these bats. These data suggest the introduction of multiple species of filoviruses in the migratory bat population and point to the need for continued surveillance of filovirus infection of wild animals in sub-Saharan Africa, including hitherto nonendemic countries. C1 [Ogawa, Hirohito; Ishii, Akihiro; Thomas, Yuka; Nakagawa, Emiko; Moonga, Ladslav] Hokudai Ctr Zoonosis Control, Lusaka, Zambia. [Ogawa, Hirohito; Nakamura, Ichiro; Sawa, Hirofumi; Ishii, Akihiro; Thomas, Yuka; Nakagawa, Emiko; Simulundu, Edgar; Nambota, Andrew; Sugimoto, Chihiro; Mweene, Aaron; Takada, Ayato] Univ Zambia, Sch Vet Med, Dept Dis Control, Lusaka, Zambia. [Changula, Katendi; Hang'ombe, Bernard; Namangala, Boniface; Moonga, Ladslav] Univ Zambia, Sch Vet Med, Dept Paraclin Studies, Lusaka, Zambia. [Katampi, Jackson] Zambia Wildlife Author, Chilanga, Zambia. [Miyamoto, Hiroko; Nakayama, Eri; Yoshida, Reiko; Matsuno, Keita; Kajihara, Masahiro; Maruyama, Junki; Nao, Naganori; Muramatsu, Mieko; Kuroda, Makoto; Igarashi, Manabu; Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido 0010020, Japan. [Nakamura, Ichiro; Sugimoto, Chihiro] Hokkaido Univ, Res Ctr Zoonosis Control, Div Collaborat & Educ, Sapporo, Hokkaido 0010020, Japan. [Sawa, Hirofumi] Hokkaido Univ, Res Ctr Zoonosis Control, Div Mol Pathobiol, Sapporo, Hokkaido 0010020, Japan. [Ito, Kimihito] Hokkaido Univ, Res Ctr Zoonosis Control, Div Bioinformat, Sapporo, Hokkaido 0010020, Japan. [Sawa, Hirofumi; Matsuno, Keita; Igarashi, Manabu; Ito, Kimihito; Sugimoto, Chihiro; Takada, Ayato] Hokkaido Univ, Global Inst Collaborat Res & Educ, Global Stn Zoonosis Control, Sapporo, Hokkaido 0010020, Japan. [Hang'ombe, Bernard; Mweene, Aaron] Southern African Ctr Infect Dis Surveillance, Morogoro, Tanzania. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Kita Ku, Kita 20,Nishi 10, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp RI Ogawa, Hirohito/F-6918-2012; YOSHIDA, Reiko/F-6883-2012; Maruyama, Junki/H-7993-2013; Sawa, Hirofumi/F-6954-2012; Sugimoto, Chihiro/F-6583-2012; Ito, Kimihito/E-9975-2012 OI Sugimoto, Chihiro/0000-0002-8708-0140; Ito, Kimihito/0000-0003-4986-1795 FU Japan Initiative for Global Research Network on Infectious Diseases; Japan Science and Technology Agency; Japan International Cooperation Agency; Global Center Of Excellence Program "Establishment of International Collaboration Centers for Zoonosis Control" from Ministry of Education, Culture, Sports, Science and Technology, Japan [F-001]; Science and Technology Research Partnership for Sustainable Development FX This work was supported by the Japan Initiative for Global Research Network on Infectious Diseases, the Japan Science and Technology Agency, and the Japan International Cooperation Agency within the framework of the Science and Technology Research Partnership for Sustainable Development. Funding was also provided by the Global Center Of Excellence Program "Establishment of International Collaboration Centers for Zoonosis Control" (grant F-001) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. NR 25 TC 15 Z9 15 U1 4 U2 31 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 OCT 1 PY 2015 VL 212 SU 2 BP S101 EP S108 DI 10.1093/infdis/jiv063 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100005 PM 25786916 ER PT J AU Prescott, J Falzarano, D Feldmann, H AF Prescott, Joseph Falzarano, Darryl Feldmann, Heinz TI Natural Immunity to Ebola Virus in the Syrian Hamster Requires Antibody Responses SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; immune response; antibody; T cell ID NONHUMAN-PRIMATES; FILOVIRUS INFECTION; HEMORRHAGIC-FEVER; PROTECTION; MICE; MODEL AB Most ebolaviruses can cause severe disease in humans and other primates, with high case fatality rates during human outbreaks. Although these viruses have been studied for almost 4 decades, little is know regarding the mechanisms by which they cause disease and what is important for protection or treatment after infection. Because of the sporadic nature of the outbreaks and difficulties accessing the populations affected by ebolaviruses, little is also known about what constitutes an appropriate immune response to infection in humans that survive infection. Such knowledge would allow a targeted approach to therapies. In contrast to humans, rodents are protected from disease on infection with ebolaviruses, although adapted versions of some of the viruses are lethal in mice, hamsters and guinea pigs. Using the recently described hamster model, along with T-cell depletion strategies, we show that CD4(+) T cells are required for natural immunity to Ebola virus infection and that CD4-dependent antibody responses are required for immunity in this model. C1 [Prescott, Joseph; Falzarano, Darryl; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP Feldmann, H (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov FU Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 19 TC 1 Z9 1 U1 1 U2 12 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 OCT 1 PY 2015 VL 212 SU 2 BP S271 EP S276 DI 10.1093/infdis/jiv203 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100026 PM 25948862 ER PT J AU Sprecher, AG Caluwaerts, A Draper, M Feldmann, H Frey, CP Funk, RH Kobinger, G Le Duc, JW Spiropoulou, C Williams, WJ AF Sprecher, Armand G. Caluwaerts, An Draper, Mike Feldmann, Heinz Frey, Clifford P. Funk, Renee H. Kobinger, Gary Le Duc, James W. Spiropoulou, Christina Williams, Warren Jon TI Personal Protective Equipment for Filovirus Epidemics: A Call for Better Evidence SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola; heat stress disorders; hemorrhagic fever; protective clothing AB Personal protective equipment (PPE) is an important part of worker protection during filovirus outbreaks. The need to protect against a highly virulent fluid-borne pathogen in the tropical environment imposes a heat stress on the wearer that is itself a safety risk. No evidence supports the choice of PPE employed in recent outbreaks, and standard testing procedures employed by the protective garment industry do not well simulate filovirus exposure. Further research is needed to determine the appropriate PPE for filoviruses and the heat stress that it imposes. C1 [Sprecher, Armand G.; Caluwaerts, An] Med Sans Frontieres, Operat Ctr Brussels, B-1050 Brussels, Belgium. [Draper, Mike] Microgard Ltd, Kingston Upon Hull, Yorks, England. [Feldmann, Heinz] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Frey, Clifford P.] Personal Safety Div, St Paul, MN USA. [Funk, Renee H.] NIOSH, Emergency Preparedness & Response Off, Atlanta, GA USA. [Kobinger, Gary] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens, Winnipeg, MB, Canada. [Le Duc, James W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Spiropoulou, Christina] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Atlanta, GA USA. [Williams, Warren Jon] NIOSH, Human Factors & Ergon Lab, Pittsburgh, PA USA. RP Sprecher, AG (reprint author), Med Sans Frontieres, Dept Med, Rue Arbre Benit 46, B-1050 Brussels, Belgium. EM armand.sprecher@brussels.msf.org FU Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health. FX No financial support was provided from any external agency for this meeting. H. F. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 7 TC 9 Z9 9 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2015 VL 212 SU 2 BP S98 EP S100 DI 10.1093/infdis/jiv153 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100004 PM 25821225 ER PT J AU Tsuda, Y Hoenen, T Banadyga, L Weisend, C Ricklefs, SM Porcella, SF Ebihara, H AF Tsuda, Yoshimi Hoenen, Thomas Banadyga, Logan Weisend, Carla Ricklefs, Stacy M. Porcella, Stephen F. Ebihara, Hideki TI An Improved Reverse Genetics System to Overcome Cell-Type-Dependent Ebola Virus Genome Plasticity SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; reverse genetics system; mutation; RNA editing site ID REPLICATION; RNA; TRANSCRIPTION; GLYCOPROTEIN; POLYMERASE; PARTICLES; RECOVERY; CULTURE AB Reverse genetics systems represent a key technique for studying replication and pathogenesis of viruses, including Ebola virus (EBOV). During the rescue of recombinant EBOV from Vero cells, a high frequency of mutations was observed throughout the genomes of rescued viruses, including at the RNA editing site of the glycoprotein gene. The influence that such genomic instability could have on downstream uses of rescued virus may be detrimental, and we therefore sought to improve the rescue system. Here we report an improved EBOV rescue system with higher efficiency and genome stability, using a modified full-length EBOV clone in Huh7 cells. Moreover, by evaluating a variety of cells lines, we revealed that EBOV genome instability is cell-type dependent, a fact that has significant implications for the preparation of standard virus stocks. Thus, our improved rescue system will have an impact on both basic and translational research in the filovirus field. C1 [Tsuda, Yoshimi; Banadyga, Logan; Weisend, Carla; Ebihara, Hideki] NIAID, Mol Virol & Host Pathogen Interact Unit, NIH, Hamilton, MT 59840 USA. [Hoenen, Thomas] NIAID, Dis Modeling & Transmiss Sect, Virol Lab, NIH, Hamilton, MT 59840 USA. [Ricklefs, Stacy M.; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Tsuda, Yoshimi] Hokkaido Univ, Grad Sch Med, Dept Microbiol, Sapporo, Hokkaido, Japan. RP Ebihara, H (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural Research Program, NIH FX This work was supported by the Intramural Research Program, NIH. NR 25 TC 4 Z9 4 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2015 VL 212 SU 2 BP S129 EP S137 DI 10.1093/infdis/jiu681 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100008 PM 25810440 ER PT J AU Willet, M Kurup, D Papaneri, A Wirblich, C Hooper, JW Kwilas, SA Keshwara, R Hudacek, A Beilfuss, S Rudolph, G Pommerening, E Vos, A Neubert, A Jahrling, P Blaney, JE Johnson, RF Schnell, MJ AF Willet, Mallory Kurup, Drishya Papaneri, Amy Wirblich, Christoph Hooper, Jay W. Kwilas, Steve A. Keshwara, Rohan Hudacek, Andrew Beilfuss, Stefanie Rudolph, Grit Pommerening, Elke Vos, Adriaan Neubert, Andreas Jahrling, Peter Blaney, Joseph E. Johnson, Reed F. Schnell, Matthias J. TI Preclinical Development of Inactivated Rabies Virus-Based Polyvalent Vaccine Against Rabies and Filoviruses SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; Sudan virus; Marburg virus; rabies virus; vaccine; filovirus; polyvalent vaccine ID NEUTRALIZING ANTIBODY-RESPONSE; RHABDOVIRUS-BASED VECTORS; NONHUMAN-PRIMATES; RESPIRATORY-TRACT; EBOLA VIRUSES; GLYCOPROTEIN; CHALLENGE; HIV-1; LIVE; IMMUNIZATION AB We previously described the generation of a novel Ebola virus (EBOV) vaccine based on inactivated rabies virus (RABV) containing EBOV glycoprotein (GP) incorporated in the RABV virion. Our results demonstrated safety, immunogenicity, and protective efficacy in mice and nonhuman primates (NHPs). Protection against viral challenge depended largely on the quality of the humoral immune response against EBOV GP. Here we present the extension and improvement of this vaccine by increasing the amount of GP incorporation into virions via GP codon-optimization as well as the addition of Sudan virus (SUDV) and Marburg virus (MARV) GP containing virions. Immunogenicity studies in mice indicate similar immune responses for both SUDV GP and MARV GP compared to EBOV GP. Immunizing mice with multiple antigens resulted in immune responses similar to immunization with a single antigen. Moreover, immunization of NHP with the new inactivated RABV EBOV vaccine resulted in high titer neutralizing antibody levels and 100% protection against lethal EBOV challenge when applied with adjuvant. Our results indicate that an inactivated polyvalent vaccine against RABV filoviruses is achievable. Finally, the novel vaccines are produced on approved VERO cells and a clinical grade RABV/EBOV vaccine for human trials has been produced. C1 [Willet, Mallory; Kurup, Drishya; Wirblich, Christoph; Keshwara, Rohan; Hudacek, Andrew; Schnell, Matthias J.] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. [Papaneri, Amy; Jahrling, Peter; Blaney, Joseph E.; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Hooper, Jay W.; Kwilas, Steve A.] NIAID, US Army, Med Res Inst Infect Dis, NIH, Ft Detrick, MD USA. [Jahrling, Peter] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Beilfuss, Stefanie; Rudolph, Grit; Pommerening, Elke; Vos, Adriaan; Neubert, Andreas] IDT Biol GmbH, Dessau Rosslau, Germany. RP Schnell, MJ (reprint author), Thomas Jefferson Univ, Microbiol & Immunol, 233 S 10th St,BLSB,Ste 531, Philadelphia, PA 19107 USA. EM matthias.schnell@jefferson.edu OI Papaneri, Amy/0000-0003-2144-2441; Hooper, Jay/0000-0002-4475-0415 FU NIAID Divisions of Intramural Research and Clinical Research [HHSN2722010000061, HHSN2722012000031, R01AI105204]; Jefferson Vaccine Center FX This work was supported in part by the NIAID Divisions of Intramural Research and Clinical Research (contracts HHSN2722010000061 and HHSN2722012000031 and grant R01AI105204 to M. J. S.) and the Jefferson Vaccine Center. NR 43 TC 8 Z9 8 U1 0 U2 9 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 OCT 1 PY 2015 VL 212 SU 2 BP S414 EP S424 DI 10.1093/infdis/jiv251 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100046 PM 26063224 ER PT J AU Wong, G Qiu, XG Ebihara, H Feldmann, H Kobinger, GP AF Wong, Gary Qiu, Xiangguo Ebihara, Hideki Feldmann, Heinz Kobinger, Gary P. TI Characterization of a Bivalent Vaccine Capable of Inducing Protection Against Both Ebola and Cross-clade H5N1 Influenza in Mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Ebola virus; H5N1 influenza virus; mice; vaccine; vesicular stomatitis virus ID VESICULAR STOMATITIS-VIRUS; LONG-TERM PROTECTION; AVIAN INFLUENZA; HONG-KONG; NONHUMAN-PRIMATES; A VIRUSES; INFECTION; IMMUNIZATION; ANTIBODIES; HEMAGGLUTININ AB Background. Ebola virus (EBOV) is a lethal pathogen that causes up to 90% mortality in humans, whereas H5N1 avian influenza has a 60% fatality rate. Both viruses are considered pandemic threats. The objective was to evaluate the protective efficacy of a bivalent, recombinant vesicular stomatitis virus vaccine expressing both the A/Hanoi/30408/2005 H5N1 hemagglutinin and the EBOV glycoprotein (VSV Delta G-HA-ZGP) in a lethal mouse model of infection. Methods. Mice were vaccinated 28 days before or 30 minutes after a lethal challenge with mouse-adapted EBOV or selected H5N1 influenza viruses from clades 0, 1, and 2. Animals were monitored for weight loss and survival, in addition to humoral and cell-mediated responses after immunization. Results. A single VSV Delta G-HA-ZGP injection was efficacious when administered 28 days before a homologous H5N1 and/or mouse-adapted EBOV challenge, as well as a heterologous H5N1 challenge. Postexposure protection was only observed in vaccinated animals challenged with homologous H5N1 and/or mouse-adapted EBOV. Analysis of the adaptive immune response postvaccination revealed robust specific T-and B-cell responses, including a potent hemagglutinin inhibition antibody response against all H5N1 strains tested. Conclusions. The results highlight the ability of vesicular stomatitis virus-vectored vaccines to rapidly confer protection against 2 unrelated pathogens and stimulate cross-protection against H5N1 influenza viruses. C1 [Wong, Gary; Qiu, Xiangguo; Kobinger, Gary P.] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB R3E 3R2, Canada. [Wong, Gary; Qiu, Xiangguo; Feldmann, Heinz; Kobinger, Gary P.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Ebihara, Hideki; Feldmann, Heinz] NIAID, Rocky Mt Labs, Virol Lab, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Kobinger, Gary P.] Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada. [Kobinger, Gary P.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Kobinger, GP (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. EM gary.kobinger@phac-aspc.gc.ca FU Public Health Agency of Canada; Chemical, Biological, Radiological or Nuclear Research and Technology Initiative [CRTI-06-0218RD, CRTI-09-453TD]; National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Canadian Institutes of Health Research (CIHR) FX This work was supported by the Public Health Agency of Canada and the Chemical, Biological, Radiological or Nuclear Research and Technology Initiative (grant #CRTI-06-0218RD and CRTI-09-453TD, awarded to G. P. K.). H. E. and H. F. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). G. W. is the recipient of a Doctoral Research Award from the Canadian Institutes of Health Research (CIHR). NR 37 TC 2 Z9 2 U1 1 U2 7 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 OCT 1 PY 2015 VL 212 SU 2 BP S435 EP S442 DI 10.1093/infdis/jiv257 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CU0EP UT WOS:000363189100048 PM 26022441 ER PT J AU Wendler, D Shah, S AF Wendler, David Shah, Seema TI Involving Communities in Deciding What Benefits They Receive in Multinational Research SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Article DE benefits; clinical research; exploitation; risks ID DEVELOPING-COUNTRIES; FAIR BENEFITS; CLINICAL-TRIALS; EXPLOITATION; WORLD; TRANSMISSION; PARTICIPANTS; PRINCIPLE; AFRICA AB There is wide agreement that communities in lower-income countries should benefit when they participate in multinational research. Debate now focuses on how and to what extent these communities should benefit. This debate has identified compelling reasons to reject the claim that whatever benefits a community agrees to accept are necessarily fair. Yet, those who conduct clinical research may conclude from this rejection that there is no reason to involve communities in the process of deciding how they benefit. Against this possibility, the present manuscript argues that involving host communities in this process helps to promote four important goals: (1) protecting host communities, (2) respecting host communities, (3) promoting transparency, and (4) enhancing social value. C1 [Wendler, David; Shah, Seema] NIH, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU NIH FX Thanks to Christine Grady, Joseph Millum, and Alan Wertheimer for helpful comments on previous versions of the manuscript. The authors have no conflicts of interest with respect to the present work. This work was supported by NIH intramural funds and was completed as part of the authors' official duties as an employees of the US NIH Clinical Center. The NIH had no role in the analysis, writing of the manuscript, or the decision to submit it for publication. The views expressed are the authors' own. They do not represent the position or policy of the NIH, DHHS, or US government. NR 29 TC 2 Z9 2 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0360-5310 EI 1744-5019 J9 J MED PHILOS JI J. Med. Philos. PD OCT PY 2015 VL 40 IS 5 BP 584 EP 600 DI 10.1093/jmp/jhv017 PG 17 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA CT9QT UT WOS:000363152400006 PM 26224724 ER PT J AU Raiten, DJ AF Raiten, Daniel J. TI Iron: Current Landscape and Efforts to Address a Complex Issue in a Complex World SO JOURNAL OF PEDIATRICS LA English DT Article ID INTESTINAL INFLAMMATION; MALARIA TRANSMISSION; SYSTEMATIC ANALYSIS; RANDOMIZED-TRIAL; YOUNG-CHILDREN; DEFICIENCY; FORTIFICATION; NUTRITION; ANEMIA; WOMEN C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd Rm 4B-11, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov FU Bill and Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health Division of Nutrition Research Coordination; Office of Dietary Supplements FX D.R. received support for the projects described in this article by Bill and Melinda Gates Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health Division of Nutrition Research Coordination, and the Office of Dietary Supplements. NR 39 TC 2 Z9 2 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2015 VL 167 IS 4 SU S BP S3 EP S7 DI 10.1016/j.jpeds.2015.07.013 PG 5 WC Pediatrics SC Pediatrics GA CU4ZO UT WOS:000363541000002 PM 26364022 ER PT J AU Tempero, M AF Tempero, Margaret TI Putting an End to It! SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article C1 [Tempero, Margaret] UCSF Pancreas Ctr, Med, Omaha, NE 68198 USA. [Tempero, Margaret] UCSF Pancreas Ctr, San Francisco, CA USA. [Tempero, Margaret] ASCO, Zurich, Switzerland. [Tempero, Margaret] AACR ASCO Methods Clin Canc Res, Zurich, Switzerland. [Tempero, Margaret] NCI, CONC, Bethesda, MD 20892 USA. [Tempero, Margaret] Mayo Clin, Rochester, MN USA. [Tempero, Margaret] UAB Minnesota, Minneapolis, MN USA. [Tempero, Margaret] Univ Arizona, GI SPORE, Tucson, AZ 85721 USA. [Tempero, Margaret] Lustgarten Fdn, San Francisco, CA USA. [Tempero, Margaret] Pancreat Canc Act Network, Manhattan Beach, CA USA. [Tempero, Margaret] V Fdn, London, England. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Omaha, NE USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA USA. [Tempero, Margaret] UCSF, Helen Diller Family Comprehens Canc, Res Programs, San Francisco, CA USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, Med, Omaha, NE 68198 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD OCT PY 2015 VL 13 IS 10 BP 1167 EP 1167 PG 1 WC Oncology SC Oncology GA CU3OF UT WOS:000363434000001 PM 26483055 ER PT J AU Sato, T Shimosato, T Ueda, A Ishigatsubo, Y Klinman, DM AF Sato, Takashi Shimosato, Takeshi Ueda, Atsuhisa Ishigatsubo, Yoshiaki Klinman, Dennis M. TI Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID RECEPTOR 9 AGONIST; TLR9 AGONIST; T-CELLS; DENDRITIC CELLS; DRUG-DELIVERY; CONTAINING OLIGODEOXYNUCLEOTIDES; POLYKETAL MICROPARTICLES; INHALED DOXORUBICIN; COMPUTED-TOMOGRAPHY; ESTABLISHED TUMORS AB CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non-small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8(+) T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer. (C) 2015 AACR. C1 [Sato, Takashi; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Sato, Takashi; Ueda, Atsuhisa; Ishigatsubo, Yoshiaki] Yokohama City Univ, Grad Sch Internal Med & Clin Immunol, Yokohama, Kanagawa 232, Japan. [Shimosato, Takeshi] Shinshu Univ, Grad Sch Agr, Nagano, Japan. RP Klinman, DM (reprint author), NCI, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU NCI; Ministry of Education, Culture, Sports, Science, and Technology of Japan [21790778, 23790917, 15K09224] FX D.M. Klinman's lab is internally funded by the NCI. T. Sato received grants (no. 21790778, 23790917, and 15K09224) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 49 TC 3 Z9 3 U1 5 U2 11 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 OCT PY 2015 VL 14 IS 10 BP 2198 EP 2205 DI 10.1158/1535-7163.MCT-15-0401 PG 8 WC Oncology SC Oncology GA CU3EA UT WOS:000363405600004 PM 26206336 ER PT J AU Beedie, SL Peer, CJ Pisle, S Gardner, ER Mahony, C Barnett, S Ambrozak, A Gutschow, M Chau, CH Vargesson, N Figg, WD AF Beedie, Shaunna L. Peer, Cody J. Pisle, Steven Gardner, Erin R. Mahony, Chris Barnett, Shelby Ambrozak, Agnieszka Guetschow, Michael Chau, Cindy H. Vargesson, Neil Figg, William D. TI Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID REFRACTORY MULTIPLE-MYELOMA; PHASE-II TRIAL; INDEPENDENT PROSTATE-CANCER; ERYTHEMA-NODOSUM LEPROSUM; TRANSGENIC ZEBRAFISH; ANGIOGENESIS; THERAPY; SURVIVAL; INHIBITORS; MECHANISM AB Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 mu mol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1: EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo: GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action. (C) 2015 AACR. C1 [Beedie, Shaunna L.; Chau, Cindy H.; Figg, William D.] NCI, Mol Pharmacol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Beedie, Shaunna L.; Mahony, Chris; Barnett, Shelby; Vargesson, Neil] Univ Aberdeen, Sch Med Sci, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Peer, Cody J.; Pisle, Steven; Gardner, Erin R.; Figg, William D.] NCI, Clin Pharmacol Program, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Ambrozak, Agnieszka; Guetschow, Michael] Univ Bonn, Inst Pharmaceut, Bonn, Germany. RP Figg, WD (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10 Room 5A01, Bethesda, MD 20892 USA. EM n.vargesson@abdn.ac.uk; figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Vargesson, Neil/0000-0001-8027-114X FU NIH, National Cancer Institute, Center for Cancer Research; Wellcome Trust-NIH PhD Studentship [098252/Z/12/Z] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by a Wellcome Trust-NIH PhD Studentship (ref: 098252/Z/12/Z) to S.L. Beedie, W.D. Figg, and N. Vargesson. NR 42 TC 6 Z9 6 U1 0 U2 12 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 OCT PY 2015 VL 14 IS 10 BP 2228 EP 2237 DI 10.1158/1535-7163.MCT-15-0320 PG 10 WC Oncology SC Oncology GA CU3EA UT WOS:000363405600007 PM 26269604 ER PT J AU Rao, VH Vogel, K Yanagida, JK Marwaha, N Kandel, A Trempus, C Repertinger, SK Hansen, LA AF Rao, Velidi H. Vogel, Kristen Yanagida, Jodi K. Marwaha, Nitin Kandel, Amrit Trempus, Carol Repertinger, Susan K. Hansen, Laura A. TI Erbb2 Up-Regulation of ADAM12 Expression Accelerates Skin Cancer Progression SO MOLECULAR CARCINOGENESIS LA English DT Article DE nonmelanoma skin cancer; ultraviolet irradiation; tumor progression; Erbb2/HER2; ADAM12 ID EPIDERMAL-GROWTH-FACTOR; ULTRAVIOLET-IRRADIATION; CELL-PROLIFERATION; FACTOR-RECEPTOR; TUMOR PROGRESSION; BLADDER-CANCER; OVARIAN-CANCER; DISINTEGRIN; CARCINOMA; MOUSE AB Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness. (C) 2014 Wiley Periodicals, Inc. C1 [Rao, Velidi H.; Vogel, Kristen; Yanagida, Jodi K.; Marwaha, Nitin; Kandel, Amrit; Hansen, Laura A.] Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA. [Trempus, Carol] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Repertinger, Susan K.] Creighton Univ, Dept Pathol, Omaha, NE 68178 USA. RP Hansen, LA (reprint author), Creighton Univ, Sch Med, Dept Biomed Sci, 2500 Calif Plaza, Omaha, NE 68178 USA. FU National Institutes of Health [1R01 ES015585]; State of Nebraska Cancer and Smoking-related Diseases Program FX Grant sponsor: National Institutes of Health; Grant number: 1R01 ES015585; Grant sponsor: State of Nebraska Cancer and Smoking-related Diseases Program NR 52 TC 1 Z9 1 U1 0 U2 3 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 OCT PY 2015 VL 54 IS 10 BP 1026 EP 1036 DI 10.1002/mc.22171 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CU0PW UT WOS:000363220600008 PM 24798404 ER PT J AU Li, WD Hua, BJ Saud, SM Lin, HS Hou, W Matter, MS Jia, LB Colburn, NH Young, MR AF Li, Weidong Hua, Baojin Saud, Shakir M. Lin, Hongsheng Hou, Wei Matter, Matthias S. Jia, Libin Colburn, Nancy H. Young, Matthew R. TI Berberine Regulates AMP-Activated Protein Kinase Signaling Pathways and Inhibits Colon Tumorigenesis in Mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE berberine; colorectal cancer treatment; AMP-activated protein kinase; mammalian target of rapamycin; proliferation; prevention ID COLORECTAL-CANCER; MOUSE MODEL; ENERGY HOMEOSTASIS; INTESTINAL CANCER; INDUCED COLITIS; CELL-GROWTH; IN-VITRO; INFLAMMATION; METABOLISM; METFORMIN AB Colorectal cancer, a leading cause of cancer death, has been linked to inflammation and obesity. Berberine, an isoquinoline alkaloid, possesses anti-inflammatory, anti-diabetes and anti-tumor properties. In the azoxymethane initiated and dextran sulfate sodium (AOM/DSS) promoted colorectal carcinogenesis mouse model, berberine treated mice showed a 60% reduction in tumor number (P = 0.009), a 48% reduction in tumors < 2 mm, (P = 0.05); 94% reduction in tumors 2-4 mm, (P = 0.001), and 100% reduction in tumors > 4mm (P = 0.02) compared to vehicle treated mice. Berberine also decreased AOM/DSS induced Ki-67 and COX-2 expression. In vitro analysis showed that in addition to its anti-proliferation activity, berberine also induced apoptosis in colorectal cancer cell lines. Berberine activated AMP-activated protein kinase (AMPK), a major regulator of metabolic pathways, and inhibited mammalian target of rapamycin (mTOR), a downstream target of AMPK. Furthermore, 4E-binding protein-1 and p70 ribosomal S6 kinases, downstream targets of mTOR, were down regulated by berberine treatment. Berberine did not affect Liver kinase B1 (LKB1) activity or the mitogen-activated protein kinase pathway. Berberine inhibited Nuclear Factor kappa-B (NF-kappa B) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro. Berberine inhibition of mTOR activity and p53 phosphorylation was found to be AMPK dependent, while inhibition NF-kappa B was AMPK independent. In vivo, berberine also activated AMPK, inhibited mTOR and p65 phosphorylation and activated caspase-3 cleavage. Our data suggests that berberine suppresses colon epithelial proliferation and tumorigenesis via AMPK dependent inhibition of mTOR activity and AMPK independent inhibition of NF-kappa B. (C) 2014 Wiley Periodicals, Inc. C1 [Li, Weidong; Saud, Shakir M.; Colburn, Nancy H.; Young, Matthew R.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Li, Weidong; Hua, Baojin; Lin, Hongsheng; Hou, Wei] China Acad Chinese Med Sci, Guanganmen Hosp, Dept Oncol, Beijing, Peoples R China. [Matter, Matthias S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Jia, Libin] NCI, Off Canc Complementary & Alternat Med, Div Canc Treatment & Diag, NIH, Rockville, MD USA. RP Li, WD (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21702 USA. FU National Cancer Institute; National Institutes of Health [ZIA BC 011159]; National Natural Science Foundation of China [81273718, 81102587]; China Postdoctoral Science Foundation [20110490559, 2012T50199] FX Grant sponsor: National Cancer Institute; Grant sponsor: National Institutes of Health intramural funding; Grant number: ZIA BC 011159; Grant sponsor: National Natural Science Foundation of China; Grant numbers: 81273718; 81102587; Grant sponsor: China Postdoctoral Science Foundation; Grant numbers: 20110490559; 2012T50199 NR 54 TC 13 Z9 13 U1 5 U2 26 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 OCT PY 2015 VL 54 IS 10 BP 1096 EP 1109 DI 10.1002/mc.22179 PG 14 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CU0PW UT WOS:000363220600014 PM 24838344 ER PT J AU Bae, WK Yoo, KH Lee, JS Kim, Y Chung, IJ Park, MH Yoon, JH Furth, PA Hennighausen, L AF Bae, Woo Kyun Yoo, Kyung Hyun Lee, Ji Shin Kim, Young Chung, Ik-Joo Park, Min Ho Yoon, Jung Han Furth, Priscilla A. Hennighausen, Lothar TI The Methyltransferase EZH2 is not Required for Mammary Cancer Development, Although High EZH2 and Low H3K27me3 Correlate With Poor Prognosis of ER-Positive Breast Cancers SO MOLECULAR CARCINOGENESIS LA English DT Article DE histone modification; EZH2; UTX; cancer; prognosis ID GLOBAL HISTONE MODIFICATIONS; POLYCOMB GROUP PROTEINS; GENE-EXPRESSION; PEDIATRIC GLIOBLASTOMA; DUCTAL MORPHOGENESIS; EPITHELIAL-CELLS; STEM-CELLS; MUTATIONS; TAMOXIFEN; H3 AB Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size> 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue. (C) 2014 Wiley Periodicals, Inc. C1 [Bae, Woo Kyun; Yoo, Kyung Hyun; Hennighausen, Lothar] NIH, Lab Genet & Physiol, Bethesda, MD 20892 USA. [Bae, Woo Kyun; Chung, Ik-Joo] Chonnam Natl Univ, Sch Med, Dept Internal Med, Kwangju, South Korea. [Lee, Ji Shin; Kim, Young] Chonnam Natl Univ, Sch Med, Dept Pathol, Kwangju, South Korea. [Park, Min Ho; Yoon, Jung Han] Chonnam Natl Univ, Sch Med, Dept Surg, Kwangju, South Korea. [Furth, Priscilla A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol & Med, Washington, DC 20057 USA. RP Furth, PA (reprint author), Georgetown Univ, Res Bldg,Room 520A,3970 Reservoir Rd,NW, Washington, DC 20057 USA. FU Korea Research Foundation - Korean Government; IRP of NIDDK; NCI; NIH [5P30CA051008] FX Grant sponsor: Korea Research Foundation Grant funded by the Korean Government; Grant sponsor: IRP of NIDDK and NCI; Grant sponsor: NIH; Grant number: 5P30CA051008 NR 41 TC 9 Z9 9 U1 2 U2 4 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 OCT PY 2015 VL 54 IS 10 BP 1172 EP 1180 DI 10.1002/mc.22188 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA CU0PW UT WOS:000363220600020 PM 25043748 ER PT J AU Buell, TJ Heiss, JD Oldfield, EH AF Buell, Thomas J. Heiss, John D. Oldfield, Edward H. TI Pathogenesis and Cerebrospinal Fluid Hydrodynamics of the Chiari I Malformation SO NEUROSURGERY CLINICS OF NORTH AMERICA LA English DT Article DE Chiari I malformation; Hydrocephalus; Posterior fossa ID POSTERIOR CRANIAL FOSSA; CLINICAL ARTICLE; SYRINGOMYELIA; PATHOPHYSIOLOGY; HYDROCEPHALUS; DIAGNOSIS AB This article summarizes the current understanding of the pathophysiology of the Chiari I malformation that is based on observations of the anatomy visualized by modern imaging with MRI and prospective studies of the physiology of patients before and after surgery. The pathogenesis of a Chiari I malformation of the cerebellar tonsils is grouped into 4 general mechanisms. C1 [Buell, Thomas J.; Oldfield, Edward H.] Univ Virginia Hlth Syst, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Heiss, John D.] NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), Univ Virginia Hlth Syst, Dept Neurol Surg, POB 800212, Charlottesville, VA 22908 USA. EM EHO4U@hscmail.mcc.virginia.edu OI Heiss, John/0000-0002-3890-0165 FU Intramural NIH HHS [ZIA NS003050-06] NR 23 TC 2 Z9 2 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1042-3680 EI 1558-1349 J9 NEUROSURG CLIN N AM JI Neurosurg. Clin. N. Am. PD OCT PY 2015 VL 26 IS 4 BP 495 EP + DI 10.1016/j.nec.2015.06.003 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CU3ON UT WOS:000363434800003 PM 26408057 ER PT J AU Rutten, LJF Blake, KD Agunwamba, AA Grana, RA Wilson, PM Ebbert, JO Okamoto, J Leischow, SJ AF Rutten, Lila J. Finney Blake, Kelly D. Agunwamba, Amenah A. Grana, Rachel A. Wilson, Patrick M. Ebbert, Jon O. Okamoto, Janet Leischow, Scott J. TI Use of E-Cigarettes Among Current Smokers: Associations Among Reasons for Use, Quit Intentions, and Current Tobacco Use SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID DEVICE E-CIGARETTE; ELECTRONIC CIGARETTES; SMOKING REDUCTION; CESSATION; ADULTS; AWARENESS; PREVALENCE AB Introduction: Research has documented growing availability and use of e-cigarettes in the United States over the last decade. Methods: We conducted a national panel survey of current adult cigarette smokers to assess attitudes, beliefs, and behaviors relating to e-cigarette use in the United States (N = 2,254). Results: Among current cigarette smokers, 20.4% reported current use of e-cigarettes on some days and 3.7% reported daily use. Reported reasons for e-cigarette use included: quit smoking (58.4%), reduce smoking (57.9%), and reduce health risks (51.9%). No significant differences in sociodemographic characteristics between e-cigarette users and nonusers were observed. Prior quit attempts were reported more frequently among e-cigarette users (82.8%) than nonusers (74.0%). Intention to quit was reported more frequently among e-cigarette users (64.7%) than nonusers (46.8%). Smokers intending to quit were more likely to be e-cigarette users than those not intending to quit (odds ratio [OR] = 1.90, CI = 1.36-2.65). Those who used e-cigarettes to try to quit smoking (OR = 2.25, CI = 1.25-4.05), reduce stress (OR = 3.66, CI = 1.11-12.09), or because they cost less (OR = 3.42, CI = 1.64-7.13) were more likely to report decreases in cigarette smoking than those who did not indicate these reasons. Smokers who reported using e-cigarettes to quit smoking (OR = 16.25, CI = 8.32-31.74) or reduce stress (OR = 4.30, CI = 1.32-14.09) were significantly more likely to report an intention to quit than those who did not indicate those reasons for using e-cigarettes. Conclusions: Nearly a quarter of smokers in our study reported e-cigarettes use, primarily motivated by intentions to quit or reduce smoking. These findings identify a clinical and public health opportunity to re-engage smokers in cessation efforts. C1 [Rutten, Lila J. Finney; Agunwamba, Amenah A.; Wilson, Patrick M.; Ebbert, Jon O.] Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, Rochester, MN 55902 USA. [Blake, Kelly D.; Grana, Rachel A.] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. [Okamoto, Janet; Leischow, Scott J.] Mayo Clin, Hlth Sci Res, Scottsdale, AZ USA. RP Rutten, LJF (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55902 USA. EM rutten.lila@mayo.edu OI Okamoto, Janet/0000-0002-3164-2183 FU National Institutes of Health [R01CA128638] FX This work was supported by the National Institutes of Health (R01CA128638). NR 31 TC 18 Z9 18 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2015 VL 17 IS 10 BP 1228 EP 1234 DI 10.1093/ntr/ntv003 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CT9ZQ UT WOS:000363175500007 PM 25589678 ER PT J AU Butrick, M Kelly, S Peshkin, BN Luta, G Nusbaum, R Hooker, GW Graves, K Feeley, L Isaacs, C Valdimarsdottir, HB Jandorf, L DeMarco, T Wood, M McKinnon, W Garber, J McCormick, SR Schwartz, MD AF Butrick, Morgan Kelly, Scott Peshkin, Beth N. Luta, George Nusbaum, Rachel Hooker, Gillian W. Graves, Kristi Feeley, Lisa Isaacs, Claudine Valdimarsdottir, Heiddis B. Jandorf, Lina DeMarco, Tiffani Wood, Marie McKinnon, Wendy Garber, Judy McCormick, Shelley R. Schwartz, Marc D. TI Disparities in Uptake of BRCA1/2 Genetic Testing in a Randomized Trial of Telephone Counseling SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Genetic counseling via telephone (TC) has emerged as a potential avenue of care for women at risk of breast and ovarian cancers and open to BRCA1 and BRCA2 genetic testing. However, although TC has been shown to be on level with usual care (UC) methods in terms of knowledge, satisfaction, decisional quality, quality of life, and distress, all while yielding high cost savings to the patient and increasing patient accessibility, studies have also shown that patients randomized to TC are less like to complete the genetic testing process. In order to determine the factors leading to lower rates of genetic testing uptake after TC, the authors of this study examined sociodemographic, medical, and psychosocial predictors of genetic testing uptake and evaluated patient-related moderators (knowledge, numeracy, race/ethnicity, education level, etc) in a large cohort of women. In this noninferiority trial, 669 women (21-85 years old) seeking BRCA1/2 genetic testing, with no history of counseling or testing, were randomized into 2 groups, a TC group (n = 335) and an in-person counseling or UC group (n = 334). Measures included sociodemographics, medical history, intentions for risk-reducing surgery, perceived risk of BRCA mutation, perceived risk of breast and ovarian cancer, knowledge, numeracy, decisional conflict, cancer-specific distress, and quality of life. Analysis, logistic regression with backward elimination, was conducted within an intention-to-treat (ITT) sample, which included all randomized participants regardless of genetic counseling session completion, and with a per-protocol (PP) sample, limited to participants who completed genetic counseling as assigned. Within both the ITT and PP samples, genetic testing uptake was lower in the TC group than in the UC group (ITT: 74.9% vs 81.4%, P = 0.04; PP: 84.2% vs 90.1%, P = 0.03). In the ITT population, independently associated significant predictors of completing genetic testing were non-Hispanic white race/ethnicity (odds ratio [OR], 1.96; P = 0.007), randomization to UC (OR, 1.48; P = 0.045), higher knowledge (OR, 1.12; P = 0.018), and lower perceived stress (OR, 0.89; P = 0.017). In the PP sample, independently associated predictors were marital status (OR, 1.85; P = 0.017), objective mutation risk (OR, 1.22; P = 0.007), knowledge (OR, 1.13; P = 0.050), and randomization to UC (OR, 1.65; P =0.050). Considering both ITT and PP analyses, it is of note that knowledge, perceived stress, and objective risk did not interact with group assignment in either analysis (marital status was not tested). In regard to potential moderator variables, the only variable that reached statistical and clinical significance in both samples was race/ethnicity (ITT: P =0.054; PP: P = 0.028). Overall, the strongest moderator affecting genetic testing uptake after TC was race/ethnicity. When randomized to TC, minority women were less likely to complete BRCA1/2 genetic testing. Despite these lower rates, which may be due in part to practical barriers (unlike UC patients, TC patients need to travel to an alternate location to provide a DNA sample), this finding needs to be balanced with the possibility that TC may increase access in the first place. Further studies on availability of TC and its effect on overall rates should be conducted as other modes of delivery emerge for genetic counseling and testing. C1 [Butrick, Morgan] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kelly, Scott; Peshkin, Beth N.; Nusbaum, Rachel; Graves, Kristi; Feeley, Lisa; Isaacs, Claudine; DeMarco, Tiffani; Schwartz, Marc D.] Georgetown Univ, Dept Oncol, Canc Prevent & Control Program, Washington, DC USA. [Kelly, Scott; Peshkin, Beth N.; Nusbaum, Rachel; Graves, Kristi; Feeley, Lisa; Isaacs, Claudine; DeMarco, Tiffani; Schwartz, Marc D.] Georgetown Univ, Fisher Ctr Familial Canc Res, Washington, DC USA. [Luta, George] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Hooker, Gillian W.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Valdimarsdottir, Heiddis B.; Jandorf, Lina] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Wood, Marie; McKinnon, Wendy] Univ Vermont, Coll Med, Vermont Canc Ctr, Familial Canc Program, Burlington, VT USA. [Garber, Judy; McCormick, Shelley R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. RP Butrick, M (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD OCT PY 2015 VL 70 IS 10 BP 614 EP 616 DI 10.1097/01.ogx.0000472122.98775.a5 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CU1WC UT WOS:000363311700008 ER PT J AU Felix, AS Brinton, LA McMeekin, DS Creasman, WT Mutch, D Cohn, DE Walker, JL Moore, RG Downs, LS Soslow, RA Zaino, R Sherman, ME AF Felix, Ashley S. Brinton, Louise A. McMeekin, D. Scott Creasman, William T. Mutch, David Cohn, David E. Walker, Joan L. Moore, Richard G. Downs, Levi S. Soslow, Robert A. Zaino, Richard Sherman, Mark E. TI Relationships of Tubal Ligation to Endometrial Carcinoma Stage and Mortality in the NRG Oncology/Gynecologic Oncology Group 210 Trial SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Stage is the strongest prognostic factor among patients with endometrial cancer, irrespective of histology or grade. Patterns of metastasis, however, vary by tumor subtype suggesting that characterizing routes of metastasis may help improve staging procedures and lead to better management. Metastasis of endometrial cancer occurs via lymphatics, blood vessels, invasion through the uterine wall, or passage through the fallopian tube into the peritoneum. The importance of the fallopian tube as a conduit for the spread of endometrial carcinoma into peritoneal cavity is ill defined. Assessment of the tube's role in metastasis of this cancer could have implications for staging, management, and understanding of its pathogenesis. The present study was designed to test the hypothesis that tubal ligation (TL), which should impede transtubal passage of tumor cells, is associated with lower endometrial carcinoma stage at presentation and, consequently, lower mortality. Associations between TL, cancer stage, extrauterine metastasis, and mortality in patients with endometrial cancer were examined. Participants in the NRG Oncology/Gynecologic Oncology Group (GOG) 210 Trial were women with presurgical diagnoses of endometrial carcinoma (carcinoma or carcinosarcoma) who were eligible for surgery. None had undergone prior retroperitoneal surgery or pelvic/abdominal radiation. Four thousand four hundred eighty nine eligible patients from 62 US institutions were available for analysis. Cases were oversampled for aggressive tumor types. After exclusions, patients completed a risk factor questionnaire that included TL history. Twenty-eight percent of the subjects reported a previous TL at a median age of 32 years. Pathology data derived from clinical reports and central review were examined. Tumor subtypes, including high-grade endometrioid, serous, and clear cell carcinomas, were examined as an effect modifier of relationships between TL, stage, and peritoneal metastasis. Logistic regression models were used to assess associations between TL with stage and peritoneal metastasis, overall and by tumor subtype. Cox proportional hazards regression models were used to assess the relationship between TL and mortality. All statistical tests (P values) were 2-sided. There was an inverse relationship between TL and both stage III (odds ratio [OR], 63; 95% confidence interval [CI], 0.52-0.78) and stage IV carcinomas (OR, 0.14; 95% CI, 0.08-0.24) overall and among individual tumor subtypes compared with stage I. Tubal ligation was also inversely associated with peritoneal metastasis overall (OR, 0.39; 95% CI; 0.22-0.68) and among serous carcinoma cases (OR, 0.28; 95% CI, 0.11-0.68). Cox multivariable models adjusted for covariates except stage showed an inverse association between TL and endometrial carcinoma-specific mortality; the hazard ratio was 0.74, with a 95% CI of 0.61 to 0.91. After adjustment for stage, however, this survival advantage was eliminated. Similar relationships were observed with all-cause mortality. These findings provide evidence that transtubal spread is an important mechanism for metastasis of aggressive histological types of endometrial carcinoma. The association of TL with lower stage and mortality among women with aggressive endometrial carcinomas may have prognostic implications. C1 [Felix, Ashley S.; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Div, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [McMeekin, D. Scott; Walker, Joan L.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Creasman, William T.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Mutch, David] Washington Univ, Sch Med, St Louis, MO USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, Columbus, OH 43210 USA. [Moore, Richard G.] Brown Univ, Women & Infants Hosp, Providence, RI 02912 USA. [Downs, Levi S.] Univ Minnesota, Minneapolis, MN USA. [Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zaino, Richard] Penn State Milton S Hershey Med Ctr, Anat Pathol, Hershey, PA USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Felix, AS (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. OI Soslow, Robert/0000-0002-7269-5898 NR 0 TC 0 Z9 0 U1 0 U2 1 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 OCT PY 2015 VL 70 IS 10 BP 624 EP 626 DI 10.1097/OGX.0000000000000241 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CU1WC UT WOS:000363311700013 ER PT J AU Kothari, S Foster, CS Pistilli, M Liesegang, TL Daniel, E Sen, HN Suhler, EB Thorne, JE Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Lawrence, SD Kempen, JH AF Kothari, Srishti Foster, C. Stephen Pistilli, Maxwell Liesegang, Teresa L. Daniel, Ebenezer Sen, H. Nida Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Lawrence, Scott D. Kempen, John H. CA Systemic Immunosuppressive Therapy TI The Risk of Intraocular Pressure Elevation in Pediatric Noninfectious Uveitis SO OPHTHALMOLOGY LA English DT Article ID SECONDARY GLAUCOMA; REGRESSION-ANALYSIS; STANDARDIZATION; PATHOGENESIS; DISEASE; DEXAMETHASONE; NOMENCLATURE; CHILDHOOD; CHILDREN; STEROIDS AB Purpose: To characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis. Design: Multicenter retrospective cohort study. Participants: Nine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States. Methods: Medical records review by trained, certified experts. Main Outcome Measures: Prevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use. Results: Initially, 251 (15.8%) and 46 eyes (2.9%) had IOP >= 21 mmHg and >= 30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis >= 6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow-up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to >= 21 mmHg, to >= 30 mmHg, and increase in IOP by >= 10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids. Conclusions: Intraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present. (C) 2015 by the American Academy of Ophthalmology. C1 [Kothari, Srishti; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Waltham, MA USA. [Kothari, Srishti; Foster, C. Stephen] Ocular Immunol & Uveitis Fdn, Waltham, MA USA. [Kothari, Srishti; Pistilli, Maxwell; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Pistilli, Maxwell; Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Scheie Eye Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Liesegang, Teresa L.; Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] Tampa Bay Uveitis Ctr, Safety Harbor, FL USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Rosenbaum, James T.] Devers Eye Inst, Portland, OR USA. [Lawrence, Scott D.] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. [Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Kempen, JH (reprint author), Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu FU National Eye Institute; National Eye Institute, National Institutes of Health, Bethesda, Maryland [EY014943]; Research to Prevent Blindness, Inc., New York, New York; Paul and Evanina Mackall Foundation; Lois Pope Life Foundation (New York, NY); Research to Prevent Blindness James S. Adams Special Scholar Award; Research to Prevent Blindness Harrington Special Scholar Award; Research to Prevent Blindness Senior Scientific Investigator Award; Department of Veterans' Affairs, Washington, DC FX Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: EY014943 [J.H.K.]); Research to Prevent Blindness, Inc., New York, New York; the Paul and Evanina Mackall Foundation; the Lois Pope Life Foundation (New York, NY); J.H.K. was a Research to Prevent Blindness James S. Adams Special Scholar Award recipient; J.E.T. was a Research to Prevent Blindness Harrington Special Scholar Award recipient; and D.A.J. and J.T.R. were Research to Prevent Blindness Senior Scientific Investigator Award recipients during the course of the study; G.A.L.-C. previously was supported by and R.B.N. and H.N.S. continue to be supported by intramural funds from the National Eye Institute; E.B.S. receives support from the Department of Veterans' Affairs, Washington, DC. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of this manuscript. NR 44 TC 3 Z9 3 U1 1 U2 1 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 OCT PY 2015 VL 122 IS 10 BP 1987 EP 2001 DI 10.1016/j.ophtha.2015.06.041 PG 15 WC Ophthalmology SC Ophthalmology GA CU4IP UT WOS:000363491500015 PM 26233626 ER PT J AU Flamendorf, J Agron, E Wong, WT Thompson, D Wiley, HE Doss, EL Al-Holou, S Ferris, FL Chew, EY Cukras, C AF Flamendorf, Jason Agron, Elvira Wong, Wai T. Thompson, Darby Wiley, Henry E. Doss, E. Lauren Al-Holou, Shaza Ferris, Frederick L., III Chew, Emily Y. Cukras, Catherine TI Impairments in Dark Adaptation Are Associated with Age-Related Macular Degeneration Severity and Reticular Pseudodrusen SO OPHTHALMOLOGY LA English DT Article ID SUBRETINAL DRUSENOID DEPOSITS; FUNDUS AUTOFLUORESCENCE; MULTIFOCAL ELECTRORETINOGRAPHY; EYE DISEASE; HIGH-RISK; SENSITIVITY; MACULOPATHY; PREVALENCE; AREDS; CLASSIFICATION AB Purpose: We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA). Design: Cross-sectional, single-center, observational study. Participants: One hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity. Methods: Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons. Main Outcome Measures: The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5x10(-3) cd/m(2) (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. Results: A total of 116 study eyes from 116 participants (mean age, 75.4 +/- 9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age (r = 0.34; P = 0.0002), decreasing BCVA (r = -0.54; P < 0.0001), pseudophakia (P = 0.03), and decreasing subfoveal choroidal thickness (r = -0.27; P = 0.003). Study eyes with RPD (15/116 [13%]) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group (P < 0.02 for all comparisons), with 80% reaching the DA test ceiling. Conclusions: Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD (R-2 = 0.56), with the presence of RPD conferring the largest parameter estimate. (C) 2015 by the American Academy of Ophthalmology C1 [Flamendorf, Jason; Agron, Elvira; Wong, Wai T.; Thompson, Darby; Wiley, Henry E.; Doss, E. Lauren; Al-Holou, Shaza; Ferris, Frederick L., III; Chew, Emily Y.; Cukras, Catherine] NEI, NIH, Bethesda, MD 20892 USA. RP Cukras, C (reprint author), NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. EM cukrasc@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland; NIH Medical Research Scholars Program; NIH; Pfizer, Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute FX Supported by the National Eye Institute Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland; and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc., Mr. and Mrs. Joel S. Marcus, the Howard Hughes Medical Institute, as well as other private donors. NR 34 TC 14 Z9 15 U1 1 U2 3 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 OCT PY 2015 VL 122 IS 10 BP 2053 EP 2062 DI 10.1016/j.ophtha.2015.06.023 PG 10 WC Ophthalmology SC Ophthalmology GA CU4IP UT WOS:000363491500022 PM 26253372 ER PT J AU Chew, EY Klein, ML Clemons, TE Agron, E Abecasis, GR AF Chew, Emily Y. Klein, Michael L. Clemons, Traci E. Agron, Elvira Abecasis, Goncalo R. TI Re: Chew et al.: Genetic testing in persons with age-related macular degeneration and the use of the AREDS supplements: to test or not to test? (Ophthalmology 2015; 122: 212-5) REPLY SO OPHTHALMOLOGY LA English DT Letter ID EYE DISEASE; CFH C1 [Chew, Emily Y.; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 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 FU NEI NIH HHS [N01 EY002127] NR 4 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD OCT PY 2015 VL 122 IS 10 BP E61 EP E62 PG 3 WC Ophthalmology SC Ophthalmology GA CU4IP UT WOS:000363491500007 PM 26398060 ER PT J AU Chew, EY Klein, ML Clemons, TE Agron, E Abecasis, GR AF Chew, Emily Y. Klein, Michael L. Clemons, Traci E. Agron, Elvira Abecasis, Goncalo R. TI Re: Chew et al.: Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? (Ophthalmology 2015; 122: 212-5) REPLY SO OPHTHALMOLOGY LA English DT Letter C1 [Chew, Emily Y.; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 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 FU Intramural NIH HHS; NEI NIH HHS [N01 EY002127, N01-EY-0-2127] NR 5 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD OCT PY 2015 VL 122 IS 10 BP E63 EP E63 PG 1 WC Ophthalmology SC Ophthalmology GA CU4IP UT WOS:000363491500009 PM 26398062 ER PT J AU Chew, EY Klein, ML Clemons, TE Agron, E Abecasis, GR AF Chew, Emily Y. Klein, Michael L. Clemons, Traci E. Agron, Elvira Abecasis, Goncalo R. TI Re: Awh et al.: Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study (Ophthalmology 2015; 122: 162-9) REPLY SO OPHTHALMOLOGY LA English DT Letter ID SUPPLEMENTS C1 [Chew, Emily Y.; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 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 FU Intramural NIH HHS; NEI NIH HHS [N01 EY002127, N01-EY-0-2127] NR 4 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD OCT PY 2015 VL 122 IS 10 BP E58 EP E59 PG 3 WC Ophthalmology SC Ophthalmology GA CU4IP UT WOS:000363491500002 PM 26398054 ER PT J AU Segall, SK Shabalina, SA Meloto, CB Wen, X Cunningham, D Tarantino, LM Wiltshire, T Gauthier, J Tohyama, S Martin, LJ Mogil, JS Diatchenko, L AF Segall, Samantha K. Shabalina, Svetlana A. Meloto, Carolina B. Wen, Xia Cunningham, Danielle Tarantino, Lisa M. Wiltshire, Tim Gauthier, Josee Tohyama, Sarasa Martin, Loren J. Mogil, Jeffrey S. Diatchenko, Luda TI Molecular genetic mechanisms of allelic specific regulation of murine Comt expression SO PAIN LA English DT Article DE Alternative splicing; miRNA; Molecular genetics; Transcription regulation; Comt ID CATECHOL-O-METHYLTRANSFERASE; RNA SECONDARY STRUCTURE; SEXUAL-DIMORPHISM; SIRNA DESIGN; PAIN; DISORDER; GENOTYPE; POLYMORPHISM; METAANALYSIS; SYMPTOMS AB A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3'-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt(+)), Comt(B2t) mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3' to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt+ transcript contains regulatory miRNA signals in its 3'-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels. C1 [Segall, Samantha K.; Gauthier, Josee] Univ N Carolina, Ctr Pain Res & Innovat, Chapel Hill, NC USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Meloto, Carolina B.; Wen, Xia; Diatchenko, Luda] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 0G1, Canada. [Cunningham, Danielle] Univ N Carolina, Sch Dent, Dept Oral Biol, Chapel Hill, NC USA. [Tarantino, Lisa M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Wiltshire, Tim] Univ N Carolina, Eshelman Sch Pharm, Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Tohyama, Sarasa; Martin, Loren J.; Mogil, Jeffrey S.] McGill Univ, Dept Psychol, Montreal, PQ H3A 0G1, Canada. [Martin, Loren J.] Univ Toronto, Dept Psychol, Mississauga, ON L5L 1C6, Canada. RP Diatchenko, L (reprint author), McGill Univ, Genome Bldg,Room 2201,740 Dr Penfield Ave, Montreal, PQ H3A 0G1, Canada. EM luda.diatchenko@mcgill.ca FU National Research Service Award Institutional Research Training Program for the Next Generation of Oral Health Researchers (NextGen) [T90-DE021986]; Canadian Institutes of Health Research (CIHR) [CERC08]; National Institute of Dental and Craniofacial Research [RO1-DE16558, UO1-DE017018]; National Institute of Neurological Disorders and Stroke [PO1-NS045685]; Brazilian Federal Agency for the Support and Evaluation of Graduate Education [CAPES/PDEE 0968-11-0]; Intramural Research Program of the National Library of Medicine, NIH FX This work was supported by the National Research Service Award Institutional Research Training Program for the Next Generation of Oral Health Researchers (NextGen) [Grant No. T90-DE021986], by the Canadian Institutes of Health Research (CIHR) (Grant No. CERC08), by the National Institute of Dental and Craniofacial Research (Grant Nos. RO1-DE16558 and UO1-DE017018), by the National Institute of Neurological Disorders and Stroke (Grant No. PO1-NS045685 to L.D.), and by the Brazilian Federal Agency for the Support and Evaluation of Graduate Education (Grant No. CAPES/PDEE 0968-11-0).This research was also supported in part by the Intramural Research Program of the National Library of Medicine, NIH. NR 67 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD OCT PY 2015 VL 156 IS 10 BP 1965 EP 1977 DI 10.1097/j.pain.0000000000000258 PG 13 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CU2OG UT WOS:000363362200016 PM 26067582 ER PT J AU Meloto, CB Segall, SK Smith, S Parisien, M Shabalina, SA Rizzatti-Barbosa, CM Gauthier, J Tsao, D Convertino, M Piltonen, MH Slade, GD Fillingim, RB Greenspan, JD Ohrbach, R Knott, C Maixner, W Zaykin, D Dokholyan, NV Reenila, I Mannisto, PT Diatchenko, L AF Meloto, Carolina B. Segall, Samantha K. Smith, Shad Parisien, Marc Shabalina, Svetlana A. Rizzatti-Barbosa, Celia M. Gauthier, Josee Tsao, Douglas Convertino, Marino Piltonen, Marjo H. Slade, Gary Dmitri Fillingim, Roger B. Greenspan, Joel D. Ohrbach, Richard Knott, Charles Maixner, William Zaykin, Dmitri Dokholyan, Nikolay V. Reenilae, Ilkka Mannistoe, Pekka T. Diatchenko, Luda TI COMT gene locus: new functional variants SO PAIN LA English DT Article DE Association study; Chronic pain; COMT; Functional polymorphism; Genetics ID CATECHOL-O-METHYLTRANSFERASE; RNA SECONDARY STRUCTURE; MOLECULAR-DYNAMICS SIMULATIONS; ALTERNATIVE TRANSCRIPTION; PAIN SENSITIVITY; SIRNA DESIGN; RISK-FACTORS; EXPRESSION; EVOLUTION; ASSOCIATIONS AB Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker; rs165774, situated in the 3' untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. C1 [Meloto, Carolina B.; Parisien, Marc; Piltonen, Marjo H.; Diatchenko, Luda] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada. [Segall, Samantha K.; Smith, Shad; Tsao, Douglas; Slade, Gary Dmitri; Maixner, William; Dokholyan, Nikolay V.] Univ N Carolina, Ctr Pain Res & Innovat, Chapel Hill, NC USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rizzatti-Barbosa, Celia M.] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Prosthesis & Periodontol, Piracicaba, SP, Brazil. [Gauthier, Josee] Univ Florida, Coll Med, Dept Med, Div Gastroenterol, Gainesville, FL USA. [Convertino, Marino] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Fillingim, Roger B.; Dokholyan, Nikolay V.] Univ Florida, Coll Dent, Dept Community Dent & Behav Sci, Gainesville, FL USA. [Fillingim, Roger B.] Pain Res & Intervent Ctr Excellence, Gainesville, FL USA. [Greenspan, Joel D.] Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Baltimore, MD 21201 USA. [Greenspan, Joel D.] Univ Maryland, Sch Dent, Brotman Facial Pain Clin, Baltimore, MD 21201 USA. [Ohrbach, Richard] SUNY Buffalo, Dept Oral Diagnost Sci, Buffalo, NY 14260 USA. [Knott, Charles] Battelle Ctr Publ Hlth Res & Evaluat CPHRE, Battelle Mem Inst, Durham, NC USA. [Zaykin, Dmitri] Natl Inst Environm Hlth Sci, Durham, NC USA. [Reenilae, Ilkka; Mannistoe, Pekka T.] Univ Helsinki, Fac Pharm, Div Pharmacol & Pharmacotherapy, Helsinki, Finland. RP Diatchenko, L (reprint author), 740 Ave Dr Penfield,Room 2200, Montreal, PQ H3A 0G1, Canada. EM luda.diatchenko@mcgill.ca OI Greenspan, Joel/0000-0003-4062-9797; Reenila, Ilkka/0000-0002-9390-7351 FU Intramural Research Program of the National Library of Medicine, NIH FX The authors thank all participants from the TMD case-control and OPPERA cohorts for their contribution. The authors acknowledge Dr. Bruce Weir for his contribution for the genetic design of the OPPERA cohort, and Ms. Liisa Lappalainen, MSc, for running the high-performance liquid chromatography for the COMT activity assays shown here. This research was supported in part by the Intramural Research Program of the National Library of Medicine, NIH. NR 58 TC 2 Z9 2 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD OCT PY 2015 VL 156 IS 10 BP 2072 EP 2083 DI 10.1097/j.pain.0000000000000273 PG 12 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA CU2OG UT WOS:000363362200026 PM 26207649 ER PT J AU Yuan, ZX Rapoport, SI AF Yuan, Zhi-Xin Rapoport, Stanley I. TI Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Fluoxetine; Arachidonic; 5-HT; Brain; 20-HETE; 15-epi-LXA4 ID PROLIFERATOR-ACTIVATED RECEPTOR; TRANSPORTER KNOCKOUT MICE; CEREBRAL-BLOOD-FLOW; RAT-BRAIN; SIGNAL-TRANSDUCTION; DOCOSAHEXAENOIC ACID; CYTOCHROME-P450 4A; ENDOTHELIAL-CELLS; GENE-EXPRESSION; LINOLEIC-ACID AB Background: Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Hypothesis: Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Methods: Male mice pups were injected i.p. daily with fluoxetine (10 mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Results: Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Conclusions: Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd. C1 [Yuan, Zhi-Xin; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, 9000 Rockville Pike,Bldg 9,Rm 1S128, Bethesda, MD 20892 USA. EM sir@mail.nih.gov FU Intramural Research Programs of the National Institute on Aging; National Institute of Mental Health at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute on Aging and the National Institute of Mental Health at the National Institutes of Health. We thank Ms. Lisa Chang and Mei Chen for the helpful contributions with animal preparation and injection. No author has a conflict of interest. NR 82 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 EI 1532-2823 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD OCT PY 2015 VL 101 BP 9 EP 14 DI 10.1016/j.plefa.2015.07.002 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA CU2LR UT WOS:000363355500002 PM 26234927 ER PT J AU Wade, SL Langer, LF Ward, JM Archer, TK AF Wade, Staton L. Langer, Lee F. Ward, James M. Archer, Trevor K. TI MiRNA-Mediated Regulation of the SWI/SNF Chromatin Remodeling Complex Controls Pluripotency and Endodermal Differentiation in Human ESCs SO STEM CELLS LA English DT Article DE MicroRNAs; Chromatin; Cell differentiation; Embryonic stem cells; BAF170 ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; MOUSE; MICRORNAS; REPRESSION; SUBUNIT; SPECIFICATION; DEGRADATION; MECHANISMS; EXPRESSION AB MicroRNAs and chromatin remodeling complexes represent powerful epigenetic mechanisms that regulate the pluripotent state. miR-302 is a strong inducer of pluripotency, which is characterized by a distinct chromatin architecture. This suggests that miR-302 regulates global chromatin structure; however, a direct relationship between miR-302 and chromatin remodelers has not been established. Here, we provide data to show that miR-302 regulates Brg1 chromatin remodeling complex composition in human embryonic stem cells (hESCs) through direct repression of the BAF53a and BAF170 subunits. With the subsequent overexpression of BAF170 in hESCs, we show that miR-302's inhibition of BAF170 protein levels can affect the expression of genes involved in cell proliferation. Furthermore, miR-302-mediated repression of BAF170 regulates pluripotency by positively influencing mesendodermal differentiation. Overexpression of BAF170 in hESCs led to biased differentiation toward the ectoderm lineage during EB formation and severely hindered directed definitive endoderm differentiation. Taken together, these data uncover a direct regulatory relationship between miR-302 and the Brg1 chromatin remodeling complex that controls gene expression and cell fate decisions in hESCs and suggests that similar mechanisms are at play during early human development. C1 [Wade, Staton L.; Langer, Lee F.; Archer, Trevor K.] NIEHS, Chromatin & Gene Express Grp, Epigenet & Stem Cell Biol Lab, Dept Hlth & Human Serv,NIH, Res Triangle Pk, NC 27709 USA. [Ward, James M.] NIEHS, Integrat Bioinformat Resource, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Grp, Epigenet & Stem Cell Biol Lab, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH [Z01 ES071006-14] FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (project #Z01 ES071006-14). NR 41 TC 3 Z9 4 U1 2 U2 5 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 OCT PY 2015 VL 33 IS 10 BP 2925 EP 2935 DI 10.1002/stem.2084 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CU1FD UT WOS:000363264500005 PM 26119756 ER PT J AU Russo, MV McGavern, DB AF Russo, Matthew V. McGavern, Dorian B. TI Immune Surveillance of the CNS following Infection and Injury SO TRENDS IN IMMUNOLOGY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD-INJURY; REGULATORY T-CELLS; TRAUMATIC BRAIN-INJURY; ANTIGEN-PRESENTING CELLS; MICROGLIAL CELLS; IN-VIVO; INFLAMMASOME ACTIVATION; INDUCED DEMYELINATION; MOLECULAR-MECHANISMS AB The central nervous system (CNS) contains a sophisticated neural network that must be constantly surveyed in order to detect and mitigate a diverse array of challenges. The innate and adaptive immune systems actively participate in this surveillance, which is critical for the maintenance of CNS homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage. Infections and sterile injuries represent two common challenges imposed on the CNS that require a prompt immune response. While the inducers of these two challenges differ in origin, the resultant responses orchestrated by the CNS share some overlapping features. Here, we review how the CNS immunologically discriminates between pathogens and sterile injuries, mobilizes an immune reaction, and, ultimately, regulates local and peripherally-derived immune cells to provide a supportive milieu for tissue repair. C1 [Russo, Matthew V.; McGavern, Dorian B.] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bethesda, MD 20892 USA. RP McGavern, DB (reprint author), NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mcgavernd@mail.nih.gov FU National Institutes of Heath (NIH) intramural program FX This work was supported by the National Institutes of Heath (NIH) intramural program. We thank Ethan Tyler in the NIH Medical Arts Design Section for his help with the illustrations. NR 103 TC 12 Z9 13 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD OCT PY 2015 VL 36 IS 10 BP 637 EP 650 DI 10.1016/j.it.2015.08.002 PG 14 WC Immunology SC Immunology GA CT8MI UT WOS:000363070300008 PM 26431941 ER PT J AU Skolnick, P AF Skolnick, Phil TI Biologic Approaches to Treat Substance-Use Disorders SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID CONTROLLED EFFICACY-TRIAL; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; METHAMPHETAMINE DEPENDENCE; COCAINE DEPENDENCE; HUMAN BUTYRYLCHOLINESTERASE; SMOKING-CESSATION; NICOTINE VACCINE; IN-VIVO; ADDICTION AB In contrast to traditional pharmacodynamic approaches to treat substance-use disorders (SUDs), the use of biologics (vaccines, monoclonal antibodies, and genetically modified enzymes) is based on a pharmacokinetic principle: reduce the amount of (and, ideally, eliminate) abused drug entering the central nervous system (CNS). Preclinical studies indicate that biologics are effective in both facilitating abstinence and preventing relapse to abused substances ranging from nicotine to heroin. While data are still emerging, the results from multiple clinical trials can best be described as mixed. Nonetheless, these clinical studies have already provided important insights using 'first-generation' tools that may inform the development of effective and commercially viable biologics to treat tobacco-, cocaine-, and methamphetamine-use disorders. C1 NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. RP Skolnick, P (reprint author), NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. EM phil.skolnick@nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 39 TC 3 Z9 3 U1 4 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD OCT PY 2015 VL 36 IS 10 BP 628 EP 635 DI 10.1016/j.tips.2015.07.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CT8OQ UT WOS:000363076300005 PM 26435208 ER PT J AU He, SS Jain, P Lin, B Ferrer, M Hu, ZY Southall, N Hu, X Zheng, W Neuenswander, B Cho, CH Chen, Y Worlikar, SA Aube, J Larock, RC Schoenen, FJ Marugan, JJ Liang, TJ Frankowski, KJ AF He, Shanshan Jain, Prashi Lin, Billy Ferrer, Marc Hu, Zongyi Southall, Noel Hu, Xin Zheng, Wei Neuenswander, Benjamin Cho, Chul-Hee Chen, Yu Worlikar, Shilpa A. Aube, Jeffrey Larock, Richard C. Schoenen, Frank J. Marugan, Juan J. Liang, T. Jake Frankowski, Kevin J. TI High-Throughput Screening, Discovery, and Optimization To Develop a Benzofuran Class of Hepatitis C Virus Inhibitors SO ACS COMBINATORIAL SCIENCE LA English DT Article DE hepatitis C; HCV inhibitor; benzofuran; antiviral; HCV replication ID IN-VITRO; FUTURE; INFECTION; THERAPIES; OXIDATION; DRUGS; ASSAY; VIVO AB Using a high-throughput, cell-based HCV luciferase reporter assay to screen a diverse small-molecule compound collection (similar to 300 000 compounds), we identified a benzofuran compound class of HCV inhibitors. The optimization of the benzofuran scaffold led to the identification of several exemplars with potent inhibition (EC50 < 100 nM) of HCV, low cytotoxicity (CC50 > 25 mu M), and excellent selectivity (selective index = CC50/EC50, > 371-fold). The structure-activity studies culminated in the design and synthesis of a 45-compound library to comprehensively explore the anti-HCV activity. The identification, design, synthesis, and biological characterization for this benzofuran series is discussed. C1 [He, Shanshan; Lin, Billy; Hu, Zongyi; Liang, T. Jake] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Jain, Prashi; Aube, Jeffrey; Schoenen, Frank J.; Frankowski, Kevin J.] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA. [Neuenswander, Benjamin; Cho, Chul-Hee; Chen, Yu; Worlikar, Shilpa A.; Aube, Jeffrey; Larock, Richard C.] Univ Kansas, Chem Methodol & Lib Dev Ctr, Lawrence, KS 66047 USA. [Ferrer, Marc; Southall, Noel; Hu, Xin; Zheng, Wei; Marugan, Juan J.] NIH, Chem Genom Ctr, Div Predin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jakel@bdg10.niddk.nih.gov; kevinf@email.unc.edu RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Molecular Libraries Initiative [5U54HG005031]; National Institute for General Medical Sciences KU-CMLD [PO50-GM069663]; NIH [S10RR024664]; NSF [0320648]; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences, National Institute of Health FX We thank Patrick Porubsky for compound management services. This work was supported by grants from the Molecular Libraries Initiative 5U54HG005031 (J.A.) and the National Institute for General Medical Sciences KU-CMLD PO50-GM069663 (J.A.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant No. S10RR024664 and NSF Major Research Instrumentation Grant No. 0320648. This work was partially supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Center for Advancing Translational Sciences, National Institute of Health. NR 17 TC 6 Z9 6 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2156-8952 EI 2156-8944 J9 ACS COMB SCI JI ACS Comb. Sci. PD OCT PY 2015 VL 17 IS 10 BP 641 EP 652 DI 10.1021/acscombsci.5b00101 PG 12 WC Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary SC Chemistry; Pharmacology & Pharmacy GA CT5PT UT WOS:000362863200010 PM 26332742 ER PT J AU Li, M Gustchina, A Cruz, R Simoes, M Curto, P Martinez, J Faro, C Simoes, I Wlodawer, A AF Li, Mi Gustchina, Alla Cruz, Rui Simoes, Marisa Curto, Pedro Martinez, Juan Faro, Carlos Simoes, Isaura Wlodawer, Alexander TI Structure of RC1339/APRc from Rickettsia conorii, a retropepsin-like aspartic protease SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE aspartic proteases; enzyme evolution; bacterial proteases; dimeric proteins ID CRYSTAL-STRUCTURE; IMMUNODEFICIENCY-VIRUS; RETROVIRAL PROTEASES; PEPSIN-LIKE; INHIBITOR; PROTEINASE; COMPLEXES AB The crystal structures of two constructs of RC1339/APRc from Rickettsia conorii, consisting of either residues 105-231 or 110-231 followed by a His tag, have been determined in three different crystal forms. As predicted, the fold of a monomer of APRc resembles one-half of the mandatory homodimer of retroviral pepsin-like aspartic proteases (retropepsins), but the quaternary structure of the dimer of APRc differs from that of the canonical retropepsins. The observed dimer is most likely an artifact of the expression and/or crystallization conditions since it cannot support the previously reported enzymatic activity of this bacterial aspartic protease. However, the fold of the core of each monomer is very closely related to the fold of retropepsins from a variety of retroviruses and to a single domain of pepsin-like eukaryotic enzymes, and may represent a putative common ancestor of monomeric and dimeric aspartic proteases. C1 [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Prot Struct Sect, Ft Detrick, MD 21702 USA. [Li, Mi] Frederick Natl Lab Canc Res, Leidos Biomed Res, Basic Sci Program, Ft Detrick, MD 21702 USA. [Cruz, Rui; Simoes, Marisa; Curto, Pedro; Faro, Carlos; Simoes, Isaura] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Cruz, Rui; Simoes, Marisa; Faro, Carlos; Simoes, Isaura] Biotechnol Innovat Ctr, Biocant, P-3060197 Cantanhede, Portugal. [Curto, Pedro; Martinez, Juan] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Vector Borne Dis Labs, Baton Rouge, LA 70803 USA. RP Simoes, I (reprint author), Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. EM isimoes@biocant.pt; wlodawer@nih.gov RI Simoes, Isaura/F-3239-2010 OI Simoes, Isaura/0000-0002-9331-6340 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Fundo Europeu de Desenvolvimento Regional (FEDER) Funds through the Operational Competitiveness Programme (COMPETE); National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/SAU-MII/107942/2008]; NIH [1R21-AI111086]; FCT [SFRH/BD/96769/2013]; [PEst-C/SAU/LA0001/2013-2014] FX We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), 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 project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health under contract HHSN261200800001E and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was funded in part by Fundo Europeu de Desenvolvimento Regional (FEDER) Funds through the Operational Competitiveness Programme (COMPETE), by National Funds through the Fundacao para a Ciencia e a Tecnologia (FCT) under the project PTDC/SAU-MII/107942/2008 (to IS) and in part by NIH 1R21-AI111086 (to JM). PC is the recipient of a FCT PhD grant SFRH/BD/96769/2013. The authors would like to acknowledge grant PEst-C/SAU/LA0001/2013-2014. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 31 TC 1 Z9 1 U1 2 U2 3 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 OCT PY 2015 VL 71 BP 2109 EP 2118 DI 10.1107/S1399004715013905 PN 10 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CT5LH UT WOS:000362851300012 PM 26457434 ER PT J AU Yano, Y Ning, HY Muntner, P Reis, JP Calhoun, DA Viera, AJ Levine, DA Jacobs, DR Shimbo, D Liu, K Greenland, P Lloyd-Jones, D AF Yano, Yuichiro Ning, Hongyan Muntner, Paul Reis, Jared P. Calhoun, David A. Viera, Anthony J. Levine, Deborah A. Jacobs, David R., Jr. Shimbo, Daichi Liu, Kiang Greenland, Philip Lloyd-Jones, Donald TI Nocturnal Blood Pressure in Young Adults and Cognitive Function in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; cognitive function; hypertension; midlife; nocturnal blood pressure; young adults ID CEREBROVASCULAR-DISEASE; PSYCHOSOCIAL FACTORS; CARDIOVASCULAR RISK; HYPERTENSION; BRAIN; SLEEP; IMPAIRMENT; DEMENTIA; DECLINE; STROKE AB BACKGROUND Nocturnal blood pressure (BP) is associated with risk for cardiovascular events. However, the relationship between nocturnal BP in young adults and cognitive function in midlife remains unclear. METHODS We used data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study, including 224 participants (mean age 30 years, 45% men, 63% African Americans). At the 20-year follow-up, the Stroop test (executive function), Digit Symbol Substitution Test (psychomotor speed), and Rey Auditory Verbal Learning Test (verbal memory) were assessed. RESULTS Baseline mean office, daytime, and nocturnal BP were 109/73, 120/74, and 107/59 mm Hg, respectively. Nocturnal BP dipping, calculated as (nocturnal systolic BP [SBP]-daytime SBP) x 100/daytime SBP, was divided into quartiles (Q1: -39.3% to -16.9%; Q2: -16.8% to -13.2%, Q3 [reference]: -13.1% to -7.8%, and Q4: -7.7% to + 56.4%). In multiple regression analyses, the least nocturnal SBP dipping (Q4 vs. reference) and higher nocturnal diastolic BP level were associated with worse Stroop scores, with adjustments for demographic and clinical characteristics, and cumulative exposure to office BP during follow-up (beta [standard error]: 0.37 [0.18] and 0.19 [0.07], respectively; all P < 0.05). Digit Symbol Substitution Test and Rey Auditory Verbal Learning Test were not significantly associated with nocturnal SBP dipping or nocturnal SBP/diastolic BP levels. CONCLUSIONS Among healthy young adults, less nocturnal SBP dipping and higher nocturnal diastolic BP levels were associated with lower executive function in midlife, independent of multiple measures of office BP during long-term follow-up. C1 [Yano, Yuichiro; Ning, Hongyan; Liu, Kiang; Greenland, Philip; Lloyd-Jones, Donald] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Calhoun, David A.] Univ Alabama, Vasc Biol & Hypertens Program, Div Cardiovasc Dis, Dept Med, Birmingham, AK USA. [Viera, Anthony J.] Univ N Carolina, Hypertens Res Program, Chapel Hill, NC USA. [Viera, Anthony J.] Univ N Carolina, Dept Family Med, Chapel Hill, NC 27514 USA. [Levine, Deborah A.] Univ Michigan Hlth Syst, Dept Internal Med, Vet Affairs Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Levine, Deborah A.] Univ Michigan Hlth Syst, Dept Neurol, Vet Affairs Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Levine, Deborah A.] Univ Michigan Hlth Syst, Stroke Program, Vet Affairs Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Shimbo, Daichi] Columbia Univ, Dept Med, Ctr Behav Cardiovasc Hlth, New York, NY USA. RP Yano, Y (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM yyano@jichi.jp FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005]; National Heart, Lung, and Blood Institute [R01 HL098604]; NIH [P30DK092926, K23AG040278] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). Y.Y. received the Manpei Suzuki International Prize for Diabetes Research Grants and AHA Strategically Focused Research Network (SFRN) Fellow Grant. AJ.V. has a research grant from the National Heart, Lung, and Blood Institute (R01 HL098604) to study ambulatory blood pressure monitoring. He has also served on the medical advisory board of Suntech Medical, manufacturer of a brand of ambulatory blood pressure monitor. D.A.C. received research support from the NIH (P30DK092926 and K23AG040278). None of the other authors has any potential conflict of interest to disclose. NR 37 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD OCT PY 2015 VL 28 IS 10 BP 1240 EP 1247 DI 10.1093/ajh/hpv028 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CT5HP UT WOS:000362839900007 PM 25783740 ER PT J AU LaFave, MC Varshney, GK Burgess, SM AF LaFave, Matthew C. Varshney, Gaurav K. Burgess, Shawn M. TI GeIST: a pipeline for mapping integrated DNA elements SO BIOINFORMATICS LA English DT Article ID HUMAN GENOME; ADENOASSOCIATED VIRUS; MLV INTEGRATION AB There are several experimental contexts in which it is important to identify DNA integration sites, such as insertional mutagenesis screens, gene and enhancer trap applications, and gene therapy. We previously developed an assay to identify millions of integrations in multiplexed barcoded samples at base-pair resolution. The sheer amount of data produced by this approach makes the mapping of individual sites non-trivial without bioinformatics support. This article presents the Genomic Integration Site Tracker (GeIST), a command-line pipeline designed to map the integration sites produced by this assay and identify the samples from which they came. GeIST version 2.1.0, a more adaptable version of our original pipeline, can identify integrations of murine leukemia virus, adeno-associated virus, Tol2 transposons or Ac/Ds transposons, and can be adapted for other inserted elements. It has been tested on experimental data for each of these delivery vectors and fine-tuned to account for sequencing and cloning artifacts. C1 [LaFave, Matthew C.; Varshney, Gaurav K.; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP LaFave, MC (reprint author), NHGRI, Translat & Funct Genom Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI LaFave, Matthew/0000-0001-9165-041X NR 19 TC 4 Z9 4 U1 0 U2 5 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 OCT 1 PY 2015 VL 31 IS 19 BP 3219 EP 3221 DI 10.1093/bioinformatics/btv350 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 CT5JN UT WOS:000362845400021 PM 26049161 ER PT J AU Li, HC Keadle, SK Staudenmayer, J Assaad, H Huang, JHZ Carroll, RJ AF Li, Haocheng Keadle, Sarah Kozey Staudenmayer, John Assaad, Houssein Huang, Jianhua Z. Carroll, Raymond J. TI Methods to assess an exercise intervention trial based on 3-level functional data SO BIOSTATISTICS LA English DT Article DE Longitudinal data; Mixed-effects model; Penalized splines; Physical activity measurement; Principal components ID PRINCIPAL COMPONENT ANALYSIS; PHYSICAL-ACTIVITY; EFFECTS MODELS AB Motivated by data recording the effects of an exercise intervention on subjects' physical activity over time, we develop a model to assess the effects of a treatment when the data are functional with 3 levels (subjects, weeks and days in our application) and possibly incomplete. We develop a model with 3-level mean structure effects, all stratified by treatment and subject random effects, including a general subject effect and nested effects for the 3 levels. The mean and random structures are specified as smooth curves measured at various time points. The association structure of the 3-level data is induced through the random curves, which are summarized using a few important principal components. We use penalized splines to model the mean curves and the principal component curves, and cast the proposed model into a mixed effects model framework for model fitting, prediction and inference. We develop an algorithm to fit the model iteratively with the Expectation/Conditional Maximization Either (ECME) version of the EM algorithm and eigenvalue decompositions. Selection of the number of principal components and handling incomplete data issues are incorporated into the algorithm. The performance of the Wald-type hypothesis test is also discussed. The method is applied to the physical activity data and evaluated empirically by a simulation study. C1 [Li, Haocheng] Univ Calgary, Dept Oncol, Calgary, AB T2N 4N2, Canada. [Li, Haocheng] Univ Calgary, Dept Community Hlth Sci, Calgary, AB T2N 4N2, Canada. [Keadle, Sarah Kozey] NCI, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Staudenmayer, John] Univ Massachusetts, Dept Math & Stat, Amherst, MA 01003 USA. [Assaad, Houssein; Huang, Jianhua Z.; Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Dept Math & Stat, Broadway, NSW 2007, Australia. RP Li, HC (reprint author), Univ Calgary, Dept Oncol, Calgary, AB T2N 4N2, Canada. EM haocheng.li@ucalgary.ca OI Keadle, Sarah/0000-0002-9569-9306 FU National Cancer Institute [R37-CA057030, R25T-CA090301, R01-CA121005]; Spanish Ministry of Science and Innovation [MTM 2011-22664]; FEDER; NSF [DMS-1208952] FX H.L. and R.J.C. were supported by a grant from the National Cancer Institute (R37-CA057030). This research has been partially supported by the Spanish Ministry of Science and Innovation (project MTM 2011-22664 which is co-funded by FEDER). H.A. was supported by a postdoctoral training grant from the National Cancer Institute (R25T-CA090301). S.K.K. and J.S. were supported by a National Cancer Institute grant (R01-CA121005). J.Z.H. was supported by a NSF grant (DMS-1208952). NR 15 TC 2 Z9 2 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2015 VL 16 IS 4 BP 754 EP 771 DI 10.1093/biostatistics/kxv015 PG 18 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA CT5KE UT WOS:000362847600010 PM 25987650 ER PT J AU Chan, KCG Qin, J AF Chan, Kwun Chuen Gary Qin, Jing TI Rank-based testing of equal survivorship based on cross-sectional survival data with or without prospective follow-up SO BIOSTATISTICS LA English DT Article DE Accelerated failure time model; Backward recurrence time; Length biased sampling ID RIGHT-CENSORED DATA; NONPARAMETRIC-ESTIMATION; LIFE MODEL; REGRESSION; STATISTICS AB Existing linear rank statistics cannot be applied to cross-sectional survival data without follow-up since all subjects are essentially censored. However, partial survival information are available from backward recurrence times and are frequently collected from health surveys without prospective follow-up. Under length-biased sampling, a class of linear rank statistics is proposed based only on backward recurrence times without any prospective follow-up. When follow-up data are available, the proposed rank statistic and a conventional rank statistic that utilizes follow-up information from the same sample are shown to be asymptotically independent. We discuss four ways to combine these two statistics when follow-up is present. Simulations show that all combined statistics have substantially improved power compared with conventional rank statistics, and a Mantel-Haenszel test performed the best among the proposal statistics. The method is applied to a cross-sectional health survey without follow-up and a study of Alzheimer's disease with prospective follow-up. C1 [Chan, Kwun Chuen Gary] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Chan, KCG (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM kcgchan@uw.edu FU National Institutes of Health [R01 HL-122212] FX K.C.G.C. is partially supported by grant R01 HL-122212 from the National Institutes of Health. NR 28 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2015 VL 16 IS 4 BP 772 EP 784 DI 10.1093/biostatistics/kxv011 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA CT5KE UT WOS:000362847600011 PM 25813647 ER PT J AU Huang, CY Ning, J Qin, J AF Huang, Chiung-Yu Ning, Jing Qin, Jing TI Semiparametric likelihood inference for left-truncated and right-censored data SO BIOSTATISTICS LA English DT Article DE Biased sampling; Cross-sectional studies; Prevalent sampling; Profile likelihood; Smooth tests of goodness of fit ID SELECTION BIAS MODELS; SURVIVAL-DATA; EMPIRICAL DISTRIBUTIONS; NONPARAMETRIC-ESTIMATION; PREVALENT COHORT; LARGE-SAMPLE; STATIONARITY; AIDS AB This paper proposes a new estimation procedure for the survival time distribution with left-truncated and right-censored data, where the distribution of the truncation time is known up to a finite-dimensional parameter vector. The paper expands on the Vardis multiplicative censoring model (Vardi, 1989. Multiplicative censoring, renewal processes, deconvolution and decreasing density: non-parametric estimation. Biometrika 76, 751-761), establishes the connection between the likelihood under a generalized multiplicative censoring model and that for left-truncated and right-censored survival time data, and derives an Expectation-Maximization algorithm for model estimation. A formal test for checking the truncation time distribution is constructed based on the semiparametric likelihood ratio test statistic. In particular, testing the stationarity assumption that the underlying truncation time is uniformly distributed is performed by embedding the null uniform truncation time distribution in a smooth alternative (Neyman, 1937. Smooth test for goodness of fit. Skandinavisk Aktuarietidskrift 20, 150-199). Asymptotic properties of the proposed estimator are established. Simulations are performed to evaluate the finite-sample performance of the proposed methods. The methods and theories are illustrated by analyzing the Canadian Study of Health and Aging and the Channing House data, where the stationarity assumption with respect to disease incidence holds for the former but not the latter. C1 [Huang, Chiung-Yu] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Huang, Chiung-Yu] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Ning, Jing] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. RP Huang, CY (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. EM cyhuang@jhu.edu FU National Institutes of Health [CA016672, CA006973]; Seniors' Independence Research Program through the National Health Research and Development Program of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38 (93-2), 34 (96-1)] FX This work was supported in part by grants CA016672 and CA006973 from the National Institutes of Health. The core of the CSHA study was funded by the Seniors' Independence Research Program through the National Health Research and Development Program of Health Canada (Project no.6606-3954-MC(S)). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38 (93-2) and 34 (96-1). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. NR 28 TC 0 Z9 0 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2015 VL 16 IS 4 BP 785 EP 798 DI 10.1093/biostatistics/kxv012 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA CT5KE UT WOS:000362847600012 PM 25796430 ER PT J AU Reddy, UM AF Reddy, U. M. TI Unravelling caesarean delivery as a risk factor for antepartum stillbirth SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Editorial Material C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 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 OCT PY 2015 VL 122 IS 11 BP 1475 EP 1475 DI 10.1111/1471-0528.13531 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CT4BY UT WOS:000362752100010 PM 26234883 ER PT J AU Bunch, KP Annunziata, CM AF Bunch, Kristen P. Annunziata, Christina M. TI Are Beta-Blockers on the Therapeutic Horizon for Ovarian Cancer Treatment? SO CANCER LA English DT Editorial Material ID NF-KAPPA-B; BREAST-CANCER; SOCIAL SUPPORT; SURVIVAL; CELLS; METASTASIS; ACTIVATION; INHIBITOR; APOPTOSIS; INVASION C1 [Bunch, Kristen P.; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Annunziata, CM (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,Rm 12N 226, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 23 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2015 VL 121 IS 19 BP 3380 EP 3383 DI 10.1002/cncr.29394 PG 4 WC Oncology SC Oncology GA CT4MY UT WOS:000362782000005 PM 26301564 ER PT J AU Duska, LR Kohn, EC AF Duska, Linda R. Kohn, Elise C. TI Does One Size Fit All? The Updated Ovarian Cancer Staging: Still a Work in Progress SO CANCER LA English DT Editorial Material ID CLEAR-CELL CARCINOMA; PATHOGENESIS; ORIGIN C1 [Duska, Linda R.] Univ Virginia, Dept Obstet & Gynecol, Div Gynecol Oncol, Charlottesville, VA 22908 USA. [Kohn, Elise C.] NCI, Gynecol Canc Therapeut, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Duska, LR (reprint author), Univ Virginia, Dept Obstet & Gynecol, Div Gynecol Oncol, POB 800712, Charlottesville, VA 22908 USA. EM lduska@virginia.edu NR 10 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2015 VL 121 IS 19 BP 3384 EP 3386 DI 10.1002/cncr.29521 PG 3 WC Oncology SC Oncology GA CT4MY UT WOS:000362782000006 PM 26110592 ER PT J AU Temkin, SM Seibel, NL AF Temkin, Sarah M. Seibel, Nita L. TI Are We Missing an Opportunity for Cancer Prevention? Human Papillomavirus Vaccination for Survivors of Pediatric and Young Adult Cancers SO CANCER LA English DT Review DE childhood cancer; human papillomavirus (HPV) disease; human papillomavirus (HPV) vaccination; prevention; survivorship ID CHILDHOOD-CANCER; UNITED-STATES; HPV VACCINE; IMMUNIZATION PRACTICES; RECOMBINANT VACCINE; ADVISORY-COMMITTEE; CERVICAL LESIONS; NATURAL-HISTORY; ADOLESCENTS; WOMEN AB Survivors of pediatric and young adult cancers remain at risk for subsequent diseases, including those related to human papillomavirus (HPV) infection. Prevention of HPV acquisition through vaccination has become possible over the last decade. HPV vaccines have been shown to be safe and effective, yet rates of vaccination among childhood cancer survivors have remained low. Multiple factors, including stronger advocacy for this intervention from providers, could potentially increase vaccination and lead to lower HPV disease burdens for childhood cancer survivors. Health care providers for survivors of pediatric and adolescent cancers should prioritize counseling for HPV vaccination at follow-up visits. (C) 2015 American Cancer Society. C1 [Temkin, Sarah M.] NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Seibel, Nita L.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Temkin, SM (reprint author), NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E448-MSC 9785, Bethesda, MD 20892 USA. EM seibelnl@mail.nih.gov NR 46 TC 0 Z9 0 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2015 VL 121 IS 19 BP 3395 EP 3402 DI 10.1002/cncr.29515 PG 8 WC Oncology SC Oncology GA CT4MY UT WOS:000362782000010 PM 26110510 ER PT J AU Shnorhavorian, M Harlan, LC Smith, AW Keegan, THM Lynch, CF Prasad, PK Cress, RD Wu, XC Hamilton, AS Parsons, HM Keel, G Charlesworth, SE Schwartz, SM AF Shnorhavorian, Margarett Harlan, Linda C. Smith, Ashley Wilder Keegan, Theresa H. M. Lynch, Charles F. Prasad, Pinki K. Cress, Rosemary D. Wu, Xiao-Cheng Hamilton, Ann S. Parsons, Helen M. Keel, Gretchen Charlesworth, Sarah E. Schwartz, Stephen M. CA AYA HOPE Study Collaborative Grp TI Fertility Preservation Knowledge, Counseling, and Actions Among Adolescent and Young Adult Patients With Cancer: A Population-Based Study SO CANCER LA English DT Article DE fertility; adolescent and young adult; disparities; treatment; late effects ID SPERM BANKING; CHILDHOOD-CANCER; BREAST-CANCER; SURVIVORS; INFERTILITY; ATTITUDES; WOMEN; ONCOLOGISTS; EXPERIENCE; ISSUES AB BACKGROUND: The fertility of adolescent and young adult (AYA) patients with cancer can be threatened by treatments, but to the authors' knowledge little is known regarding the extent to which providers discuss this with patients or recommend fertility preservation, or the patient and physician characteristics associated with these interactions. METHODS: Questionnaires from 459 AYA patients with cancer who were diagnosed between 2007 and 2008 and recruited through 7 US population-based cancer registries were analyzed using sex-specific multivariable models. The authors assessed characteristics associated with not discussing therapy effects on fertility or fertility preservation options, and not making fertility preservation arrangements. RESULTS: Males without a medical oncologist were more likely not to be told that therapy might affect fertility than those with a medical oncologist (male odds ratio [OR], 2.28; 95% confidence interval [95% CI], 1.03-5.00). Individuals without insurance (male OR, 2.91 [95% CI, 1.41-5.91] and female OR, 5.46 [95% CI, 1.59-18.72]); those raising children aged <18 years; and, among males only, those who received treatment posing no or a low fertility risk (OR, 3.39; 95% CI, 1.60-7.16) were more likely not to discuss fertility preservation with providers. Finally, among males, those without a college degree (OR, 1.98; 95% CI, 1.00-3.97), lacking private insurance (OR, 2.97; 95% CI, 1.16-7.63), and raising children aged <18 years (OR, 3.53; 95% CI, 1.63-7.65) were more likely to not make fertility preservation arrangements; too few females had made fertility preservation arrangements for similar analyses to be performed. CONCLUSIONS: Discussion and action surrounding fertility preservation for AYA patients with cancer are associated with medical factors, patient socioeconomic data, and child-rearing status. These results highlight the need for insurance coverage for fertility preservation and increased awareness of fertility preservation options. Cancer 2015; 121: 3499-506. (C) 2015 American Cancer Society. C1 [Shnorhavorian, Margarett] Univ Washington, Dept Urol, Seattle Childrens Hosp, Div Pediat Urol, Seattle, WA 98105 USA. [Harlan, Linda C.; Smith, Ashley Wilder] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Prasad, Pinki K.] Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA USA. [Cress, Rosemary D.] Univ Calif Davis, Sch Med, Dept Publ Hlth, Davis, CA 95616 USA. [Wu, Xiao-Cheng] Louisiana State Univ, Sch Publ Hlth, Hlth Sci Ctr, Program Epidemiol, New Orleans, LA USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Parsons, Helen M.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Keel, Gretchen] Information Management Serv Inc, Silver Spring, MD USA. [Charlesworth, Sarah E.; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. RP Shnorhavorian, M (reprint author), Univ Washington, Dept Urol, Seattle Childrens Hosp, Div Pediat Urol, 4800 Sandpoint Way NE, Seattle, WA 98105 USA. EM margarett.shnorhavorian@seattlechildrens.org FU National Institutes of Health training grant [K12HD053984]; [N01PC-2010-00032]; [N01PC-2010-00140]; [N01PC-2010-00034]; [N01PC-2010-00035]; [N01PC-2010-00029]; [N01PC-2010-00028]; [N01PC-2010-00030] FX Supported by grants N01PC-2010-00032 (to the University of Iowa), N01PC-2010-00140 (to the Cancer Prevention Institute of California), N01PC-2010-00034 (to the Public Health Institute), N01PC-2010-00035 (to the University of Southern California), N01PC-2010-00029 (to the Fred Hutchinson Cancer Research Center), N01PC-2010-00028 (to Wayne State University), and N01PC-2010-00030 (to Louisiana State University Health Sciences Center) and a National Institutes of Health training grant (K12HD053984). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 17 TC 10 Z9 10 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2015 VL 121 IS 19 BP 3499 EP 3506 DI 10.1002/cncr.29328 PG 8 WC Oncology SC Oncology GA CT4MY UT WOS:000362782000023 PM 26214755 ER PT J AU Torabi, K Miro, R Fernandez-Jimenez, N Quintanilla, I Ramos, L Prat, E del Rey, J Pujol, N Killian, JK Meltzer, PS Fernandez, PL Ried, T Lozano, JJ Camps, J Ponsa, I AF Torabi, Keyvan Miro, Rosa Fernandez-Jimenez, Nora Quintanilla, Isabel Ramos, Laia Prat, Esther del Rey, Javier Pujol, Nuria Killian, J. Keith Meltzer, Paul S. Luis Fernandez, Pedro Ried, Thomas Jose Lozano, Juan Camps, Jordi Ponsa, Immaculada TI Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer SO CARCINOGENESIS LA English DT Article ID COPY-NEUTRAL LOH; COMPARATIVE GENOMIC HYBRIDIZATION; CIRCULAR BINARY SEGMENTATION; HEPATOCELLULAR-CARCINOMA; NUMBER; COLON; HETEROZYGOSITY; INSTABILITY; DLC1; TUMORIGENESIS AB Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs. C1 [Torabi, Keyvan; Miro, Rosa; Fernandez-Jimenez, Nora; Ramos, Laia; Prat, Esther; del Rey, Javier; Pujol, Nuria; Camps, Jordi; Ponsa, Immaculada] Univ Autonoma Barcelona, Fac Med, Dept Biol Cellular Fisiol & Immunol, Unitat Biol Cellular & Genet Med, Bellaterra 08193, Catalonia, Spain. [Miro, Rosa; Fernandez-Jimenez, Nora; Ramos, Laia; Prat, Esther; del Rey, Javier; Ponsa, Immaculada] Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Bellaterra 08193, Catalonia, Spain. [Quintanilla, Isabel; Camps, Jordi] CIBERehd, IDIBAPS, Gastrointestinal & Pancreat Oncol Grp, Barcelona 08036, Catalonia, Spain. [Killian, J. Keith; Meltzer, Paul S.; Ried, Thomas; Camps, Jordi] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Luis Fernandez, Pedro] Univ Barcelona, Hosp Clin, IDIBAPS, Dept Pathol, E-08036 Barcelona, Catalonia, Spain. [Jose Lozano, Juan] CIBERehd, Bioinformat Unit, Barcelona 08036, Catalonia, Spain. RP Ponsa, I (reprint author), Univ Autonoma Barcelona, Fac Med, Dept Biol Cellular Fisiol & Immunol, Unitat Biol Cellular & Genet Med, Bellaterra 08193, Catalonia, Spain. EM imma.ponsa@uab.cat FU National Institutes of Health; Ministerio de Educacion y Ciencia [SAF2007-64167]; Ministerio de Economia y Competitividad [SAF2012-40017-C02-02]; RTICC; FEDER [RD06/0020/1020]; Generalitat de Catalunya [2009 SGR 1107, 2014 SGR 0135, 2014 SGR 0903]; Catalonian Biobank Network; European Comission (COLONGEVA); Universitat Autonoma de Barcelona; Asociacion Espanola Contra el Cancer [AIO2011]; Instituto de Salud Carlos III [CP13/00160]; CIBERehd program; International Agency for Research on Cancer; Spanish Ministry (FPU program) FX Intramural program of National Institutes of Health; Ministerio de Educacion y Ciencia (SAF2007-64167); Ministerio de Economia y Competitividad (SAF2012-40017-C02-02); RTICC and FEDER (RD06/0020/1020); Generalitat de Catalunya (2009 SGR 1107, 2014 SGR 0135, 2014 SGR 0903); Catalonian Biobank Network; the European Comission (COLONGEVA); the Universitat Autonoma de Barcelona (PIF fellowship to K.T.); Asociacion Espanola Contra el Cancer (AIO2011 to J.C.); Instituto de Salud Carlos III (CP13/00160 to J.C.); CIBERehd program (J.J.L); the International Agency for Research on Cancer (Fellowship program to N.F.J) and Spanish Ministry (FPU program to I.Q.). NR 44 TC 1 Z9 1 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2015 VL 36 IS 10 BP 1103 EP 1110 DI 10.1093/carcin/bgv115 PG 8 WC Oncology SC Oncology GA CT5KZ UT WOS:000362850200003 PM 26243311 ER PT J AU Pan, P Skaer, CW Wang, HT Stirdivant, SM Young, MR Oshima, K Stoner, GD Lechner, JF Huang, YW Wang, LS AF Pan, Pan Skaer, Chad W. Wang, Hsin-Tzu Stirdivant, Steven M. Young, Matthew R. Oshima, Kiyoko Stoner, Gary D. Lechner, John F. Huang, Yi-Wen Wang, Li-Shu TI Black raspberries suppress colonic adenoma development in Apc(Min/+) mice: relation to metabolite profiles SO CARCINOGENESIS LA English DT Article ID COLORECTAL-CANCER; MOUSE MODELS; TISSUE; ACID; METHYLATION; PREVENTION; BERRIES; PATHWAY; DIETARY; GENES AB Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients. C1 [Pan, Pan; Skaer, Chad W.; Wang, Hsin-Tzu; Stoner, Gary D.; Lechner, John F.; Wang, Li-Shu] Med Coll Wisconsin, Dept Med, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Stirdivant, Steven M.] Metabolon Inc, Clin Res & Dev, Durham, NC 27713 USA. [Young, Matthew R.] NCI, Canc Prevent Div, Frederick, MD 20850 USA. [Oshima, Kiyoko] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Huang, Yi-Wen] Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA. RP Wang, LS (reprint author), Med Coll Wisconsin, Dept Med, Div Hematol & Oncol, Milwaukee, WI 53226 USA. EM liswang@mcw.edu FU NIH [5 R01 CA148818]; American Cancer Society [RSG-13-138-01-CNE] FX NIH (5 R01 CA148818); American Cancer Society (RSG-13-138-01-CNE) to L.-S.W. NR 39 TC 3 Z9 3 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2015 VL 36 IS 10 BP 1245 EP 1253 DI 10.1093/carcin/bgv117 PG 9 WC Oncology SC Oncology GA CT5KZ UT WOS:000362850200018 PM 26246425 ER PT J AU Taiwo, BO Chan, ES Fichtenbaum, CJ Ribaudo, H Tsibris, A Klingman, KL Eron, JJ Berzins, B Robertson, K Landay, A Ofotokun, I Brown, T AF Taiwo, Babafemi O. Chan, Ellen S. Fichtenbaum, Carl J. Ribaudo, Heather Tsibris, Athe Klingman, Karin L. Eron, Joseph J. Berzins, Baiba Robertson, Kevin Landay, Alan Ofotokun, Igho Brown, Todd CA AIDS Clinical Trials Grp A5303 Stu TI Less Bone Loss With Maraviroc-Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE maraviroc; tenofovir; bone; darunavir ID MINERAL DENSITY; DISOPROXIL FUMARATE; ABACAVIR-LAMIVUDINE; RANDOMIZED-TRIAL; NAIVE PATIENTS; IN-VITRO; INHIBITOR; INITIATION; ADULTS; CCR5 AB Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. Methods. This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) > 1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1: 1), stratified by VL < 100 000 or >= 100 000 copies/mL and age <30 or >= 30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. Results. We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log(10) copies/mL and CD4 count was 390 cells/mu L. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of - 1.51% [- 2.93%, - 0.11%] vs - 2.40% [- 4.30%, - 1.32%] for TDF (P <.001). Lumbar spine BMD decline was also less with MVC (median - 0.88% vs - 2.35%; P <.001). Similar proportions of subjects in both arms achieved VL <= 50 copies/mL in as-treated and ITT analyses. Conclusions. MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. C1 [Taiwo, Babafemi O.; Berzins, Baiba] Northwestern Univ, Div Infect Dis, Chicago, IL 60611 USA. [Chan, Ellen S.; Ribaudo, Heather] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Fichtenbaum, Carl J.] Univ Cincinnati, Div Infect Dis, Cincinnati, OH 45221 USA. [Tsibris, Athe] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Klingman, Karin L.] NIAID, HIV Res Branch, Div Aids, Bethesda, MD 20892 USA. [Eron, Joseph J.] Univ N Carolina, Dept Infect Dis, Chapel Hill, NC 27515 USA. [Robertson, Kevin] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27515 USA. [Landay, Alan] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Ofotokun, Igho] Emory Univ, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA. [Brown, Todd] Johns Hopkins Univ, Div Endocrinol Diabet & Metab, Baltimore, MD USA. RP Taiwo, BO (reprint author), Northwestern Univ, Div Infect Dis, 645 N Michigan Ave,Ste 900, Chicago, IL 60611 USA. EM b-taiwo@northwestern.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health; National Institute of Dental and Craniofacial Research; NIH [AI068634, AI068636]; National Center for Advancing Translational Sciences/NIH [UMAI069494, UMAI069432, UM1AI 069471, UM1AI069452, UM1 AI069501, 2UM1AI069432, UL1 TR001082, 1U01AI069477-01, P30AI073961, 5UM1 AI068636]; ViiV; Gilead; The National Center for Advancing Translational Sciences/NIH [2UM1AI069503, UM1 AI069471, 2UM1AI069439-08, UL1 TR000445, AI69439, UM1 AI069496, 5UM1AI069412, UM1 AI069423, 1UL1TR001111, P30 AI50410, 2UMIA1069423-08, 2UM1AI069418-08, 2P30 AI 50409-10, UL1TR000454]; [AI069501]; [5UM1AI069415-10]; [2UM1AI069412-08]; [AI069424]; [UL1 RR025780]; [2UM1-AI069470-08]; [UM1AI069472]; [2UMAI069432]; [AI 69501]; [UM1AI069471]; [UM1A 068636-09]; [5 P30 AI-045008-15]; [U01AI069447]; [NO1-HD-3-3345]; [UMI AI069511]; [UM1 AI069465]; [UL1TR001079]; [UL1 RR024160]; [UL1 TR000042] FX This work was supported by the National Institute of Allergy and Infectious Diseases (award number U01AI068636); the National Institute of Mental Health; and the National Institute of Dental and Craniofacial Research. This work was also supported by grants from the NIH (grant numbers AI068634 and AI068636 to the ACTG Statistical Data Analysis Center [ to E. S. C. and H. R.] and to the research sites that participated in the study [grant numbers UMAI069494, UMAI069432, UM1AI 069471, UM1AI069452, UM1 AI069501, 2UM1AI069432, UL1 TR001082, 1U01AI069477-01, P30AI073961, 5UM1 AI068636, 2UM1AI069503, UM1 AI069471, 2UM1AI069439-08, and UL1 TR000445 from the National Center for Advancing Translational Sciences/NIH, AI69439, UM1 AI069496, 5UM1AI069412, UM1 AI069423, 1UL1TR001111, P30 AI50410, 2UMIA1069423-08, 2UM1AI069418-08, 2P30 AI 50409-10, UL1TR000454, AI069501, 5UM1AI069415-10, 2UM1AI069412-08, AI069424, UL1 RR025780, 2UM1-AI069470-08, UM1AI069472, 2UMAI069432, AI 69501, UM1AI069471, UM1A 068636-09, 5 P30 AI-045008-15, U01AI069447, NO1-HD-3-3345, UMI AI069511, UM1 AI069465, UL1TR001079, UL1 RR024160, and UL1 TR000042]). ViiV, Gilead, and AbbVie provided study drugs. ViiV provided funding for DXA scanning. NR 42 TC 9 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 1 PY 2015 VL 61 IS 7 BP 1179 EP 1188 DI 10.1093/cid/civ455 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT6VZ UT WOS:000362952100026 PM 26060295 ER PT J AU Edwards, JK Cole, SR Westreich, D Mugavero, MJ Eron, JJ Moore, RD Mathews, WC Hunt, P Williams, C AF Edwards, Jessie K. Cole, Stephen R. Westreich, Daniel Mugavero, Michael J. Eron, Joseph J. Moore, Richard D. Mathews, William C. Hunt, Peter Williams, Carolyn CA Ctr AIDS Res Network Integrated Cl TI Age at Entry Into Care, Timing of Antiretroviral Therapy Initiation, and 10-Year Mortality Among HIV-Seropositive Adults in the United States SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; antiretroviral therapy; aging; epidemiologic methods ID PARAMETRIC G-FORMULA; HIV-1-INFECTED PATIENTS; COLLABORATIVE ANALYSIS; AIDS; COHORT AB Background. The goal of targeted antiretroviral therapy initiation is to minimize disease progression among patients with human immunodeficiency virus while minimizing the therapeutic burden on these patients. We examine whether the effect of delaying therapy initiation from 500 cells/mm(3) to 350 or 200 cells/mm(3) is modified by age at entry into care. Methods. We used the parametric g-formula to compare 10-year mortality under 3 CD4 cell count thresholds for therapy initiation among 3532 patients who entered care at 1 of 8 sites in the United States between 1998 and 2013. Results are reported separately for patients 18 to 34, 35 to 44, and 45 to 65 years of age at study entry. Results. In the observed data, 10-year mortality was 13% (165 deaths). Mortality increased from 11% under therapy initiation at 500 cells/mm(3) to 12% at 350 cells/mm3 (risk difference [RD]: 0.87; 95% confidence interval [CI]:.56, 2.17) and to 14% at 200 cells/mm(3) (RD: 2.71; 95% CI: 1.79, 5.38). The effect of delaying therapy became greater with age: RDs comparing the 350-cells/mm(3) threshold with the 500-cells/mm(3) threshold ranged from -0.03 (95% CI: -0.15, 1.76) for patients 18 to 34 years of age to 0.99 (95% CI: -.27, 1.98) for patients 35 to 44 and to 2.30 (95% CI: 1.29, 5.42) for patients 45 to 65. Conclusions. Delaying therapy increased 10-year mortality in the full cohort. Subgroup analysis highlights that patients entering care at older ages may be more vulnerable to the consequences of delayed ART initiation than younger patients. C1 [Edwards, Jessie K.; Cole, Stephen R.; Westreich, Daniel] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Mugavero, Michael J.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Eron, Joseph J.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Moore, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Mathews, William C.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Hunt, Peter] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Williams, Carolyn] NIAID, Basic Sci Program, Div Aids, NIH, Rockville, MD USA. RP Edwards, JK (reprint author), Univ N Carolina, Dept Epidemiol, 135 Dauer Dr,2101 McGavran Greenberg Hall CB 743, Chapel Hill, NC 27599 USA. EM jessedwards@unc.edu FU National Institutes of Health (NIH) [R01AI100654, R24AI067039, DP2 HD084070 01, P30AI50410] FX This work was funded, in part, by the National Institutes of Health (NIH; R01AI100654, R24AI067039, DP2 HD084070 01, and P30AI50410). NR 17 TC 7 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 1 PY 2015 VL 61 IS 7 BP 1189 EP 1195 DI 10.1093/cid/civ463 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CT6VZ UT WOS:000362952100027 PM 26082505 ER PT J AU Yi, LY Liang, X Liu, DM Sun, B Ying, S Yang, DB Li, QB Jiang, CL Han, Y AF Yi, Li-Ye Liang, Xia Liu, Da-Ming Sun, Bo Ying, Sun Yang, Dong-Bo Li, Qing-Bin Jiang, Chuan-Lu Han, Ying TI Disrupted Topological Organization of Resting-State Functional Brain Network in Subcortical Vascular Mild Cognitive Impairment SO CNS NEUROSCIENCE & THERAPEUTICS LA English DT Article DE Connectomics; Executive-control network; Module; Small-worldness; Subcortical vascular mild cognitive impairment ID WHITE-MATTER LESIONS; SMALL-WORLD NETWORKS; DEFAULT-MODE; CEREBROVASCULAR-DISEASE; CORTICAL DISCONNECTION; COMMUNITY STRUCTURE; CONNECTIVITY MRI; DEMENTIA; CORTEX; MOTION AB Aims: Neuroimaging studies have demonstrated both structural and functional abnormalities in widespread brain regions in patients with subcortical vascular mild cognitive impairment (svMCI). However, whether and how these changes alter functional brain network organization remains largely unknown. Methods: We recruited 21 patients with svMCI and 26 healthy control (HC) subjects who underwent resting-state functional magnetic resonance imaging scans. Graph theory-based network analyses were used to investigate alterations in the topological organization of functional brain networks. Results: Compared with the HC individuals, the patients with svMCI showed disrupted global network topology with significantly increased path length and modularity. Modular structure was also impaired in the svMCI patients with a notable rearrangement of the executive control module, where the parietal regions were split out and grouped as a separate module. The svMCI patients also revealed deficits in the intra- and/or intermodule connectivity of several brain regions. Specifically, the within-module degree was decreased in the middle cingulate gyrus while it was increased in the left anterior insula, medial prefrontal cortex and cuneus. Additionally, increased intermodule connectivity was observed in the inferior and superior parietal gyrus, which was associated with worse cognitive performance in the svMCI patients. Conclusion: Together, our results indicate that svMCI patients exhibit dysregulation of the topological organization of functional brain networks, which has important implications for understanding the pathophysiological mechanism of svMCI. C1 [Yi, Li-Ye; Liu, Da-Ming; Sun, Bo; Ying, Sun; Yang, Dong-Bo; Li, Qing-Bin; Jiang, Chuan-Lu] Harbin Med Univ, Dept Neurosurg, Affiliated Hosp 2, Harbin, Peoples R China. [Liang, Xia] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. [Han, Ying] Beijing Inst Brain Disorders, Ctr Alzheimers Dis, Beijing, Peoples R China. [Han, Ying] Capital Med Univ, XuanWu Hosp, Dept Neurol, Beijing, Peoples R China. RP Jiang, CL (reprint author), Harbin Med Univ, Dept Neurosurg, Affiliated Hosp 2, Harbin, Peoples R China. EM jcl6688@163.com; 13621011941@163.com FU National Natural Science Foundation of China (NSFC) [81372700, 31371007]; Special Fund for Scientific Research in the Public Interest [201402008]; Scientific Research Foundation of Graduate School of Harbin Medical University; National Key Department of Neurology - Chinese Health and Family Planning Committee FX This article was supported by National Natural Science Foundation of China (NSFC No. 81372700 and 31371007), Special Fund for Scientific Research in the Public Interest (No. 201402008), Scientific Research Foundation of Graduate School of Harbin Medical University and National Key Department of Neurology funded by Chinese Health and Family Planning Committee. NR 75 TC 4 Z9 4 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-5930 EI 1755-5949 J9 CNS NEUROSCI THER JI CNS Neurosci. Ther. PD OCT PY 2015 VL 21 IS 10 SI SI BP 846 EP 854 DI 10.1111/cns.12424 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CT8BV UT WOS:000363040900011 PM 26257386 ER PT J AU Beliveau, P Cheriet, F Anderson, SA Taylor, JL Arai, AE Hsu, LY AF Beliveau, Pascale Cheriet, Farida Anderson, Stasia A. Taylor, Joni L. Arai, Andrew E. Hsu, Li-Yueh TI Quantitative assessment of myocardial fibrosis in an age-related rat model by ex vivo late gadolinium enhancement magnetic resonance imaging with histopathological correlation SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Diffuse myocardial fibrosis; Gadolinium; Magnetic resonance imaging; Texture analysis; Computer quantification; Aging ID EXTRACELLULAR VOLUME FRACTION; HYPERTROPHIC CARDIOMYOPATHY; HEART-DISEASE; MRI; QUANTIFICATION; COLLAGEN; VALIDATION; CMR; ATHEROSCLEROSIS; DYSFUNCTION AB Late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR) imaging can detect the presence of myocardial infarction from ischemic cardiomyopathies (ICM). However, it is more challenging to detect diffuse myocardial fibrosis from non-ischemic cardiomyopathy (NICM) with this technique due to more subtle and heterogeneous enhancement of the myocardium. This study investigates whether high-resolution LGE CMR can detect age-related myocardial fibrosis using quantitative texture analysis with histological validation. LGE CMR of twenty-four rat hearts (twelve 6-week-old and twelve 2-year-old) was performed using a 7 T MRI scanner. Picrosirius red was used as the histopathology reference for collagen staining. Fibrosis in the myocardium was quantified with standard deviation (SD) threshold methods from the LGE CMR images and 3D contrast texture maps that were computed from gray level co-occurrence matrix of the CMR images. There was a significant increase of collagen fibers in the aged compared to the young rat histology slices (2.60 +/- 0.27 %LV vs. 1.24 +/- 0.29 %LV, p < 0.01). Both LGE CMR and texture images showed a significant increase of myocardial fibrosis in the elderly compared to the young rats. Fibrosis in the LGE CMR images correlated strongly with histology with the 3 SD threshold (r=0.84, y=0.99x+0.00). Similarly, fibrosis in the contrast texture maps correlated with the histology using the 4 SD threshold (r=0.89, y=1.01x+0.00). High resolution ex-vivo LGE CMR can detect the presence of diffuse fibrosis that naturally developed in elderly rat hearts. Our results suggest that texture analysis may improve the assessment of myocardial fibrosis in LGE CMR images. Published by Elsevier Ltd. C1 [Beliveau, Pascale; Anderson, Stasia A.; Taylor, Joni L.; Arai, Andrew E.; Hsu, Li-Yueh] NHLBI, NIH, Bethesda, MD 20892 USA. [Beliveau, Pascale; Cheriet, Farida] Ecole Polytech, Inst Biomed Engn, Montreal, PQ H3C 3A7, Canada. RP Hsu, LY (reprint author), NHLBI, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM lyhsu@mail.nih.gov FU Intramural Research Program of National Heart Lung and Blood Institute; Fonds de Recherche Nature et Technologie du Quebec; Ecole Polytechnique of Montreal FX Funded by the Intramural Research Program of National Heart Lung and Blood Institute, Ecole Polytechnique of Montreal and Fonds de Recherche Nature et Technologie du Quebec. NR 48 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 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD OCT 1 PY 2015 VL 65 BP 103 EP 113 DI 10.1016/j.compbiomed.2015.07.027 PG 11 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA CT5OW UT WOS:000362860700011 PM 26313531 ER PT J AU Liuzzi, AR McLaren, JE Price, DA Eberl, M AF Liuzzi, Anna Rita McLaren, James E. Price, David A. Eberl, Matthias TI Early innate responses to pathogens: pattern recognition by unconventional human T-cells SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID VITAMIN-B METABOLITES; MAIT CELLS; ANTIGEN RECEPTOR; MOLECULAR-BASIS; MR1; REPERTOIRE; ACTIVATION; INFECTION; PHOSPHOANTIGENS; LYMPHOCYTES AB Although typically viewed as a feature of innate immune responses, microbial pattern recognition is increasingly acknowledged as a function of particular cells nominally categorized within the adaptive immune system. Groundbreaking research over the past three years has shown how unconventional human T-cells carrying invariant or semi-invariant TCRs that are not restricted by classical MHC molecules sense microbial compounds via entirely novel antigen presenting pathways. This review will focus on the innate-like recognition of non-self metabolites by V gamma 9/V delta 2 T-cells, mucosal-associated invariant T (MAIT) cells and germline-encoded mycolyl-reactive (GEM) T-cells, with an emphasis on early immune responses in acute infection. C1 [Liuzzi, Anna Rita; McLaren, James E.; Price, David A.; Eberl, Matthias] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Eberl, M (reprint author), Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. EM eberlm@cf.ac.uk RI Eberl, Matthias/A-5970-2009; Price, David/C-7876-2013 OI Eberl, Matthias/0000-0002-9390-5348; Price, David/0000-0001-9416-2737 FU National Institute for Social Care and Health Research (NISCHR); EU-FP7 Marie Curie Initial Training Network EuTRiPD; Kidney Research UK FX We thank members of our research teams and our collaborators for helpful discussions, and David Vermijlen for critical review of the manuscript. Our research has received support from the National Institute for Social Care and Health Research (NISCHR), the EU-FP7 Marie Curie Initial Training Network EuTRiPD and Kidney Research UK. D.A.P. is a Wellcome Trust Senior Investigator. We apologize to colleagues whose work we could not cite due to space constraints or unintentional oversight. NR 60 TC 5 Z9 5 U1 1 U2 10 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2015 VL 36 BP 31 EP 37 DI 10.1016/j.coi.2015.06.002 PG 7 WC Immunology SC Immunology GA CT8MF UT WOS:000363070000007 PM 26182978 ER PT J AU Bonnelykke, K Sparks, R Waage, J Milner, JD AF Bonnelykke, Klaus Sparks, Rachel Waage, Johannes Milner, Joshua D. TI Genetics of allergy and allergic sensitization: common variants, rare mutations SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID GENOME-WIDE ASSOCIATION; SEVERE COMBINED IMMUNODEFICIENCY; HYPER-IGE SYNDROME; COMPLETE DIGEORGE-SYNDROME; WISKOTT-ALDRICH-SYNDROME; REGULATORY T-CELLS; ATOPIC-DERMATITIS; IMMUNE DYSREGULATION; OMENN SYNDROME; CUTANEOUS MANIFESTATIONS AB Our understanding of the specific genetic lesions in allergy has improved in recent years due to identification of common risk variants from genome-wide association studies (GWAS) and studies of rare, monogenic diseases. Large-scale GWAS have identified novel susceptibility loci and provided information about shared genetics between allergy, related phenotypes and autoimmunity. Studies of monogenic diseases have elucidated critical cellular pathways and protein functions responsible for allergy. These complementary approaches imply genetic mechanisms involved in Th2 immunity, T-cell differentiation, TGF beta signaling, regulatory T-cell function and skin/mucosal function as well as yet unknown mechanisms associated with newly identified genes. Future studies, in combination with data on gene expression and epigenetics, are expected to increase our understanding of the pathogenesis of allergy. C1 [Bonnelykke, Klaus; Waage, Johannes] Copenhagen Prospect Studies Asthma Childhood, COPSAC, Herlev, Denmark. [Bonnelykke, Klaus; Waage, Johannes] Univ Copenhagen, Gentofte Hosp, Copenhagen, Denmark. [Sparks, Rachel] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Milner, Joshua D.] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Bonnelykke, K (reprint author), Copenhagen Prospect Studies Asthma Childhood, COPSAC, Herlev, Denmark. EM kb@copsac.com FU children and families of the COPSAC; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; Lundbeck Foundation; Danish Ministry of Health; Danish Council for Strategic Research; Danish Council for Independent Research; Capital Region Research Foundation FX We gratefully express our gratitude to the children and families of the COPSAC studies for all their support and commitment. We acknowledge and appreciate the unique efforts of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) research team.; COPSAC is funded by private and public research funds all listed on www. copsac.com. The Lundbeck Foundation; The Danish Ministry of Health; Danish Council for Strategic Research; The Danish Council for Independent Research and The Capital Region Research Foundation have provided core support for COPSAC.; This research was further supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 78 TC 7 Z9 7 U1 7 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2015 VL 36 BP 115 EP 126 DI 10.1016/j.coi.2015.08.002 PG 12 WC Immunology SC Immunology GA CT8MF UT WOS:000363070000019 PM 26386198 ER PT J AU Akolkar, B Hilner, J Nierras, CR AF Akolkar, Beena Hilner, Joan Nierras, Concepcion R. TI Design and Measurement of Nonislet-Specific Autoantibodies for the Type 1 Diabetes Genetics Consortium Autoantibody Workshop SO DIABETES CARE LA English DT Article ID SUSCEPTIBILITY LOCI; MULTIPLEX FAMILIES; COLLECTION; LINKAGE AB The Type 1 Diabetes Genetics Consortium(T1DGC) comprised groups of investigators from many countries throughout the world, with a common goal of identifying genes predisposing to type 1 diabetes. The T1DGC ascertained and collected samples from families with two or more affected siblings with type 1 diabetes and generated a broad array of clinical, genetic, and immunologic data. The T1DGC Autoantibody Workshop was designed to distribute data for analyses to discover genes associated with autoantibodies in those with type 1 diabetes. In the T1DGC-affected sibling pair families, three T1DGC Network laboratories measured antibodies to the islet autoantigens GAD65 and the intracellular portion of protein tyrosine phosphatase (IA-2A). The availability of extensive genetic data provided an opportunity to investigate the associations between type 1 diabetes and other autoimmune diseases for which autoantibodies could be measured. Measurements of additional nonislet autoantibodies, including thyroid peroxidase, tissue transglutaminase, 21-hydroxylase, and the potassium/hydrogen ion transporter H+/K+-ATPase, were performed by the T1DGC laboratory at the Barbara Davis Center for Childhood Diabetes, Aurora, CO. Measurements of all autoantibodies were transmitted to the T1DGC Coordinating Center, and the data were made available to members of the T1DGC Autoantibody Working Groups for analysis in conjunction with existing T1DGC genetic data. This article describes the design of the T1DGC Autoantibody Workshop and the quality-control procedures to maintain and monitor the performance of each laboratory and provides the quality-control results for the nonislet autoantibody measurements. C1 [Akolkar, Beena] NIDDKD, NIH, Bethesda, MD USA. [Hilner, Joan] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Nierras, Concepcion R.] JDRF, New York, NY 10004 USA. RP Nierras, CR (reprint author), JDRF, New York, NY 10004 USA. EM concepcion.nierras@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF; [U01 DK062418] FX This research uses resources provided by the T1DGC, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and JDRF and supported by grant U01 DK062418. NR 12 TC 1 Z9 1 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2015 VL 38 SU 2 BP S4 EP S7 DI 10.2337/dcs15-2002 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CT7CF UT WOS:000362970200002 PM 26405071 ER PT J AU Vidak, S Kubben, N Dechat, T Foisner, R AF Vidak, Sandra Kubben, Nard Dechat, Thomas Foisner, Roland TI Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2 alpha (LAP2 alpha) through expression of extracellular matrix proteins SO GENES & DEVELOPMENT LA English DT Article DE A-type lamins; nuclear lamina; Hutchinson Gilford progeria; extracellular matrix; cell proliferation regulation; nucleoplasmic lamins; lamina-associated polypeptide ID HUTCHINSON-GILFORD-PROGERIA; NUCLEAR LAMINA; RETINOBLASTOMA PROTEIN; LEM PROTEINS; PRELAMIN-A; CHROMATIN; MUTANT; PHOSPHORYLATION; COMPLEXES; DEFECTS AB Lamina-associated polypeptide 2 alpha (LAP2 alpha) localizes throughout the nucleoplasm and interacts with the fraction of lamins A/C that is not associated with the peripheral nuclear lamina. The LAP2 alpha lamin A/C complex negatively affects cell proliferation. Lamins A/C are encoded by LMNA, a single heterozygous mutation of which causes Hutchinson-Gilford progeria syndrome (HGPS). This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2 alpha and nucleoplasmic lamins A/C, impaired proliferation, and down-regulation of extracellular matrix components. Surprisingly, contrary to wild-type cells, ectopic expression of LAP2 alpha in cells expressing progerin restores proliferation and extracellular matrix expression but not the levels of nucleoplasmic lamins A/C. We conclude that, in addition to its cell cycle-inhibiting function with lamins A/C, LAP2 alpha can also regulate extracellular matrix components independently of lamins A/C, which may help explain the proliferation-promoting function of LAP2 alpha in cells expressing progerin. C1 [Vidak, Sandra; Dechat, Thomas; Foisner, Roland] Med Univ Vienna, Dept Med Biochem, MFPL, Vienna Bioctr VBC, A-1030 Vienna, Austria. [Kubben, Nard] NCI, NIH, Bethesda, MD 20892 USA. RP Foisner, R (reprint author), Med Univ Vienna, Dept Med Biochem, MFPL, Vienna Bioctr VBC, A-1030 Vienna, Austria. EM thomas.dechat@meduniwien.ac.at; roland.foisner@meduniwien.ae.at FU Austrian Science Fund (FWF) [P26492-B20, DK W1220]; Herzfelder'sche Familien-stiftung; Progeria Research Foundation [PRF2011-37]; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research FX We thank T. Misteli (National Cancer Institute, National Institutes of Health, Bethesda, MD) for critical reading of the manuscript and helpful input. We also thank Kevin Gesson (Max F. Pemtz Laboratories, Vienna, Austria) for valuable advice and help with ChIP experiments, and Maciej Szafraniec (Max F. Perutz Laboratories, Vienna, Austria) for help with the cloning of retroviral constructs. We are grateful to R. Goldman (Feinberg School of Medicine, Northwestern University, Chicago, IL) and I. Yudushkin, D. Blaas, and E. Ogris (all Max F. Perutz Laboratories, Vienna, Austria) for generous gifts of reagents and tools. We acknowledge grant support from the Austrian Science Fund (FWF grant P26492-B20) to R.F., and the Herzfelder'sche Familien-stiftung and Progeria Research Foundation (Innovator Award, PRF2011-37) to T.D. S.V. was supported by a doctoral program funded by the Austrian Science Fund (FWF, DK W1220). This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. S.V. conceived, performed, and analyzed the experiments; prepared figures; and cowrote the manuscript. N.K. generated and initially tested progerin-expressing and lamin A-expressing hTERT cell lines. T.D. conceived and analyzed the experiments and cowrote the manuscript. R.F. conceived and analyzed the experiments and cowrote the manuscript. NR 59 TC 12 Z9 12 U1 1 U2 10 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 OCT 1 PY 2015 VL 29 IS 19 BP 2022 EP 2036 DI 10.1101/gad.263939.115 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA CT7NV UT WOS:000363002700006 PM 26443848 ER PT J AU Felix, AS McMeekin, DS Mutch, D Walker, JL Creasman, WT Cohn, DE Ali, S Moore, RG Downs, LS Ioffe, OB Park, KJ Sherman, ME Brinton, LA AF Felix, Ashley S. McMeekin, D. Scott Mutch, David Walker, Joan L. Creasman, William T. Cohn, David E. Ali, Shamshad Moore, Richard G. Downs, Levi S. Ioffe, Olga B. Park, Kay J. Sherman, Mark E. Brinton, Louise A. TI Associations between etiologic factors and mortality after endometrial cancer diagnosis: The NRG Oncology/Gynecologic Oncology Group 210 trial SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; NRG; Etiologic factors; GOG; Prognosis ID BODY-MASS INDEX; PROGNOSTIC-FACTOR; UTERINE-CANCER; INDIVIDUALIZED PREDICTION; PHYSICAL-ACTIVITY; POORER SURVIVAL; ELDERLY-WOMEN; CORPUS UTERI; STAGE-II; CARCINOMA AB Background. Few studies have analyzed relationships between risk factors for endometrial cancer, especially with regard to aggressive (non-endometrioid) histologic subtypes, and prognosis. We examined these relationships in the prospective NRG Oncology/Gynecologic Oncology Group 210 trial. Methods. Prior to surgery, participants completed a questionnaire assessing risk factors for gynecologic cancers. Pathology data were derived from clinical reports and central review. We used the Fine and Gray subdistribution hazards model to estimate subhazard ratios (HRs) and 95% confidence intervals (Cls) for associations between etiologic factors and cause-specific subhazards in the presence of competing risks. These models were stratified by tumor subtype and adjusted for stage and socioeconomic status indicators. Results. Median follow-up was 60 months after enrollment (range: 1 day-118 months). Among 4609 participants, a total of 854 deaths occurred, of which, 582 deaths were attributed to endometrial carcinoma. Among low-grade endometrioid cases, endometrial carcinoma-specific subhazards were significantly associated with age at diagnosis (HR = 1.04, 95% CI = 1.01-1.06 per year, P-trend) and BMI (class II obesity vs. normal BMI: HR = 2.29, 95% CI = 1.06-4.98, P-trend = 0.01). Among high-grade endometrioid cases, endometrial carcinoma-specific subhazards were associated with age at diagnosis (HR = 1.05, 95% CI = 1.02-1.07 per year, P-trend < 0.001). Among non-endometrioid cases, endometrial carcinoma-specific subhazards were associated with parity relative to nulliparity among serous (HR = 0.55, 95% Cl = 0.36-0.82) and carcinosarcoma cases (HR = 2.01,95% Cl = 1.00-4.05). Discussion. Several endometrial carcinoma risk factors are associated with prognosis, which occurs in a tumor-subtype specific context. If confirmed, these results would suggest that factors beyond histopathologic features and stage are related to prognosis. ClinicalTrials.gov Identifier: NCT00340808. Published by Elsevier Inc. C1 [Felix, Ashley S.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [McMeekin, D. Scott; Walker, Joan L.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Mutch, David] Washington Univ, Sch Med, St Louis, MO USA. [Creasman, William T.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, Columbus, OH 43210 USA. [Ali, Shamshad] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA. [Moore, Richard G.] Brown Univ, Women & Infants Hosp, Dept Obstet & Gynecol, Program Womens Oncol, Providence, RI USA. [Downs, Levi S.] Univ Minnesota, Gynecol Oncol, Minneapolis, MN USA. [Ioffe, Olga B.] Univ Maryland, Anat Pathol, College Pk, MD 20742 USA. [Park, Kay J.] Mem Sloan Kettering Canc Ctr, Surg Pathol, New York, NY 10021 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. RP Felix, AS (reprint author), 1841 Neil Ave,300-C Cunz Hall, Columbus, OH 43210 USA. EM Felix.20@osu.edu OI Park, Kay/0000-0001-8989-2938 FU National Cancer Institute [CA 27469]; Gynecologic Oncology Group Statistical and Data Center [CA 37517]; NRG [U10 CA180822]; National Cancer Institute, National Institutes of Health FX This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517) and the NRG Oncology Grant number: U10 CA180822. In addition, this research was supported in part by funds provided by the intramural research program of the National Cancer Institute, National Institutes of Health. NR 63 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD OCT PY 2015 VL 139 IS 1 BP 70 EP 76 DI 10.1016/j.ygyno.2015.08.022 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CT6ND UT WOS:000362928800012 PM 26341710 ER PT J AU Buske, OJ Girdea, M Dumitriu, S Gallinger, B Hartley, T Trang, H Misyura, A Friedman, T Beaulieu, C Bone, WP Links, AE Washington, NL Haendel, MA Robinson, PN Boerkoel, CF Adams, D Gahl, WA Boycott, KM Brudno, M AF Buske, Orion J. Girdea, Marta Dumitriu, Sergiu Gallinger, Bailey Hartley, Taila Trang, Heather Misyura, Andriy Friedman, Tal Beaulieu, Chandree Bone, William P. Links, Amanda E. Washington, Nicole L. Haendel, Melissa A. Robinson, Peter N. Boerkoel, Cornelius F. Adams, David Gahl, William A. Boycott, Kym M. Brudno, Michael TI PhenomeCentral: A Portal for Phenotypic and Genotypic Matchmaking of Patients with Rare Genetic Diseases SO HUMAN MUTATION LA English DT Article DE deep phenotyping; HPO; patient matchmaking; semantic similarity; Matchmaker Exchange ID SEMANTIC SIMILARITY; DISORDERS; DISCOVERY; ONTOLOGY; EXCHANGE; ACCURATE; SEARCHES; PROJECT; BIOLOGY; TOOL AB The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered. (C) 2015 Wiley Periodicals, Inc. C1 [Buske, Orion J.; Girdea, Marta; Friedman, Tal; Brudno, Michael] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. [Buske, Orion J.; Girdea, Marta; Brudno, Michael] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada. [Buske, Orion J.; Girdea, Marta; Dumitriu, Sergiu; Gallinger, Bailey; Trang, Heather; Misyura, Andriy; Brudno, Michael] Hosp Sick Children, Ctr Computat Med, Toronto, ON M5G 1X8, Canada. [Gallinger, Bailey; Trang, Heather] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Hartley, Taila; Beaulieu, Chandree; Boycott, Kym M.] Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON K1H 8L1, Canada. [Bone, William P.; Links, Amanda E.; Boerkoel, Cornelius F.; Adams, David; Gahl, William A.] NIH, Undiagnosed Dis Program, Common Fund, Off Director, Bethesda, MD 20892 USA. [Washington, Nicole L.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Haendel, Melissa A.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Robinson, Peter N.] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany. RP Brudno, M (reprint author), 10 Kings Coll Rd,SF3304, Toronto, ON M5S 3G4, Canada. EM brudno@cs.toronto.edu FU Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Foundation; Hospital for Sick Children; NSERC/CIHR Collaborative Health Research Project (CHRP); Garron Family Cancer Centre and Hospital for Sick Children Foundation Student Scholarship Program; NSERC Undergraduate Student Research Award FX Contract grant sponsors: Care4Rare Canada Consortium funded by Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Foundation; Hospital for Sick Children; NSERC/CIHR Collaborative Health Research Project (CHRP); Garron Family Cancer Centre and Hospital for Sick Children Foundation Student Scholarship Program; NSERC Undergraduate Student Research Award. NR 31 TC 16 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD OCT PY 2015 VL 36 IS 10 SI SI BP 931 EP 940 DI 10.1002/humu.22851 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CT7IX UT WOS:000362989500003 PM 26251998 ER PT J AU Ayres-De-Campos, D Spong, CY Chandraharan, E AF Ayres-de-Campos, Diogo Spong, Catherine Y. Chandraharan, Edwin CA FIGO Intrapartum Fetal Monitoring TI FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Editorial Material ID HEART-RATE PATTERNS; VARIABLE DECELERATIONS; PLACENTAL ABRUPTION; LABOR; CLASSIFICATION; INTERMITTENT; POSITION C1 [Ayres-de-Campos, Diogo] Univ Porto, S Joao Hosp, Inst Biomed Engn, Sch Med, P-4100 Oporto, Portugal. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Chandraharan, Edwin] Univ London St Georges Hosp, NHS Fdn Trust, London, England. RP Ayres-De-Campos, D (reprint author), Univ Porto, S Joao Hosp, Inst Biomed Engn, Sch Med, Rua Campo Alegre 823, P-4100 Oporto, Portugal. RI FMUP, CINTESIS/C-6631-2014; Bernardes, Joao/L-8032-2013; OI FMUP, CINTESIS/0000-0001-7248-2086; Valent, Sandor/0000-0003-1098-1861; Santo, Susana/0000-0002-3871-5218; Berghella, Vincenzo/0000-0003-2854-0239 NR 56 TC 20 Z9 21 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD OCT PY 2015 VL 131 IS 1 BP 13 EP 24 DI 10.1016/j.ijgo.2015.06.020 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CT5NG UT WOS:000362856500005 PM 26433401 ER PT J AU Naik, HB Steinberg, SM Middelton, LA Hewitt, SM Zuo, RC Linehan, WM Kong, HH Cowen, EW AF Naik, Haley B. Steinberg, Seth M. Middelton, Lindsay A. Hewitt, Stephen M. Zuo, Rena C. Linehan, W. Marston Kong, Heidi H. Cowen, Edward W. TI Efficacy of Intralesional Botulinum Toxin A for Treatment of Painful Cutaneous Leiomyomas A Randomized Clinical Trial SO JAMA DERMATOLOGY LA English DT Article ID LATERAL CANTHAL LINES; RENAL-CELL CANCER; TOPICAL GEL; INNERVATION; MODULATION; MODERATE; SAFETY AB IMPORTANCE Cutaneous leiomyomas can be associated with severe paroxysmal pain in which nerve conduction may have a key role. Medical management of painful cutaneous leiomyomas is generally unsatisfactory. OBJECTIVE To assess the efficacy of intralesional botulinum toxin A in the management of pain associated with cutaneous leiomyomas. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled pilot study conducted from January 5, 2009, to March 27, 2014. The setting was a single-center study at the National Institutes of Health among participants 18 years or older with cutaneous leiomyomas characterized by pain at least once weekly and pain of at least 4 on a pain scale ranging from 0 to 10. INTERVENTIONS Eighteen participants were randomized to receive intralesional botulinum toxin A (5 U per 1 cm(2)) or equivalent volumes of intralesional saline placebo. MAIN OUTCOMES AND MEASURES The primary outcomes were the differences in average lesional pain assessed by the Brief Pain Inventory and visual analog scale before and after ice provocation over a 4-week period. RESULTS No significant difference in average lesional pain was observed between the study arms. Decreased pain was reported in the botulinum toxin vs placebo arms by visual analog scale scores before ice provocation (median, 0.00; range, -3.30 to 0.70 for botulinum toxin and median, 0.40; range, -1.30 to 1.50 for placebo; P = .06); however, this finding was nonsignificant. No significant difference was observed in change in pain after ice provocation. A significant difference was seen between the arms in skin-related quality of life by total Dermatology Life Quality Index (median, -4.00; range, -8.00 to 2.00 for botulinum toxin and median, 0.00; range, -1.00 to 4.00 for placebo; P =.007) and with the specific skin pain-related question on the Dermatology Life Quality Index (median, -1.00; range, -2.00 to 1.00 for botulinum toxin and median, 0.00; range, -1.00 to 0.00 for placebo; P = .048). No significant difference was found in pain as ascertained by Patient Global Impression of Change at week 4. No serious adverse events related to botulinum toxin use were observed. CONCLUSIONS AND RELEVANCE The use of botulinum toxin to treat painful cutaneous leiomyomas was associated with improved quality of life and with a trend toward improved pain at rest. C1 [Naik, Haley B.; Zuo, Rena C.; Kong, Heidi H.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Middelton, Lindsay A.; Linehan, W. Marston] NCI, Urol Surg, Ctr Canc Res, Bethesda, MD 20892 USA. [Middelton, Lindsay A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, 10 Ctr Dr,Mail Stop Code 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Kong, Heidi/0000-0003-4424-064X FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Botulinum toxin A was provided by Allergan through a material transfer agreement with the National Institutes of Health. NR 17 TC 2 Z9 2 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD OCT PY 2015 VL 151 IS 10 BP 1096 EP 1102 DI 10.1001/jamadermatol.2015.1793 PG 7 WC Dermatology SC Dermatology GA CT6XF UT WOS:000362955700010 PM 26244563 ER PT J AU Olivera, A Lejbman, N Jeromin, A French, LM Kim, HS Cashion, A Mysliwiec, V Diaz-Arrastia, R Gill, J AF Olivera, Anlys Lejbman, Natasha Jeromin, Andreas French, Louis M. Kim, Hyung-Suk Cashion, Ann Mysliwiec, Vincent Diaz-Arrastia, Ramon Gill, Jessica TI Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment SO JAMA NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; HEAD-INJURY; ALZHEIMERS-DISEASE; MOUSE MODEL; RISK; ENCEPHALOPATHY; BIOMARKERS; ASSOCIATION; CONCUSSION; ACTIVATION AB IMPORTANCE Approximately one-third of military personnel who deploy for combat operations sustain 1 or more traumatic brain injuries (TBIs), which increases the risk for chronic symptoms of postconcussive disorder, posttraumatic stress disorder, and depression and for the development of chronic traumatic encephalopathy. Elevated concentrations of tau are observed in blood shortly following a TBI, but, to our knowledge, the role of tau elevations in blood in the onset and maintenance of chronic symptoms after TBI has not been investigated. OBJECTIVES To assess peripheral tau levels in military personnel exposed to TBI and to examine the relationship between chronic neurological symptoms and tau elevations. DESIGN, SETTING, AND PARTICIPANTS Observational assessment from September 2012 to August 2014 of US military personnel at the Madigan Army Medical Center who had been deployed within the previous 18 months. Plasma total tau concentrations were measured using a novel ultrasensitive single-molecule enzyme-linked immunosorbent assay. Classification of participants with and without self-reported TBI was made using the Warrior Administered Retrospective Casualty Assessment Tool. Self-reported symptoms of postconcussive disorder, posttraumatic stress disorder, and depression were determined by the Neurobehavioral Symptom Inventory, the Posttraumatic Stress Disorder Checklist Military Version, and the Quick Inventory of Depressive Symptomatology, respectively. Group differences in tau concentrations were determined through analysis of variance models, and area under the receiver operating characteristic curve determined the sensitivity and specificity of tau concentrations in predicting TBI and chronic symptoms. Seventy participants with self-reported TBI on theWarrior Administered Retrospective Casualty Assessment Tool and 28 control participants with no TBI exposure were included. MAIN OUTCOMES AND MEASURES Concentration of total tau in peripheral blood. RESULTS Concentrations of plasma tau were significantly elevated in the 70 participants with self-reported TBI compared with the 28 controls (mean [SD], 1.13 [0.78] vs 0.63 [0.48] pg/mL, respectively; F-1,F-97 = 4.97; P = .03). Within the self-reported TBI cases, plasma total tau concentrations were significantly associated with having a medical record of TBI compared with self-reported TBI only (mean [SD], 1.57 [0.92] vs 0.85 [0.52] pg/mL, respectively; F1,69 = 6.15; P = .02) as well as reporting the occurrence of 3 of more TBIs during deployment compared with fewer than 3 TBIs (mean [SD], 1.52 [0.82] vs 0.82 [0.60] pg/mL, respectively; F1,69 = 8.57; P = .008). The severity of total postconcussive symptoms correlated with total tau concentrations in the self-reported TBI group (r = 0.37; P = .003). CONCLUSIONS AND RELEVANCE Military personnel who report multiple TBIs have long-term elevations in total tau concentration. The total tau concentration relates to symptoms of postconcussive disorder. C1 [Olivera, Anlys; Lejbman, Natasha; Kim, Hyung-Suk; Cashion, Ann; Gill, Jessica] NINR, NIH, Bethesda, MD 20814 USA. [Jeromin, Andreas] Quantenx Corp, Lexington, MA USA. [French, Louis M.] Natl Intrepid Ctr Excellence, Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [French, Louis M.; Diaz-Arrastia, Ramon] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Mysliwiec, Vincent] Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. RP Gill, J (reprint author), NINR, NIH, One Cloister Court,Room 256, Bethesda, MD 20814 USA. EM gillj@mail.nih.gov FU Intramural Research Program of the National Institutes of Nursing Research; Center for Neuroscience and Regenerative Medicine [60855] FX This work was supported by the Intramural Research Program of the National Institutes of Nursing Research and in part by grant 60855 from the Center for Neuroscience and Regenerative Medicine. NR 48 TC 19 Z9 20 U1 9 U2 23 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 OCT PY 2015 VL 72 IS 10 BP 1109 EP 1116 DI 10.1001/jamaneurol.2015.1383 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CT6ZQ UT WOS:000362963000005 PM 26237304 ER PT J AU Park, JE Alter, K Hallett, M AF Park, Jung E. Alter, Katharine Hallett, Mark TI Isolated Lingual Dyskinesia in Multiple Sclerosis SO JAMA NEUROLOGY LA English DT Editorial Material ID FACIAL MYOKYMIA C1 [Park, Jung E.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Alter, Katharine] NIH, Funct & Appl Biomech Sect, Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Alter, Katharine] Eunice Schriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD 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 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD OCT PY 2015 VL 72 IS 10 BP 1196 EP 1197 DI 10.1001/jamaneurol.2015.1456 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CT6ZQ UT WOS:000362963000018 PM 26280873 ER PT J AU Jampol, LM Ferris, FL Bishop, RJ AF Jampol, Lee M. Ferris, Frederick L., III Bishop, Rachel J. TI Ebola and the Eye SO JAMA OPHTHALMOLOGY LA English DT Editorial Material ID VIRUS; MANIFESTATIONS; KIKWIT; CONGO C1 [Jampol, Lee M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferris, Frederick L., III; Bishop, Rachel J.] NEI, NIH, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), 10 Ctr Dr,Bldg 10 CRC,Room 3-2531, Bethesda, MD 20892 USA. EM rickferris@nei.nih.gov NR 7 TC 2 Z9 2 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD OCT PY 2015 VL 133 IS 10 BP 1105 EP 1106 DI 10.1001/jamaophthalmol.2015.2400 PG 2 WC Ophthalmology SC Ophthalmology GA CT7AL UT WOS:000362965300005 PM 26204253 ER PT J AU Rand, LI Ferris, FL AF Rand, Lawrence I. Ferris, Frederick L., III TI Long-term Contributions From the Diabetes Control and Complications Trial Cohort SO JAMA OPHTHALMOLOGY LA English DT Editorial Material ID INTENSIVE THERAPY; MELLITUS C1 [Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), NEI, 10 Ctr Dr,Bldg 10 CRC,Room 3-2531, Bethesda, MD 20892 USA. EM rickferris@nei.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD OCT PY 2015 VL 133 IS 10 BP 1107 EP 1108 DI 10.1001/jamaophthalmol.2015.2735 PG 2 WC Ophthalmology SC Ophthalmology GA CT7AL UT WOS:000362965300006 PM 26270553 ER PT J AU Goldman, D AF Goldman, David TI America's Cannabis Experiment SO JAMA PSYCHIATRY LA English DT Editorial Material C1 NIAAA, Neurogenet Lab, Off Clin Director, NIH, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, Off Clin Director, NIH, 5625 Fishers Ln,Room 3S32, Rockville, MD 20852 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 5 TC 2 Z9 2 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD OCT PY 2015 VL 72 IS 10 BP 969 EP 970 DI 10.1001/jamapsychiatry.2015.1332 PG 2 WC Psychiatry SC Psychiatry GA CT7CW UT WOS:000362972000007 PM 26308765 ER PT J AU Ma, CS Wong, N Rao, G Avery, DT Torpy, J Hambridge, T Bustamante, J Okada, S Stoddard, JL Deenick, EK Pelham, SJ Payne, K Boisson-Dupuis, S Puel, A Kobayashi, M Arkwright, PD Kilic, SS El Baghdadi, J Nonoyama, S Minegishi, Y Mahdaviani, SA Mansouri, D Bousfiha, A Blincoe, AK French, MA Hsu, P Campbell, DE Stormon, MO Wong, M Adelstein, S Smart, JM Fulcher, DA Cook, MC Phan, TG Stepensky, P Boztug, K Kansu, A Ikinciogullari, A Baumann, U Beier, R Roscioli, T Ziegler, JB Gray, P Picard, C Grimbacher, B Warnatz, K Holland, SM Casanova, JL Uzel, G Tangye, SG AF Ma, Cindy S. Wong, Natalie Rao, Geetha Avery, Danielle T. Torpy, James Hambridge, Thomas Bustamante, Jacinta Okada, Satoshi Stoddard, Jennifer L. Deenick, Elissa K. Pelham, Simon J. Payne, Kathryn Boisson-Dupuis, Stephanie Puel, Anne Kobayashi, Masao Arkwright, Peter D. Kilic, Sara Sebnem El Baghdadi, Jamila Nonoyama, Shigeaki Minegishi, Yoshiyuki Mahdaviani, Seyed Alireza Mansouri, Davood Bousfiha, Aziz Blincoe, Annaliesse K. French, Martyn A. Hsu, Peter Campbell, Dianne E. Stormon, Michael O. Wong, Melanie Adelstein, Stephen Smart, Joanne M. Fulcher, David A. Cook, Matthew C. Phan, Tri Giang Stepensky, Polina Boztug, Kaan Kansu, Aydan Ikinciogullari, Aydan Baumann, Ulrich Beier, Rita Roscioli, Tony Ziegler, John B. Gray, Paul Picard, Capucine Grimbacher, Bodo Warnatz, Klaus Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Tangye, Stuart G. TI Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Follicular helper T cells; humoral immunity; primary immunodeficiencies; cytokine signaling ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TRANSCRIPTION FACTOR STAT3; CLASS-SWITCH RECOMBINATION; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; B-CELLS; INTERFERON-GAMMA; IL-21 RECEPTOR; TH17 CELLS; IFN-GAMMA AB Background: Follicular helper T (T-FH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T-FH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T-FH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective: We sought to determine the signaling pathways and cellular interactions required for the development and function of T-FH cells in human subjects. Methods: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT(FH)) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cT(FH) cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT(FH) cell differentiation toward a phenotype characterized by overexpression of IFN-gamma and programmed death 1. IFN-gamma inhibited cT(FH) cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion: Specific mutations affect the quantity and quality of cT(FH) cells, highlighting the need to assess T-FH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-gamma functions in vivo to restrain T-FH cell-induced B-cell differentiation. These findings shed new light on T-FH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs. C1 [Ma, Cindy S.; Wong, Natalie; Rao, Geetha; Avery, Danielle T.; Torpy, James; Hambridge, Thomas; Deenick, Elissa K.; Pelham, Simon J.; Payne, Kathryn; Phan, Tri Giang; Tangye, Stuart G.] Garvan Inst Med Res, Immunol Res Program, Darlinghurst, NSW, Australia. [Ma, Cindy S.; Deenick, Elissa K.; Pelham, Simon J.; Phan, Tri Giang; Roscioli, Tony; Tangye, Stuart G.] UNSW Australia, St Vincents Clin Sch, Melbourne, Vic, Australia. [Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Puel, Anne; Picard, Capucine; Casanova, Jean-Laurent] Univ Paris 05, Necker Med Sch, Inst IMAGINE, Lab Human Genet Infect Dis,Necker Branch,INSERMU1, Paris, France. [Bustamante, Jacinta; Picard, Capucine] Necker Hosp Sick Children, AP HP, Study Ctr Primary Immunodeficiencies, Paris, France. [Okada, Satoshi; Kobayashi, Masao] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima, Japan. [Stoddard, Jennifer L.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9PL, Lancs, England. [Kilic, Sara Sebnem] Uludag Univ, Fac Med, Dept Pediat Immunol, Gorukle, Bursa, Turkey. [El Baghdadi, Jamila] Mil Hosp Mohamed V, Genet Unit, Rabat, Morocco. [Nonoyama, Shigeaki] Natl Def Med Coll, Dept Pediat, Tokorozawa, Saitama 359, Japan. [Minegishi, Yoshiyuki] Univ Tokushima, Inst Genome Res, Div Mol Med, Tokushima, Japan. [Mahdaviani, Seyed Alireza; Mansouri, Davood] Shahid Beheshti Univ Med Sci, NRITLD, Pediat Resp Dis Res Ctr, Tehran, Iran. [Bousfiha, Aziz] King Hasan II Univ, Averroes Univ Hosp, Pediat Infect Dis Dept, Clin Immunol Unit, Casablanca, Morocco. [Blincoe, Annaliesse K.] Starship Childrens Hosp, Auckland, New Zealand. [French, Martyn A.] Royal Perth Hosp, Dept Clin Immunol, Perth, WA, Australia. [French, Martyn A.] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia. [Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O.; Wong, Melanie] Childrens Hosp Westmead, Westmead, NSW, Australia. [Adelstein, Stephen] Royal Prince Alfred Hosp, Clin Immunol, Sydney, NSW, Australia. [Smart, Joanne M.] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Melbourne, Vic, Australia. [Fulcher, David A.] Univ Sydney, Westmead Hosp, Dept Immunol, Sydney, NSW 2006, Australia. [Cook, Matthew C.] Australian Natl Univ, Sch Med, Canberra, ACT 0200, Australia. [Cook, Matthew C.] Australian Natl Univ, John Curtin Sch Med Res, Acton, ACT, Australia. [Cook, Matthew C.] Canberra Hosp, Dept Immunol, Acton, ACT, Australia. [Stepensky, Polina] Hebrew Univ Jerusalem, Med Ctr, Pediat Hematol Oncol & Bone Marrow Transplantat H, Jerusalem, Israel. [Boztug, Kaan] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1010 Vienna, Austria. [Boztug, Kaan] Med Univ Vienna, Dept Paediat & Adolescent Med, Vienna, Austria. [Kansu, Aydan] Ankara Univ, Sch Med, Dept Pediat Gastroenterol, TR-06100 Ankara, Turkey. [Ikinciogullari, Aydan] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, TR-06100 Ankara, Turkey. [Baumann, Ulrich] Hannover Med Sch, Paediat Pulmonol Allergy & Neonatol, Hannover, Germany. [Beier, Rita] Univ Hosp Essen, Pediat Haematol & Oncol, Essen, Germany. [Roscioli, Tony] Kinghorn Ctr Clin Genom, Darlinghurst, NSW, Australia. [Roscioli, Tony] Sydney Childrens Hosp, Dept Med Genet, Randwick, NSW, Australia. [Ziegler, John B.; Gray, Paul] Sydney Childrens Hosp, Randwick, NSW, Australia. [Ziegler, John B.; Gray, Paul] Univ New S Wales, Sch Womens & Childrens Hlth, Sydney, NSW, Australia. [Grimbacher, Bodo; Warnatz, Klaus] Univ Freiburg, Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Casanova, Jean-Laurent] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, Paris, France. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY USA. RP Tangye, SG (reprint author), Garvan Inst Med Res, Immunol Res Program, Darlinghurst, NSW, Australia. EM c.ma@garvan.org.au; s.tangye@garvan.org.au RI Okada, Satoshi/B-8901-2011; Adelstein, Stephen/I-7936-2016; OI Okada, Satoshi/0000-0002-4622-5657; Adelstein, Stephen/0000-0001-7221-6298; mahdaviani, alireza/0000-0001-6224-4797; mansouri, davood/0000-0002-0564-8282; Arkwright, Peter/0000-0002-7411-5375 FU Howard Hughes Medical Institute; NCRR NIH HHS [5UL1RR024143, UL1 RR024143] NR 61 TC 21 Z9 23 U1 1 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 OCT PY 2015 VL 136 IS 4 BP 993 EP + DI 10.1016/j.jaci.2015.05.036 PG 15 WC Allergy; Immunology SC Allergy; Immunology GA CT7EJ UT WOS:000362976300018 PM 26162572 ER PT J AU Visness, CM Sandel, MT O'Connor, G Gern, JE Jaffee, KF Wood, RA Kattan, M Bloomberg, GR Dresen, A Gergen, PJ Gold, DR Lemanske, RF Rajamanickam, V Camargo, CA Jackson, DJ AF Visness, Cynthia M. Sandel, Megan T. O'Connor, George Gern, James E. Jaffee, Katy F. Wood, Robert A. Kattan, Meyer Bloomberg, Gordon R. Dresen, Amy Gergen, Peter J. Gold, Diane R. Lemanske, Robert F. Rajamanickam, Victoria Camargo, Carlos A. Jackson, Daniel J. TI Cord blood vitamin D concentrations are unrelated to atopy and wheeze in 2 diverse birth cohort studies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID 25-HYDROXYVITAMIN D LEVELS; ASTHMA; SENSITIZATION; PREGNANCY; CHILDREN; RISK C1 [Visness, Cynthia M.; Jaffee, Katy F.] Rho Fed Syst Div Inc, Chapel Hill, NC 27515 USA. [Sandel, Megan T.; O'Connor, George] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gern, James E.; Dresen, Amy; Lemanske, Robert F.; Rajamanickam, Victoria; Jackson, Daniel J.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kattan, Meyer] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Bloomberg, Gordon R.] Washington Univ, Sch Med, St Louis, MO USA. [Gergen, Peter J.] NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Gold, Diane R.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Camargo, Carlos A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Visness, CM (reprint author), Rho Fed Syst Div Inc, Chapel Hill, NC 27515 USA. EM djj@medicine.wisc.edu FU NCATS NIH HHS [UL1 TR000427, UL1 TR000448]; NCRR NIH HHS [M01 RR000052, UL1 RR025771, RR00052, M01RR00533, M01 RR000533, UL1 RR024156, M01 RR03186, M01 RR003186, M01 RR000071, UL1 RR024992, 1UL1RR025771, 1UL1RR024156, M01RR00071, 5UL1RR024992-02]; NHLBI NIH HHS [R01 HL61879, P01 HL070831, P01 HL70831]; NIAID NIH HHS [UM1 AI114271, N01-AI-25482, HHSN272200900052C, N01AI25482, N01-AI-25496, N01AI25496, HHSN272201000052I]; NICHD NIH HHS [R01 HD061879]; NIMH NIH HHS [R01 MH061879]; PHS HHS [HHSN272200900052C, HHSN272201000052I] NR 11 TC 2 Z9 2 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 OCT PY 2015 VL 136 IS 4 BP 1108 EP 1110 DI 10.1016/j.jaci.2015.03.046 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA CT7EJ UT WOS:000362976300035 PM 25979524 ER PT J AU Jagodinsky, JC Sulima, A Cao, YQ Poprawski, JE Blackman, BN Lloyd, JR Swenson, RE Gottesman, MM Hall, MD AF Jagodinsky, Justin C. Sulima, Agnieszka Cao, Yiqi Poprawski, Joanna E. Blackman, Burchelle N. Lloyd, John R. Swenson, Rolf E. Gottesman, Michael M. Hall, Matthew D. TI Evaluation of fluorophore-tethered platinum complexes to monitor the fate of cisplatin analogs SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE Accumulation; Trafficking; Platinum; Resistance ID RESISTANT CELL-LINES; OVARIAN-CARCINOMA CELLS; CANCER-CELLS; EXTRACELLULAR-MATRIX; ANTICANCER AGENTS; LABELED PLATINUM; OXIDATION-STATE; CLICK CHEMISTRY; IN-VITRO; DNA AB The platinum drugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence have been extensively studied in the laboratory setting, sometimes by generating fluorophore-tagged analogs. Here, we synthesized two Pt(II) complexes containing ethane-1,2-diamine ligands linked to a BODIPY fluorophore, and compared their biological activity with previously reported Pt(II) complexes conjugated to carboxyfluorescein and carboxyfluorescein diacetate. The cytotoxicity and DNA damage capacity of Pt-fluorophore complexes was compared to cisplatin, and the Pt-BODIPY complexes were found to be more cytotoxic with reduced cytotoxicity in cisplatin-resistant cells. Microscopy revealed a predominately cytosolic localization, with nuclear distribution at higher concentrations. Spheroids grown from parent and resistant cells revealed penetration of Pt-BODIPY into spheroids, and retention of the cisplatin-resistant spheroid phenotype. While most activity profiles were retained for the Pt-BODIPY complexes, accumulation in resistant cells was only slightly affected, suggesting that some aspects of Pt-fluorophore cellular pharmacology deviate from cisplatin. C1 [Jagodinsky, Justin C.; Cao, Yiqi; Poprawski, Joanna E.; Gottesman, Michael M.; Hall, Matthew D.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sulima, Agnieszka; Blackman, Burchelle N.; Swenson, Rolf E.] NIH, Imaging Probe Dev Ctr, Rockville, MD USA. [Lloyd, John R.] NIDDK, Adv Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. We thank George Leiman for editorial assistance, and Robert O'Connor (NIDDK) for assistance with NMR acquisition. NR 57 TC 0 Z9 0 U1 5 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-8257 EI 1432-1327 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD OCT PY 2015 VL 20 IS 7 BP 1081 EP 1095 DI 10.1007/s00775-015-1290-2 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA CT6WO UT WOS:000362953900001 PM 26323351 ER PT J AU McGarvey, KM Goldfarb, T Cox, E Farrell, CM Gupta, T Joardar, VS Kodali, VK Murphy, MR O'Leary, NA Pujar, S Rajput, B Rangwala, SH Riddick, LD Webb, D Wright, MW Murphy, TD Pruitt, KD AF McGarvey, Kelly M. Goldfarb, Tamara Cox, Eric Farrell, Catherine M. Gupta, Tripti Joardar, Vinita S. Kodali, Vamsi K. Murphy, Michael R. O'Leary, Nuala A. Pujar, Shashikant Rajput, Bhanu Rangwala, Sanjida H. Riddick, Lillian D. Webb, David Wright, Mathew W. Murphy, Terence D. Pruitt, Kim D. TI Mouse genome annotation by the RefSeq project SO MAMMALIAN GENOME LA English DT Article ID HUMAN PROTEOME; RECEPTOR; LANDSCAPE; DATABASE; DRAFT; CELLS; NCBI AB Complete and accurate annotation of the mouse genome is critical to the advancement of research conducted on this important model organism. The National Center for Biotechnology Information (NCBI) develops and maintains many useful resources to assist the mouse research community. In particular, the reference sequence (RefSeq) database provides high-quality annotation of multiple mouse genome assemblies using a combinatorial approach that leverages computation, manual curation, and collaboration. Implementation of this conservative and rigorous approach, which focuses on representation of only full-length and non-redundant data, produces high-quality annotation products. RefSeq records explicitly link sequences to current knowledge in a timely manner, updating public records regularly and rapidly in response to nomenclature updates, addition of new relevant publications, collaborator discussion, and user feedback. Whole genome re-annotation is also conducted at least every 12-18 months, and often more frequently in response to assembly updates or availability of informative data. This article highlights key features and advantages of RefSeq genome annotation products and presents an overview of NCBI processes to generate these data. Further discussion of NCBI's resources highlights useful features and the best methods for accessing our data. C1 [McGarvey, Kelly M.; Goldfarb, Tamara; Cox, Eric; Farrell, Catherine M.; Gupta, Tripti; Joardar, Vinita S.; Kodali, Vamsi K.; Murphy, Michael R.; O'Leary, Nuala A.; Pujar, Shashikant; Rajput, Bhanu; Rangwala, Sanjida H.; Riddick, Lillian D.; Webb, David; Wright, Mathew W.; Murphy, Terence D.; Pruitt, Kim D.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM Pruitt@ncbi.nlm.nih.gov RI Kodali, Vamsi/A-8530-2010 OI Kodali, Vamsi/0000-0001-8941-9761 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This work and funding for open access charge was provided by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 25 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2015 VL 26 IS 9-10 SI SI BP 379 EP 390 DI 10.1007/s00335-015-9585-8 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA CT6AT UT WOS:000362893400003 PM 26215545 ER PT J AU Schmidt, LS Linehan, WM AF Schmidt, Laura S. Linehan, W. Marston TI Molecular genetics and clinical features of Birt-Hogg-Dube syndrome SO NATURE REVIEWS UROLOGY LA English DT Review ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; MULTIPLE LUNG CYSTS; BHD GENE; SPONTANEOUS PNEUMOTHORAX; INTESTINAL POLYPOSIS; KIDNEY CANCER; POLYCYSTIC KIDNEYS; COLORECTAL-CANCER; MTOR ACTIVATION AB Birt-Hogg-Dube (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome-BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGF beta signalling, PGC1 alpha-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease. C1 [Schmidt, Laura S.; Linehan, W. Marston] NCI, NIH, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Schmidt, LS (reprint author), NCI, NIH, Ctr Canc Res, Urol Oncol Branch, Bldg 10,CRC Room 15940, Bethesda, MD 20892 USA. EM schmidtl@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute (NCI), Centre for Cancer Research; Federal funds from the Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Centre for Cancer Research. This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E (L.S.S.). 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 endorsements by the US Government. L.S.S. is an employee of Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702. NR 113 TC 14 Z9 14 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD OCT PY 2015 VL 12 IS 10 BP 558 EP 569 DI 10.1038/nrurol.2015.206 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CT7OA UT WOS:000363003200004 PM 26334087 ER PT J AU Bharucha-Goebel, D Ezzo, D Jain, M Waite, M Nichols, C Lehky, T Mohassel, P Donkervoort, S Leach, M Dastgir, J Marra, J Zein, W Bonnemann, C AF Bharucha-Goebel, D. Ezzo, D. Jain, M. Waite, M. Nichols, C. Lehky, T. Mohassel, P. Donkervoort, S. Leach, M. Dastgir, J. Marra, J. Zein, W. Boennemann, C. TI Giant axonal neuropathy - clinical trial preparedness and evaluation of markers of disease severity SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Bharucha-Goebel, D.; Jain, M.; Waite, M.; Nichols, C.; Lehky, T.; Mohassel, P.; Donkervoort, S.; Leach, M.; Zein, W.] NIH, Bethesda, MD 20892 USA. [Bharucha-Goebel, D.] NINDS, Childrens Natl Med Ctr, Neurogenet Branch, Bethesda, MD 20892 USA. [Ezzo, D.; Boennemann, C.] NINDS, NIH, Neurogenet Branch, Bethesda, MD 20892 USA. [Leach, M.] Childrens Natl Med Ctr, Bethesda, MD USA. [Dastgir, J.; Marra, J.] Columbia Univ, Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 25 SU 2 MA G.P.329 BP S284 EP S284 DI 10.1016/j.nmd.2015.06.353 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400349 ER PT J AU Donkervoort, S Yang, M Leach, M Medne, L Yum, S Hotchkiss, L Rutkowski, A Chatfield, K Auerbach, S Miyamoto, S Bonnemann, C AF Donkervoort, S. Yang, M. Leach, M. Medne, L. Yum, S. Hotchkiss, L. Rutkowski, A. Chatfield, K. Auerbach, S. Miyamoto, S. Boennemann, C. TI Cardiomyopathy in patients with ACTA1-myopathy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Donkervoort, S.; Leach, M.; Hotchkiss, L.; Boennemann, C.] NIH, Bethesda, MD 20892 USA. [Yang, M.; Chatfield, K.; Auerbach, S.; Miyamoto, S.] Univ Colorado, Sch Med, Aurora, CO USA. [Medne, L.; Yum, S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Rutkowski, A.] Kaiser SCPMG, Cure CMD, Olathe, KS USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 25 SU 2 MA G.P.337 BP S287 EP S287 DI 10.1016/j.nmd.2015.06.361 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400357 ER PT J AU Donkervoort, S Chan, S Bradley, N Foley, A Nguyen, D Hu, Y Leach, M Thangarajh, M Reyes, C Nance, J Moore, S Bonnemann, C AF Donkervoort, S. Chan, S. Bradley, N. Foley, A. Nguyen, D. Hu, Y. Leach, M. Thangarajh, M. Reyes, C. Nance, J. Moore, S. Boennemann, C. TI Cytoplasmic body pathology in severe ACTA1-myopathy in the absence of typical nemaline-rod histology SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Donkervoort, S.; Bradley, N.; Foley, A.; Nguyen, D.; Hu, Y.; Leach, M.; Boennemann, C.] NIH, Bethesda, MD 20892 USA. [Chan, S.] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Thangarajh, M.; Reyes, C.] Childrens Natl Hlth Syst, Washington, DC USA. [Nance, J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Moore, S.] Univ Iowa Hosp & Clin, Dept Pathol, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.336 BP S286 EP S287 DI 10.1016/j.nmd.2015.06.360 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400356 ER PT J AU Jain, M Meilleur, K Nichols, C Waite, M Parks, R Hodsdon, B Bendixen, R Hsia, N Glanzman, A Nelson, L Keller, K Duong, T McGuire, M Dastgir, J Donkervoort, S Leach, M Collins, J Vuillerot, C Rutkowski, A Bonnemann, C AF Jain, M. Meilleur, K. Nichols, C. Waite, M. Parks, R. Hodsdon, B. Bendixen, R. Hsia, N. Glanzman, A. Nelson, L. Keller, K. Duong, T. McGuire, M. Dastgir, J. Donkervoort, S. Leach, M. Collins, J. Vuillerot, C. Rutkowski, A. Boennemann, C. TI Comparison of upper extremity measures in individuals with COL6 and LAMA2-muscular dystrophies SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Jain, M.; Nichols, C.; Waite, M.; Parks, R.; Hodsdon, B.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Meilleur, K.] NINR, NIH, Bethesda, MD 20892 USA. [Bendixen, R.] Univ Pittsburgh, Pittsburgh, PA USA. [Hsia, N.; Glanzman, A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Nelson, L.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Keller, K.] Rady Childrens Hosp, San Diego, CA USA. [Duong, T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [McGuire, M.; Collins, J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Dastgir, J.; Donkervoort, S.; Leach, M.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Vuillerot, C.] Hosp Civils Lyon, Bron, France. [Rutkowski, A.] Cure CMD, Kaiser Permanente SCPMG, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.263 BP S265 EP S265 DI 10.1016/j.nmd.2015.06.287 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400283 ER PT J AU Meilleur, K Elliott, J Linton, M Vuillerot, C Bendixen, R Arveson, I Tounkara, E Waite, M Nichols, C Yang, K Donkervoort, S Dastgir, J Leach, M Bonnemann, C Jain, M AF Meilleur, K. Elliott, J. Linton, M. Vuillerot, C. Bendixen, R. Arveson, I. Tounkara, E. Waite, M. Nichols, C. Yang, K. Donkervoort, S. Dastgir, J. Leach, M. Boennemann, C. Jain, M. TI Validation of actiGraph GT3X accelerometers in collagen 6-related muscular dystrophy and LAMA2-related muscular dystrophy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Meilleur, K.; Elliott, J.; Linton, M.; Arveson, I.; Tounkara, E.] NINR, NIH, Bethesda, MD 20892 USA. [Vuillerot, C.] Hosp Civils Lyon, Bron, France. [Bendixen, R.] Univ Pittsburgh, Pittsburgh, PA USA. [Waite, M.; Nichols, C.; Jain, M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Yang, K.; Donkervoort, S.; Leach, M.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Dastgir, J.] Columbia Univ, Dept Neurol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.265 BP S265 EP S266 DI 10.1016/j.nmd.2015.06.289 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400285 ER PT J AU Mohassel, P Donkervoort, S Dastgir, J Munell, F Sanchez, A Haverlova, J Manzur, A Quijano-Roy, S Tasca, G Udd, B Muntoni, F Bonnemann, C AF Mohassel, P. Donkervoort, S. Dastgir, J. Munell, F. Sanchez, A. Haverlova, J. Manzur, A. Quijano-Roy, S. Tasca, G. Udd, B. Muntoni, F. Boennemann, C. TI Muscle MRI findings in myopathies due to FHL1 mutation SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Mohassel, P.; Donkervoort, S.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Dastgir, J.] Columbia Univ, New York, NY USA. [Munell, F.; Sanchez, A.] Hosp Univ Vall dHebron, Barcelona, Spain. [Haverlova, J.] Univ Hosp Brno, Brno, Czech Republic. [Manzur, A.; Muntoni, F.] UCL, London, England. [Quijano-Roy, S.] Hop Raymond Poincare, Garches, France. [Tasca, G.] Univ Cattolica Sacro Cuore, Sch Med, Neurol, I-00168 Rome, Italy. [Udd, B.] Univ Helsinki, Helsinki, Finland. NR 0 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 25 SU 2 MA G.P.309 BP S278 EP S278 DI 10.1016/j.nmd.2015.06.333 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400329 ER PT J AU Mohassel, P Rooney, J Zou, Y Bonnemann, C AF Mohassel, P. Rooney, J. Zou, Y. Boennemann, C. TI Col6A2 null mice are a new mouse model of collagen-VI related dystrophies and relevant to the human disease SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Mohassel, P.; Rooney, J.; Zou, Y.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.268 BP S266 EP S266 DI 10.1016/j.nmd.2015.06.292 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400288 ER PT J AU Nichols, C Lehky, T Waite, M Duong, T Nelson, L Keller, K Lott, D Meilleur, K Collins, J Dastgir, J Vuillerot, C Rutkowski, A Donkervoort, S Leach, M Jain, M Boennemann, C AF Nichols, C. Lehky, T. Waite, M. Duong, T. Nelson, L. Keller, K. Lott, D. Meilleur, K. Collins, J. Dastgir, J. Vuillerot, C. Rutkowski, A. Donkervoort, S. Leach, M. Jain, M. Boennemann, C. TI Electrical impedance myography as a potential biomarker in individuals with COL6-related dystrophy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Nichols, C.; Waite, M.; Jain, M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Lehky, T.; Dastgir, J.; Donkervoort, S.; Leach, M.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Duong, T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Nelson, L.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Keller, K.] Rady Childrens Hosp, San Diego, CA USA. [Lott, D.] Univ Florida, Gainesville, FL USA. [Meilleur, K.] NINR, NIH, Bethesda, MD 20892 USA. [Collins, J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Vuillerot, C.] Hosp Civils Lyon, Bron, France. [Rutkowski, A.] Cure CMD, Kaiser Permanente SCPMG, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.264 BP S265 EP S265 DI 10.1016/j.nmd.2015.06.288 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400284 ER PT J AU Papadaki, M Marston, S Memo, M Messer, A Donkervoort, S Bonnemann, C Nowak, K Ong, R McNamara, E AF Papadaki, M. Marston, S. Memo, M. Messer, A. Donkervoort, S. Boennemann, C. Nowak, K. Ong, R. McNamara, E. TI Molecular basis of stiff patient syndrome caused by mutations in ACTA1 and TPM3 SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Papadaki, M.; Marston, S.; Memo, M.; Messer, A.] Univ London Imperial Coll Sci Technol & Med, London, England. [Donkervoort, S.] NIH, Bethesda, MD 20892 USA. [Boennemann, C.] Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Nowak, K.] Med Res Ctr, Neuromascular Dis Lab, Perth, WA, Australia. [Ong, R.; McNamara, E.] Neuromuscular Dis Lab, Perth, WA, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.335 BP S286 EP S286 DI 10.1016/j.nmd.2015.06.359 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400355 ER PT J AU R'guiba, N Annoussamy, M Cardas, R Lilien, C Ollivier, G Muntoni, F Bonnemann, C Biancalana, V Cuisset, J Mayer, M Landy, H Ramsdell, D Nelken, M Le Moing, A Gidaro, T Mingozzi, F Buj-Bello, A Hogrel, JY Voit, T Servais, L AF R'guiba, N. Annoussamy, M. Cardas, R. Lilien, C. Ollivier, G. Muntoni, F. Boennemann, C. Biancalana, V. Cuisset, J. Mayer, M. Landy, H. Ramsdell, D. Nelken, M. Le Moing, A. Gidaro, T. Mingozzi, F. Buj-Bello, A. Hogrel, J. Y. Voit, T. Servais, L. TI Natural history and functional status of patients with myotubular myopathy enrolled in a prospective and longitudinal study SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [R'guiba, N.; Annoussamy, M.; Cardas, R.; Lilien, C.; Ollivier, G.; Gidaro, T.; Mingozzi, F.; Hogrel, J. Y.; Voit, T.; Servais, L.] Assoc Inst Myol, Paris, France. [Muntoni, F.] Inst Child Hlth, UCL, London, England. [Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Biancalana, V.] Lab Diagnost Genet, Strasbourg, France. [Cuisset, J.] Hop Roger Salengro CHRU, Serv Neuropediat, Lille, France. [Mayer, M.] Hop Armand Trousseau, Serv Neurol Pediat, Paris, France. [Landy, H.; Ramsdell, D.; Nelken, M.] Valer Therapeut, Concord, MA USA. [Le Moing, A.] CHU, Serv Neurol Pediat, Assoc Inst Myol Paris, Amiens Picardie, France. [Buj-Bello, A.] INSERM, Genethon, Paris, France. RI BUJ-BELLO, Anna/J-7556-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.296 BP S274 EP S274 DI 10.1016/j.nmd.2015.06.320 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400316 ER PT J AU Rooney, J Zou, Y Cowling, B Mitchell, C Bonnemann, C AF Rooney, J. Zou, Y. Cowling, B. Mitchell, C. Boennemann, C. TI Late-onset mild myopathy with protein aggregates in two transgenic mouse models of FHL1 SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Rooney, J.] NINDS, NIH, Childrens Natl Med Ctr, Genet Med, Bethesda, MD 20892 USA. [Zou, Y.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. [Cowling, B.] Inst Genet & Biol Mol & Cellulaire, Dept Translat Med & Neurogene, Strasbourg, France. [Mitchell, C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. NR 0 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 25 SU 2 MA G.P.310 BP S279 EP S279 DI 10.1016/j.nmd.2015.06.334 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400330 ER PT J AU Tasca, G Monforte, M Brisca, G D'Amico, A Al Shaik, N Berardinelli, A Lokken, N Maggi, L Morandi, L Voermans, N Munell, F Sanchez, A Dastgir, J Bertini, E Bruno, C AF Tasca, G. Monforte, M. Brisca, G. D'Amico, A. Al Shaik, N. Berardinelli, A. Lokken, N. Maggi, L. Morandi, L. Voermans, N. Munell, F. Sanchez, A. Dastgir, J. Bertini, E. Bruno, C. CA MYO-MRI COST Study Grp TI Muscle MRI in sarcoglycanopathies SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Tasca, G.; D'Amico, A.; Bertini, E.] Bambino Gesu Childrens Res Hosp, Unit Neuromuscular Disorders, Rome, Italy. [Monforte, M.] Univ Cattolica Sacro Cuore, Sch Med, I-00168 Rome, Italy. [Brisca, G.; Bruno, C.] Giannina Gaslini Hosp, Genoa, Italy. [Al Shaik, N.] Dubowitz Neuromuscular Ctr, London, England. [Berardinelli, A.] C Mondino Natl Neurol Inst, Pavia, Italy. [Lokken, N.] Univ Copenhagen, Rigshosp, DK-2100 Copenhagen, Denmark. [Maggi, L.; Morandi, L.] Fdn Neurol Inst Carlo Besta, Milan, Italy. [Voermans, N.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Munell, F.; Sanchez, A.] Vall dHebron Univ Hosp, Barcelona, Spain. [Dastgir, J.] NIH, Bethesda, MD 20892 USA. [MYO-MRI COST Study Grp] Study Grp, London, England. RI d'amico, adele/J-9203-2016 OI d'amico, adele/0000-0003-2438-2624 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 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.161 BP S233 EP S233 DI 10.1016/j.nmd.2015.06.176 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400172 ER PT J AU Waite, M Bharucha-Goebel, D Moulton, T Zampieri, C Nichols, C Alter, K Averion, G Donkervoort, S Leach, M Dastgir, J Mohassel, P Jain, M Bonnemann, C AF Waite, M. Bharucha-Goebel, D. Moulton, T. Zampieri, C. Nichols, C. Alter, K. Averion, G. Donkervoort, S. Leach, M. Dastgir, J. Mohassel, P. Jain, M. Boennemann, C. TI Comparison of two clinical motor scales in individuals with giant axonal neuropathy (GAN) SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Waite, M.; Moulton, T.; Zampieri, C.; Nichols, C.; Alter, K.; Jain, M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Bharucha-Goebel, D.; Averion, G.; Donkervoort, S.; Leach, M.; Dastgir, J.; Mohassel, P.; Boennemann, C.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 OCT PY 2015 VL 25 SU 2 MA G.P.330 BP S284 EP S285 DI 10.1016/j.nmd.2015.06.354 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400350 ER PT J AU Wells, D Heslop, E Csimma, C Straub, V McCall, J Nagaraju, K Wagner, K Caizergues, D Korinthenberg, R Flanigan, K Mendell, J Kelly, M Kaufmann, P McNeil, E Robertson, A Johnston, L Bushby, K AF Wells, D. Heslop, E. Csimma, C. Straub, V. McCall, J. Nagaraju, K. Wagner, K. Caizergues, D. Korinthenberg, R. Flanigan, K. Mendell, J. Kelly, M. Kaufmann, P. McNeil, E. Robertson, A. Johnston, L. Bushby, K. TI The TREAT-NMD Advisory Committee for Therapeutics (TACT): An innovative de-risking model to foster orphan drug development SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Wells, D.] Univ London Royal Vet Coll, London, England. [Heslop, E.; Straub, V.; Robertson, A.; Johnston, L.; Bushby, K.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Csimma, C.] Cydan LLC, Cambridge, MA USA. [McCall, J.] PharMac LLC, Boca Grande, FL USA. [Nagaraju, K.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Wagner, K.] Johns Hopkins Univ, Baltimore, MD USA. [Caizergues, D.] Genethon, Evry, France. [Korinthenberg, R.] Univ Freiburg, D-79106 Freiburg, Germany. [Flanigan, K.; Mendell, J.] Nationwide Childrens Hosp, Columbus, OH USA. [Kelly, M.] Myotherix, San Jose, CA USA. [Kaufmann, P.] Natl Ctr Adv Translat Sci, Washington, DC USA. [McNeil, E.] NINDS, Washington, DC USA. NR 0 TC 0 Z9 0 U1 2 U2 5 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 OCT PY 2015 VL 25 SU 2 MA G.P.284 BP S271 EP S271 DI 10.1016/j.nmd.2015.06.308 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400304 ER PT J AU Willcocks, R Triplett, W Lott, D Forbes, S Dastgir, J Bonnemann, C Vandenbome, K Walter, G AF Willcocks, R. Triplett, W. Lott, D. Forbes, S. Dastgir, J. Boennemann, C. Vandenbome, K. Walter, G. TI Quantitative MRI and MRS detect alterations in muscle quality in both congenital muscular dystrophy and Duchenne muscular dystrophy SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Willcocks, R.; Lott, D.; Forbes, S.; Vandenbome, K.] Univ Florida, Dept Phys Therapy, Gainesville, FL USA. [Triplett, W.; Walter, G.] Univ Florida, Dept Physiol & Funct Genom, Gainesville, FL USA. [Dastgir, J.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Boennemann, C.] NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. OI Triplett, William/0000-0002-9546-1306 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.369 BP S296 EP S296 DI 10.1016/j.nmd.2015.06.393 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400389 ER PT J AU Witherspoon, J Jam, M Meilleur, K AF Witherspoon, J. Jam, M. Meilleur, K. TI Literature synthesis of RyR1 and its interacting proteins SO NEUROMUSCULAR DISORDERS LA English DT Meeting Abstract CT 20th International Congress of the World-Muscle-Society CY SEP 30-OCT 04, 2015 CL Brighton, ENGLAND SP World Muscle Soc C1 [Witherspoon, J.; Meilleur, K.] NINR, NIH, Bethesda, MD 20892 USA. [Jam, M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 EI 1873-2364 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD OCT PY 2015 VL 25 SU 2 MA G.P.241 BP S258 EP S259 DI 10.1016/j.nmd.2015.06.266 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CT6LV UT WOS:000362925400262 ER PT J AU Chen, HL Ding, D Wang, J Zhao, QH Meng, HJ Li, HL Gao, YT Shu, XO Tanner, CM Hong, Z Yang, G AF Chen, Honglei Ding, Ding Wang, Jian Zhao, Qianhua Meng, Haijiao Li, Honglan Gao, Yu-Tang Shu, Xiao-Ou Tanner, Caroline M. Hong, Zhen Yang, Gong TI Parkinson's disease research in a prospective cohort in China SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease/Parkinsonism; Risk factors in epidemiology; Cohort studies ID ORGANOCHLORINE PESTICIDES; DIETARY PATTERNS; RISK; PREVALENCE; SMOKING; HEALTH; SERUM; EPIDEMIOLOGY; ASSOCIATION; POPULATION AB Introduction: China has the largest population of Parkinson's disease (PD) patients; however few etiological studies of PD have been conducted in China. Methods: The Shanghai Women's Health Study recruited 74,941 women in urban Shanghai, aged 40 to 70, from 1996 to 2000. Self-reported PD cases were invited for a neurological examination and diagnoses were made by a movement disorder specialist. Results: This cohort had very few smokers (2.7%), alcohol drinkers (2.3%), and post-menopausal hormone users (4.3%); however, tea drinking (29.9%) and exposure to tobacco smoke from husbands (61.8%) were common. A total of 301 participants reported PD diagnosis during the follow-up. The diagnosis was confirmed in 76 (57%) of the 133 clinically examined patients. An additional 19 (53%) PD cases were identified out of 36 participants who self-confirmed the diagnosis and provided a history on PD symptoms and treatments. As expected, increasing age was strongly associated with PD risk. Further, PD risk appears to be inversely associated with exposures to second-hand tobacco smoke from husbands and tea drinking, and positively with education, although none of these reached statistical significance. The age-adjusted odds ratio (OR) was 0.7 (95% confidence interval; 0.4-1.1) for participants whose husbands were current smokers at baseline and 0.8 (0.5-1.3) for ever tea-drinkers. Compared with primary education or lower, the age-adjusted OR was 1.3 (0.7-2.4) for middle school and 1.6 (1.0-2.7) for high school or above. Conclusion: PD research in this unique cohort is feasible and, with extended follow-up, will allow for prospective PD etiological research in China. Published by Elsevier Ltd. C1 [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Ding, Ding; Wang, Jian; Zhao, Qianhua; Meng, Haijiao; Hong, Zhen] Fudan Univ, Huashan Hosp, Dept Neurol, Shanghai 200433, Peoples R China. [Shu, Xiao-Ou; Yang, Gong] Vanderbilt Univ, Nashville, TN 37235 USA. [Li, Honglan; Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Tanner, Caroline M.] Univ Calif San Francisco, Dis Res Educ & Clin Ctr, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779 FU Intramural Research Program of NIH; National Institute of Environmental Health Sciences [Z01-ES-101986]; NIH [R37CA070867, UM1CA182910] FX The study was supported by the Intramural Research Program of NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986) and in part by NIH Grant R37CA070867 and UM1CA182910. NR 30 TC 3 Z9 3 U1 3 U2 10 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 OCT PY 2015 VL 21 IS 10 BP 1200 EP 1204 DI 10.1016/j.parkreldis.2015.08.020 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CT5OB UT WOS:000362858600011 PM 26318964 ER PT J AU Brock, JW Carr, MC Adzick, NS Burrows, PK Thomas, JC Thom, EA Howell, LJ Farrell, JA Dabrowiak, ME Farmer, DL Cheng, EY Kropp, BP Caldamone, AA Bulas, DI Tolivaisa, S Baskin, LS AF Brock, John W., III Carr, Michael C. Adzick, N. Scott Burrows, Pamela K. Thomas, John C. Thom, Elizabeth A. Howell, Lori J. Farrell, Jody A. Dabrowiak, Mary E. Farmer, Diana L. Cheng, Earl Y. Kropp, Bradley P. Caldamone, Anthony A. Bulas, Dorothy I. Tolivaisa, Susan Baskin, Laurence S. CA MOMS Investigators TI Bladder Function After Fetal Surgery for Myelomeningocele SO PEDIATRICS LA English DT Article ID NEUROGENIC BLADDER; WALL THICKNESS; CHILDREN; CLOSURE; MYELODYSPLASIA; DYSFUNCTION; NEWBORNS AB BACKGROUND: A substudy of the Management of Myelomeningocele Study evaluating urological outcomes was conducted. METHODS: Pregnant women diagnosed with fetal myelomeningocele were randomly assigned to either prenatal or standard postnatal surgical repair. The substudy included patients randomly assigned after April 18, 2005. The primary outcome was defined in their children as death or the need for clean intermittent catheterization (GIG) by 30 months of age characterized by prespecified criteria. Secondary outcomes included bladder and kidney abnormalities observed by urodynamics and renal/bladder ultrasound at 12 and 30 months, which were analyzed as repeated measures. RESULTS Of the 115 women enrolled in the substudy, the primary outcome occurred in 52% of children in the prenatal surgery group and 66% in the postnatal surgery group (relative risk [RR]: 0.78; 95% confidence interval [CI]: 0.57-1.07). Actual rates of GIG use were 38% and 51% in the prenatal and postnatal surgery groups, respectively (RR: 0.74; 95% CI: 0.48-1.12). Prenatal surgery resulted in less trabeculation (RR: 0.39; 95% CI: 0.19-0.79) and fewer cases of open bladder neck on urodynamics (RR: 0.61; 95% CI: 0.40-0.92) after adjustment by child's gender and lesion level. The difference in trabeculation was confirmed by ultrasound. CONCLUSIONS: Prenatal surgery did not significantly reduce the need for GIG by 30 months of age but was associated with less bladder trabeculation and open bladder neck. The implications of these findings are unclear now, but support the need for long-term urologic follow-up of patients with myelomeningocele regardless of type of surgical repair. C1 [Brock, John W., III; Thomas, John C.] Vanderbilt Univ, Med Ctr, Dept Urol, Nashville, TN USA. [Dabrowiak, Mary E.] Vanderbilt Univ, Med Ctr, Fetal Ctr, Dept Pediat, Nashville, TN USA. [Carr, Michael C.] Childrens Hosp Philadelphia, Div Pediat Urol, Philadelphia, PA 19104 USA. [Adzick, N. Scott; Howell, Lori J.] Childrens Hosp Philadelphia, Ctr Fetal Diag & Treatment, Philadelphia, PA 19104 USA. [Carr, Michael C.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Burrows, Pamela K.; Thom, Elizabeth A.] George Washington Univ, Biostat Ctr, Washington, DC USA. [Farrell, Jody A.; Farmer, Diana L.] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Surg, San Francisco, CA 94143 USA. [Baskin, Laurence S.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Cheng, Earl Y.] Lurie Childrens Hosp, Chicago, IL USA. [Cheng, Earl Y.] Northwestern Univ, Chicago, IL 60611 USA. [Kropp, Bradley P.] Univ Oklahoma, Hlth Sci Ctr, Dept Urol, Oklahoma City, OK USA. [Caldamone, Anthony A.] Brown Univ, Warren Alpert Med Sch, Div Urol, Providence, RI 02912 USA. [Bulas, Dorothy I.] Childrens Natl Med Ctr, Dept Diagnost Imaging & Radiol, Washington, DC 20010 USA. [Tolivaisa, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Bethesda, MD USA. RP Brock, JW (reprint author), Monroe Carell Jr Childrens Hosp Vanderbilt, Vanderbilt Childrens Hosp, Pediat Urol, 4102 Doctors Off Tower, Nashville, TN 37232 USA. EM john.brock@vanderbilt.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10-HD041669, U10-HD041667, U10-041666, U01-HD041665]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health (NIH) FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10-HD041669, U10-HD041667, U10-041666, and U01-HD041665) and the National Institute of Diabetes and Digestive and Kidney Diseases. Funded by the National Institutes of Health (NIH). NR 14 TC 5 Z9 5 U1 2 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD OCT PY 2015 VL 136 IS 4 BP E906 EP E913 PG 8 WC Pediatrics SC Pediatrics GA CT6TC UT WOS:000362944300016 PM 26416930 ER PT J AU Xiong, JH AF Xiong, Jianhua TI BMPR2 spruces up the endothelium in pulmonary hypertension SO PROTEIN & CELL LA English DT News Item ID MORPHOGENETIC PROTEIN-RECEPTOR; HETEROZYGOUS BMPR2-MUTANT MICE; TO-MESENCHYMAL TRANSITION; ARTERIAL-HYPERTENSION; INCREASED SUSCEPTIBILITY; GENETIC ABLATION; II RECEPTOR; DYSFUNCTION; EXPRESSION; MUTATIONS C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Xiong, JH (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jianhua.xiong@nih.gov RI Xiong, Jianhua/D-6099-2015 OI Xiong, Jianhua/0000-0002-2740-4027 FU Intramural NIH HHS NR 51 TC 2 Z9 2 U1 0 U2 0 PU HIGHER EDUCATION PRESS PI BEIJING PA NO 4 DEWAI DAJIE, BEIJING 100120, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD OCT PY 2015 VL 6 IS 10 BP 703 EP 708 DI 10.1007/s13238-015-0208-7 PG 6 WC Cell Biology SC Cell Biology GA CT2SD UT WOS:000362653100001 PM 26373550 ER PT J AU Xiong, JH AF Xiong, Jianhua TI Atg7 in development and disease: panacea or Pandora's Box? SO PROTEIN & CELL LA English DT Review DE autophagy; Atg7; mouse model; development; disease ID PROGRAMMED CELL-DEATH; LIFE-SPAN EXTENSION; INTESTINAL EPITHELIUM; INDUCED AUTOPHAGY; OXIDATIVE STRESS; EPIDERMAL-KERATINOCYTES; PROTEOMICS ANALYSIS; CROHN-DISEASE; CANCER CELLS; PANETH CELLS AB Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Xiong, JH (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jianhua.xiong@nih.gov RI Xiong, Jianhua/D-6099-2015 OI Xiong, Jianhua/0000-0002-2740-4027 FU National Institutes of Health (NIH) Intramural Program; Leducq Foundation FX The author is grateful for the support from the National Institutes of Health (NIH) Intramural Program and the Leducq Foundation. The author thanks the NIH Fellows Editorial Board and Cindy Clark, NIH Library Writing Center, for manuscript editing assistance, and apologizes to colleagues whose work could not be cited or fully discussed due to space limitations. NR 111 TC 6 Z9 6 U1 0 U2 5 PU HIGHER EDUCATION PRESS PI BEIJING PA NO 4 DEWAI DAJIE, BEIJING 100120, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD OCT PY 2015 VL 6 IS 10 BP 722 EP 734 DI 10.1007/s13238-015-0195-8 PG 13 WC Cell Biology SC Cell Biology GA CT2SD UT WOS:000362653100004 PM 26404030 ER PT J AU Vannucci, A Nelson, EE Bongiorno, DM Pine, DS Yanovski, JA Tanofsky-Kraff, M AF Vannucci, A. Nelson, E. E. Bongiorno, D. M. Pine, D. S. Yanovski, J. A. Tanofsky-Kraff, M. TI Behavioral and neurodevelopmental precursors to binge-type eating disorders: support for the role of negative valence systems SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Binge eating; development; eating disorders; loss of control eating; Research Domain Criteria (RDoC) ID ECOLOGICAL MOMENTARY ASSESSMENT; RESEARCH DOMAIN CRITERIA; BORDERLINE PERSONALITY-DISORDER; COMORBIDITY-SURVEY-REPLICATION; DEXAMETHASONE-SUPPRESSION TEST; SOCIAL APPEARANCE ANXIETY; CORTISOL STRESS-RESPONSE; PITUITARY-ADRENAL-AXIS; LABORATORY TEST MEAL; SHARED RISK-FACTORS AB Background. Pediatric loss-of-control (LOC) eating is a robust behavioral precursor to binge-type eating disorders. Elucidating precursors to LOC eating and binge-type eating disorders may refine developmental risk models of eating disorders and inform interventions. Method. We review evidence within constructs of the Negative Valence Systems (NVS) domain, as specified by the Research Domain Criteria framework. Based on published studies, we propose an integrated NVS model of binge-type eating-disorder risk. Results. Data implicate altered corticolimbic functioning, neuroendocrine dysregulation, and self-reported negative affect as possible risk factors. However, neuroimaging and physiological data in children and adolescents are sparse, and most prospective studies are limited to self-report measures. Conclusions. We discuss a broad NVS framework for conceptualizing early risk for binge-type eating disorders. Future neural and behavioral research on the developmental trajectory of LOC and binge-type eating disorders is required. C1 [Vannucci, A.; Tanofsky-Kraff, M.] Univ Hlth Sci, Uniformed Serv, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Vannucci, A.; Yanovski, J. A.; Tanofsky-Kraff, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD USA. [Nelson, E. E.; Bongiorno, D. M.; Pine, D. S.] NIMH, Sect Dev & Affect Neurosci, NIH, DHHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Univ Hlth Sci, Uniformed Serv, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Nelson, Eric/0000-0002-3376-2453 FU Intramural Research Program, NIH from NICHD [1ZIAHD000641]; Intramural Research Program, NIMH; NIMHD FX Intramural Research Program, NIH, grant 1ZIAHD000641 from the NICHD with supplemental funding from NIMHD; Intramural Research Program, NIMH. NR 166 TC 1 Z9 1 U1 8 U2 21 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 OCT PY 2015 VL 45 IS 14 BP 2921 EP 2936 DI 10.1017/S003329171500104X PG 16 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CT7EQ UT WOS:000362977100002 PM 26040923 ER PT J AU Wade, JL Petrelli, NJ McCaskill-Stevens, W AF Wade, James Lloyd, III Petrelli, Nicholas J. McCaskill-Stevens, Worta TI Cooperative Group Trials in the Community Setting SO SEMINARS IN ONCOLOGY LA English DT Review ID CLINICAL ONCOLOGY PROGRAM; NATIONAL-CANCER-INSTITUTE; BARRIERS AB Over the last 40 years the National Cancer Institute (NCI) has created a vibrant public-private partnership for the implementation of NCI-sponsored cooperative group (Network) clinical trials throughout the United States and Canada. Over these four decades, the cancer clinical trials process has become more complex more precise and more resource intensive. During this same time period, financial resources to support the NCI community research initiative have become more constrained. The newest manifestation of NCI-sponsored community based cancer clinical trial research, known as the National Community Oncology Research Program (NCORP) began initial operation August 1, 2014. We describe several key strategies that community sites may use to not only be successful but to thrive in this new financially austere research environment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wade, James Lloyd, III; Petrelli, Nicholas J.] Heartland Natl Community Oncol Res Program NCORP, Decatur, IL USA. [McCaskill-Stevens, Worta] NCI, Commun Oncol & Prevent Trials Res Grp, Bethesda, MD 20892 USA. RP Wade, JL (reprint author), Heartland NCORP, Canc Care Ctr Decatur, 410 W McKinley Ave, Decatur, IL 62526 USA. EM jlwade3@sbcglobal.net NR 8 TC 1 Z9 1 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 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2015 VL 42 IS 5 BP 686 EP 692 DI 10.1053/j.seminoncol.2015.07.011 PG 7 WC Oncology SC Oncology GA CT4UG UT WOS:000362802200003 ER PT J AU Schott, AF Welch, JJ Verschraegen, CF Kurzrock, R AF Schott, Anne F. Welch, John J. Verschraegen, Claire F. Kurzrock, Razelle TI The National Clinical Trials Network: Conducting Successful Clinical Trials of New Therapies for Rare Cancers SO SEMINARS IN ONCOLOGY LA English DT Review ID TARGETED THERAPY; VEMURAFENIB; LEUKEMIA; MUTATION; DISEASES; LESSONS; REALITY; TUMORS AB Rare cancers account for 27% of neoplasms diagnosed each year, and 25% of cancer-related deaths in the United States. However, rare cancers show some of the highest response rates to targeted therapies, probably due to identification of oncogenic drivers with little interpatient variability. Although the low incidence of rare cancers makes large-scale randomized trials involving single histologies difficult to perform, drugs have been successfully developed in rare cancers using clinical trial designs that combine microscopic histologies. Such trials are being pursued within the National Clinical Trials Network (NCTN), which possesses unique qualifications to perform widespread molecular screening of tumors for patient enrollment onto therapeutic clinical trials. When larger clinical trials are needed to determine optimum treatment strategies in rare cancers, the NCTN's broad reach in North America and internationally, and their ability to partner with both United States based and international research organizations, can make these challenging studies feasible. (C) 2015 Elsevier Inc. All rights reserved. C1 [Schott, Anne F.] Univ Michigan, Dept Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Welch, John J.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Verschraegen, Claire F.] Univ Vermont, Ctr Canc, Div Hematol Oncol, Burlington, VT 05405 USA. [Kurzrock, Razelle] Univ Calif San Diego, Moores Canc Ctr, Div Hematol & Oncol, Ctr Personalized Therapy, San Diego, CA 92103 USA. [Kurzrock, Razelle] Univ Calif San Diego, Moores Canc Ctr, Clin Trials Off, San Diego, CA 92103 USA. RP Schott, AF (reprint author), Univ Michigan, Dept Med, Div Hematol Oncol, Med, C349 Med Inn Bldg,1500 E Med Ctr Dr,SPC 5848, Ann Arbor, MI 48109 USA. EM aschott@med.umich.edu FU NCI NIH HHS [U10 CA180888] NR 35 TC 5 Z9 5 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2015 VL 42 IS 5 BP 731 EP 739 DI 10.1053/j.seminoncol.2015.07.010 PG 9 WC Oncology SC Oncology GA CT4UG UT WOS:000362802200007 PM 26433554 ER PT J AU Minasian, LM Tangen, CM Wickerham, L AF Minasian, Lori M. Tangen, Catherine M. Wickerham, Lawrence TI Ongoing Use of Data and Specimens From National Cancer Institute-Sponsored Cancer Prevention Clinical Trials in the Community Clinical Oncology Program SO SEMINARS IN ONCOLOGY LA English DT Review ID SURGICAL ADJUVANT BREAST; QUALITY-OF-LIFE; BRCA2 MUTATION CARRIERS; BOWEL PROJECT P-1; REDUCING SALPINGO-OOPHORECTOMY; RANDOMIZED CONTROLLED-TRIAL; RAT MAMMARY-CARCINOMA; BONE-MINERAL DENSITY; 2ND PRIMARY TUMORS; CELL LUNG-CANCER AB Large cancer prevention trials provide opportunities to collect a wide array of data and biospecimens at study entry and longitudinally, for a healthy, aging population without cancer. This provides an opportunity to use pre-diagnostic data and specimens to evaluate hypotheses about the initial development of cancer. We report on strides made by, and future possibilities for, the use of accessible biorepositories developed from precisely annotated samples obtained through large-scale National Cancer Institute (NCI)-sponsored cancer prevention clinical trials conducted by the NCI Cooperative Groups. These large cancer prevention studies, which have enrolled more than 80,000 volunteers, continue to contribute to our understanding of cancer development more than 10 years after they were closed. Published by Elsevier Inc. C1 [Minasian, Lori M.] US Natl Canc Inst, Div Canc Prevent, Rockville, MD USA. [Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA. [Wickerham, Lawrence] Temple Univ, Sch Med, Dept Human Oncol, Pittsburgh, PA USA. RP Minasian, LM (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM minasilo@mail.nih.gov FU US National Cancer Institute [CA37447, CA37404, CA37400, CA37379, CA37403, CA69974, CA37377, CA37422, CA101165, CA37429, CA37420, CA81851, CA81920, CA45809]; [UM1 CA182883]; [AG019241]; [EY014418]; [HL071722]; [CA041108]; [N01-AG-2106] FX The work reported was from the US National Cancer Institute and supported by the following primary grants to the Community Clinical Oncology Program (CCOP) Legacy Research Bases: CA37447 (Cancer and Leukemia Group B (CALGB)); CA37404 (North Central Cancer Treatment Group (NCCTG)); CA37400 (Children's Cancer Group); CA37379 (Pediatric Oncology Group); CA37403 (Eastern Cooperative Oncology Group (ECOG)); CA69974 and CA37377 (National Surgical Adjuvant Breast and Bowel Project (NSABP)); CA37422 (Radiation Therapy Oncology Group); CA101165 (Gynecologic Oncology Group); CA37429 (Southwest Oncology Group (SWOG)); CA37420 (University of Rochester Cancer Center (URCC)); CA81851 (Wake Forest University Cancer Center); CA81920 (SunCoast CCOP Research Base at the University of South Florida); and CA45809 (University of Texas MD Anderson Cancer Center). Additional funding support: UM1 CA182883 (PCPT/SELECT), AG019241 (SELECT- PREADVISE), EY014418 (SELECT-SELECT Eye Endpoints/SEE), HL071722 (SELECT-Respiratory Ancillary Study), CA041108 (SELECT- Colon Polyps Sub Study), and N01-AG-2106 (STAR - Cognition in STAR/Co-STAR). NR 95 TC 0 Z9 0 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2015 VL 42 IS 5 BP 748 EP 763 DI 10.1053/j.seminoncol.2015.07.006 PG 16 WC Oncology SC Oncology GA CT4UG UT WOS:000362802200009 PM 26433556 ER PT J AU Giuliani, F Ohuma, E Spada, E Bertino, E Al Dhaheri, AS Altman, DG Conde-Agudelo, A Kennedy, SH Villar, J Ismail, LC AF Giuliani, Francesca Ohuma, Eric Spada, Elena Bertino, Enrico Al Dhaheri, Ayesha S. Altman, Douglas G. Conde-Agudelo, Agustin Kennedy, Stephen H. Villar, Jose Ismail, Leila Cheikh TI Systematic review of the methodological quality of studies designed to create neonatal anthropometric charts SO ACTA PAEDIATRICA LA English DT Review DE Neonatal anthropometric charts; Newborn head circumference; Newborn length; Newborn weight; Systematic review ID CHILD GROWTH STANDARDS; GESTATIONAL-AGE; BIRTH-WEIGHT; HEAD CIRCUMFERENCE; INTRAUTERINE GROWTH; POPULATION; CURVES; LENGTH; IMPLEMENTATION; REFERENCES AB Babies all over the world are assessed at birth using neonatal anthropometric charts as a matter of clinical routine. This systematic review evaluated the methodological quality of studies designed to create neonatal anthropometric charts and to highlight features in the charts that could affect clinical decision-making and comparisons between populations. The variety and quality of available charts could affect how newborns at risk are identified, together with the indications for treatment, especially nutritional interventions. Conclusion: The studies that generated the charts currently recommended for clinical use have major methodological limitations and international and regional comparisons are very difficult. C1 [Giuliani, Francesca; Bertino, Enrico] Univ Turin, Dipartimento Sci Sanita Pubbl & Pediat, Neonatal Unit, Turin, Italy. [Ohuma, Eric; Kennedy, Stephen H.; Villar, Jose; Ismail, Leila Cheikh] Univ Oxford, Green Templeton Coll, Nuffield Dept Obstet & Gynaecol, Oxford, England. [Ohuma, Eric; Kennedy, Stephen H.; Villar, Jose; Ismail, Leila Cheikh] Univ Oxford, Green Templeton Coll, Oxford Maternal & Perinatal Hlth Inst, Oxford, England. [Ohuma, Eric; Altman, Douglas G.] Univ Oxford, Ctr Stat Med, Botnar Res Ctr, Oxford, England. [Al Dhaheri, Ayesha S.] United Arab Emirates Univ, Coll Food & Agr, Dept Nutr & Hlth, Al Ain, U Arab Emirates. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Bethesda, MD USA. [Conde-Agudelo, Agustin] NIH, Dept Hlth & Human Serv, Detroit, MI USA. RP Giuliani, F (reprint author), SCDU Neonatol, Via Ventimiglia 3, Turin, Italy. EM giuliani.pediatria@gmail.com OI Giuliani, Francesca/0000-0002-4265-207X NR 40 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0803-5253 EI 1651-2227 J9 ACTA PAEDIATR JI Acta Paediatr. PD OCT PY 2015 VL 104 IS 10 BP 987 EP 996 DI 10.1111/apa.13112 PG 10 WC Pediatrics SC Pediatrics GA CT0UG UT WOS:000362512100016 PM 26154879 ER PT J AU Jankovic, N Geelen, A Streppel, MT de Groot, LCPGM Kiefte-de Jong, JC Orfanos, P Bamia, C Trichopoulou, A Boffetta, P Bobak, M Pikhart, H Kee, F O'Doherty, MG Buckland, G Woodside, J Franco, OH Ikram, MA Struijk, EA Pajak, A Malyutina, S Kubinova, R Wennberg, M Park, Y Bueno-de-Mesquita, HB Kampman, E Feskens, EJ AF Jankovic, Nicole Geelen, Anouk Streppel, Martinette T. de Groot, Lisette C. P. G. M. Kiefte-de Jong, Jessica C. Orfanos, Philippos Bamia, Christina Trichopoulou, Antonia Boffetta, Paolo Bobak, Martin Pikhart, Hynek Kee, Frank O'Doherty, Mark G. Buckland, Genevieve Woodside, Jayne Franco, Oscar H. Ikram, M. Arfan Struijk, Ellen A. Pajak, Andrzej Malyutina, Sofia Kubinova, Ruzena Wennberg, Maria Park, Yikyung Bueno-de-Mesquita, H. Bas Kampman, Ellen Feskens, Edith J. TI WHO guidelines for a healthy diet and mortality from cardiovascular disease in European and American elderly: the CHANCES project SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE aging; CHANCES; cardiovascular disease; cohort; meta-analysis ID FOOD-FREQUENCY QUESTIONNAIRE; CORONARY-HEART-DISEASE; RETIRED-PERSONS DIET; ALL-CAUSE MORTALITY; NATIONAL-INSTITUTES; MEDITERRANEAN DIET; PROSPECTIVE COHORT; 10-YEAR MORTALITY; EATING INDEX-2005; HALE PROJECT AB Background: Cardiovascular disease (CVD) represents a leading cause of mortality worldwide, especially in the elderly. Lowering the number of CVD deaths requires preventive strategies targeted on the elderly. Objective: The objective was to generate evidence on the association between WHO dietary recommendations and mortality from CVD, coronary artery disease (CAD), and stroke in the elderly aged >= 60 y. Design: We analyzed data from 10 prospective cohort studies from Europe and the United States comprising a total sample of 281,874 men and women free from chronic diseases at baseline. Components of the Healthy Diet Indicator (HDI) included saturated fatty acids, polyunsaturated fatty acids, mono- and disaccharides, protein, cholesterol, dietary fiber, and fruit and vegetables. Cohort-specific HRs adjusted for sex, education, smoking, physical activity, and energy and alcohol intakes were pooled by using a random-effects model. Results: During 3,322,768 person-years of follow-up, 12,492 people died of CVD. An increase of 10 HDI points (complete adherence to an additional WHO guideline) was, on average, not associated with CVD mortality (HR: 0.94; 95% CI: 0.86, 1.03), CAD mortality (HR: 0.99; 95% CI: 0.85, 1.14), or stroke mortality (HR: 0.95; 95% CI: 0.88, 1.03). However, after stratification of the data by geographic region, adherence to the HDI was associated with reduced CVD mortality in the southern European cohorts (HR: 0.87; 95% CI: 0.79, 0.96; I2 = 0%) and in the US cohort (HR: 0.85; 95% CI: 0.83, 0.87; I2 = not applicable). Conclusion: Overall, greater adherence to the WHO dietary guidelines was not significantly associated with CVD mortality, but the results varied across regions. Clear inverse associations were observed in elderly populations in southein Europe and the United States. C1 [Jankovic, Nicole; Geelen, Anouk; Streppel, Martinette T.; de Groot, Lisette C. P. G. M.; Kampman, Ellen; Feskens, Edith J.] Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. [Jankovic, Nicole] Univ Duisburg Essen, Univ Hosp, Inst Med Informat Biometry & Epidemiol, Ctr Clin Epidemiol, Essen, Germany. [Kiefte-de Jong, Jessica C.; Franco, Oscar H.; Ikram, M. Arfan] Univ Med Ctr, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Kiefte-de Jong, Jessica C.] Leiden Univ Coll, Global Publ Hlth, The Hague, Netherlands. [Orfanos, Philippos; Bamia, Christina; Trichopoulou, Antonia; Boffetta, Paolo] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Orfanos, Philippos; Bamia, Christina; Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Bobak, Martin; Pikhart, Hynek] UCL, Dept Epidemiol & Publ Hlth, London, England. [Kee, Frank; O'Doherty, Mark G.; Woodside, Jayne] Queens Univ Belfast, Sch Med Dent & Biomed Sci, UKCRC Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland. [Buckland, Genevieve] Catalan Inst Oncol, Canc Epidemiol Res Programme, Unit Nutr Environm & Canc, Barcelona, Spain. [Struijk, Ellen A.] Julius Ctr, Dept Epidemiol, Utrecht, Netherlands. [Pajak, Andrzej] Jagiellonian Univ, Dept Epidemiol & Populat Studies, Krakow, Poland. [Malyutina, Sofia] Russian Acad Med Sci, Siberian Branch, Inst Internal & Prevent Med, Novosibirsk, Russia. [Malyutina, Sofia] Novosibirsk State Med Univ, Novosibirsk, Russia. [Kubinova, Ruzena] Natl Inst Publ Hlth, Prague, Czech Republic. [Wennberg, Maria] Umea Univ, Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden. [Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, Dept Determinants Chron Dis, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. RP Feskens, EJ (reprint author), Wageningen Univ, Div Human Nutr, NL-6700 AP Wageningen, Netherlands. EM edith.feskens@wur.nl OI Pikhart, Hynek/0000-0001-5277-4049; Feskens, Edith/0000-0001-5819-2488; Kiefte-de Jong, Jessica/0000-0002-8136-0918 FU regional government of Andalucia; regional government of Asturias; regional government of Basque Country; regional government of Murcia; regional government of Navarra; Spanish Ministry of Health [ISCIII RETICC RD06/0020/0091]; Catalan Institute of Oncology (EPIC-Spain); regional government of Vasterbotten, Sweden (EPIC-Sweden); Dutch Ministry of Public Health, Welfare and Sports (EPIC-Netherlands); Netherlands Cancer Registry (EPIC-Netherlands); LK Research Funds (EPIC-Netherlands); Dutch Prevention Funds (EPIC-Netherlands); Dutch ZON (EPIC-Netherlands); World Cancer Research Fund (EPIC-Netherlands); Statistics Netherlands (EPIC-Netherlands); Hellenic Health Foundation (EPIC-Elderly Greece); Stavros Niarchos Foundation (EPIC-Elderly Greece); Intramural Research Program of the NIH National Cancer Institute (NIH-AARP); Wellcome Trust [064947/Z/01/Z]; MacArthur Foundation; National Institute on Aging [1R01 AG23522]; European Community's Seventh Framework Programme (FP7) [HEALTH -F3-2010-242244]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Ministry of Education, Culture and Science; Ministry of Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam FX The included cohorts were financially supported by regional governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra, The Spanish Ministry of Health (ISCIII RETICC RD06/0020/0091), and the Catalan Institute of Oncology (EPIC-Spain); regional government of Vasterbotten, Sweden (EPIC-Sweden); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON, World Cancer Research Fund, Statistics Netherlands (EPIC-Netherlands); Hellenic Health Foundation, Stavros Niarchos Foundation (EPIC-Elderly Greece); Intramural Research Program of the NIH National Cancer Institute (NIH-AARP), the Wellcome Trust "Determinants of Cardiovascular Diseases in Eastern Europe: A multi-centre cohort study" (064947/Z/01/Z), MacArthur Foundation "Health and Social Upheaval (a research network)" and National Institute on Aging "Health disparities and aging in societies in transition (the HAPIEE study)" (grant no. 1R01 AG23522). The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH -F3-2010-242244. The Rotterdam Study 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; the Research Institute for Diseases in the Elderly; The Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. SENECA was a Concerted Action within the EURONUT programme of the European Union. This is an open access article distributed under the CC-BY license (http://creativecommons.org/licenses/by/3.0/). NR 56 TC 2 Z9 2 U1 2 U2 19 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 OCT PY 2015 VL 102 IS 4 BP 745 EP 756 DI 10.3945/ajcn.114.095117 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS7CO UT WOS:000362241900006 PM 26354545 ER PT J AU Kunzmann, AT Coleman, HG Huang, WY Kitahara, CM Cantwell, MM Berndt, SI AF Kunzmann, Andrew T. Coleman, Helen G. Huang, Wen-Yi Kitahara, Cari M. Cantwell, Marie M. Berndt, Sonja I. TI Dietary fiber intake and risk of colorectal cancer and incident and recurrent adenoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE cancer risk; colorectal adenoma; colorectal cancer; dietary fiber; epidemiology ID FRUIT; WOMEN; METAANALYSIS; VEGETABLES; COHORT; HEALTH; FOOD; MEN AB Background: Dietary fiber has been associated with a reduced risk of colorectal cancer. However, it remains unclear at which stage in the carcinogenic pathway fiber may act or which food sources of dietary fiber may be most beneficial against colorectal cancer development. Objective: The objective was to prospectively evaluate the association between dietary fiber intake and the risk of incident and recurrent colorectal adenoma and incident colorectal cancer. Design: Study participants were identified from the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants received flexible sigmoidoscopy at baseline and 3 or 5 y after. Dietary fiber intake was measured by using a self-reported dietary questionnaire. The colorectal cancer, incident adenoma, and recurrent adenoma analyses were based on 57,774, 16,980, and 1667 participants, respectively. Unconditional logistic regression was used to assess the risk of incident and recurrent adenoma, and Cox proportional hazards models were used to assess the risk of colorectal cancer across categories of dietary fiber intake, with adjustment for potential confounders. Results: Elevated total dietary fiber intake was associated with a significantly reduced risk of incident distal colorectal adenoma (ORhighest (vs.) (lowest tertile of intake): 0.76; 95% CI: 0.63, 0.91; P-trend = 0.003) but not recurrent adenoma (P-trend = 0.67). Although the association was not statistically significant for colorectal cancer overall (HR: 0.85; 95% CI: 0.70, 1.03; P-trend = 0.10), a reduced risk of distal colon cancer was observed with increased total fiber intake (FIR: 0.62; 95% CI: 0.41, 0.94; P-trend = 0.03). Protective associations were most notable for fiber originating from cereals or fruit. Conclusions: This large, prospective study within a population-based screening trial suggests that individuals consuming the highest intakes of dietary fiber have reduced risks of incident colorectal adenoma and distal colon cancer and that this effect of dietary fiber, particularly from cereals and fruit, may begin early in colorectal carcinogenesis. C1 [Kunzmann, Andrew T.; Coleman, Helen G.; Cantwell, Marie M.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT7 1NN, Antrim, North Ireland. [Huang, Wen-Yi; Kitahara, Cari M.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Coleman, HG (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Belfast BT7 1NN, Antrim, North Ireland. EM h.coleman@qub.ac.uk RI Kitahara, Cari/R-8267-2016; OI Coleman, Helen/0000-0003-4872-7877 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX Supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. NR 32 TC 10 Z9 11 U1 2 U2 24 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 OCT PY 2015 VL 102 IS 4 BP 881 EP 890 DI 10.3945/ajcn.115.113282 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS7CO UT WOS:000362241900020 PM 26269366 ER PT J AU Schliep, KC Zarek, SM Schisterman, EF Wactawski-Wende, J Trevisan, M Sjaarda, LA Perkins, NJ Mumford, SL AF Schliep, Karen C. Zarek, Shvetha M. Schisterman, Enrique F. Wactawski-Wende, Jean Trevisan, Maurizio Sjaarda, Lindsey A. Perkins, Neil J. Mumford, Sunni L. TI Alcohol intake, reproductive hormones, and menstrual cycle function: a prospective cohort study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE alcohol; estradiol; menstrual cycle; ovulation; progesterone ID MARGINAL STRUCTURAL MODELS; PREMENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN; LIFE-STYLE; LUTEINIZING-HORMONE; CIGARETTE-SMOKING; BINGE DRINKING; BREAST-CANCER; UNITED-STATES; SEX-HORMONES AB Background: Although habitual low-to-moderate alcohol intake has been linked with reduced all-cause mortality and morbidity, the effect of recent alcohol intake on female reproductive function has not been clearly established. Objective: We assessed the relation between acute alcohol consumption, reproductive hormones, and markers of menstrual cycle dysfunction including sporadic anovulation, irregular cycle length, luteal phase deficiency, long menses, and heavy blood loss. Design: A total of 259 healthy, premenopausal women from Western New York were followed for <= 2 menstrual cycles (2005-2007) and provided fasting blood specimens during <= 8 visits/cycle and four 24-h dietary recalls/cycle. Linear mixed models were used to estimate associations between previous day's alcohol intake and hormone concentrations, whereas Poisson regression was used to assess RR of cycle-average alcohol intake and menstrual cycle function. Results: For every alcoholic drink consumed, the geometric mean total and free estradiol, total and free testosterone, and luteinizing hormone were higher by 5.26% (95% CI: 1.27%, 9.41%), 5.82% (95% CI: 1.81%, 9.99%), 1.56% (95% CI: 0.23%, 2.90%), 1.42% (95% CI: 0.02%, 2.84%), and 6.18% (95% CI: 2.02%, 10.52%), respectively, after adjustment for age, race, percentage of body fat, perceived stress, pain-medication use, sexual activity, caffeine, and sleep. Binge compared with nonbinge drinking (defined as reporting >= 4 compared with <4 drinks/d, respectively) was associated with 64.35% (95% CI: 18.09%, 128.71%) and 63.53% (95% CI: 17.41%, 127.73%) higher total and free estradiol. No statistically significant associations were shown between cycle-average alcohol intake and menstrual cycle function. Conclusion: Although recent moderate alcohol intake does not appear to have adverse short-term effects on menstrual cycle function, including sporadic anovulation, potential protective and deleterious long-term effects of alterations in reproductive hormones on other chronic diseases warrant additional investigation. C1 [Schliep, Karen C.; Zarek, Shvetha M.; Schisterman, Enrique F.; Sjaarda, Lindsey A.; Perkins, Neil J.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zarek, Shvetha M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIB, Dept Hlth & Human Serv, Bethesda, MD USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Trevisan, Maurizio] CUNY City Coll, Sophie Davis Sch Biomed Educ, New York, NY 10031 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275200403394C, HHSN275201100002I, Task 1 HHSN27500001] FX Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (contracts HHSN275200403394C and HHSN275201100002I, and Task 1 HHSN27500001). NR 53 TC 5 Z9 5 U1 5 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 OCT PY 2015 VL 102 IS 4 BP 933 EP 942 DI 10.3945/ajcn.114.102160 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS7CO UT WOS:000362241900026 PM 26289438 ER PT J AU Gardner, K Thein, SL AF Gardner, Kate Thein, Swee Lay TI Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID LACTATE-DEHYDROGENASE C1 [Gardner, Kate; Thein, Swee Lay] Kings Coll London, Fac Life Sci & Med Mol Haematol, Div Canc Studies, London SE5 9NU, England. [Gardner, Kate; Thein, Swee Lay] Kings Coll Hosp NHS Fdn Trust, Dept Haematol Med, London SE5 9RS, England. [Thein, Swee Lay] NHLBI, Sickle Cell Branch, NIH, Bethesda, MD 20892 USA. RP Thein, SL (reprint author), NHLBI, NIH, Bldg 10 CRC-5E-5142,10 Ctr Dr, Bethesda, MD 20892 USA. EM sl.thein@kcl.ac.uk NR 6 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD OCT PY 2015 VL 90 IS 10 BP E206 EP E207 DI 10.1002/ajh.24126 PG 2 WC Hematology SC Hematology GA CT2VV UT WOS:000362663900004 PM 26205137 ER PT J AU Symoens, S Barnes, AM Gistelinck, C Malfait, F Guillemyn, B Steyaert, W Syx, D D'hondt, S Biervliet, M De Backer, J Witten, EP Leikin, S Makareeva, E Gillessen-Kaesbach, G Huysseune, A Vleminckx, K Willaert, A De Paepe, A Marini, JC Coucke, PJ AF Symoens, Sofie Barnes, Aileen M. Gistelinck, Charlotte Malfait, Fransiska Guillemyn, Brecht Steyaert, Wouter Syx, Delfien D'hondt, Sanne Biervliet, Martine De Backer, Julie Witten, Eckhard P. Leikin, Sergey Makareeva, Elena Gillessen-Kaesbach, Gabriele Huysseune, Ann Vleminckx, Kris Willaert, Andy De Paepe, Anne Marini, Joan C. Coucke, Paul J. TI Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RECESSIVE OSTEOGENESIS IMPERFECTA; PRIMARY CILIA; I COLLAGEN; CRANIOFACIAL DEVELOPMENT; LINEAGE COMMITMENT; MUTATION CAUSES; BONE FRAGILITY; ZEBRAFISH; SKELETON; IDENTIFICATION AB The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells. C1 [Symoens, Sofie; Gistelinck, Charlotte; Malfait, Fransiska; Guillemyn, Brecht; Steyaert, Wouter; Syx, Delfien; D'hondt, Sanne; De Backer, Julie; Vleminckx, Kris; Willaert, Andy; De Paepe, Anne; Coucke, Paul J.] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Barnes, Aileen M.; Marini, Joan C.] NICHD, NIH, Bone & Extracellular Matrix Branch, Bethesda, MD 20892 USA. [Biervliet, Martine] Brussels Univ Hosp, Ctr Med Genet, B-1090 Brussels, Belgium. [Witten, Eckhard P.; Huysseune, Ann] Univ Ghent, Biol Dept, B-9000 Ghent, Belgium. [Leikin, Sergey; Makareeva, Elena] NICHD, NIH, Sect Phys Biochem, Bethesda, MD 20892 USA. [Gillessen-Kaesbach, Gabriele] Univ Lubeck, Inst Humangenet Lubeck, D-23538 Lubeck, Germany. [Vleminckx, Kris] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. RP Coucke, PJ (reprint author), Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. EM paul.coucke@ugent.be RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU FWO [G.0171.05]; Methusalem grant [08/01M01108]; NICHD, NIH; Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program [TAP P7/43-BeMGI]; Hercules Foundation, Flanders [AUGE/11/14] FX We wish to thank P. Tapaneeyaphan, J. Weytens, P. Vermassen, L. Demuynck, P. Simoens, H. De Saffel and M. Soenens for excellent technical assistance. We are grateful to E. Parthoens and Dr. C. Guerin for access to the BioImaging Core, Ghent Platform, VIB. A.M.B. and J.C.M. acknowledge the NICHD Microscopy and Imaging Core. F.M. is a senior clinical investigator at the Fund for Scientific Research-Flanders. Contract grants include FWO grant number G.0171.05 to A.D.P. and Methusalem grant number 08/01M01108 to A.D.P. and NICHD, NIH Intramural Funding went to J.C.M. This work was also supported by funding from the Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) program through the project TAP P7/43-BeMGI. The Leica TCS LSI Super Zoom confocal microscope is supported by the Hercules Foundation, Flanders (grant AUGE/11/14). NR 66 TC 3 Z9 3 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 1 PY 2015 VL 97 IS 4 BP 521 EP 534 DI 10.1016/j.ajhg.2015.08.009 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CT2FL UT WOS:000362617300003 PM 26365339 ER PT J AU Galfalvy, H Haghighi, F Hodgkinson, C Goldman, D Oquendo, MA Burke, A Huang, YY Giegling, I Rujescu, D Bureau, A Turecki, G Mann, JJ AF Galfalvy, Hanga Haghighi, Fatemeh Hodgkinson, Colin Goldman, David Oquendo, Maria A. Burke, Ainsley Huang, Yung-yu Giegling, Ina Rujescu, Dan Bureau, Alexandre Turecki, Gustavo Mann, J. John TI A genome-wide association study of suicidal behavior SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE suicide; GWAS; immune response; suicide attempt; suicidal ideation ID POPULATION; DISEASE; GENE AB Genome wide array studies have reported limited success in identifying genetic markers conferring risk for suicidal behavior (SB). This may be attributable to study designs with primary outcome other than SB. We performed a GWAS on suicides and cases with a history of nonfatal suicide attempts compared with psychiatric controls and healthy volunteers. A consortium of USA, Canadian and German teams assembled two groups of cases (suicide attempters and suicides, N=577) and non-attempter psychiatric and healthy controls (N=1,233). Logistic regression was used to test genotype-suicidal behavior association. The test was repeated separating suicide attempt and completed suicide as outcomes. No SNP reached genome-wide significance, but several SNPs within STK3, ADAMTS14, PSME2, and TBX20 genes reached P<1x10(-5). The top SNPs for the suicide attempt analysis included two from DPP10, one from CTNNA3 and one from STK32B. In the suicide analysis we found seven SNPs from the TBX20 gene in the top hits. Pathway analysis identified the following pathways: Cellular Assembly and Organization, Nervous System Development and Function, Cell Death and Survival, Immunological Disease, Infectious Disease, and Inflammatory Response. The top genes in the SB analysis did not overlap with those in the ideation analysis. No genome wide significant results suggest that susceptibility to SB has genetic risk factors with smaller effect sizes. The strongest candidate genes, ADAMTS14, and PSME2 (both linked to inflammatory response), STK3 (neuronal cell death), and TBX20 (brainstem motor neuron development), have not been previously reported in association with suicide and warrant further study. (c) 2015 Wiley Periodicals, Inc. C1 [Galfalvy, Hanga; Haghighi, Fatemeh; Oquendo, Maria A.; Burke, Ainsley; Huang, Yung-yu; Mann, J. John] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Galfalvy, Hanga] Columbia Univ, Dept Biostat, New York, NY USA. [Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Giegling, Ina; Rujescu, Dan] Univ Halle Wittenberg, Psychiat Clin, Munich, Germany. [Bureau, Alexandre] Univ Laval, Ctr Rech, Inst Univ Sante Mentale Quebec, Quebec City, PQ, Canada. [Bureau, Alexandre] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. [Turecki, Gustavo] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. RP Mann, JJ (reprint author), Columbia Univ, Dept Psychiat, New York, NY 10027 USA. EM jjm@columbia.edu RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bureau, Alexandre/0000-0001-8220-9999 FU NIMH PHS [MH082041] FX Grant sponsor: NIMH PHS; Grant number: MH082041. NR 27 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT PY 2015 VL 168 IS 7 BP 557 EP 563 DI 10.1002/ajmg.b.32330 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA CR3GZ UT WOS:000361221200005 PM 26079190 ER PT J AU Yeung, TL Leung, CS Yip, KP Yeung, CLA Wong, STC Mok, SC AF Yeung, Tsz-Lun Leung, Cecilia S. Yip, Kay-Pong Yeung, Chi Lam Au Wong, Stephen T. C. Mok, Samuel C. TI Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Review DE ovarian cancer; metastasis; stromal-tumoral interaction; passive dissemination; hematogenous metastasis ID ENDOTHELIAL-GROWTH-FACTOR; CARCINOMA-ASSOCIATED FIBROBLASTS; TUMOR-ASSOCIATED MACROPHAGES; MILKY SPOT MACROPHAGES; EPITHELIAL OVARIAN; BREAST-CANCER; LYSOPHOSPHATIDIC ACID; STROMAL FIBROBLASTS; GENE-EXPRESSION; ADVANCED-STAGE AB Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease. C1 [Yeung, Tsz-Lun; Leung, Cecilia S.; Yeung, Chi Lam Au; Mok, Samuel C.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Leung, Cecilia S.; Mok, Samuel C.] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. [Yip, Kay-Pong] Univ S Florida, Dept Mol Pharmacol & Physiol, Tampa, FL USA. [Wong, Stephen T. C.] Houston Methodist Res Inst, Weill Cornell Med Coll, Dept Syst Med & Bioengn, Houston, TX USA. [Wong, Stephen T. C.] NCI, Ctr Modeling Canc Dev, Houston Methodist Res Inst, Houston, TX USA. RP Mok, SC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM scmok@mdanderson.org FU National Cancer Institute [R01 CA-133057, R01 CA-142832]; Cancer Prevention Research Institute of Texas [RP100094]; Mary K. Chapman Foundation FX This work was supported in part by National Cancer Institute Grants R01 CA-133057 and R01 CA-142832, Cancer Prevention Research Institute of Texas Grant RP100094, and a grant from the Mary K. Chapman Foundation. NR 170 TC 12 Z9 12 U1 3 U2 16 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD OCT 1 PY 2015 VL 309 IS 7 BP C444 EP C456 DI 10.1152/ajpcell.00188.2015 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CS7LM UT WOS:000362265100002 PM 26224579 ER PT J AU Ross, JM Cattamanchi, A Miller, CR Tatem, AJ Katamba, A Haguma, P Handley, MA Davis, JL AF Ross, Jennifer M. Cattamanchi, Adithya Miller, Cecily R. Tatem, Andrew J. Katamba, Achilles Haguma, Priscilla Handley, Margaret A. Davis, J. Lucian TI Investigating Barriers to Tuberculosis Evaluation in Uganda Using Geographic Information Systems SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PULMONARY TUBERCULOSIS; HEALTH-SERVICES; RURAL UGANDA; SOUTH-AFRICA; CARE; ACCESSIBILITY; PATIENT; IMPACT; HIV; DISPARITIES AB Reducing geographic barriers to tuberculosis (TB) care is a priority in high-burden countries where patients frequently initiate, but do not complete, the multi-day TB evaluation process. Using routine cross-sectional study from six primary-health clinics in rural Uganda from 2009 to 2012, we explored whether geographic barriers affect completion of TB evaluation among adults with unexplained chronic cough. We measured distance from home parish to health center and calculated individual travel time using a geographic information systems technique incorporating roads, land cover, and slope, and measured its association with completion of TB evaluation. In 264,511 patient encounters, 4,640 adults (1.8%) had sputum smear microscopy ordered; 2,783 (60%) completed TB evaluation. Median travel time was 68 minutes for patients with TB examination ordered compared with 60 minutes without (P < 0.010). Travel time differed between those who did and did not complete TB evaluation at only one of six clinics, whereas distance to care did not differ at any of them. Neither distance nor travel time predicted completion of TB evaluation in rural Uganda, although limited detail in road and village maps restricted full implementation of these mapping techniques. Better data are needed on geographic barriers to access clinics offering TB services to improve TB diagnosis. C1 [Ross, Jennifer M.] Univ Washington, Div Infect Dis, Seattle, WA 98195 USA. Curry Int TB Ctr, Div Pulm & Crit Care Med, San Francisco, CA USA. San Francisco Gen Hosp, Dept Med, Div Gen Internal Med, Ctr Vulnerable Populat, San Francisco, CA 94110 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Makerere Univ, Mulago Hosp, MU UCSF Res Collaborat, Clin Epidemiol Unit,Dept Med, Kampala, Uganda. Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. Yale Univ, Sch Med, Pulm Crit Care & Sleep Med Sect, New Haven, CT USA. RP Ross, JM (reprint author), Univ Washington, Div Infect Dis, 1959 NE Pacific St,Box 356423, Seattle, WA 98195 USA. EM jross3@uw.edu FU NIH/NIAID [T32AI007140, U19AI089674, K23AI080147]; RAPIDD program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [49446, 1032350]; NIH/NHLBI [K23HL094141] FX Jennifer M. Ross acknowledges funding support from NIH/NIAID (T32AI007140). Andrew J. Tate acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#49446 and #1032350). J. Lucian Davis acknowledges support from NIH/NIAID (K23AI080147). Adithya Cattamanchi acknowledges support from NIH/NHLBI (K23HL094141). NR 45 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD OCT PY 2015 VL 93 IS 4 BP 733 EP 738 DI 10.4269/ajtmh.14-0754 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CS8BX UT WOS:000362311800013 PM 26217044 ER PT J AU Paik, JJ Wigley, FM Lloyd, TE Corse, AM Casciola-Rosen, L Shah, AA Boin, F Hummers, LK Mammen, AL AF Paik, Julie J. Wigley, Fredrick M. Lloyd, Thomas E. Corse, Andrea M. Casciola-Rosen, Livia Shah, Ami A. Boin, Francesco Hummers, Laura K. Mammen, Andrew L. TI Spectrum of Muscle Histopathologic Findings in Forty-Two Scleroderma Patients With Weakness SO ARTHRITIS CARE & RESEARCH LA English DT Article ID PROGRESSIVE SYSTEMIC-SCLEROSIS; INFLAMMATORY MYOPATHIES; MANIFESTATIONS; ASSOCIATION; INVOLVEMENT; POPULATION; ANTIBODIES; PHENOTYPE; FEATURES; DISEASE AB Objective. To determine if distinct muscle pathologic features exist in scleroderma subjects with weakness. Methods. This retrospective study included weak scleroderma subjects with muscle biopsies available for review. Biopsies were systematically assessed for individual pathologic features, including inflammation, necrosis, fibrosis, and acute neurogenic atrophy. Based on the aggregate individual features, biopsies were assigned a histopathologic category of polymyositis, dermatomyositis, necrotizing myopathy, nonspecific myositis, "acute denervation," "fibrosis only," or "other." Clinical data analyzed included autoantibody profiles, scleroderma subtype and disease duration, Medsger muscle severity scores, creatine kinase, electromyography, and muscle magnetic resonance imaging. Results. A total of 42 subjects (79% female and 64% diffuse scleroderma) were included in this study. Necrosis (67%), inflammation (48%), acute neurogenic atrophy (48%), and fibrosis (33%) were the most prevalent pathologic features. The presence of fibrosis was strongly associated with anti-PM-Scl antibodies. Histopathologic categories included nonspecific myositis (36%), necrotizing myopathy (21%), dermatomyositis (7%), "acute denervation" (7%), "fibrosis only" (7%), and polymyositis (5%). Disease duration of scleroderma at the time of muscle biopsy was shorter in polymyositis than other histopathologic categories. Patients with anti-PM-Scl and Scl-70 antibodies also had a shorter disease duration than those with other autoantibody profiles. Conclusion. Nonspecific myositis and necrotizing myopathy were the most common histopathologic categories in weak scleroderma subjects. Surprisingly, nearly half of the subjects studied had histologic evidence of acute motor denervation (acute neurogenic atrophy); this has not been previously reported. Taken together, these observations suggest that a variety of pathologic mechanisms may underlie the development of myopathy in scleroderma. C1 [Paik, Julie J.; Wigley, Fredrick M.; Lloyd, Thomas E.; Corse, Andrea M.; Casciola-Rosen, Livia; Shah, Ami A.; Boin, Francesco; Hummers, Laura K.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Mammen, Andrew L.] Johns Hopkins Univ, Sch Med, Bethesda, MD USA. [Mammen, Andrew L.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1146,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM lhummers@jhmi.edu; andrew.mammen@nih.gov FU Scleroderma Research Foundation; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH; NIH [P30-AR-053503, R56-AR-062615]; Huayi and Siuling Zhang Discovery Fund; Clinical to Research Transition Award from the Arthritis Foundation; Donald B. and Dorothy L. Stabler Foundation FX Supported by the Scleroderma Research Foundation and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH. The Johns Hopkins Rheumatic Disease Research Core Center, where some of the autoantibody assays were performed, was supported by the NIH (grant P30-AR-053503). The immunostaining of the muscle biopsy slides was supported by The Huayi and Siuling Zhang Discovery Fund. Dr. Paik's work was supported by the Clinical to Research Transition Award from the Arthritis Foundation. Dr. Casciola-Rosen's work was supported by the NIH (grant R56-AR-062615) and funding from the Donald B. and Dorothy L. Stabler Foundation. Drs. Hummers and Mammen's work was supported by funding from the Donald B. and Dorothy L. Stabler Foundation. NR 34 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD OCT PY 2015 VL 67 IS 10 BP 1416 EP 1425 DI 10.1002/acr.22620 PG 10 WC Rheumatology SC Rheumatology GA CT2ZJ UT WOS:000362675300010 PM 25989455 ER PT J AU Joo, JH Ueda, E Bortner, CD Yang, XP Liao, G Jetten, AM AF Joo, Joung Hyuck Ueda, Eiichiro Bortner, Carl D. Yang, Xiao-Ping Liao, Grace Jetten, Anton M. TI Farnesol activates the intrinsic pathway of apoptosis and the ATF4-ATF3-CHOP cascade of ER stress in human T lymphoblastic leukemia Molt4 cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Leukemia; Molt4; ER stress; Apoptosis; Gene expression ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; LUNG-CARCINOMA CELLS; CYTOCHROME-C; SACCHAROMYCES-CEREVISIAE; SIGNALING PATHWAY; PERILLYL ALCOHOL; RISK-FACTORS; MOUSE MODEL; DEATH AB In this study, we demonstrate that treatment of T lymphoblastic leukemic Molt4 cells with farnesol activates the apoptosome via the intrinsic pathway of apoptosis. This induction was associated with changes in the level of intracellular potassium and calcium, the dissipation of the mitochondria] and plasma membrane potential, release of cytochrome c, activation of several caspases, and PARP cleavage. The induction of apoptosis by farnesol was inhibited by the addition of the pan-caspase inhibitor Z-VAD-fmk and by the exogenous expression of the anti-apoptotic protein Bcl2. Analysis of the gene expression profiles by microarray analysis revealed that farnesol increased the expression of several genes related to the unfolded protein response (UPR), including CHOP and CHAC1. This induction was associated with the activation of the PERK-eIF2 alpha-ATF3/4 cascade, but not the XBP-1 branch of the UPR. Although farnesol induced activation of the ERK1/2, p38, and JNK pathways, inhibition of these MAPKs had little effect on farnesol-induced apoptosis or the induction of UPR-related genes. Our data indicate that the induction of apoptosis in leukemic cells by farnesol is mediated through a pathway that involves activation of the apoptosome via the intrinsic pathway and induction of the PERK-eIF2 alpha-ATF3/4 cascade in a manner that is independent of the farnesol-induced activation of MAPKs. Published by Elsevier Inc. C1 [Joo, Joung Hyuck; Ueda, Eiichiro; Yang, Xiao-Ping; Liao, Grace; Jetten, Anton M.] NIEHS, Cell Biol Sect, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Bortner, Carl D.] NIEHS, Mol Endocrinol Sect, Lab Signal Transduct, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Inflammat & Dis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU National Institute of Environmental Health Sciences, the National Institutes of Health [Z01-ES-101586] FX The authors would like to thank Drs. Gary ZeRuth and Hong Soon Kang for their comments on the manuscript and Dr. Kevin Gerrish from the Microarray Core for his assistance. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, the National Institutes of Health (Z01-ES-101586). NR 51 TC 6 Z9 8 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD OCT 1 PY 2015 VL 97 IS 3 BP 256 EP 268 DI 10.1016/j.bcp.2015.08.086 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CT2HD UT WOS:000362621700004 PM 26275811 ER PT J AU Chassine, T Bocquet, B Daien, V Avila-Fernandez, A Ayuso, C Collin, RWJ Corton, M Hejtmancik, JF van den Born, LI Klevering, BJ Riazuddin, SA Sendon, N Lacroux, A Meunier, I Hamel, CP AF Chassine, Thomas Bocquet, Beatrice Daien, Vincent Avila-Fernandez, Almudena Ayuso, Carmen Collin, Rob W. J. Corton, Marta Hejtmancik, J. Fielding van den Born, L. Ingeborgh Klevering, B. Jeroen Riazuddin, S. Amer Sendon, Nathacha Lacroux, Annie Meunier, Isabelle Hamel, Christian P. TI Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID RETINAL DYSTROPHIES; PHENOTYPE; FAMILIES; REFRACTION; RPGR AB Objective To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Methods Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed. Results arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (p<0.0001). Conversely, myopia of xlRP patients with either an RPGR mutation (-4.50 D OD; -5.25 D OS) or an RP2 mutation (-6.25 D OD; -6.88 D OS) was not significantly different from the arRP group with RP1 mutations. arRP without RP1 mutations, Usher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D). Conclusions arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations. C1 [Chassine, Thomas; Sendon, Nathacha; Meunier, Isabelle; Hamel, Christian P.] CHRU, Maladies Sensorielles Genet, Montpellier, France. [Bocquet, Beatrice; Lacroux, Annie; Meunier, Isabelle; Hamel, Christian P.] INSERM, Inst Neurosci Montpellier, U1051, Montpellier, France. [Bocquet, Beatrice; Daien, Vincent; Lacroux, Annie; Meunier, Isabelle; Hamel, Christian P.] Univ Montpellier I, Montpellier, France. [Bocquet, Beatrice; Lacroux, Annie; Meunier, Isabelle; Hamel, Christian P.] Univ Montpellier 2, Montpellier, France. [Daien, Vincent] INSERM, U1061, Montpellier, France. [Daien, Vincent] CHRU, Dept Ophthalmol, Montpellier, France. [Avila-Fernandez, Almudena; Ayuso, Carmen; Corton, Marta] Fdn Jimenez Diaz, Univ Hosp, Inst Invest Sanitaria, Dept Genet, E-28040 Madrid, Spain. [Avila-Fernandez, Almudena; Ayuso, Carmen; Corton, Marta] Ctr Biomed Network Res Rare Dis CIBERER, ISCIII, Madrid, Spain. [Collin, Rob W. J.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Collin, Rob W. J.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [van den Born, L. Ingeborgh] Rotterdam Eye Hosp, Rotterdam, Netherlands. [Klevering, B. Jeroen] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands. [Riazuddin, S. Amer] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. RP Hamel, CP (reprint author), Hop St Eloi, Inst Neurosci Montpellier, INSERM U1051, BP 74103,80,Rue Augustin Fliche, F-34091 Montpellier 5, France. EM christian.hamel@inserm.frTC FU Federation des Aveugles et Handicapes Visuels de France; Information Recherche sur la Retinite Pigmentaire; Retina France; SOS Retinite; UNADEV; Spanish National Organization for the Blind-ONCE; Spanish Foundation Fighting Blindness-FUNDALUCE; Miguel Servet programme of the Instituto de Salud Carlos III (Spanish Ministry of Health); CIBERER FX Federation des Aveugles et Handicapes Visuels de France, Information Recherche sur la Retinite Pigmentaire, Retina France, SOS Retinite, UNADEV, Spanish National Organization for the Blind-ONCE, Spanish Foundation Fighting Blindness-FUNDALUCE, Miguel Servet programme of the Instituto de Salud Carlos III (Spanish Ministry of Health), CIBERER. NR 25 TC 4 Z9 4 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD OCT PY 2015 VL 99 IS 10 BP 1360 EP 1365 DI 10.1136/bjophthalmol-2014-306224 PG 6 WC Ophthalmology SC Ophthalmology GA CT5BJ UT WOS:000362821400010 PM 25883087 ER PT J AU Huestis, MA AF Huestis, Marilyn A. TI Cannabis-Impaired Driving: A Public Health and Safety Concern SO CLINICAL CHEMISTRY LA English DT Editorial Material ID MARIJUANA; CRASHES C1 [Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, IRP, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov NR 16 TC 2 Z9 2 U1 3 U2 11 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD OCT PY 2015 VL 61 IS 10 BP 1223 EP 1225 DI 10.1373/clinchem.2015.245001 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CT3FM UT WOS:000362692600001 PM 26283691 ER PT J AU Wright, DG Wright, EC Narva, AS Noguchi, CT Eggers, PW AF Wright, Daniel G. Wright, Elizabeth C. Narva, Andrew S. Noguchi, Constance T. Eggers, Paul W. TI Association of Erythropoietin Dose and Route of Administration with Clinical Outcomes for Patients on Hemodialysis in the United States SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; RED-CELL APLASIA; ANEMIA MANAGEMENT; EPOETIN-ALPHA; MAINTENANCE HEMODIALYSIS; INTRAVENOUS EPOETIN; ENDOTHELIAL-CELLS; DIALYSIS PATIENTS AB Background and objectives Recombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated. Design, setting, participants, & measurements A retrospective cohort study of 62,710 adult patients on hemo dialysis treated with either intravenous or subcutaneous epoetin-a and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters. Results Epoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]). Conclusions This study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment. C1 [Wright, Daniel G.; Noguchi, Constance T.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Wright, Elizabeth C.] NIDDK, Biostat Program, NIH, Bethesda, MD 20892 USA. [Narva, Andrew S.; Eggers, Paul W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Wright, DG (reprint author), NIDDK, Mol Med Branch, NIH, Bldg 10,Room 9N312,10 Ctr Dr MSC 1822, Bethesda, MD 20892 USA. EM daniel.wright@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This study was supported by intramural programs of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 47 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD OCT PY 2015 VL 10 IS 10 BP 1822 EP 1830 DI 10.2215/CJN.01590215 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CT2JK UT WOS:000362627600018 PM 26358266 ER PT J AU Kalil, RS Lynch, CF Engels, EA AF Kalil, Roberto S. Lynch, Charles F. Engels, Eric A. TI Risk of cancer in retransplants compared to primary kidney transplants in the United States SO CLINICAL TRANSPLANTATION LA English DT Article DE cancer; immunosuppression; kidney retransplantation ID RENAL-CELL CARCINOMA; ORGAN-TRANSPLANTATION; RECIPIENTS; DISEASE; DIALYSIS; OUTCOMES AB Recipients of kidney transplantation have elevated risk of developing cancer. There are limited data on cancer risk in recipients of kidney retransplantation. We used data from the Transplant Cancer Match Study, which links the U.S. transplant registry with 15 cancer registries. Cancer incidence in recipients of kidney retransplantation and primary kidney transplants was compared utilizing Poisson regression, adjusting for demographic and medical characteristics. We assessed 109224 primary recipients and 6621 retransplants. Compared to primary recipients, retransplants were younger (median age 40 vs. 46yr), had higher PRA, and more often received induction with polyclonal antibodies (43% vs. 25%). A total of 5757 cancers were observed in primary recipients and 245 in retransplants. Overall cancer risk was similar in retransplants compared with primary recipients (incidence rate ratio [IRR] 1.06, 95% CI 0.93-1.20, adjusted for age, gender, race/ethnicity, PRA, and use of polyclonal induction). However, renal cell carcinoma (RCC) occurred in excess among retransplants (adjusted IRR 2.03, 95% CI 1.45-2.77), based on 514 cases in primary recipients and 43 cases in retransplants. Overall cancer risk did not differ in retransplants compared to primary recipients. Increased risk of RCC may be explained by the presence of acquired cystic kidney disease, which is more likely to develop with additional time with kidney disease and time spent on dialysis waiting for retransplantation. C1 [Kalil, Roberto S.] Univ Iowa, Carver Coll Med, Div Nephrol, Iowa City, IA USA. [Kalil, Roberto S.] Iowa City VA Healthcare Syst, Comprehens Access & Delivery Res & Evaluat CADRE, Iowa City, IA USA. [Lynch, Charles F.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kalil, RS (reprint author), Univ Iowa Hosp & Clin, Dept Med, Div Nephrol, T311-GH, Iowa City, IA 52240 USA. EM Roberto-kalil@uiowa.edu FU National Cancer Institute; National Program of Cancer Registry of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Illinois [5658DP000805-04]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Michigan [5U58DP000812-03]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: New York [U58DP003879]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Texas [5U58DP0 00824-04]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261 201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute: Connecticut [H HSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201000037C, N0 1-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN2612010000 32C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN26120130 0021I, 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 [HHSN261201000026C]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative) [14-2491]; state of Texas; state of Washington; Fred Hutchinson Cancer Research Center in Seattle, WA; [HHSH234200537009C] FX The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Tina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa, Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu), New York (Amy Kahn), 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, Ruth Parsons). This study was presented at the World Transplant Congress on July 27, 2014, in San Francisco, CA. The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries, or their contractors. This research was supported in part by the Intramural Research Program of the National Cancer Institute. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). 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 (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832), and Texas (5U58DP0 00824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261 201000035C, and HHSN261201000034C), Connecticut (H HSN261201000024C), Hawaii (HHSN261201000037C, N0 1-PC-35137, and N01-PC-35139), Iowa (HSN2612010000 32C and N01-PC-35143), New Jersey (HHSN26120130 0021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA. NR 16 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-0063 EI 1399-0012 J9 CLIN TRANSPLANT JI Clin. Transplant. PD OCT PY 2015 VL 29 IS 10 BP 944 EP 950 DI 10.1111/ctr.12601 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA CT0RN UT WOS:000362504100011 PM 26255999 ER PT J AU Lantos, JD Wendler, D Septimus, E Wahba, S Madigan, R Bliss, G AF Lantos, John D. Wendler, David Septimus, Edward Wahba, Sarita Madigan, Rosemary Bliss, Geraldine TI Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials SO CLINICAL TRIALS LA English DT Article DE Common Rule; pragmatic clinical trial; minimal risk; patient-centered outcomes research; institutional review board; ethics committees; research; ethics ID ELEVATION MYOCARDIAL-INFARCTION; PEDIATRIC RESEARCH; THROMBUS ASPIRATION; INFORMED-CONSENT; SESSION LENGTH; DIRECT BENEFIT; MORTALITY; BOARD; HEMODIALYSIS; MULTICENTER AB Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes minimal risk, there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients' perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials. C1 [Lantos, John D.] Univ Missouri, Childrens Mercy Hosp, Dept Pediat, Childrens Mercy Bioeth Ctr, Kansas City, MO 64108 USA. [Wendler, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, Houston, TX USA. [Septimus, Edward] Hosp Corp Amer, Clin Serv Grp, Nashville, TN USA. [Wahba, Sarita] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Madigan, Rosemary] Univ Penn Hlth Syst, Perelman Sch Med, Philadelphia, PA USA. [Bliss, Geraldine] Phelan McDermid Syndrome Fdn, Res Support Comm, Venice, FL USA. RP Lantos, JD (reprint author), Univ Missouri, Childrens Mercy Hosp, Dept Pediat, Childrens Mercy Bioeth Ctr, 2401 Gilham Rd, Kansas City, MO 64108 USA. EM jlantos@cmh.edu FU National Institutes of Health (NIH) from the Office of Strategic Coordination within the Office of the NIH Director [U54 AT007748]; Patient-Centered Outcomes Research Institute (PCORI) Award for development of the National Patient-Centered Clinical Research Network (PCORnet) FX This work is supported by the National Institutes of Health (NIH) Common Fund, through a cooperative agreement (U54 AT007748) from the Office of Strategic Coordination within the Office of the NIH Director. Additional support was provided by the Patient-Centered Outcomes Research Institute (PCORI) Award for development of the National Patient-Centered Clinical Research Network (PCORnet). The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee, or other participants in PCORnet. NR 51 TC 7 Z9 7 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2015 VL 12 IS 5 BP 485 EP 493 DI 10.1177/1740774515597687 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS9YM UT WOS:000362450000008 PM 26374686 ER PT J AU Ke, BL Zhao, ZY Ye, X Gao, ZG Manganiello, V Wu, B Ye, JP AF Ke, Bilun Zhao, Zhiyun Ye, Xin Gao, Zhanguo Manganiello, Vincent Wu, Bin Ye, Jianping TI Inactivation of NF-kappa B p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway SO DIABETES LA English DT Article ID IKK-BETA; ADIPOSE-TISSUE; PHOSPHODIESTERASE 3B; ENERGY HOMEOSTASIS; MICE; RESISTANCE; OBESITY; INFLAMMATION; ACTIVATION; ALPHA AB The transcription factor nuclear factor-kappa B (NF-kappa B) mediates inflammation and stress signals in cells. To test NF-kappa B in the control of hepatic insulin sensitivity, we inactivated NF-kappa B in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-kappa B activity. NF-kappa B was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-alpha. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-kappa B inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription. C1 [Ke, Bilun; Wu, Bin] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Gastroenterol, Guangzhou 510275, Guangdong, Peoples R China. [Ke, Bilun; Zhao, Zhiyun; Ye, Xin; Ye, Jianping] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Antioxidant & Gene Regulat Lab, Baton Rouge, LA 70803 USA. [Gao, Zhanguo] Xinxiang Med Univ, Collaborat Innovat Ctr Mol Diag & Lab Med Henan, Sch Lab Med, Xinxiang, Peoples R China. [Manganiello, Vincent] NHLBI, Pulm Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Ye, JP (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Antioxidant & Gene Regulat Lab, Baton Rouge, LA 70803 USA. EM wubin6@mail.sysu.edu.cn; yej@pbrc.edu FU Intramural NIH HHS; NCRR NIH HHS [P20 RR021945, P20-RR-021945]; NIDDK NIH HHS [R01 DK085495, DK068036, DK085495, P30 DK072476, P30-DK-072476, R01 DK068036, R56 DK068036] NR 27 TC 8 Z9 9 U1 2 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2015 VL 64 IS 10 BP 3355 EP 3362 DI 10.2337/db15-0242 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CT2IG UT WOS:000362624600007 PM 26038580 ER PT J AU Price, JD Hotta-Iwamura, C Zhao, YG Beauchamp, NM Tarbell, KV AF Price, Jeffrey D. Hotta-Iwamura, Chie Zhao, Yongge Beauchamp, Nicole M. Tarbell, Kristin V. TI DCIR2(+) cDC2 DCs and Zbtb32 Restore CD4(+) T-Cell Tolerance and Inhibit Diabetes SO DIABETES LA English DT Article ID ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; NOD MICE; IN-VIVO; DYING CELLS; PATHOGENESIS; EXPRESSION; REPRESSOR; PEPTIDE; ISLETS AB During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit tolerance in the steady state may not be effective. To determine which DC subsets induce tolerance in the context of chronic autoimmunity, we used chimeric antibodies specific for DC inhibitory receptor 2 (DCIR2) or DEC-205 to target self-antigen to CD11b(+) (cDC2) DCs and CD8(+) (cDC1) DCs, respectively, in autoimmune-prone nonobese diabetic (NOD) mice. Antigen presentation by DCIR2(+) DCs but not DEC-205(+) DCs elicited tolerogenic CD4(+) T-cell responses in NOD mice. p-Cell antigen delivered to DCIR2(+) DCs delayed diabetes induction and induced increased T-cell apoptosis without interferon-gamma (IFN-gamma) or sustained expansion of autoreactive CD4(+) T cells. These divergent responses were preceded by differential gene expression in T cells early after in vivo stimulation. Zbtb32 was higher in T cells stimulated with DCIR2(+) DCs, and overexpression of Zbtb32 in T cells inhibited diabetes development, T-cell expansion, and IFN-gamma production. Therefore, we have identified DCIR2(+) DCs as capable of inducing antigen-specific tolerance in the face of ongoing autoimmunity and have also identified Zbtb32 as a suppressive transcription factor that controls T cell-mediated autoimmunity. C1 [Price, Jeffrey D.; Hotta-Iwamura, Chie; Zhao, Yongge; Beauchamp, Nicole M.; Tarbell, Kristin V.] NIDDKD, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Tarbell, KV (reprint author), NIDDKD, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM tarbellk@niddk.nih.gov OI Tarbell, Kristin/0000-0003-3738-379X FU Division of Intramural Research, NIDDK; JDRF FX This work was supported by the Division of Intramural Research, NIDDK, and JDRF. NR 50 TC 5 Z9 5 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD OCT PY 2015 VL 64 IS 10 BP 3521 EP 3531 DI 10.2337/db14-1880 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CT2IG UT WOS:000362624600022 PM 26070317 ER PT J AU Akiyama, T Xin, L Oda, M Sharov, AA Amano, M Piao, Y Cadet, JS Dudekula, DB Qian, Y Wang, WD Ko, SBH Ko, MSH AF Akiyama, Tomohiko Xin, Li Oda, Mayumi Sharov, Alexei A. Amano, Misa Piao, Yulan Cadet, J. Scotty Dudekula, Dawood B. Qian, Yong Wang, Weidong Ko, Shigeru B. H. Ko, Minoru S. H. TI Transient bursts of Zscan4 expression are accompanied by the rapid derepression of heterochromatin in mouse embryonic stem cells SO DNA RESEARCH LA English DT Article DE heterochromatin; pericentromere; embryonic stem cells ID PREIMPLANTATION DEVELOPMENT; MAMMALIAN TELOMERES; SATELLITE REPEATS; GENE-EXPRESSION; 2-CELL EMBRYOS; GROUND-STATE; ES CELLS; PLURIPOTENT; TRANSCRIPTION; CULTURE AB Mouse embryonic stem cells (mESCs) have a remarkable capacity to maintain normal genome stability and karyotype in culture. We previously showed that infrequent bursts of Zscan4 expression (Z4 events) are important for the maintenance of telomere length and genome stability in mESCs. However, the molecular details of Z4 events remain unclear. Here we show that Z4 events involve unexpected transcriptional derepression in heterochromatin regions that usually remain silent. During a Z4 event, we see rapid derepression and rerepression of heterochromatin leading to a burst of transcription that coincides with transient histone hyperacetylation and DNA demethylation, clustering of pericentromeric heterochromatin around the nucleolus, and accumulation of activating and repressive chromatin remodelling complexes. This heterochromatin-based transcriptional activity suggests that mESCs may maintain their extraordinary genome stability at least in part by transiently resetting their heterochromatin. C1 [Akiyama, Tomohiko; Oda, Mayumi; Ko, Shigeru B. H.; Ko, Minoru S. H.] Keio Univ, Sch Med, Dept Syst Med, Tokyo 160, Japan. [Akiyama, Tomohiko; Xin, Li; Sharov, Alexei A.; Amano, Misa; Piao, Yulan; Cadet, J. Scotty; Dudekula, Dawood B.; Qian, Yong; Wang, Weidong; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), Keio Univ, Sch Med, Dept Syst Med, Tokyo 160, Japan. EM ko.minoru@keio.jp RI Oda, Mayumi/K-5404-2013; OI Oda, Mayumi/0000-0001-5102-7076; Ko, Minoru/0000-0002-3530-3015; Dudekula, Dawood/0000-0002-4054-1827 FU Keio University Medical Science Fund-The Mitsunada Sakaguchi Laboratory; Takeda Science Foundation; Intramural Research Program of the National Institutes of Health, National Institute on Aging [AG000656, AG000702] FX This work was in part supported by the Keio University Medical Science Fund-The Mitsunada Sakaguchi Laboratory, the Takeda Science Foundation, and the Intramural Research Program of the National Institutes of Health (AG000656, AG000702), National Institute on Aging. Funding to pay the Open Access publication charges for this article was provided by the Keio University Medical Science Fund-The Mitsunada Sakaguchi Laboratory. NR 59 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1340-2838 EI 1756-1663 J9 DNA RES JI DNA Res. PD OCT PY 2015 VL 22 IS 5 BP 307 EP 318 DI 10.1093/dnares/dsv013 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CT5AY UT WOS:000362820100001 PM 26324425 ER PT J AU Newmeyer, MN Concheiro, M da Costa, JL Flegel, R Gorelick, DA Huestis, MA AF Newmeyer, Matthew N. Concheiro, Marta da Costa, Jose Luiz Flegel, Ronald Gorelick, David A. Huestis, Marilyn A. TI Oral fluid with three modes of collection and plasma methamphetamine and amphetamine enantiomer concentrations after controlled intranasal l-methamphetamine administration SO DRUG TESTING AND ANALYSIS LA English DT Article DE oral fluid; plasma; methamphetamine; chiral analysis; Vicks (R) VapoInhaler (TM) ID DEVICES AB Methamphetamine is included in drug testing programmes due to its high abuse potential. d-Methamphetamine is a scheduled potent central nervous system stimulant, while l-methamphetamine is the unscheduled active ingredient in the over-the-counter nasal decongestant Vicks (R) VapoInhaler. No data are available in oral fluid (OF) and few in plasma after controlled Vicks (R) VapoInhaler administration. We quantified methamphetamine and amphetamine enantiomers in OF collected with two different devices and plasma via a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Additionally, OF were analyzed with an on-site screening device. Sixteen participants received 7 Vicks (R) VapoInhaler doses according to manufacturer's recommendations. Specimens were collected before and up to 32 h after the first dose. No d-methamphetamine or d-amphetamine was detected in any sample. All participants had measurable OF l-methamphetamine with median maximum concentrations 14.8 and 16.1 g/L in Quantisal and Oral-Eze (R) devices, respectively, after a median of 5 doses. One participant had measurable OF l-amphetamine with maximum concentrations 3.7 and 5.5 g/L after 6 doses with the Quantisal and Oral-Eze (R) devices, respectively. There were no positive DrugTest (R) 5000 results. In the cutoff range 20-50 g/L methamphetamine with amphetamine limit of detection, 3.1-10.1% of specimens were positive; first positive results were observed after 1-4 doses. Two participants had detectable plasma l-methamphetamine, with maximum observed concentrations 6.3 and 10.0 g/L after 2 and 5 doses, respectively. Positive OF and plasma methamphetamine results are possible after Vicks (R) VapoInhaler administration. Chiral confirmatory analyses are necessary to rule out VapoInhaler intake. Implementing a selective d-methamphetamine screening assay can help eliminate false-positive OF results. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Newmeyer, Matthew N.; Concheiro, Marta; da Costa, Jose Luiz; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD 21224 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Flegel, Ronald] Substance Abuse Mental Hlth Serv Adm, Dept Hlth & Human Serv, Div Workplace Programs, Rockville, MD USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Costa, Jose/C-1741-2012; OI Costa, Jose/0000-0001-9954-0899; Newmeyer, Matthew/0000-0002-0653-1553 FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health; Substance Abuse and Mental Health Services Administration; Brazilian National Counsel of Technological and Scientific Development FX We acknowledge the clinical staffs of the NIDA IRP, Johns Hopkins Behavioral Pharmacology Research Unit and Clinical Research Unit, Johns Hopkins Bayview Medical Center; and the Graduate Partnership Program, National Institutes of Health. Funding for this research was provided by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health and the Substance Abuse and Mental Health Services Administration. Dr. Jose Luiz da Costa received a postdoctoral fellowship from Brazilian National Counsel of Technological and Scientific Development to conduct this research. The authors also thank Megan Taylor, NIDA IRP, for her valuable assistance. NR 13 TC 0 Z9 0 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD OCT PY 2015 VL 7 IS 10 BP 877 EP 883 DI 10.1002/dta.1784 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA CT3FE UT WOS:000362691800003 PM 25786659 ER PT J AU Zhang, HB Guan, MP Townsend, KL Huang, TL An, D Yan, X Xue, RD Schulz, TJ Winnay, J Mori, M Hirshman, MF Kristiansen, K Tsang, JS White, AP Cypess, AM Goodyear, LJ Tseng, YH AF Zhang, Hongbin Guan, Meiping Townsend, Kristy L. Huang, Tian Lian An, Ding Yan, Xu Xue, Ruidan Schulz, Tim J. Winnay, Jonathon Mori, Marcelo Hirshman, Michael F. Kristiansen, Karsten Tsang, John S. White, Andrew P. Cypess, Aaron M. Goodyear, Laurie J. Tseng, Yu-Hua TI MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1 signaling network SO EMBO REPORTS LA English DT Article DE brown adipogenesis; differentiation; metabolism; microRNA; UCP1 ID ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; ADIPOSE-TISSUE; SKELETAL-MUSCLE; GENE-EXPRESSION; C/EBP-BETA; WHITE FAT; MITOCHONDRIAL BIOGENESIS; ADIPOCYTE PROGENITORS; ENERGY-EXPENDITURE AB Brown adipose tissue (BAT) dissipates chemical energy as heat and can counteract obesity. MicroRNAs are emerging as key regulators in development and disease. Combining microRNA and mRNA microarray profiling followed by bioinformatic analyses, we identified miR-455 as a new regulator of brown adipogenesis. miR-455 exhibits a BAT-specific expression pattern and is induced by cold and the browning inducer BMP7. In vitro gain- and loss-of-function studies show that miR-455 regulates brown adipocyte differentiation and thermogenesis. Adipose-specific miR-455 transgenic mice display marked browning of subcutaneous white fat upon cold exposure. miR-455 activates AMPK1 by targeting HIF1an, and AMPK promotes the brown adipogenic program and mitochondrial biogenesis. Concomitantly, miR-455 also targets the adipogenic suppressors Runx1t1 and Necdin, initiating adipogenic differentiation. Taken together, the data reveal a novel microRNA-regulated signaling network that controls brown adipogenesis and may be a potential therapeutic target for human metabolic disorders. C1 [Zhang, Hongbin; Guan, Meiping; Townsend, Kristy L.; Huang, Tian Lian; An, Ding; Yan, Xu; Xue, Ruidan; Schulz, Tim J.; Winnay, Jonathon; Mori, Marcelo; Hirshman, Michael F.; Cypess, Aaron M.; Goodyear, Laurie J.; Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Zhang, Hongbin] Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark. [Guan, Meiping] Southern Med Univ, Nanfang Hosp, Dept Endocrinol & Metab, Guangzhou, Guangdong, Peoples R China. [Schulz, Tim J.] German Inst Human Nutr, Adipocyte Dev Res Grp, Potsdam, Germany. [Mori, Marcelo] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo, Brazil. [Kristiansen, Karsten] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, Bethesda, MD 20892 USA. [Tsang, John S.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [White, Andrew P.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Orthopaed Surg, Boston, MA 02115 USA. [Tseng, Yu-Hua] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Zhang, HB (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. EM hongbin@sund.ku.dk; yu-hua.tseng@joslin.harvard.edu RI Kristiansen, Karsten/J-5148-2014; Schulz, Tim/F-4842-2013 OI Kristiansen, Karsten/0000-0002-6024-0917; Schulz, Tim/0000-0002-8413-3972 FU NIH [R01 DK077097, R01AR042238, T32 DK007260-33, NIH F32 DK091996]; Joslin Diabetes Center's Diabetes Research Center (DRC from the NIDDK) [P30 DK036836]; American Diabetes Association [ADA 7-12-BS-191]; Novo Nordisk Foundation; Lundbeck Foundation; Augustinus Foundation; American Diabetes Association Mentor-Based Award [7-12-MN]; Intramural Program of the NIAID/NIH FX We thank Dr. Yong-Xu Wang for providing the brown preadipocyte cell line, Exiqon A/S for providing microRNA mimics, and Dr. Marc Uldry and Dr. Bruce Spiegelman for providing the PGC1 alpha KO brown preadipocyte cell line. We thank Elizabeth Caniano for administrative assistance to the manuscript. We also thank Dr. Nils Billestrup and Dr. Jens Hoiriis Nielsen for help with experimental materials. This work was supported in part by NIH grants R01 DK077097 (Y.-H.T.), and Joslin Diabetes Center's Diabetes Research Center (DRC; P30 DK036836 from the NIDDK), a research grant from the American Diabetes Association (ADA 7-12-BS-191 to Y.-H.T.), research grants from the Novo Nordisk Foundation, Lundbeck Foundation and Augustinus Foundation (to H.Z.), NIH grant R01AR042238, and American Diabetes Association Mentor-Based Award 7-12-MN (to L.J.G.) and partially supported by the Intramural Program of the NIAID/NIH (to J.S.T.). K.L.T was funded by NIH T32 DK007260-33 and NIH F32 DK091996. NR 59 TC 12 Z9 13 U1 5 U2 17 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 OCT PY 2015 VL 16 IS 10 BP 1378 EP 1393 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CT1KV UT WOS:000362558100016 PM 26303948 ER PT J AU Wang, Y Zhao, N Qiu, J He, X Zhou, M Cui, H Lv, L Lin, X Zhang, C Zhang, H Xu, R Zhu, D Dang, Y Han, X Zhang, H Bai, H Chen, Y Tang, Z Lin, R Yao, T Su, J Xu, X Liu, X Wang, W Ma, B Liu, S Qiu, W Huang, H Liang, J Wang, S Ehrenkranz, RA Kim, C Liu, Q Zhang, Y AF Wang, Y. Zhao, N. Qiu, J. He, X. Zhou, M. Cui, H. Lv, L. Lin, X. Zhang, C. Zhang, H. Xu, R. Zhu, D. Dang, Y. Han, X. Zhang, H. Bai, H. Chen, Y. Tang, Z. Lin, R. Yao, T. Su, J. Xu, X. Liu, X. Wang, W. Ma, B. Liu, S. Qiu, W. Huang, H. Liang, J. Wang, S. Ehrenkranz, R. A. Kim, C. Liu, Q. Zhang, Y. TI Folic acid supplementation and dietary folate intake, and risk of preeclampsia SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PERICONCEPTIONAL MULTIVITAMIN USE; PLASMA HOMOCYSTEINE LEVELS; HOMOCYST(E)INE CONCENTRATIONS; GESTATIONAL HYPERTENSION; PREGNANCY OUTCOMES; WOMEN; FORTIFICATION; MORTALITY; ECLAMPSIA; DISEASE AB BACKGROUND/OBJECTIVES: Folic acid supplementation has been suggested to reduce the risk of preeclampsia. However, results from few epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of preeclampsia. SUBJECTS/ METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. A total of 10 041 pregnant women without chronic hypertension or gestational hypertension were enrolled. RESULTS: Compared with nonusers, folic acid supplement users had a reduced risk of preeclampsia (OR = 0.61, 95% CI: 0.43-0.87). A significant dose-response of duration of use was observed among women who used folic acid supplemention during pregnancy only (P-trend = 0.007). The reduced risk associated with folic acid supplement was similar for mild or severe preeclampsia and for early-or late-onset preeclampsia, although the statistical significant associations were only observed for mild (OR = 0.50, 95% CI: 0.30-0.81) and late-onset (OR = 0.60, 95% CI: 0.42-0.86) preeclampsia. The reduced risk associated with dietary folate intake during pregnancy was only seen for severe preeclampsia (OR = 0.52, 95% CI: 0.31-0.87, for the highest quartile of dietary folate intake compared with the lowest). CONCLUSIONS: Our study results suggest that folic acid supplementation and higher dietary folate intake during pregnancy reduce the risk of preeclampsia. Future studies are needed to confirm the associations. C1 [Wang, Y.; Qiu, J.; He, X.; Zhou, M.; Cui, H.; Lv, L.; Lin, X.; Zhang, C.; Zhang, H.; Xu, R.; Zhu, D.; Dang, Y.; Han, X.; Zhang, H.; Bai, H.; Chen, Y.; Tang, Z.; Lin, R.; Yao, T.; Su, J.; Xu, X.; Liu, X.; Wang, W.; Ma, B.; Liu, S.; Qiu, W.; Liu, Q.] Gansu Prov Matern & Child Care Hosp, Lanzhou 730050, Gansu, Peoples R China. [Zhao, N.; Huang, H.; Liang, J.; Zhang, Y.] Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA. [Wang, S.] Shanxi Med Univ, Sch Publ Hlth, Dept Epidemiol, Taiyuan, Shanxi, Peoples R China. [Ehrenkranz, R. A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Kim, C.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Sci, Bethesda, MD 20892 USA. RP Liu, Q (reprint author), Gansu Prov Matern & Child Care Hosp, 143 North Rd Qilihe Dist, Lanzhou 730050, Gansu, Peoples R China. EM 2305470816@qq.com; yawei.zhang@yale.edu FU Gansu Provincial Maternity and Child Care Hospital; National Institutes of Health [K02HD70324] FX We thank all the study personnel from the Gansu Provincial Maternity and Child Care Hospital for their exceptional efforts on study subject recruitment. This work was supported by internal funding from the Gansu Provincial Maternity and Child Care Hospital, and the National Institutes of Health grants (K02HD70324). NR 35 TC 5 Z9 5 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD OCT PY 2015 VL 69 IS 10 BP 1145 EP 1150 DI 10.1038/ejcn.2014.295 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CT0RM UT WOS:000362504000012 PM 25626412 ER PT J AU Blobel, GA Bodine, D Brand, M Crispino, J de Bruijn, MFTR Nathan, D Papayannopoulou, T Porcher, C Strouboulis, J Zon, L Higgs, DR Stamatoyannopoulos, G Engel, JD AF Blobel, Gerd A. Bodine, David Brand, Marjorie Crispino, John de Bruijn, Marella F. T. R. Nathan, David Papayannopoulou, Thalia Porcher, Catherine Strouboulis, John Zon, Len Higgs, Douglas R. Stamatoyannopoulos, George Engel, James Douglas TI An international effort to cure a global health problem: A report on the 19th Hemoglobin Switching Conference SO EXPERIMENTAL HEMATOLOGY LA English DT Review ID CAUSES HEREDITARY PERSISTENCE; FETAL-HEMOGLOBIN; GENE-EXPRESSION; BETA-THALASSEMIA; ERYTHROID-CELLS; GAMMA-GLOBIN; TRANSCRIPTION FACTORS; CHROMATIN OCCUPANCY; BCL11A; ERYTHROPOIESIS AB Every 2 years since 1978, an international group of scientists, physicians, and other researchers meet to discuss the latest developments in the underlying etiology, mechanisms of action, and developmental acquisition of cellular and systemic defects exhibited and elicited by the most common inherited human disorders, the hemoglobinopathies. The 19th Hemoglobin Switching Conference, held in September 2014 at St. John's College in Oxford, once again exceeded all expectations by describing cutting edge research in cellular, molecular, developmental, and genomic advances focused on these diseases. The conference comprised about 60 short talks over 3 days by leading investigators in the field. This meeting report describes the highlights of the conference. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. C1 [Blobel, Gerd A.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Div Hematol, Philadelphia, PA 19104 USA. [Bodine, David] NHGRI, NIH, Bethesda, MD 20892 USA. [Brand, Marjorie] Ottawa Hosp Res Inst, Sprott Ctr Stem Cell Res, Ottawa, ON, Canada. [Crispino, John] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA. [de Bruijn, Marella F. T. R.; Porcher, Catherine; Higgs, Douglas R.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DU, England. [de Bruijn, Marella F. T. R.; Porcher, Catherine; Higgs, Douglas R.] Oxford Univ Hosp, NIHR Oxford Biomed Ctr, BRC Blood Theme, Oxford, England. [Nathan, David] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Pediat,Dept Pediat Onc, Div Hematol & Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Nathan, David] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol,Dept Med, Div Hematol & Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Papayannopoulou, Thalia; Stamatoyannopoulos, George] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Strouboulis, John] Biomed Sci Res Ctr Alexander Fleming, Div Mol Oncol, Vari, Greece. [Zon, Len] Boston Childrens Hosp, HHMI, Boston, MA USA. [Engel, James Douglas] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI USA. RP Engel, JD (reprint author), Univ Michigan, Sch Med, Dept Cell & Dev Biol, Biomed Sci Res 3035, 109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM engel@umich.edu RI Porcher, Catherine/D-7026-2016; OI Crispino, John/0000-0002-8182-8306 FU Medical Research Council [MC_U137961144, G1000801, MC_U137961145, MC_UU_12009/2, MC_UU_12009/9]; NHLBI NIH HHS [U01 HL117658] NR 74 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD OCT PY 2015 VL 43 IS 10 BP 821 EP 837 DI 10.1016/j.exphem.2015.06.008 PG 17 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA CT3GF UT WOS:000362694500001 PM 26143582 ER PT J AU Rodriguez-Pena, AB Gomez-Rodriguez, J Kortum, RL Palmer, DC Yu, Z Guittard, GC Wohlfert, EA Silver, PB Misplon, JA Sommers, CL Feigenbaum, L Epstein, SL Caspi, RR Belkaid, Y Restifo, NP Samelson, LE Balagopalan, L AF Rodriguez-Pena, A. B. Gomez-Rodriguez, J. Kortum, R. L. Palmer, D. C. Yu, Z. Guittard, G. C. Wohlfert, E. A. Silver, P. B. Misplon, J. A. Sommers, C. L. Feigenbaum, L. Epstein, S. L. Caspi, R. R. Belkaid, Y. Restifo, N. P. Samelson, L. E. Balagopalan, L. TI Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules SO GENE THERAPY LA English DT Article ID SUPERIOR ANTITUMOR IMMUNITY; ADOPTIVE IMMUNOTHERAPY; NAIVE RATHER; EFFECTOR; RECEPTOR; UBIQUITYLATION; AUTOIMMUNITY; INFECTION; PROTEIN; KINASE AB Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wildtype (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T-cell differentiation. C1 [Rodriguez-Pena, A. B.; Kortum, R. L.; Guittard, G. C.; Sommers, C. L.; Samelson, L. E.; Balagopalan, L.] NIH, Cellular & Mol Biol Lab, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. [Rodriguez-Pena, A. B.] Ctr Invest Cacn, Salamanca, Spain. [Rodriguez-Pena, A. B.] Univ Salamanca, Inst Biol Mol & Celular Canc, Consejo Super Invest Cientif, E-37008 Salamanca, Spain. [Gomez-Rodriguez, J.] NIH, Cell Signaling & Immun Sect, NHGRI, Bethesda, MD 20892 USA. [Kortum, R. L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Palmer, D. C.; Yu, Z.; Restifo, N. P.] NIH, Tumor Immunol Sect, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. [Wohlfert, E. A.; Belkaid, Y.] NIAID, Immun Barrier Sites Initiat, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Wohlfert, E. A.; Belkaid, Y.] NIAID, Parasit Dis Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. [Wohlfert, E. A.] SUNY Buffalo, Dept Microbiol & Immunol, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Silver, P. B.; Caspi, R. R.] NIH, Immunoregulat Sect, NEI, Bethesda, MD 20892 USA. [Misplon, J. A.; Epstein, S. L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Feigenbaum, L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. RP Balagopalan, L (reprint author), NIH, Cellular & Mol Biol Lab, Ctr Canc Res, NCI, Bldg 37,Rm 2064, Bethesda, MD 20892 USA. EM balagopl@mail.nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580; Caspi, Rachel/0000-0002-7140-7671; Guittard, Geoffrey/0000-0002-6061-8553 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain FX We thank Paul Love for providing the dLck expression vector, Wenmei Li and Terri Stull for technical support, F Zhao, Jennifer Cannons and Kristina Lu for helpful advice in cytotoxicity and immunization experiments, The EL4 mouse thymoma (H-2Kb) cell line was a kind gift from Carol Clayberger. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Ana B Rodriguez-Pena was additionally supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain. NR 47 TC 3 Z9 3 U1 0 U2 3 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 OCT PY 2015 VL 22 IS 10 BP 781 EP 792 DI 10.1038/gt.2015.48 PG 12 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 CT1BT UT WOS:000362532800002 PM 26018935 ER PT J AU Menze, BH Jakab, A Bauer, S Kalpathy-Cramer, J Farahani, K Kirby, J Burren, Y Porz, N Slotboom, J Wiest, R Lanczi, L Gerstner, E Weber, MA Arbel, T Avants, BB Ayache, N Buendia, P Collins, DL Cordier, N Corso, JJ Criminisi, A Das, T Delingette, H Demiralp, C Durst, CR Dojat, M Doyle, S Festa, J Forbes, F Geremia, E Glocker, B Golland, P Guo, XT Hamamci, A Iftekharuddin, KM Jena, R John, NM Konukoglu, E Lashkari, D Mariz, JA Meier, R Pereira, S Precup, D Price, SJ Raviv, TR Reza, SMS Ryan, M Sarikaya, D Schwartz, L Shin, HC Shotton, J Silva, CA Sousa, N Subbanna, NK Szekely, G Taylor, TJ Thomas, OM Tustison, NJ Unal, G Vasseur, F Wintermark, M Ye, DH Zhao, L Zhao, BS Zikic, D Prastawa, M Reyes, M Van Leemput, K AF Menze, Bjoern H. Jakab, Andras Bauer, Stefan Kalpathy-Cramer, Jayashree Farahani, Keyvan Kirby, Justin Burren, Yuliya Porz, Nicole Slotboom, Johannes Wiest, Roland Lanczi, Levente Gerstner, Elizabeth Weber, Marc-Andre Arbel, Tal Avants, Brian B. Ayache, Nicholas Buendia, Patricia Collins, D. Louis Cordier, Nicolas Corso, Jason J. Criminisi, Antonio Das, Tilak Delingette, Herve Demiralp, Cagatay Durst, Christopher R. Dojat, Michel Doyle, Senan Festa, Joana Forbes, Florence Geremia, Ezequiel Glocker, Ben Golland, Polina Guo, Xiaotao Hamamci, Andac Iftekharuddin, Khan M. Jena, Raj John, Nigel M. Konukoglu, Ender Lashkari, Danial Mariz, Jose Antonio Meier, Raphael Pereira, Sergio Precup, Doina Price, Stephen J. Raviv, Tammy Riklin Reza, Syed M. S. Ryan, Michael Sarikaya, Duygu Schwartz, Lawrence Shin, Hoo-Chang Shotton, Jamie Silva, Carlos A. Sousa, Nuno Subbanna, Nagesh K. Szekely, Gabor Taylor, Thomas J. Thomas, Owen M. Tustison, Nicholas J. Unal, Gozde Vasseur, Flor Wintermark, Max Ye, Dong Hye Zhao, Liang Zhao, Binsheng Zikic, Darko Prastawa, Marcel Reyes, Mauricio Van Leemput, Koen TI The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE MRI; Brain; Oncology/tumor; Image segmentation; Benchmark ID MULTIPLE-SCLEROSIS LESIONS; MAGNETIC-RESONANCE IMAGES; CONDITIONAL RANDOM-FIELDS; ATLAS-BASED SEGMENTATION; GRAPH CUTS; MR-IMAGES; DEFORMABLE REGISTRATION; AUTOMATIC SEGMENTATION; UNIFIED SEGMENTATION; ENERGY MINIMIZATION AB In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low-and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource. C1 [Menze, Bjoern H.] Tech Univ Munich, Inst Adv Study, D-80290 Munich, Germany. [Menze, Bjoern H.] Tech Univ Munich, Dept Comp Sci, D-80290 Munich, Germany. [Menze, Bjoern H.; Jakab, Andras; Szekely, Gabor] ETH, Comp Vis Lab, Zurich, Switzerland. [Menze, Bjoern H.] Inria, Asclepios Project, Sophia Antipolis, France. [Menze, Bjoern H.; Golland, Polina; Lashkari, Danial] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Jakab, Andras; Lanczi, Levente] Univ Debrecen, Debrecen, Hungary. [Bauer, Stefan] Univ Bern, Inst Surg Technol & Biomech, CH-3012 Bern, Switzerland. [Bauer, Stefan; Burren, Yuliya; Porz, Nicole; Slotboom, Johannes; Wiest, Roland] Univ Hosp Bern, Inselspital, SCAN, Inst Diagnost & Intervent Neuroradiol, Bern, Switzerland. [Kalpathy-Cramer, Jayashree] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Farahani, Keyvan; Kirby, Justin] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. [Gerstner, Elizabeth] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurooncol, Boston, MA USA. [Glocker, Ben] Univ London Imperial Coll Sci Technol & Med, BioMedIA Grp, London, England. [Arbel, Tal; Subbanna, Nagesh K.] McGill Univ, Ctr Intelligent Machines, Montreal, PQ H3A 2T5, Canada. [Avants, Brian B.] Univ Penn, Dept Radiol, Penn Image Comp & Sci Lab, Philadelphia, PA 19104 USA. [Ayache, Nicholas; Cordier, Nicolas; Delingette, Herve; Geremia, Ezequiel] INRIA, Asclepios Project, Sophia Antipolis, France. [Buendia, Patricia; John, Nigel M.; Ryan, Michael; Taylor, Thomas J.] INFOTECH Soft Inc, Miami, FL USA. [Collins, D. Louis] McGill Univ, McConnell Brain Imaging Ctr, Montreal, PQ H3A 2T5, Canada. [Corso, Jason J.; Sarikaya, Duygu; Zhao, Liang] SUNY Buffalo, Comp Sci & Engn, Buffalo, NY 14260 USA. [Criminisi, Antonio; Shotton, Jamie; Zikic, Darko] Microsoft Res, Cambridge, England. [Das, Tilak; Jena, Raj; Price, Stephen J.; Thomas, Owen M.] Cambridge Univ Hosp, Cambridge, England. [Demiralp, Cagatay] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Dojat, Michel; Doyle, Senan; Forbes, Florence; Vasseur, Flor] INRIA Rhone Alpes, Grenoble, France. [Dojat, Michel; Doyle, Senan; Forbes, Florence; Vasseur, Flor] INSERM, U836, Grenoble, France. [Durst, Christopher R.; Tustison, Nicholas J.; Wintermark, Max] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA USA. [Festa, Joana; Pereira, Sergio; Silva, Carlos A.] Univ Minho, Dept Elect, P-4719 Braga, Portugal. [Guo, Xiaotao; Schwartz, Lawrence; Zhao, Binsheng] Columbia Univ, Dept Radiol, New York, NY USA. [Hamamci, Andac; Unal, Gozde] Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey. [Iftekharuddin, Khan M.; Reza, Syed M. S.] Old Dominion Univ, Dept Elect & Comp Engn, Vis Lab, Norfolk, VA USA. [John, Nigel M.] Univ Miami, Dept Elect & Comp Engn, Coral Gables, FL 33124 USA. [Konukoglu, Ender] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Konukoglu, Ender] Harvard Univ, Sch Med, Boston, MA USA. [Mariz, Jose Antonio; Sousa, Nuno] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal. [Mariz, Jose Antonio; Sousa, Nuno] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Meier, Raphael; Reyes, Mauricio] Univ Bern, Inst Surg Technol & Biomech, CH-3014 Bern, Switzerland. [Precup, Doina] McGill Univ, Sch Comp Sci, Montreal, PQ H3A 2T5, Canada. [Precup, Doina] Ben Gurion Univ Negev, Dept Elect & Comp Engn, IL-84105 Beer Sheva, Israel. [Weber, Marc-Andre] Univ Hosp, Diagnost & Intervent Radiol, Heidelberg, Germany. [Ye, Dong Hye] Purdue Univ, Dept Elect & Comp Engn, W Lafayette, IN 47907 USA. [Prastawa, Marcel] GE Global Res, Niskayuna, NY USA. [Van Leemput, Koen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Van Leemput, Koen] Tech Univ Denmark, Lyngby, Denmark. [Van Leemput, Koen] Aalto Univ, Espoo, Finland. RP Menze, BH (reprint author), Tech Univ Munich, Inst Adv Study, D-80290 Munich, Germany. RI Van Leemput, Koen/A-9197-2009; Dojat, Michel/G-7758-2011; Unal, Gozde/A-2360-2013; Weber, Marc-Andre/C-4452-2016; Silva, Carlos/J-1190-2014; Price, Stephen/B-1068-2011; Riklin Raviv, Tammy/A-3462-2013; OI Durst, Christopher/0000-0003-4236-7524; Glocker, Ben/0000-0002-4897-9356; Van Leemput, Koen/0000-0001-6466-5309; Dojat, Michel/0000-0003-2747-6845; Unal, Gozde/0000-0001-5942-8966; Silva, Carlos/0000-0002-1015-5095; Price, Stephen/0000-0002-7535-3009; Cordier, Nicolas/0000-0002-8794-8747; Das, Tilak/0000-0003-0655-412X FU NIH NCRR [P41-RR14075]; NIH NIBIB [R01EB013565]; Academy of Finland [133611]; TEKES (ComBrain); Lundbeck Foundation [R141-2013-13117]; Swiss Cancer League; Swiss Institute for Computer Assisted Surgery (SICAS); NIH NIBIB NAMIC [U54-EB005149]; NIH NCRR NAC [P41-RR13218]; NIH NIBIB NAC [P41-EB-015902]; NIH NCI [R15CA115464]; European Research Council through ERC [MedYMA 2011-291080]; FCT; COMPETE [FCOM-01-0124-FEDER-022674]; MICAT Project (EU) [PIRG-GA-2008-231052]; European Union [600841]; Swiss NSF project Computer Aided and Image Guided Medical Interventions (NCCR CO-ME); Technische Universitat Munchen-Institute for Advanced Study - German Excellence Initiative; Technische Universitat Munchen-Institute for Advanced Study - European Union [291763]; Marie Curie COFUND program of the European Union FX This research was supported by the NIH NCRR (P41-RR14075), the NIH NIBIB (R01EB013565), the Academy of Finland (133611), TEKES (ComBrain), the Lundbeck Foundation (R141-2013-13117), the Swiss Cancer League, the Swiss Institute for Computer Assisted Surgery (SICAS), the NIH NIBIB NAMIC (U54-EB005149), the NIH NCRR NAC (P41-RR13218), the NIH NIBIB NAC (P41-EB-015902), the NIH NCI (R15CA115464), the European Research Council through the ERC Advanced Grant MedYMA 2011-291080 (on Biophysical Modeling and Analysis of Dynamic Medical Images), the FCT and COMPETE (FCOM-01-0124-FEDER-022674), the MICAT Project (EU FP7 Marie Curie Grant No. PIRG-GA-2008-231052), the European Union Seventh Framework Programme under grant agreement no. 600841, the Swiss NSF project Computer Aided and Image Guided Medical Interventions (NCCR CO-ME), the Technische Universitat Munchen-Institute for Advanced Study (funded by the German Excellence Initiative and the European Union Seventh Framework Programme under Grant agreement 291763), the Marie Curie COFUND program of the European Union (Rudolf Mossbauer Tenure-Track Professorship to BHM). NR 132 TC 62 Z9 62 U1 11 U2 42 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD OCT PY 2015 VL 34 IS 10 BP 1993 EP 2024 DI 10.1109/TMI.2014.2377694 PG 32 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA CS8SF UT WOS:000362358000001 PM 25494501 ER PT J AU Candemir, S Borovikov, E Santosh, KC Antani, S Thoma, G AF Candemir, Sema Borovikov, Eugene Santosh, K. C. Antani, Sameer Thoma, George TI RSILC: Rotation- and Scale-Invariant, Line-based Color-aware descriptor SO IMAGE AND VISION COMPUTING LA English DT Article DE Image descriptor; Local features; Spatial features; Rotation invariance; Scale invariance; Color aware ID FACE-RECOGNITION; IMAGE CLASSIFICATION; ROBUST FEATURES; KEYPOINTS; SURF AB Modern appearance-based object recognition systems typically involve feature/descriptor extraction and matching stages. The extracted descriptors are expected to be robust to illumination changes and to reasonable (rigid or affine) image/object transformations. Some descriptors work well for general object matching, but gray-scale key-point-based methods may be suboptimal for matching line-rich color scenes/objects such as cars, buildings, and faces. We present a Rotation- and Scale-Invariant, Line-based Color-aware descriptor (RSILC), which allows matching of objects/scenes in terms of their key-lines, line-region properties, and line spatial arrangements. An important special application is face matching, since face characteristics are best captured by lines/curves. We tested RSILC performance on publicly available datasets and compared it with other descriptors. Our experiments show that RSILC is more accurate in line-rich object description than other well-known generic object descriptors. (C) 2015 Elsevier B.V. All rights reserved. C1 [Candemir, Sema; Borovikov, Eugene; Santosh, K. C.; Antani, Sameer; Thoma, George] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. RP Candemir, S (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. EM sema.candemir@nih.gov; eugene.borovikov@nih.gov; santosh.kc@nih.gov; sameer.antani@nih.gov; george.thoma@nih.gov OI Santosh, K.C./0000-0003-4176-0236 FU National Institutes of Health, National Library of Medicine and Lister Hill National Center for Biomedical Communications FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine and Lister Hill National Center for Biomedical Communications. We would like to acknowledge the editorial assistance of the NIH Fellows Editorial board. NR 55 TC 1 Z9 1 U1 9 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0262-8856 EI 1872-8138 J9 IMAGE VISION COMPUT JI Image Vis. Comput. PD OCT PY 2015 VL 42 BP 1 EP 12 DI 10.1016/j.imavis.2015.06.010 PG 12 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering; Computer Science, Theory & Methods; Engineering, Electrical & Electronic; Optics SC Computer Science; Engineering; Optics GA CT2BV UT WOS:000362607900001 ER PT J AU Herrera, R Anderson, C Kumar, K Molina-Cruz, A Nguyen, V Burkhardt, M Reiter, K Shimp, R Howard, RF Srinivasan, P Nold, MJ Ragheb, D Shi, LR DeCotiis, M Aebig, J Lambert, L Rausch, KM Muratova, O Jin, A Reed, SG Sinnis, P Barillas-Mury, C Duffy, PE MacDonald, NJ Narum, DL AF Herrera, Raul Anderson, Charles Kumar, Krishan Molina-Cruz, Alvaro Vu Nguyen Burkhardt, Martin Reiter, Karine Shimp, Richard, Jr. Howard, Randall F. Srinivasan, Prakash Nold, Michael J. Ragheb, Daniel Shi, Lirong DeCotiis, Mark Aebig, Joan Lambert, Lynn Rausch, Kelly M. Muratova, Olga Jin, Albert Reed, Steven G. Sinnis, Photini Barillas-Mury, Carolina Duffy, Patrick E. MacDonald, Nicholas J. Narum, David L. TI Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains SO INFECTION AND IMMUNITY LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; RTS,S/AS01 MALARIA VACCINE; CELL INVASION; PHASE-3 TRIAL; FULL-LENGTH; SPOROZOITES; PARASITES; SURFACE; VIVAX; LOCALIZATION AB The extended rod-like Plasmodium falciparum circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS, S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine. Using a panel of CSP-specific monoclonal antibodies, well-characterized recombinant CSPs, label-free quantitative proteomics, and in vitro inhibition of sporozoite invasion, we show that native CSP is N-terminally processed in the mosquito host and undergoes a reversible conformational change to mask some epitopes in the N- and C-terminal domains until the sporozoite interacts with the liver hepatocyte. Our findings show the importance of understanding processing and the biophysical change in conformation, possibly due to a mechanical or molecular signal, and may aid in the development of a new CSP vaccine. C1 [Herrera, Raul; Anderson, Charles; Kumar, Krishan; Vu Nguyen; Burkhardt, Martin; Reiter, Karine; Shimp, Richard, Jr.; DeCotiis, Mark; Aebig, Joan; Lambert, Lynn; Rausch, Kelly M.; Muratova, Olga; Duffy, Patrick E.; MacDonald, Nicholas J.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Molina-Cruz, Alvaro; Srinivasan, Prakash; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Howard, Randall F.; Reed, Steven G.] Infect Dis Res Inst, Seattle, WA USA. [Nold, Michael J.] Waters Corp, Milford, MA USA. [Ragheb, Daniel; Shi, Lirong; Sinnis, Photini] Johns Hopkins Univ, Johns Hopkins Malaria Res Inst, Baltimore, MD USA. [Ragheb, Daniel; Shi, Lirong; DeCotiis, Mark; Sinnis, Photini] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Jin, Albert] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Narum, DL (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. EM dnarum@niaid.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU Intramural Research Program of the NIH, NIAID; Intramural Research Program of NIH, NIBIB; Bill and Melinda Gates Foundation [42387] FX This research was supported by the Intramural Research Program of the NIH, including NIAID and NIBIB, and was also supported in part with funding from the Bill and Melinda Gates Foundation under grant number 42387 to S. G. Reed. NR 38 TC 6 Z9 6 U1 0 U2 11 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 OCT PY 2015 VL 83 IS 10 BP 3771 EP 3780 DI 10.1128/IAI.02676-14 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NJ UT WOS:000362492600002 PM 26169272 ER PT J AU Bhattacharya, P Dey, R Dagur, PK Kruhlak, M Ismail, N Debrabant, A Joshi, AB Akue, A Kukuruga, M Takeda, K Selvapandiyan, A McCoy, JP Nakhasi, HL AF Bhattacharya, Parna Dey, Ranadhir Dagur, Pradeep K. Kruhlak, Michael Ismail, Nevien Debrabant, Alain Joshi, Amritanshu B. Akue, Adovi Kukuruga, Mark Takeda, Kazuyo Selvapandiyan, Angamuthu McCoy, John Philip, Jr. Nakhasi, Hira L. TI Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL VISCERAL LEISHMANIASIS; CENTRIN DELETED PARASITES; ARGINASE-I INDUCTION; ANTIGEN PRESENTATION; DENDRITIC CELLS; NITRIC-OXIDE; INFECTED MACROPHAGES; PROTECTIVE IMMUNITY; MEMBRANE-FLUIDITY; TH1/TH2 PARADIGM AB Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modified Leishmania donovani parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice both in vitro and in vivo. In vitro infection of macrophages with live attenuated parasites (compared to that with wild-type [WT] L. donovani parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin-12 [IL-12], gamma interferon [IFN-gamma], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1 alpha/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4(+) T cell activation in vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1 beta, TNF-alpha, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT L. donovani-infected mice. Furthermore, an ex vivo antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-alpha and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4(+) T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB/c mice. C1 [Bhattacharya, Parna; Dey, Ranadhir; Ismail, Nevien; Debrabant, Alain; Joshi, Amritanshu B.; Nakhasi, Hira L.] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Dagur, Pradeep K.; McCoy, John Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Kruhlak, Michael] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Akue, Adovi; Kukuruga, Mark; Takeda, Kazuyo] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Selvapandiyan, Angamuthu] Inst Mol Med, New Delhi, India. RP Nakhasi, HL (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Hira.Nakhasi@fda.hhs.gov FU Critical Path Initiative of the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration FX Funding for these studies was provided by intramural funds and the Critical Path Initiative of the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration. NR 67 TC 6 Z9 7 U1 2 U2 9 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 OCT PY 2015 VL 83 IS 10 BP 3800 EP 3815 DI 10.1128/IAI.00184-15 PG 16 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NJ UT WOS:000362492600005 PM 26169275 ER PT J AU Moitra, P Zheng, H Anantharaman, V Banerjee, R Takeda, K Kozakai, Y Lepore, T Krause, PJ Aravind, L Kumar, S AF Moitra, Prasun Zheng, Hong Anantharaman, Vivek Banerjee, Rajdeep Takeda, Kazuyo Kozakai, Yukiko Lepore, Timothy Krause, Peter J. Aravind, L. Kumar, Sanjai TI Expression, Purification, and Biological Characterization of Babesia microti Apical Membrane Antigen 1 SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA VACCINE CANDIDATE; ERYTHROCYTE-BINDING ACTIVITY; HOST-CELL INVASION; RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; TOXOPLASMA-GONDII; PROTEINS; RECEPTOR; BOVIS; PARASITES AB The intraerythrocytic apicomplexan Babesia microti, the primary causative agent of human babesiosis, is a major public health concern in the United States and elsewhere. Apicomplexans utilize a multiprotein complex that includes a type I membrane protein called apical membrane antigen 1 (AMA1) to invade host cells. We have isolated the full-length B. microti AMA1 (BmAMA1) gene and determined its nucleotide sequence, as well as the amino acid sequence of the AMA1 protein. This protein contains an N-terminal signal sequence, an extracellular region, a transmembrane region, and a short conserved cytoplasmic tail. It shows the same domain organization as the AMA1 orthologs from piroplasm, coccidian, and haemosporidian apicomplexans but differs from all other currently known piroplasmida, including other Babesia and Theileria species, in lacking two conserved cysteines in highly variable domain III of the extracellular region. Minimal polymorphism was detected in BmAMA1 gene sequences of parasite isolates from six babesiosis patients from Nantucket. Immunofluorescence microscopy studies showed that BmAMA1 is localized on the cell surface and cytoplasm near the apical end of the parasite. Native BmAMA1 from parasite lysate and refolded recombinant BmAMA1 (rBmAMA1) expressed in Escherichia coli reacted with a mouse anti-BmAMA1 antibody using Western blotting. In vitro binding studies showed that both native BmAMA1 and rBmAMA1 bind to human red blood cells (RBCs). This binding is trypsin and chymotrypsin treatment sensitive but neuraminidase independent. Incubation of B. microti parasites in human RBCs with a mouse anti-BmAMA1 antibody inhibited parasite growth by 80% in a 24-h assay. Based on its antigenically conserved nature and potential role in RBC invasion, BmAMA1 should be evaluated as a vaccine candidate. C1 [Moitra, Prasun; Zheng, Hong; Banerjee, Rajdeep; Kozakai, Yukiko; Kumar, Sanjai] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Anantharaman, Vivek; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Takeda, Kazuyo] US FDA, Microscopy & Imaging Core Facil, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Lepore, Timothy] Nantucket Cottage Hosp, Nantucket, MA USA. [Krause, Peter J.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Krause, Peter J.] Yale Univ, Sch Med, New Haven, CT USA. RP Kumar, S (reprint author), US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Sanjai.Kumar@fda.hhs.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU funds of the Intramural Research Programs of the U.S. Food and Drug Administration; National Library of Medicine, National Institutes of Health (NIH) FX This research was supported by the funds of the Intramural Research Programs of the U.S. Food and Drug Administration and the National Library of Medicine, National Institutes of Health (NIH). NR 65 TC 5 Z9 5 U1 0 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 OCT PY 2015 VL 83 IS 10 BP 3890 EP 3901 DI 10.1128/IAI.00168-15 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CT0NJ UT WOS:000362492600013 PM 26195550 ER PT J AU Lee, S Almeida, DM Davis, KD King, RB Hammer, LB Kelly, EL AF Lee, Soomi Almeida, David M. Davis, Kelly D. King, Rosalind B. Hammer, Leslie B. Kelly, Erin L. TI Latent Profiles of Perceived Time Adequacy for Paid Work, Parenting, and Partner Roles SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article DE latent profiles; perceived time adequacy; conservation of resources theory; work-family conflict; partner support ID DUAL-EARNER COUPLES; FAMILY CONFLICT; STRESS PROCESS; CHILDREN; RESOURCES; GENDER; PERSPECTIVE; VALIDATION; SQUEEZE; STRAIN AB This study examined feelings of having enough time (i.e., perceived time adequacy) in a sample of employed parents (N = 880) in information technology and extended-care industries. Adapting a person-centered latent profile approach, we identified 3 profiles of perceived time adequacy for paid work, parenting, and partner roles: family time protected, family time sacrificed, and time balanced. Drawing upon the conservation of resources theory (Hobfoll, 1989), we examined the associations of stressors and resources with the time adequacy profiles. Parents in the family time sacrificed profile were more likely to be younger, women, have younger children, work in the extended-care industry, and have nonstandard work schedules compared to those in the family time protected profile. Results from multinomial logistic regression analyses revealed that, with the time balanced profile as the reference group, having fewer stressors and more resources in the family context (less parent-child conflict and more partner support), work context (longer company tenure, higher schedule control and job satisfaction), and work-family interface (lower work-to-family conflict) was linked to a higher probability of membership in the family time protected profile. By contrast, having more stressors and fewer resources, in the forms of less partner support and higher work-to-family conflict, predicted a higher likelihood of being in the family time sacrificed profile. Our findings suggest that low work-to-family conflict is the most critical predictor of membership in the family time protected profile, whereas lack of partner support is the most important factor to be included in the family time sacrificed profile. C1 [Lee, Soomi; Almeida, David M.; Davis, Kelly D.] Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. [King, Rosalind B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Hammer, Leslie B.] Portland State Univ, Dept Psychol, Portland, OR 97207 USA. [Kelly, Erin L.] Univ Minnesota, Dept Sociol, Minneapolis, MN 55455 USA. RP Lee, S (reprint author), Penn State Univ, 422 Biobehav Hlth Bldg, University Pk, PA 16802 USA. EM smlee@psu.edu OI Lee, Soomi/0000-0002-7623-3770 FU NCATS NIH HHS [UL1 TR001425]; NICHD NIH HHS [U01 HD051217] NR 47 TC 0 Z9 0 U1 7 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 EI 1939-1293 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD OCT PY 2015 VL 29 IS 5 BP 788 EP 798 DI 10.1037/a0039433 PG 11 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA CT0TO UT WOS:000362510200013 PM 26075739 ER PT J AU Chung, HK Pise-Masison, CA Muthiah, A Radonovich, MF Lee, EM Lee, JK Pal, R AF Chung, Hye Kyung Pise-Masison, Cynthia A. Muthiah, Annamalai Radonovich, Michael F. Lee, Eun Mi Lee, Jae K. Pal, Ranajit TI Transcription profiling of CD4(+) T cells in rhesus macaques that infected with simian-human immunodeficiency virus and re-challenged with SIVmac251 SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE gene expression; HIV; immune activation; microarray; protective marker; simian-immunodeficiency virus; vaccine ID CELLULAR GENE-EXPRESSION; HIV-1 INFECTION; HUMAN MX2; REPLICATION; RESPONSES; PROTECTION; INHIBITOR; DISEASE; MODELS; VIVO AB Background Insights into the host factors that contribute to an effective antiviral immune response may be obtained by examining global gene expression in simian-human immunodeficiency virus (SHIV)-infected non-human primates that exhibit different virological outcomes. Methods Six chronically SHIN-infected macaques were rectally challenged with SIVmac251. Viral RNA and proviral DNA load in blood were measured. Gene expression profiles in CD4+ T cells were examined and compared between animals with different levels of infection following challenge. Results and Conclusions Viral RNA was markedly controlled in four challenged animals, whereas two animals had persistent high viremia. Analysis of the gene expression profiles at early infection revealed gene expression signatures between protectors and non-protectors and identified potential protective biomarkers. Pathway analyses revealed that IFN pathway genes are down-regulated in protectors compared to unprotectors. This study suggests that high levels of expression of type 1 IFN-related genes may paradoxically promote virus replication. C1 [Chung, Hye Kyung; Lee, Eun Mi; Pal, Ranajit] Adv BioSci Labs Inc, Rockville, MD 20850 USA. [Pise-Masison, Cynthia A.; Radonovich, Michael F.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Muthiah, Annamalai; Lee, Jae K.] Univ S Florida, Morsani Coll Med, Moffitte Canc Ctr, Dept Biostat & Bioinformat, Tampa, FL USA. RP Chung, HK (reprint author), Adv BioSci Labs Inc, 9800 Med Ctr Dr,Bldg D, Rockville, MD 20850 USA. EM hye.chung@ablinc.com; Jae.Lee@moffitt.org NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI BP 263 EP 274 DI 10.1111/jmp.12185 PG 12 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000006 PM 26332118 ER PT J AU Hessell, A Pandey, S Sutton, W Legasse, A Planer, S Stanton, J Kahl, C Siess, D Sacha, J Connors, M Graham, B Mascola, J Haigwood, N AF Hessell, Ann Pandey, Shilpi Sutton, William Legasse, Alfred Planer, Shannon Stanton, Jeffrey Kahl, Christoph Siess, Don Sacha, Jonah Connors, Mark Graham, Barney Mascola, John Haigwood, Nancy TI POST-EXPOSURE TREATMENT WITH NEUTRALIZING MONOCLONAL ANTIBODIES PREVENTS SHIV INFECTION IN INFANT RHESUS MACAQUES AND LIMITS ESTABLISHMENT OF LATENT VIRAL RESERVOIRS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Hessell, Ann; Pandey, Shilpi; Sutton, William; Legasse, Alfred; Planer, Shannon; Stanton, Jeffrey; Kahl, Christoph; Siess, Don; Sacha, Jonah; Haigwood, Nancy] OHSU, ONPRC, Beaverton, OR USA. [Connors, Mark; Graham, Barney] NIAID, NIH, Bethesda, MD 20892 USA. [Mascola, John] NIH, VRC, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O1.01 BP 306 EP 306 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000014 ER PT J AU Micci, L Ryan, E McGary, C Paganini, S Silvestri, G Lifson, J Villinger, F Brenchley, J Paiardini, M AF Micci, Luca Ryan, Emily McGary, Colleen Paganini, Sara Silvestri, Guido Lifson, Jeffery Villinger, Francois Brenchley, Jason Paiardini, Mirko TI INTERLEUKIN-21 REDUCES RESIDUAL INFLAMMATION AND VIRUS PERSISTENCE IN ART-TREATED SIV-INFECTED RHESUS MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Micci, Luca; Ryan, Emily; McGary, Colleen; Paganini, Sara; Silvestri, Guido; Villinger, Francois; Paiardini, Mirko] Emory Univ, Atlanta, GA 30322 USA. [Lifson, Jeffery] Leidos Biomed Res, Bethesda, MD USA. [Brenchley, Jason] NIAID, NIH, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O1.02 BP 306 EP 307 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000015 ER PT J AU Riddick, NE Goeken, RM Whitted, S Matsuda, K Brenchley, JM Hirsch, VM AF Riddick, Nadeene E. Goeken, Robert M. Whitted, Sonya Matsuda, Kenta Brenchley, Jason M. Hirsch, Vanessa M. TI SIVAGM FROM VERVET AFRICAN GREEN MONKEYS UTILIZE NON-CCR5 ENTRY PATHWAYS IN VITRO AND EX VIVO SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Riddick, Nadeene E.; Goeken, Robert M.; Whitted, Sonya; Matsuda, Kenta; Brenchley, Jason M.; Hirsch, Vanessa M.] NIAID, NIH, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O2.02 BP 310 EP 311 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000026 ER PT J AU Torben, W Pahar, B Aye, P Schiro, F Breed, M Piatak, M Lifson, J Keele, B Hoxie, J Lackner, A AF Torben, Workineh Pahar, Bapi Aye, Pyone Schiro, Faith Breed, Matthew Piatak, Mike Lifson, Jeffrey Keele, Brandon Hoxie, James Lackner, Andrew TI CELLULAR IMMUNE CORRELATES OF ELITE CONTROL OF SIVMAC239 Delta GY AND PROTECTION FROM A HETEROLOGOUS SIV CHALLENGE IN PIGTAIL MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Torben, Workineh; Pahar, Bapi; Aye, Pyone; Schiro, Faith; Breed, Matthew; Lackner, Andrew] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. [Piatak, Mike; Lifson, Jeffrey; Keele, Brandon] NCI SAIC Frederick, Frederick, MD USA. [Hoxie, James] Univ Penn, Philadelphia, PA 19104 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O2.10 BP 313 EP 313 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000034 ER PT J AU Byrareddy, S Arthos, J Cicala, C Reimann, K Parslow, T Santangelo, P Villinger, F Fauci, A Ansari, A AF Byrareddy, Siddappa Arthos, James Cicala, Claudia Reimann, Keith Parslow, Tristram Santangelo, Philip Villinger, Francois Fauci, Anthony Ansari, Aftab TI BLOCKADE OF alpha 4 beta 7 INTEGRIN REDUCES INTRAVAGINAL SIV TRANSMISSION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Byrareddy, Siddappa; Parslow, Tristram; Santangelo, Philip; Villinger, Francois; Ansari, Aftab] Emory Univ, Atlanta, GA 30322 USA. [Arthos, James; Cicala, Claudia; Fauci, Anthony] NIAID, Bethesda, MD 20892 USA. [Reimann, Keith] Univ Massachuseets, Mass Biol, Sch Med, Boston, MA USA. [Santangelo, Philip] Georgia Inst Technol, Atlanta, GA 30332 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O3.02 BP 314 EP 314 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000037 ER PT J AU Wu, F Ourmanov, I Matsuda, K Riddick, N Whitted, S LaBranche, C Buckler-White, A Montefiori, D Hirsch, V AF Wu, Fan Ourmanov, Ilnour Matsuda, Kenta Riddick, Nadeene Whitted, Sonya LaBranche, Celia Buckler-White, Alicia Montefiori, David Hirsch, Vanessa TI CHARACTERIZATION OF SIVSME660 CLONES WITH DIFFERENT NEUTRALIZATION SENSITIVITY IN RHESUS MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Wu, Fan; Ourmanov, Ilnour; Matsuda, Kenta; Riddick, Nadeene; Whitted, Sonya; Buckler-White, Alicia; Hirsch, Vanessa] NIAID, LMM, NIH, Bethesda, MD 20892 USA. [LaBranche, Celia; Montefiori, David] Duke Univ, Dept Surg, Durham, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O3.03 BP 315 EP 315 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000038 ER PT J AU Blackburn, M Ma, ZM Francesca, C McKinnon, KM Luca, S Gorini, G Nicolo', B Gordon, SN Miller, CJ Franchini, G Vaccari, M AF Blackburn, Matthew Ma Zhong-Min Francesca, Caccuri McKinnon, Katherine M. Luca, Schifanella Gorini, Giacomo Nicolo', Binello Gordon, Shari Noelle Miller, Chris J. Franchini, Genoveffa Vaccari, Monica TI IMBALANCE OF REGULATORY AND HELPER FOLLICULAR T CELLS IN THE GERMINAL CENTERS OF SIVMAC251 INFECTED MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Blackburn, Matthew; McKinnon, Katherine M.; Luca, Schifanella; Gorini, Giacomo; Nicolo', Binello; Franchini, Genoveffa; Vaccari, Monica] NCI, NIH, Bethesda, MD 20892 USA. [Ma Zhong-Min; Miller, Chris J.] Univ Calif Davis, Davis, CA 95616 USA. [Francesca, Caccuri] Univ Brescia, Brescia, Lombardia, Italy. [Gordon, Shari Noelle] GSK, Durham, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O4.04 BP 319 EP 319 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000050 ER PT J AU Schneider, J Carias, A Liyanage, N Cianci, G Anderson, M Maric, D Veazey, R Franchini, G Hope, T AF Schneider, Jeff Carias, Ann Liyanage, Namal Cianci, Gianguido Anderson, Meegan Maric, Danijela Veazey, Ronald Franchini, Genoveffa Hope, Thomas TI LOCALIZATION AND STABILITY OF EXOGENOUSLY APPLIED ANTIBODIES FOR NHP MUCOSAL CHALLENGE STUDIES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Schneider, Jeff; Carias, Ann; Cianci, Gianguido; Anderson, Meegan; Maric, Danijela; Hope, Thomas] Northwestern Univ, Chicago, IL 60611 USA. [Liyanage, Namal; Franchini, Genoveffa] NCI, NIH, Bethesda, MD 20892 USA. [Veazey, Ronald] TNPRC, Covington, LA 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O5.01 BP 319 EP 320 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000052 ER PT J AU Foulds, K Donaldson, M Kao, SF Letukas, V Korber, B Keele, B Mascola, J Roederer, M AF Foulds, Kathryn Donaldson, Mitzi Kao, Shing-Fen Letukas, Valerie Korber, Bette Keele, Brandon Mascola, John Roederer, Mario TI IMMUNOLOGICAL CORRELATES OF PROTECTION AGAINST SIV PATHOGENESIS FOLLOWING VACCINATION WITH MOSAIC AND NATURAL PROTEINS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Foulds, Kathryn; Donaldson, Mitzi; Kao, Shing-Fen; Letukas, Valerie; Mascola, John; Roederer, Mario] NIAID, NIH, VRC, Bethesda, MD 20892 USA. [Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Keele, Brandon] AIDS & Canc Virus Program, Frederick, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O6.01 BP 321 EP 321 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000057 ER PT J AU Hu, XT Kulkarni, V Valentin, A Rosati, M Alicea, C Rolland, M Le Gall, S Sardesai, NY Mothe, B Brander, C Mullins, JI Pavlakis, GN Felber, BK AF Hu, Xintao Kulkarni, Viraj Valentin, Antonio Rosati, Margherita Alicea, Candido Rolland, Morgane Le Gall, Sylvie Sardesai, Niranjan Y. Mothe, Beatriz Brander, Christian Mullins, James I. Pavlakis, George N. Felber, Barbara K. TI REVERSE VACCINOLOGY IDENTIFIED PROMISING VACCINE CANDIDATES FOCUSING RESPONSES TO RELATIVELY CONSERVED REGIONS ASSOCIATED WITH CONTROL OF VIREMIA SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Hu, Xintao; Kulkarni, Viraj; Valentin, Antonio; Rosati, Margherita; Alicea, Candido; Pavlakis, George N.; Felber, Barbara K.] NCI, Frederick, MD 21701 USA. [Rolland, Morgane; Mullins, James I.] Univ Washington, Seattle, WA 98195 USA. [Le Gall, Sylvie] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Mothe, Beatriz; Brander, Christian] Autonomous Univ Barcelona, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA O6.10 BP 324 EP 325 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000066 ER PT J AU Wang, RJ Abdulkerim, H Price, AA Belli, A Li, JC Dabkowski, NS Wang, XY Reinhart, TA Flynn, JL Wong, E DiFazio, R Okoye, AA Ansari, AA Arthos, J Reimann, KA AF Wang, Rijian Abdulkerim, Hayat Price, Andrew A. Belli, Aaron Li, Jichu Dabkowski, Nicole S. Wang, Xinyue Reinhart, Todd A. Flynn, JoAnne L. Wong, Eileen DiFazio, Robert Okoye, Afam A. Ansari, Aftab A. Arthos, James Reimann, Keith A. TI NEW RHESUS RECOMBINANT ANTIBODIES FOR USE IN NONHUMAN PRIMATE MODELS: UPDATES FROM THE NHP REAGENT RESOURCE SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Wang, Rijian; Abdulkerim, Hayat; Price, Andrew A.; Belli, Aaron; Li, Jichu; Dabkowski, Nicole S.; Wang, Xinyue; Reimann, Keith A.] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. [Reinhart, Todd A.; Flynn, JoAnne L.; Wong, Eileen; DiFazio, Robert] Univ Pittsburgh, Pittsburgh, PA USA. [Okoye, Afam A.] OHSU, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Ansari, Aftab A.] Emory Univ, Atlanta, GA 30322 USA. [Arthos, James] NIAID, NIH, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P1.04 BP 326 EP 326 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000070 ER PT J AU Del Prete, G Oswald, K Newman, L Reid, C Shoemaker, R Bess, J Smedley, J Macallister, R Picker, L Piatak, M Lifson, J Keele, B AF Del Prete, Gregory Oswald, Kelli Newman, Laura Reid, Carolyn Shoemaker, Rebecca Bess, Julian Smedley, Jeremy Macallister, Rhonda Picker, Louis Piatak, Michael Lifson, Jeffrey Keele, Brandon TI EXAMINING THE INFLUENCE OF NON-VIRAL STOCK CONSTITUENTS ON IN VIVO MUCOSAL INFECTIVITY FOR TRANSFECTION- AND INFECTION-DERIVED SIV CHALLENGE STOCKS SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Del Prete, Gregory; Oswald, Kelli; Newman, Laura; Reid, Carolyn; Shoemaker, Rebecca; Bess, Julian; Smedley, Jeremy; Macallister, Rhonda; Piatak, Michael; Lifson, Jeffrey; Keele, Brandon] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Picker, Louis] Oregon Hlth & Sci Univ, Beaverton, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P2.04 BP 328 EP 328 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000075 ER PT J AU Yuan, Z Demers, A Ma, FR Keele, B Li, QS AF Yuan, Zhe Demers, Andrew Ma, Fangrui Keele, Brandon Li, Qingsheng TI THE DETERMINANT SIGNATURES OF FOUNDER VIRUSES FOR SIV RECTAL TRANSMISSION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Yuan, Zhe; Demers, Andrew; Li, Qingsheng] Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA. [Ma, Fangrui] Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE USA. [Keele, Brandon] SAIC Frederick Inc, NCI Frederick, AIDS & Canc Virus Program, Frederick, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P2.08 BP 330 EP 330 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000079 ER PT J AU Park, H Fukazawa, Y Okoye, A Hansen, S Bae, JY Delos Reyes, M Hagen, S Rohankhedkar, M Legasse, A Axthelm, M Piatak, M Lifson, J Picker, L AF Park, Haesun Fukazawa, Yoshi Okoye, Afam Hansen, Scott Bae, Jin Young Delos Reyes, Marcelo, III Hagen, Shoko Rohankhedkar, Mukta Legasse, Alfred Axthelm, Michael Piatak, Michael Lifson, Jeffrey Picker, Louis TI INDUCTION OF CD169 ON MONOCYTES IS INDICATIVE OF SYSTEMIC VIRAL REPLICATION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Park, Haesun; Fukazawa, Yoshi; Okoye, Afam; Hansen, Scott; Bae, Jin Young; Hagen, Shoko; Rohankhedkar, Mukta; Picker, Louis] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Delos Reyes, Marcelo, III; Legasse, Alfred; Axthelm, Michael] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Piatak, Michael; Lifson, Jeffrey] NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21701 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P2.11 BP 331 EP 331 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000082 ER PT J AU Kuwata, T Yoshimura, K Wu, F Ourmanov, I Hirsch, VM Yokoyama, M Sato, H Matsushita, S AF Kuwata, Takeo Yoshimura, Kazuhisa Wu, Fan Ourmanov, Ilnour Hirsch, Vanessa M. Yokoyama, Masaru Sato, Hironori Matsushita, Shuzo TI MUTATIONS IN GP41 IS CRITICAL TO ESCAPE FROM B404, A BROAD NEUTRALIZING ANTIBODY AGAINST SIV, WHICH RECOGNIZES A V3/V4 CONFORMATIONAL EPITOPE SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Kuwata, Takeo; Matsushita, Shuzo] Kumamoto Univ, Kumamoto, Kumamoto, Japan. [Yoshimura, Kazuhisa; Yokoyama, Masaru; Sato, Hironori] Natl Inst Infect Dis, Tokyo, Japan. [Wu, Fan; Ourmanov, Ilnour; Hirsch, Vanessa M.] NIAID, NIH, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.07 BP 336 EP 336 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000096 ER PT J AU Trivett, M Coren, LV Barsov, EV Ott, DE Ohlen, C AF Trivett, Matthew Coren, Lori V. Barsov, Eugene V. Ott, David E. Ohlen, Claes TI PREFERENTIAL TAGGING AND RAPID ENRICHMENT OF ANTIGEN SPECIFIC T CELLS FROM PRIMARY TISSUE BY RETROVIRAL TRANSDUCTION SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Trivett, Matthew; Coren, Lori V.; Barsov, Eugene V.; Ott, David E.; Ohlen, Claes] NCI, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD 21701 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.06 BP 336 EP 336 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000095 ER PT J AU Sui, YJ Hogg, A Wang, YC Frey, B Yu, HF Xia, Z Venzon, D McKinnon, K Smedley, J Gathuka, M Klinman, D Keele, B Langermann, S Liu, LD Franchini, G Berzofsky, J AF Sui, Yongjun Hogg, Alison Wang, Yichuan Frey, Blake Yu, Huifeng Xia, Zheng Venzon, David McKinnon, Katherine Smedley, Jeremy Gathuka, Mercy Klinman, Dennis Keele, Brandon Langermann, Sol Liu, Linda Franchini, Genoveffa Berzofsky, Jay TI VACCINE-INDUCED MYELOID CELL POPULATION DAMPENS PROTECTIVE IMMUNITY TO SIV SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Sui, Yongjun; Hogg, Alison; Wang, Yichuan; Frey, Blake; Yu, Huifeng; Xia, Zheng; Venzon, David; McKinnon, Katherine; Smedley, Jeremy; Gathuka, Mercy; Klinman, Dennis; Keele, Brandon; Franchini, Genoveffa; Berzofsky, Jay] NCI, Bethesda, MD 20892 USA. [Langermann, Sol; Liu, Linda] Amplimmune Inc, Gaithersburg, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.15 BP 339 EP 339 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000104 ER PT J AU Thomas, M Tuero, I Demberg, T Vargas-Inchaustegui, D Musich, T Xiao, P Venzon, D LaBranche, C Montefiori, D Dipasquale, J Reed, S DeVico, A Fouts, T Lewis, G Gallo, R Robert-Guroff, M AF Thomas, Michael Tuero, Iskra Demberg, Thorsten Vargas-Inchaustegui, Diego Musich, Thomas Xiao, Peng Venzon, David LaBranche, Celia Montefiori, David Dipasquale, Janet Reed, Steven DeVico, Anthony Fouts, Timothy Lewis, George Gallo, Robert Robert-Guroff, Marjorie TI HIV-1 CD4-INDUCED (CD4I) GP120 EPITOPE VACCINES PROMOTE B AND T-CELL RESPONSES THAT CONTRIBUTE TO REDUCED VIRAL LOADS IN RHESUS MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Thomas, Michael; Tuero, Iskra; Demberg, Thorsten; Vargas-Inchaustegui, Diego; Musich, Thomas; Dipasquale, Janet; Robert-Guroff, Marjorie] NCI, Vaccince Branch, NIH, Bethesda, MD 20892 USA. [Xiao, Peng] Emery, Atlanta, GA USA. [Xiao, Peng] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Venzon, David] Duke Univ, Durham, NC USA. [LaBranche, Celia; Montefiori, David] Infect Dis Res Inst, Seattle, WA USA. [Reed, Steven] Inst Human Virol, Baltimore, MD USA. [DeVico, Anthony; Lewis, George; Gallo, Robert] Profectus BioSci, Baltimore, MD 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.17 BP 339 EP 340 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000106 ER PT J AU Torben, W Pahar, B Aye, P Schiro, F Breed, M Jordan, A Piatak, M Lifson, J Hoxie, J Lackner, A AF Torben, Workineh Pahar, Bapi Aye, Pyone Schiro, Faith Breed, Matthew Jordan, Andrea Piatak, Mike Lifson, Jeffrey Hoxie, James Lackner, Andrew TI CELLULAR IMMUNE CORRELATES OF ELITE CONTROL OF SIVMAC239 Delta GY IN PIGTAIL MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Torben, Workineh; Pahar, Bapi; Aye, Pyone; Schiro, Faith; Breed, Matthew; Lackner, Andrew] Tulane Natl Primate Res Ctr, Covington, LA USA. [Jordan, Andrea; Hoxie, James] Univ Penn, Philadelphia, PA 19104 USA. [Piatak, Mike; Lifson, Jeffrey] NCI SAIC Frederick, Frederick, 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.18 BP 340 EP 340 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000107 ER PT J AU Tuero, I Mohanram, V Musich, T Vargas-Inchaustegui, D Demberg, T Kalisz, I Kalyanaraman, VS Pal, R Venzon, D LaBranche, C Montefiori, DC Barnett, SW Robert-Guroff, M AF Tuero, Iskra Mohanram, Venkatramanan Musich, Thomas Vargas-Inchaustegui, Diego Demberg, Thorsten Kalisz, Irene Kalyanaraman, V. S. Pal, Ranajit Venzon, David LaBranche, Celia Montefiori, David C. Barnett, Susan W. Robert-Guroff, Marjorie TI VACCINE-INDUCED MUCOSAL B CELLS ARE CORRELATED WITH DELAYED SIVMAC251 ACQUISITION FOLLOWING RECTAL CHALLENGE OF FEMALE BUT NOT MALE RHESUS MACAQUES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Tuero, Iskra; Mohanram, Venkatramanan; Musich, Thomas; Vargas-Inchaustegui, Diego; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Kalisz, Irene; Kalyanaraman, V. S.; Pal, Ranajit] Adv BioSci Labs Inc, Bethesda, MD USA. [Venzon, David] NCI, NIH, Bethesda, MD 20892 USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Barnett, Susan W.] Novartis Vaccines & Diagnost, Cambridge, MA USA. RI Mohanram, Venkatramanan/I-3652-2016 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.20 BP 341 EP 341 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000109 ER PT J AU Valentin, A Li, JY Jalah, R Patel, V Rosati, M Kulkarni, V Alicea, C Vargas-Inchaustegui, DA Guan, YJ Venzon, D Sardesai, NY Fouts, TR Pinter, A Robert-Guroff, M Montefiori, DC Shen, XY Tomaras, GD Pavlakis, GN Felber, BK AF Valentin, Antonio Li, Jinyao Jalah, Rashmi Patel, Vainav Rosati, Margherita Kulkarni, Viraj Alicea, Candido Vargas-Inchaustegui, Diego A. Guan, Yongjun Venzon, David Sardesai, Niranjan Y. Fouts, Timothy R. Pinter, Abraham Robert-Guroff, Marjorie Montefiori, David C. Shen, Xiaoying Tomaras, Georgia D. Pavlakis, George N. Felber, Barbara K. TI DNA AND PROTEIN CO-IMMUNIZATION IMPROVES THE MAGNITUDE, LONGEVITY, AND MUCOSAL DISSEMINATION OF IMMUNE RESPONSES SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Valentin, Antonio; Li, Jinyao; Jalah, Rashmi; Patel, Vainav; Rosati, Margherita; Kulkarni, Viraj; Alicea, Candido; Pavlakis, George N.; Felber, Barbara K.] NCI, Frederick, MD 21701 USA. [Vargas-Inchaustegui, Diego A.; Venzon, David; Robert-Guroff, Marjorie] NCI, Bethesda, MD 20892 USA. [Guan, Yongjun] Inst Human Virol, Baltimore, MD USA. [Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Fouts, Timothy R.] Profectus BioSci Inc, Baltimore, MD USA. [Pinter, Abraham] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Montefiori, David C.; Shen, Xiaoying; Tomaras, Georgia D.] Duke Univ, Med Ctr, Durham, NC USA. RI Tomaras, Georgia/J-5041-2016 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P3.21 BP 341 EP 341 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000110 ER PT J AU Chung, HK Pise-Masison, CA Muthiah, A Radonovich, MF Brady, J Lee, EM Lee, M Narasimhan, G Lee, JK Pal, R AF Chung, Hye Kyung Pise-Masison, Cynthia A. Muthiah, Annamalai Radonovich, Michael F. Brady, John Lee, Eun Mi Lee, Michael Narasimhan, Ganga Lee, Jae K. Pal, Ranajit TI TRANSCRIPTIONAL PROFILING OF CD4+T CELLS IN SIMIAN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED RHESUS MACAQUES RE-CHALLENGED WITH SIVMAC251 SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract C1 [Chung, Hye Kyung; Lee, Michael; Narasimhan, Ganga; Pal, Ranajit] ABL, Rockville, MD USA. [Pise-Masison, Cynthia A.] NCI, NIH, Bethesda, MD 20892 USA. [Lee, Eun Mi] NIAID, NIH, Bethesda, MD USA. [Lee, Jae K.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 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 0047-2565 EI 1600-0684 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2015 VL 44 IS 5 SI SI MA P4.04 BP 344 EP 344 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CS3IM UT WOS:000361966000117 ER PT J AU Zhang, JJ Lang, LX Zhu, ZH Li, F Niu, G Chen, XY AF Zhang, Jingjing Lang, Lixin Zhu, Zhaohui Li, Fang Niu, Gang Chen, Xiaoyuan TI Clinical Translation of an Albumin-Binding PET Radiotracer Ga-68-NEB SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE truncated Evans blue; albumin; blood pool; first-in-human; hemangioma ID IN-VIVO; BLOOD-VOLUME; EVANS BLUE; POOL; CT; HEMANGIOMA; DOSIMETRY; DIAGNOSIS; PEPTIDES; MRI AB Suitably labeled Evans blue dye has been successfully applied to evaluate cardiac function, vascular permeability, and lymphatic imaging in preclinical settings. This study documented the first-inhuman application of Ga-68-1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA)-NEB. Methods: The NOTA-conjugated truncated form of Evans blue, NEB, was labeled with Ga-68 and tested in BALB/C mice for dynamic PET and ex vivo biodistribution studies. Three healthy volunteers (2 men and 1 woman) underwent 90-min whole-body dynamic PET. The absorbed doses for major organs and whole body were calculated using OLINDA/EXM software. Eleven patients with focal hepatic lesions diagnosed by enhanced CT or MR imaging were subjected to whole-body PET/CT acquisitions at 30 min after intravenous injection of 111-148 MBq (3-4 mCi) of Ga-68-NEB. Results: NEB dye was labeled with Ga-68 (half-time, 68 min) with high yield and purity. After intravenous injection, Ga-68-NEB formed a complex with serum albumin, thus most of the radioactivity was retained in blood circulation. The tracer was demonstrated to be safe in both healthy volunteers and recruited patients without side effects or allergies. Among the 11 patients, hemangiomas showed much higher Ga-68-NEB signal intensity than the surrounding normal hepatic tissues, whereas no apparent difference between lesions and hepatic tissues was identified on F-18-FDG PET. All other focal hepatic lesions including hepatocellular carcinoma, hepatic cysts, and neuroendocrine tumor liver metastases showed negative Ga-68-NEB contrast to hepatic tissues. Conclusion: As a blood-pool imaging agent, Ga-68-NEB is safe to use in the clinic, and our preliminary studies demonstrate the value of differentiating hepatic hemangioma from other benign or malignant focal hepatic lesions. Easy labeling with different positron emitters of various half-lives, excellent pharmacokinetics, and imaging quality warrant further clinical applications of NEB-based PET tracers. C1 [Zhang, Jingjing; Zhu, Zhaohui; Li, Fang] Chinese Acad Med Sci, PUMCH, Dept Nucl Med, Beijing 100730, Peoples R China. [Zhang, Jingjing; Zhu, Zhaohui; Li, Fang] Peking Union Med Coll, CAMS, Beijing 100021, Peoples R China. [Zhang, Jingjing; Zhu, Zhaohui; Li, Fang] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhang, Jingjing; Lang, Lixin; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Li, F (reprint author), Peking Union Med Coll, 9 Dongdan 3rd Alley, Beijing 100021, Peoples R China. EM lifang@pumch.cn; shawn.chen@nih.gov FU Intramural NIH HHS [, Z99 EB999999, ZIA EB000073-07] NR 37 TC 6 Z9 6 U1 2 U2 12 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 OCT PY 2015 VL 56 IS 10 BP 1609 EP 1614 DI 10.2967/jnumed.115.159640 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS9DF UT WOS:000362388600026 PM 26251416 ER PT J AU Ozaki, M Molloy, AM Mills, JL Fan, RZ Wang, YF Gibney, ER Shane, B Brody, LC Parle-McDermott, A AF Ozaki, Mari Molloy, Anne M. Mills, James L. Fan, Ruzong Wang, Yifan Gibney, Eileen R. Shane, Barry Brody, Lawrence C. Parle-McDermott, Anne TI The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake SO JOURNAL OF NUTRITION LA English DT Article DE DHFR; 19 bp polymorphism; rs70991108; red cell folate; homocysteine; plasma folate; folic acid ID BLOOD-CELL FOLATE; PAIR DELETION POLYMORPHISM; SPINA-BIFIDA; MICROBIOLOGICAL ASSAY; VITAMIN-B-12 STATUS; TOTAL HOMOCYSTEINE; GENE; PLASMA; DHFR; SERUM AB Background: Dihydrofolate reductase (DHFR) is essential for the conversion of folic acid to active folate needed for onecarbon metabolism. Common genetic variation within DHFR is restricted to the noncoding regions, and previous studies have focused on a 19 bp deletion/insertion polymorphism (rs70991108) within intron 1. Reports of an association between this polymorphism and blood folate biomarker concentrations are conflicting. Objective: In this study, we evaluated whether the DHFR 19 bp deletion/insertion polymorphism affects circulating folate biomarkers in, to our knowledge, the largest cohort to address this question to date. Methods: Healthy young Irish individuals (n = 2507) between 19 and 36 y of age were recruited between February 2003 and February 2004. Folic acid intake from supplements and fortified foods was assessed with the use of a customized food intake questionnaire. Concentrations of serum folate and vitamin B-12, red blood cell (RBC) folate, and plasma total homocysteine (tHcy) were measured. Data were analyzed with the use of linear regression models. Results: Folic acid intake was positively associated with serum (P < 0.0001) and RBC (P= 0.0005) folate concentration and was inversely associated with plasma tHcy (P = 0.001) as expected. The DHFR 19 bp polymorphism was not significantly associated with either serum (P= 0.82) or RBC (P= 0.21) folate, or plasma tHcy (P= 0.20), even in those within the highest quintile of folic acid intake (>326 mu g folic acid/d; P= 0.96). A nonsignificant trend toward lower RBC folate by genotype (P= 0.09) was observed in the lowest folic acid intake quintile (0-51 mu g/d). Conclusion: In this cohort of healthy young individuals, the DHFR 19 bp deletion allele did not significantly affect circulating folate status, irrespective of folic acid intake. Our data rule out a strong functional effect from this polymorphism on blood folate concentrations. C1 [Ozaki, Mari; Parle-McDermott, Anne] Dublin City Univ, Sch Biotechnol, Nutr Genom Grp, Dublin 9, Ireland. [Molloy, Anne M.] Trinity Coll Dublin, Sch Med, Dept Clin Med, Dublin, Ireland. [Mills, James L.; Fan, Ruzong; Wang, Yifan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Brody, Lawrence C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Gibney, Eileen R.] Univ Coll Dublin, Inst Food & Hlth, Dublin 2, Ireland. [Shane, Barry] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Parle-McDermott, A (reprint author), Dublin City Univ, Sch Biotechnol, Nutr Genom Grp, Dublin 9, Ireland. EM anne.parle-mcdermott@dcu.ie OI Molloy, Anne/0000-0002-1688-9049 FU Health Research Board of Ireland [HRA_PHS/2010/20]; Intramural Research Program, NICHD (National Institute of Child Health and Human Development) [NO1HD 33348] FX This study was cofunded by the Health Research Board of Ireland (HRA_PHS/2010/20) and the Intramural Research Program, NICHD (National Institute of Child Health and Human Development) (contract NO1HD 33348). NR 33 TC 2 Z9 2 U1 2 U2 6 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 OCT PY 2015 VL 145 IS 10 BP 2207 EP 2211 DI 10.3945/jn.115.216101 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS9CW UT WOS:000362387700003 PM 26269242 ER PT J AU Reinders, U Murphy, RA Song, XL Mitche, GF Visser, M Cotch, MF Garcia, ME Launer, LJ Eiriksdottir, G Gudnason, V Harris, TB Brouwers, IA AF Reinders, Use Murphy, Rachel A. Song, Xiaoling Mitche, Gary F. Visser, Marjolein Cotch, Mary Frances Garcia, Melissa E. Launer, Lenore J. Eiriksdottir, Gudny Gudnason, Vilmundur Harris, Tamara B. Brouwers, Ingeborg A. TI Higher Plasma Phospholipid n-3 PUFAs, but Lower n-6 PUFAs, Are Associated with Lower Pulse Wave Velocity among Older Adults SO JOURNAL OF NUTRITION LA English DT Article DE arterial stiffness; fish oil; polyunsaturated fatty acids; pulse wave velocity; epidemiology; aging ID POLYUNSATURATED FATTY-ACIDS; RANDOMIZED CONTROLLED-TRIALS; CARDIOVASCULAR RISK-FACTORS; EXPERT CONSENSUS DOCUMENT; CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; ARTERIAL STIFFNESS; GENE/ENVIRONMENT SUSCEPTIBILITY; INFLAMMATORY MARKERS; CARDIAC STRUCTURE AB Background: Higher intake of polyunsaturated fatty acids (PUFAs) and higher circulating PUFAs are associated with lower cardiovascular disease (CVD) risk. The positive influence of PUFAs might be via lowering arterial stiffness, resulting in a better CVD risk profile; however, studies investigating circulating PUFAs in relation to arterial stiffness in a general population are limited. Objective: We investigated the associations of plasma phospholipid n-3 (co-3) and n-6 PUFAs and fish oil intake with arterial stiffness. Methods: We used data from a subgroup of the Age, Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) Study (n = 501, 75.0 4.96 y, 46% men), a population-based study of community-dwelling older adults. Plasma phospholipid PUFAs were measured by GC at baseline, and fish oil intake was assessed at 3 time points: early life (ages 14-19 y), midlife (ages 40-50 y), and late life (ages 66-96 y, AGES-Reykjavik baseline) with the use of a validated food-frequency questionnaire. Arterial stiffness was determined as carotid femoral pulse wave velocity (cf-PVVV) with the use of an electrocardiogram after a mean follow-up of 5.2 +/- 0.3 y. Regression coefficients (95% Cls), adjusted for demographics, follow-up time, risk factors, cholesterol, triglycerides, and serum vitamin D, were calculated by linear regression per SD increment in PUFAs. Results: Plasma total n-3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid were associated with lower cf-PVVV [beta (95% Cl): -0.036 (-0.064, -0.008); -0.031 (-0.059, -0.003); -0.036 (-0.064, -0.009), respectively]. In contrast, plasma total n-6 PUFAs and linoleic acid were associated with higher cf-PWV [0.035 (0.009, 0.061) and 0.034 (0.008, 0.059)]. Regular fish oil consumption at early-, mid-, and late-life was not associated with cf-PWV. Conclusions: Our results show a positive association between plasma n-6 PUFAs and arterial stiffness, and suggest that higher concentrations of plasma long-chain n-3 PUFAs are associated with less arterial stiffness and therein may be one of the mechanisms underlying the association between plasma n-3 PUFAs and lower CVD risk. C1 [Reinders, Use; Murphy, Rachel A.; Garcia, Melissa E.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Reinders, Use; Brouwers, Ingeborg A.] Vrije Univ Amsterdam, Inst Hlth & Care Res, Dept Hlth Sci, Amsterdam, Netherlands. [Reinders, Use; Visser, Marjolein; Brouwers, Ingeborg A.] Vrije Univ Amsterdam, EMGO, Amsterdam, Netherlands. [Song, Xiaoling] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Canc Prevent Program, Seattle, WA 98104 USA. [Mitche, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, Dept Nutr & Dietet Internal Med, Amsterdam, Netherlands. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Reinders, U (reprint author), NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. EM ilse.reinders@vu.nl RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU Office of Dietary Supplements; NIH [N01-AG-12100]; NIH Intramural Research Program at the National Institute on Aging; National Eye Institute [ZIAEY00401]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIH, National Heart, Lung and Blood Institute [HL094898]; National Institute of Diabetes and Digestive and Kidney Diseases [DK082447]; Banting Postdootoral Fellowship FX This work is cofunded by the Office of Dietary Supplements. The Age, Gene/Environment Susceptibility-Reykjavik Study was supported and funded by the NIH (contract number N01-AG-12100); the NIH Intramural Research Program at the National Institute on Aging and the National Eye Institute (ZIAEY00401); Hjartavernd (the Icelandic Heart Association); the Althingi (the Icelandic Parliament), and grants from the NIH, National Heart, Lung and Blood Institute (HL094898) and National Institute of Diabetes and Digestive and Kidney Diseases (DK082447) RAM holds a Banting Postdootoral Fellowship. NR 54 TC 2 Z9 2 U1 0 U2 4 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 OCT PY 2015 VL 145 IS 10 BP 2317 EP 2324 DI 10.3945/jn.115.212282 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS9CW UT WOS:000362387700018 ER PT J AU Harford, TC Chen, CM Grant, BF AF Harford, Thomas C. Chen, Chiung M. Grant, Bridget F. TI DSM-IV PERSONALITY DISORDERS: DIMENSIONAL ORDERED CATEGORIZATION AND ASSOCIATIONS WITH DISABILITY AND SELECTED AXIS I DISORDERS IN A GENERAL POPULATION SURVEY SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE-DISORDER; PSYCHIATRIC DIAGNOSTIC MODULES; ENVIRONMENTAL RISK-FACTORS; SUBTHRESHOLD LEVELS; UNITED-STATES; AUDADIS-IV; BORDERLINE; COMORBIDITY; RELIABILITY AB The DSM approach to personality disorder (PD) diagnoses has been criticized for using arbitrary thresholds. The present study evaluated one dimensional approach with ordered threshold categories of severity by examining associations with several measures of disability and Axis I disorders for 10 PDs in the general population. Data were obtained from the National Epidemiologic Survey of Alcohol and Related Conditions, Waves 1 and 2. Respondents were categorized according to PD criteria as follows: "no symptoms" for having no positive criteria, "sub-threshold" for having at least one positive criterion but below the DSM-IV threshold, "at-threshold" for meeting the DSM-IV threshold and additionally having one or two more positive criteria, and "suprathreshold" for meeting the DSM-IV threshold plus three or more positive criteria. Findings from this national study provide support for dimensional approaches to diagnostic classifications for the majority of PDs and suggest that mild levels of severity indeed have clinical significance. C1 [Harford, Thomas C.; Chen, Chiung M.] CSR Inc, Arlington, VA 22201 USA. [Grant, Bridget F.] NIAAA, NIH, Bethesda, MD USA. RP Chen, CM (reprint author), CSR Inc, 2107 Wilson Blvd,Suite 1000, Arlington, VA 22201 USA. EM cchen@csrincorporated.com FU NICHD NIH HHS [HHSN275201300016C] NR 40 TC 0 Z9 0 U1 1 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0885-579X EI 1943-2763 J9 J PERS DISORD JI J. Pers. Disord. PD OCT PY 2015 VL 29 IS 5 BP 627 EP 640 PG 14 WC Psychiatry SC Psychiatry GA CS8BN UT WOS:000362310800003 PM 25248016 ER PT J AU Shukla, S Shankavaram, UT Nguyen, P Stanley, BA Smart, DK AF Shukla, Sudhanshu Shankavaram, Uma T. Phuongmai Nguyen Stanley, Bruce A. Smart, DeeDee K. TI Radiation-Induced Alteration of the Brain Proteome: Understanding the Role of the Sirtuin 2 Deacetylase in a Murine Model SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE SIRT2; brain; radiation; neurotoxicity; iTRAQ neurodegeneration ID CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; INDUCED APOPTOSIS; PARKINSONS-DISEASE; IONIZING-RADIATION; MUTANT HUNTINGTIN; LOADING CONTROL; WESTERN BLOTS; BETA TOXICITY; MOUSE-BRAIN AB Whole brain radiotherapy (WBRT) produces unwanted sequelae, albeit via unknown mechanisms. A deacetylase expressed in the central nervous system, Sirtuin 2 (SIRT2), has been linked to neurodegeneration. Therefore, we sought to challenge the notion that a single disease pathway is responsible for radiation-induced brain injury in Sirt2 wild-type (WT) and knockout (KO) mice at the proteomic level. We utilized isobaric tag for relative and absolute quantitation to analyze brain homogenates from Sirt2 WT and KO mice with and without WBRT. Selected proteins were independently verified, followed by ingenuity pathway analysis. Canonical pathways for Huntington's, Parkinson's, and Alzheimer's were acutely affected by radiation within 72 h of treatment. Although loss of Sirt2 preferentially affected both Huntington's and Parkinson's pathways, WBRT most significantly affected Huntington's-related proteins in the absence of Sirt2. Identical protein expression patterns were identified in Mog following WBRT in both Sirt2 WT and KO mice, revealing a proteomic radiation signature; however, long-term radiation effects were found to be associated with altered levels of a small number of key neurodegeneration-related proteins, identified as Mapt, Mog, Snap2.5, and Dnm1. Together, these data demonstrate the principle that the presence of Sirt2 can have significant effects on the brain proteome and its response to ionizing radiation. C1 [Shukla, Sudhanshu; Shankavaram, Uma T.; Phuongmai Nguyen; Smart, DeeDee K.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stanley, Bruce A.] Penn State Coll Med, Prote & Mass Spectrometry Core Facil, Hershey, PA 17033 USA. RP Smart, DK (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM smartd@mail.nih.gov OI Shukla, Sudhanshu/0000-0002-7091-7215 FU National Institutes of Health, Center for Cancer Research, National Cancer Institute [ZIA BC 011222] FX We gratefully acknowledge Anne Stanley and other members of the Proteomics and Mass Spectrometry Core Research Facility of the College of Medicine, Pennsylvania State University, Hershey, PA for technical assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute, project number ZIA BC 011222: CNS sirtuins in radiation-induced vascular permeability and neurodegeneration. NR 58 TC 1 Z9 1 U1 1 U2 5 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 OCT PY 2015 VL 14 IS 10 BP 4104 EP 4117 DI 10.1021/acs.jproteome.5b0083 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CS9BW UT WOS:000362385100002 PM 26373435 ER PT J AU Cologna, SM Crutchfield, CA Searle, BC Blank, PS Toth, CL Ely, AM Picache, JA Backlund, PS Wassif, CA Porter, FD Yergey, AL AF Cologna, Stephanie M. Crutchfield, Christopher A. Searle, Brian C. Blank, Paul S. Toth, Cynthia L. Ely, Alexa M. Picache, Jaqueline A. Backlund, Peter S. Wassif, Christopher A. Porter, Forbes D. Yergey, Alfred L. TI An Efficient Approach to Evaluate Reporter Ion Behavior from MALDI-MS/MS Data for Quantification Studies Using Isobaric Tags SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE MALDI-MS; time-of-flight; iTRAQ; quantitative proteomics; quality control; fold-change ID MASS-SPECTROMETRY DATA; PROTEIN QUANTIFICATION; STATISTICAL-MODEL; RATIO COMPRESSION; ITRAQ; QUANTITATION; PROTEOMICS; IDENTIFICATION; ACCURACY; MS AB Protein quantification, identification, and abundance determination are important aspects of proteome characterization and are crucial in understanding biological mechanisms and human diseases. Different strategies are available to quantify proteins using mass spectrometric detection, and most are performed at the peptide level and include both targeted and untargeted methodologies. Discovery-based or untargeted approaches oftentimes use covalent tagging strategies (i.e., iTRAQ, TMT), where reporter ion signals collected in the tandem MS experiment are used for quantification. Herein we investigate the behavior of the iTRAQ8-plex chemistry using MALDI-TOF/TOF instrumentation. The experimental design and data analysis approach described is simple and straightforward, which allows researchers to optimize data collection and proper analysis within a laboratory. iTRAQ reporter ion signals were normalized within each spectrum to remove peptide biases. An advantage of this approach is that missing reporter ion values can be accepted for purposes of protein identification and quantification without the need for ANOVA analysis. We investigate the distribution of reporter ion peak areas in an equimolar system and a mock biological system and provide recommendations for establishing fold-change cutoff values at the peptide level for iTRAQ data sets. These data provide a unique data set available to the community for informatics training and analysis. C1 [Cologna, Stephanie M.; Toth, Cynthia L.; Ely, Alexa M.; Picache, Jaqueline A.; Wassif, Christopher A.; Porter, Forbes D.] DHHS, Program Dev Endocrinol & Genet, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Crutchfield, Christopher A.; Backlund, Peter S.; Yergey, Alfred L.] DHHS, Biomed Mass Spectrometry Facil, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Searle, Brian C.] Proteome Software Inc, Portland, OR 97219 USA. [Blank, Paul S.] DHHS, Sect Membrane & Cellular Biophys, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Yergey, AL (reprint author), DHHS, Biomed Mass Spectrometry Facil, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM aly@helix.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services; National Niemann-Pick Disease Foundation; RSH/Smith Lemli Opitz Research Foundation FX This work has been supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. Partial support was provided by the National Niemann-Pick Disease Foundation (Peter Pentchev Fellowship to S.M.C.). Funding for this work was also provided in part by the RSH/Smith Lemli Opitz Research Foundation (to S.M.C.) NR 34 TC 0 Z9 0 U1 3 U2 10 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 OCT PY 2015 VL 14 IS 10 BP 4169 EP 4178 DI 10.1021/acs.jproteome.5b00254 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CS9BW UT WOS:000362385100008 PM 26288259 ER PT J AU Bellgowan, JF Molfese, P Marx, M Thomason, M Glen, D Santiago, J Gotlib, IH Drevets, WC Hamilton, JP AF Bellgowan, Julie Frost Molfese, Peter Marx, Michael Thomason, Moriah Glen, Daniel Santiago, Jessica Gotlib, Ian H. Drevets, Wayne C. Hamilton, J. Paul TI A Neural Substrate for Behavioral Inhibition in the Risk for Major Depressive Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE depression risk; default-mode; ventral striatum; behavioral inhibition; fMRI ID SOCIAL-ANXIETY-DISORDER; RESTING-STATE FMRI; FUNCTIONAL CONNECTIVITY; UNIPOLAR DEPRESSION; NUCLEUS-ACCUMBENS; RESPONSE FUNCTION; DEFAULT NETWORK; MOOD DISORDERS; FAMILIAL RISK; HUMAN BRAIN AB Objective: Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI. Method: We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n = 16) or low familial risk (LR; n = 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses. Results: The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity. Conclusion: Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety. C1 [Bellgowan, Julie Frost; Santiago, Jessica; Drevets, Wayne C.; Hamilton, J. Paul] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne C.] Janssen Pharmaceut, B-2340 Beerse, Belgium. [Hamilton, J. Paul] Linkoping Univ, Ctr Social & Affect Neurosci, Linkoping, Sweden. [Molfese, Peter] Haskins Labs Inc, New Haven, CT USA. [Marx, Michael; Gotlib, Ian H.] Stanford Univ, Stanford, CA 94305 USA. [Thomason, Moriah] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA. [Glen, Daniel] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. RP Hamilton, JP (reprint author), Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. EM paul.hamilton@cal.berkeley.edu FU Warren Foundation FX The authors thank the Warren Foundation for funding the research presented in this article NR 66 TC 3 Z9 3 U1 5 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD OCT PY 2015 VL 54 IS 10 BP 841 EP 848 DI 10.1016/j.jaac.2015.08.001 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA CS4PA UT WOS:000362056800012 ER PT J AU Flynn, A Li, Q Panagia, M Abdelbaky, A MacNabb, M Samir, A Cypess, AM Weyman, AE Tawakol, A Scherrer-Crosbie, M AF Flynn, Aidan Li, Qian Panagia, Marcello Abdelbaky, Amr MacNabb, Megan Samir, Anthony Cypess, Aaron M. Weyman, Arthur E. Tawakol, Ahmed Scherrer-Crosbie, Marielle TI Contrast-Enhanced Ultrasound: A Novel Noninvasive, Nonionizing Method for the Detection of Brown Adipose Tissue in Humans SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Brown adipose tissue; Contrast-enhanced ultrasound; Imaging; Positron emission tomography; Activation ID BLOOD-FLOW; NONSHIVERING THERMOGENESIS; CORONARY STENOSIS; ADULT HUMANS; REAL-TIME; COLD; ECHOCARDIOGRAPHY; OBESITY; MICE; RAT AB Background: Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT). The investigators recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). Here, they report the application of this method in healthy humans. Methods: Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (beta) of microbubble replenishment curves. All underwent F-18-FDG PET/CT after cold exposure. Results: An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by F-18-FDGPET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median A beta = 3.3 AU/s [interquartile range, 0.5-5.7AU/s] vs 1.25AU/s [interquartile range, 0.5-2.6 AU/s]; P = .02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by F-18-FDG PET/CT (median maximal standardized uptake value, 2.25 [interquartile range, 1.53-4.57] vs 0.51 [interquartile range, 0.47-0.73]; P = .02). Conclusions: The present study demonstrates the feasibility of using CEUS as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies. C1 [Flynn, Aidan; Panagia, Marcello; Weyman, Arthur E.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Div Cardiol, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Li, Qian; Samir, Anthony] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Abdelbaky, Amr; MacNabb, Megan; Tawakol, Ahmed] Massachusetts Gen Hosp, Dept Nucl Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Cypess, Aaron M.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab,Res Div, Boston, MA 02115 USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 254,55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com FU National Institutes of Health (Bethesda, MD) [R21-DK092909, K23-DK081604]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by grants R21-DK092909 (M.S.-C.) and K23-DK081604 (A.M.C.) from the National Institutes of Health (Bethesda, MD); and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 32 TC 7 Z9 7 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD OCT PY 2015 VL 28 IS 10 BP 1247 EP 1254 DI 10.1016/j.echo.2015.06.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS9KT UT WOS:000362410700015 PM 26255029 ER PT J AU Uflacker, A Lim, S Ragosta, M Haskal, ZJ Lederman, RJ Kern, J Upchurch, G Huber, T Angle, JF Ailawadi, G AF Uflacker, Andre Lim, Scott Ragosta, Michael Haskal, Ziv J. Lederman, Robert J. Kern, John Upchurch, Gilbert Huber, Timothy Angle, John F. Ailawadi, Gorav TI Transcaval Aortic Access for Percutaneous Thoracic Aortic Aneurysm Repair: Initial Human Experience SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID ILIAC CONDUITS AB Transcaval aortic access has been used for deployment of transcatheter aortic valves in patients in whom conventional arterial approaches are not feasible. The present report describes its use for thoracic endovascular aortic repair (TEVAR) in a 61-year-old man with a descending thoracic aneurysm. Transcaval access was performed in lieu of a surgical iliac conduit in view of small atherosclerotic pelvic arteries. TEVAR was successfully performed, followed by intervascular tract occlusion with the use of a ventricular septal occluder. Computed tomography 2 d later demonstrated no extravasation. At 1 mo, the aneurysm was free of endoleaks, the aortocaval tract had healed, and the patient had returned to baseline functional status. C1 [Uflacker, Andre; Haskal, Ziv J.; Huber, Timothy; Angle, John F.] Univ Virginia, Div Intervent Radiol, Dept Radiol & Med Imaging, Charlottesville, VA 22908 USA. [Lim, Scott; Ragosta, Michael] Univ Virginia, Div Cardiovasc Med, Dept Med, Charlottesville, VA 22908 USA. [Kern, John; Upchurch, Gilbert] Univ Virginia, Div Vasc Surg, Dept Surg, Charlottesville, VA 22908 USA. [Ailawadi, Gorav] Univ Virginia, Div Cardiothorac Surg, Dept Surg, Charlottesville, VA 22908 USA. [Lederman, Robert J.] NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Haskal, ZJ (reprint author), Univ Virginia, Div Intervent Radiol, Dept Radiol & Med Imaging, 1215 Lee St, Charlottesville, VA 22908 USA. EM ziv2@mac.com OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [ZIA HL006040-06] NR 9 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2015 VL 26 IS 10 BP 1437 EP 1441 DI 10.1016/j.jvir.2015.07.024 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA CT2GT UT WOS:000362620700003 PM 26408210 ER PT J AU Levy, EB Johnson, CG Jacobs, G Woods, DL Sharma, KV Bacher, JD Lewis, AL Dreher, MR Wood, BJ AF Levy, Elliot B. Johnson, Carmen Gacchina Jacobs, Genevieve Woods, David L. Sharma, Karun V. Bacher, John D. Lewis, Andrew L. Dreher, Matthew R. Wood, Bradford J. TI Direct Quantification and Comparison of Intratumoral Hypoxia following Transcatheter Arterial Embolization of VX2 Liver Tumors with Different Diameter Microspheres SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID DRUG-ELUTING BEADS; HEPATOCELLULAR-CARCINOMA; INDUCIBLE FACTOR-1-ALPHA; OXYGEN-PRESSURE; RABBIT LIVER; CHEMOEMBOLIZATION; MODEL; RESPIRATION; EXPRESSION; EFFICACY AB Purpose: To evaluate the effect of embolic diameter on achievement of hypoxia after embolization in an animal model of liver tumors. Materials and Methods: Inoculation of VX2 tumors in the left liver lobe was performed successfully in 12 New Zealand white rabbits weighing 3.7 kg +/- 0.5 (mean +/- SD). Tumors were deemed eligible for oxygen measurements when the maximum transverse diameter measured 15 mm or more by ultrasound examination. Direct monitoring of oxygenation of implanted rabbit hepatic VX2 tumors was performed with a fiberoptic electrode during and after transarterial embolization of the proper hepatic artery to angiographic flow stasis with microspheres measuring 70-150 mu m, 100-300 mu m, or 300-500 mu m in diameter. Results: Failure to achieve tumor hypoxia as defined despite angiographic flow stasis was observed in 10 of 11 animals. Embolization microsphere size effect failed to demonstrate a significant trend on hypoxia outcome among the diameters tested, and pair-wise comparisons of different embolic diameter treatment groups showed no difference in hypoxia outcome. All microsphere diameters tested resulted in similar absolute reduction (24.3 mm Hg +/- 18.3, 29.1 mm Hg +/- 1.8, and 19.9 mm Hg +/- 9.3, P =.66) and percentage decrease in oxygen (56.0 mm Hg +/- 23.9, 56.0 mm Hg +/- 6.4, and 35.8 mm Hg +/- 20.6, P =.65). Pair-wise comparisons for percent tumor area occupied by embolic agents showed a significantly reduced fraction for 300-500 pm diameters compared with 70-150 pm diameters (P <.05). Conclusions: In the rabbit VX2 liver tumor model, three tested microsphere diameters failed to cause tumor hypoxia as measured by a fiberoptic probe sensor according to the adopted hypoxia defmitions. C1 [Levy, Elliot B.; Johnson, Carmen Gacchina; Jacobs, Genevieve; Woods, David L.; Sharma, Karun V.; Dreher, Matthew R.; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Div Vet Resources, Bethesda, MD 20892 USA. [Bacher, John D.] NIH, Ctr Clin, Div Vet Resources, Bethesda, MD 20892 USA. [Bacher, John D.] NIH, NCI, Div Vet Resources, Bethesda, MD 20892 USA. [Bacher, John D.] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Sharma, Karun V.] Georgetown Univ Hosp, Dept Radiol, Washington, DC 20007 USA. [Lewis, Andrew L.] Biocompatibles UK Ltd, Farnham, Surrey, England. RP Levy, EB (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Div Vet Resources, 9000 Rockville Pike,Bldg 10,Room 1C367, Bethesda, MD 20892 USA. EM levyeb@cc.nih.gov OI Lewis, Andrew/0000-0001-5779-5631 FU Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health [ZID BC 011242-06] FX This research was supported by the Center for Interventional Oncology in the Intramural Research Program (Grant No. ZID BC 011242-06) of the National Institutes of Health. The National Institutes of Health and Biocompatibles BTG are parties to a Cooperative Research and Development Agreement. We thank the Division of Veterinary Resources staff for their expertise and assistance with the animal studies, Dr. Mariam Anver and the National Cancer Institute Pathology/Histotechnology Laboratory Staff for assistance with histologic sample preparation, and Dr. Robert Wesley of the National Institutes of Health for assistance in statistical analyses. Also, we thank Drs. Jeff Geschwind, Eleni Liapi, and others from Johns Hopkins University for providing VX2 cells and propagation expertise. NR 24 TC 1 Z9 1 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD OCT PY 2015 VL 26 IS 10 BP 1567 EP 1573 DI 10.1016/j.jvir.2015.06.011 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA CT2GT UT WOS:000362620700026 PM 26231108 ER PT J AU Obeidat, M Hao, K Bosse, Y Nickle, DC Nie, YL Postma, DS Laviolette, M Sandford, AJ Daley, DD Hogg, JC Elliott, WM Fishbane, N Timens, W Hysi, PG Kaprio, J Wilson, JF Hui, J Rawal, R Schulz, H Stubbe, B Hayward, C Polasek, O Jarvelin, MR Zhao, JH Jarvis, D Kahonen, M Franceschini, N North, KE Loth, DW Brusselle, GG Smith, AV Gudnason, V Bartz, TM Wilk, JB O'Connor, GT Cassano, PA Tang, WB Wain, LV Artigas, MS Gharib, SA Strachan, DP Sin, DD Tobin, MD London, SJ Hall, IP Pare, PD AF Obeidat, Ma'en Hao, Ke Bosse, Yohan Nickle, David C. Nie, Yunlong Postma, Dirkje S. Laviolette, Michel Sandford, Andrew J. Daley, Denise D. Hogg, James C. Elliott, W. Mark Fishbane, Nick Timens, Wim Hysi, Pirro G. Kaprio, Jaakko Wilson, James F. Hui, Jennie Rawal, Rajesh Schulz, Holger Stubbe, Beate Hayward, Caroline Polasek, Ozren Jarvelin, Marjo-Riitta Zhao, Jing Hua Jarvis, Deborah Kahonen, Mika Franceschini, Nora North, Kari E. Loth, Daan W. Brusselle, Guy G. Smith, Albert Vernon Gudnason, Vilmundur Bartz, Traci M. Wilk, Jemma B. O'Connor, George T. Cassano, Patricia A. Tang, Wenbo Wain, Louise V. Artigas, Maria Soler Gharib, Sina A. Strachan, David P. Sin, Don D. Tobin, Martin D. London, Stephanie J. Hall, Ian P. Pare, Peter D. TI Molecular mechanisms underlying variations in lung function: a systems genetics analysis SO LANCET RESPIRATORY MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; GENOME-WIDE ASSOCIATION; BRANCHING MORPHOGENESIS; VITAMIN-A; EXPRESSION; COPD; CANCER; GENES; IDENTIFICATION; RECEPTORS AB Background Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. Methods The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. Findings SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. Interpretation The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. C1 [Obeidat, Ma'en; Nie, Yunlong; Sandford, Andrew J.; Daley, Denise D.; Hogg, James C.; Elliott, W. Mark; Fishbane, Nick; Sin, Don D.; Pare, Peter D.] Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC V6Z 1Y6, Canada. [Hao, Ke] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Bosse, Yohan] Univ Laval, Dept Mol Med, Quebec City, PQ, Canada. [Bosse, Yohan; Laviolette, Michel] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Nickle, David C.] Merck Res Labs, Genet & Pharmacogen, Boston, MA USA. [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands. [Timens, Wim] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, GRIAC Res Inst, Groningen, Netherlands. [Sandford, Andrew J.; Daley, Denise D.; Sin, Don D.; Pare, Peter D.] Univ British Columbia, Div Resp, Dept Med, Vancouver, BC V6Z 1Y6, Canada. [Hogg, James C.; Elliott, W. Mark] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6Z 1Y6, Canada. [Hysi, Pirro G.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Kaprio, Jaakko] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland. [Kaprio, Jaakko] Natl Inst Hlth & Welf, Helsinki, Finland. [Wilson, James F.; Polasek, Ozren] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Wilson, James F.; Hayward, Caroline] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Hui, Jennie] Busselton Populat Med Res Inst, Busselton, WA, Australia. [Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA, Australia. [Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Hui, Jennie] Univ Western Australia, Sch Pahol & Lab Med, Nedlands, WA 6009, Australia. [Rawal, Rajesh] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Rawal, Rajesh] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Schulz, Holger] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Schulz, Holger] German Ctr Lung Res, Comprehens Pneumol Ctr Munich CPC M, Munich, Germany. [Stubbe, Beate] Univ Hosp, Dept Internal Med B, Greifswald, Germany. [Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Jarvelin, Marjo-Riitta; Jarvis, Deborah] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England. [Jarvis, Deborah] Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol & Publ Hlth Grp, Natl Heart & Lung Inst, London, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Ctr Life Course Epidemiol, Fac Med,Oulu Univ Hosp, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Zhao, Jing Hua] Univ Cambridge, MRC Epidemiol Unit, Inst Metab Sci, Inst Clin Med, Cambridge, England. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, Mika] Tampere Univ Hosp, Tampere, Finland. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Ctr Genome Sci, Chapel Hill, NC USA. [Loth, Daan W.; Brusselle, Guy G.] Erasmus MC, Dept Epidemiol & Resp Med, Rotterdam, Netherlands. [Brusselle, Guy G.] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Smith, Albert Vernon; Gudnason, Vilmundur] Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Bartz, Traci M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Gharib, Sina A.] Univ Washington, Computat Med Core, Ctr Lung Biol, Seattle, WA 98195 USA. [Gharib, Sina A.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Wilk, Jemma B.] Pfizer Worldwide Res & Dev, Human Genet & Computat Biomed, Cambridge, MA USA. [O'Connor, George T.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cassano, Patricia A.; Tang, Wenbo] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Dept Healthcare Policy & Res, Div Biostat & Epidemiol, New York, NY USA. [Tang, Wenbo] Boehringer Ingelheim Pharmaceut, Ridgefield, CT USA. [Wain, Louise V.; Artigas, Maria Soler; Tobin, Martin D.] Univ Leicester, Genet Epidemiol Grp, Dept Hlth Sci, Leicester, Leics, England. [Wain, Louise V.; Artigas, Maria Soler; Tobin, Martin D.] Glenfield Gen Hosp, Leicester Resp Biomed Res Unit, NIHR, Leicester LE3 9QP, Leics, England. [Strachan, David P.] Univ London, Populat Hlth Res Inst, London, England. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Hall, Ian P.] Univ Nottingham, Div Resp Med, Univ Nottingham Hosp, Nottingham NG7 2RD, England. RP Pare, PD (reprint author), Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC V6Z 1Y6, Canada. EM peter.pare@hli.ubc.ca RI Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Schulz, Holger/J-5643-2015; Soler Artigas, Maria/L-6529-2013; Gudnason, Vilmundur/K-6885-2015; Smith, Albert Vernon/K-5150-2015; OI Wain, Louise/0000-0003-4951-1867; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Timens, Wim/0000-0002-4146-6363; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Schulz, Holger/0000-0002-1157-200X; Soler Artigas, Maria/0000-0002-3213-1107; Gudnason, Vilmundur/0000-0001-5696-0084; Hall, Ian/0000-0001-9933-3216; Smith, Albert Vernon/0000-0003-1942-5845; London, Stephanie/0000-0003-4911-5290 FU Wellcome Trust; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; NIHR; Medical Research Council Senior Clinical Fellowship [G0902313]; Great Wine Estates of the Margaret River region of Western Australia; Academy of Finland, Center of Excellence in Complex Disease Genetics and SALVE [NFBC1966, 104781, 120315, 129269, 1114194]; University Hospital Oulu; Biocenter; University of Oulu, Finland [75617]; European Commission (EURO-BLCS, Framework 5 award) [QLG1-CT-2000-01643]; NHLBI through the STAMPEED programme [5R01HL087679-02, 1RL1MH083268-01]; NIH/NIMH [5R01MH63706:02]; ENGAGE project [HEALTH-F4-2007-201413]; Medical Research Council, UK (PrevMetSyn/SALVE) [G0500539, G0600705]; EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing [277849]; Academy of Finland [213506, 129680, 265240, 263278]; Michael Smith Foundation for Health Research (MSFHR); Canadian Institute for Health Research (CIHR) Integrated and Mentored Pulmonary and Cardiovascular Training programme (IMPACT); Wellcome Trust Sanger Institute; European Commission: ENGAGE-European Network for Genetic; Genomic Epidemiology; Chief Scientist Office of the Scottish Executive; Royal Society; MRC [G0902313]; HealthWay, Western Australia; EU FP6; Ministry of Science, Education, and Sport of the Republic of Croatia; European Union framework program 6 EUROSPAN project; Academy of Finland; University Hospital Oulu, Biocenter, University of Oulu, Finland; European Commission, EURO-BLCS Framework 5 award; NHLBI grant through the STAMPEED programme; NIH/NIMH; European Commission, ENGAGE project; Medical Research Council, UK, PrevMetSyn/SALVE; European Commission, EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Coordination of the ECRHS-phenotype acquisition, EU; Gabriel project-genotyping, EU; Medical Research Fund of the Tampere University Hospital; Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval; Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec; Respiratory Health Network of the FRQS; Canadian Institutes of Health Research [MOP - 123369]; Cancer Research Society and Read for the Cure; Fonds de recherche Quebec - Sante (FRQS); Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 076113/B/04/Z, 079895]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International; National Institute for Health Research Cambridge Biomedical Research Centre; European Commission Framework Programme 6 [018996]; French Ministry of Research; 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 Institutes of Health; NIH Roadmap for Medical Research; [U01 DK062418]; [UL1RR025005] FX TwinsUK: The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. SpiroMeta consortium: The research undertaken by MDT, MSA, and LVW was part-funded by the NIHR. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MDT holds a Medical Research Council Senior Clinical Fellowship (G0902313). JH: The Busselton Health Study acknowledges the generous support for the 1994/5 follow-up study from Healthway, Western Australia, and the Busselton community volunteers who assisted with data collection and the study participants from the Shire of Busselton. The Busselton Health Study is supported by The Great Wine Estates of the Margaret River region of Western Australia. MR-J: NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED programme (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE), EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing 277849. The DNA extractions, sample quality controls, biobank up-keeping, and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland, and supported financially by the Academy of Finland and Biocentrum Helsinki. We thank Paula Rantakallio (launch of NFBC1966 and 1986), Outi Tornwall, and Minttu Jussila (DNA biobanking). IPH receives funding from the Medical Research Council (G1000861). EPIC-Norfolk study: We are grateful for the support and participation of participants in the study. We thank many colleagues who have worked on the EPIC-Norfolk study. We thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance collecting the lung tissue specimens for the eQTL study at Laval University. ARIC: We thank the staff and participants of the ARIC study for their important contributions. Funding: MO is a Postdoctoral Fellow of the Michael Smith Foundation for Health Research (MSFHR) and the Canadian Institute for Health Research (CIHR) Integrated and Mentored Pulmonary and Cardiovascular Training programme (IMPACT). JK: Wellcome Trust Sanger Institute. European Commission: ENGAGE-European Network for Genetic and Genomic Epidemiology. Academy of Finland (grant numbers 213506, 129680, 265240, 263278). JFW: Chief Scientist Office of the Scottish Executive. Royal Society. EU FP6. MDT: MRC, G0902313. JH: HealthWay, Western Australia; The Great Wine Estates of the Margaret River region of Western Australia. CH and OP: Medical Research Council; Ministry of Science, Education, and Sport of the Republic of Croatia; European Union framework program 6 EUROSPAN project.; MRJ: Academy of Finland; University Hospital Oulu, Biocenter, University of Oulu, Finland; European Commission, EURO-BLCS Framework 5 award; NHLBI grant through the STAMPEED programme; NIH/NIMH; European Commission, ENGAGE project and grant agreement; Medical Research Council, UK, PrevMetSyn/SALVE; European Commission, EU Framework Programme 7 small-scale focused research collaborative project EurHEALTHAgeing. SJL: Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. JHZ is funded by the Medical Research Council, UK. DJ: Coordination of the ECRHS-phenotype acquisition, EU; Gabriel project-genotyping, EU. MK: Medical Research Fund of the Tampere University Hospital. The lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval, the Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP - 123369), and the Cancer Research Society and Read for the Cure. YB is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec - Sante (FRQS). British 1958 Birth Cohort DNA collection: use of phenotype and genotype data, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International, and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. ARIC: The Atherosclerosis Risk in Communities 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. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. NR 73 TC 8 Z9 8 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD OCT PY 2015 VL 3 IS 10 BP 782 EP 795 DI 10.1016/S2213-2600(15)00380-X PG 14 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CS9ZJ UT WOS:000362452900022 PM 26404118 ER PT J AU Khodr, ZG Sak, MA Pfeiffer, RM Duric, N Littrup, P Bey-Knight, L Ali, H Vallieres, P Sherman, ME Gierach, GL AF Khodr, Zeina G. Sak, Mark A. Pfeiffer, Ruth M. Duric, Nebojsa Littrup, Peter Bey-Knight, Lisa Ali, Haythem Vallieres, Patricia Sherman, Mark E. Gierach, Gretchen L. TI Determinants of the reliability of ultrasound tomography sound speed estimates as a surrogate for volumetric breast density SO MEDICAL PHYSICS LA English DT Article DE breast density; ultrasound tomography; reliability; reproducibility; change in breast density; breast cancer ID MAMMOGRAPHIC DENSITY; CANCER RISK; DATA SYSTEM; TISSUE; REPRODUCIBILITY; CLASSIFICATION; VARIABILITY; CATEGORIES; REDUCTION; PREDICTOR AB Purpose: High breast density, as measured by mammography, is associated with increased breast cancer risk, but standard methods of assessment have limitations including 2D representation of breast tissue, distortion due to breast compression, and use of ionizing radiation. Ultrasound tomography (UST) is a novel imaging method that averts these limitations and uses sound speed measures rather than x-ray imaging to estimate breast density. The authors evaluated the reproducibility of measures of speed of sound and changes in this parameter using UST. Methods: One experienced and five newly trained raters measured sound speed in serial UST scans for 22 women (two scans per person) to assess inter-rater reliability. Intrarater reliability was assessed for four raters. A random effects model was used to calculate the percent variation in sound speed and change in sound speed attributable to subject, scan, rater, and repeat reads. The authors estimated the intraclass correlation coefficients (ICCs) for these measures based on data from the authors' experienced rater. Results: Median (range) time between baseline and follow-up UST scans was five (1-13) months. Contributions of factors to sound speed variance were differences between subjects (86.0%), baseline versus follow-up scans (7.5%), inter-rater evaluations (1.1%), and intrarater reproducibility (similar to 0%). When evaluating change in sound speed between scans, 2.7% and similar to 0% of variation were attributed to inter-and intrarater variation, respectively. For the experienced rater's repeat reads, agreement for sound speed was excellent (ICC = 93.4%) and for change in sound speed substantial (ICC = 70.4%), indicating very good reproducibility of these measures. Conclusions: UST provided highly reproducible sound speed measurements, which reflect breast density, suggesting that UST has utility in sensitively assessing change in density. (C) 2015 American Association of Physicists in Medicine. C1 [Khodr, Zeina G.; Pfeiffer, Ruth M.; Gierach, Gretchen L.] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sak, Mark A.; Duric, Nebojsa; Littrup, Peter; Bey-Knight, Lisa] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Duric, Nebojsa; Littrup, Peter] Delphinus Med Technol, Plymouth, MI 48170 USA. [Ali, Haythem; Vallieres, Patricia] Henry Ford Hlth Syst, Detroit, MI 48202 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Gierach, GL (reprint author), NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM GierachG@mail.nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors are indebted to the participants in the Ultrasound Study of Tamoxifen for dedicating their valuable time and to the physicians, nurses, technologists, and interviewers for their efforts in the field. The authors thank Vivian Linke and Tiffany Drane for research assistance. The authors also thank Beth Slotman and Kerry Grace Morrissey from Westat for study management support. N. Duric and P. Littrup are coinventors of and have intellectual property interests in the ultrasound technology used for the measurements described in this paper. The remaining authors declare that they have no conflicts of interest. NR 49 TC 3 Z9 3 U1 0 U2 2 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD OCT PY 2015 VL 42 IS 10 BP 5671 EP 5678 DI 10.1118/1.4929985 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CT1OY UT WOS:000362570100010 PM 26429241 ER PT J AU Williamson, P AF Williamson, P. TI Paradoxical immune responses in non-HIV related cryptococcal meningitis SO MYCOSES LA English DT Meeting Abstract C1 [Williamson, P.] NIH, 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 0933-7407 EI 1439-0507 J9 MYCOSES JI Mycoses PD OCT PY 2015 VL 58 SU 4 SI SI MA S10.1 BP 31 EP 31 PG 1 WC Dermatology; Mycology SC Dermatology; Mycology GA CT4SF UT WOS:000362796800060 ER PT J AU Walsh, TJ Gamaletsou, MN Rammaert, B Bueno, M Sipsas, N Moriyama, B Kontoyiannis, DP Roilides, E Zeller, V Saad, JTAJA Andy, OM Petraitis, V Lortholary, O Walsh, TJ AF Walsh, T. J. Gamaletsou, M. N. Rammaert, B. Bueno, M. Sipsas, N. Moriyama, B. Kontoyiannis, D. P. Roilides, E. Zeller, V. Saad, J. T. A. J. A. Andy, O. M. Petraitis, V. Lortholary, O. Walsh, T. J. TI Aspergillus Arthritis: analysis of clinical manifestations, diagnosis, and treatment of 31 cases SO MYCOSES LA English DT Meeting Abstract C1 [Walsh, T. J.; Andy, O. M.; Petraitis, V.; Walsh, T. J.] Weill Cornell Med Ctr, New York, NY USA. [Walsh, T. J.; Andy, O. M.; Petraitis, V.; Walsh, T. J.] New York Presbyterian Hosp, New York, NY USA. [Gamaletsou, M. N.; Sipsas, N.] Univ Athens, Athens, Greece. [Rammaert, B.; Zeller, V.; Lortholary, O.] Univ Paris 05, Paris, France. [Bueno, M.] Cornell Univ, Weill Cornell Med Ctr, New York, NY 10021 USA. [Moriyama, B.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kontoyiannis, D. P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Roilides, E.] Aristotle Univ Thessaloniki, GR-54006 Thessaloniki, Greece. [Saad, J. T. A. J. A.] Hamad Med Corp, Doha, Qatar. 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 0933-7407 EI 1439-0507 J9 MYCOSES JI Mycoses PD OCT PY 2015 VL 58 SU 4 SI SI MA O1.5 BP 45 EP 46 PG 2 WC Dermatology; Mycology SC Dermatology; Mycology GA CT4SF UT WOS:000362796800101 ER PT J AU Murugaiyah, V Mattson, MP AF Murugaiyah, Vikneswaran Mattson, Mark P. TI Neurohormetic phytochemicals: An evolutionary-bioenergetic perspective SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Adaptive stress response; Alzheimer's disease; AMPK; Hormesis; mTOR; Sirtuin ID PLANT SECONDARY METABOLITES; ACTIVATED PROTEIN-KINASE; LIFE-SPAN; PARKINSONS-DISEASE; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; SIGNALING PATHWAY; CALORIE RESTRICTION; INSULIN-RESISTANCE; INDUCED NEUROTOXICITY AB The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. Published by Elsevier Ltd. C1 [Murugaiyah, Vikneswaran] Univ Sains Malaysia, Sch Pharmaceut Sci, George Town 11800, Malaysia. [Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU National Institute on Aging, NIH FX This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 139 TC 11 Z9 11 U1 6 U2 33 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD OCT PY 2015 VL 89 BP 271 EP 280 DI 10.1016/j.neuint.2015.03.009 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CT2CO UT WOS:000362609800028 PM 25861940 ER PT J AU Izumi, Y Yang, WJ Zhu, J Burg, MB Ferraris, JD AF Izumi, Yuichiro Yang, Wenjing Zhu, Jun Burg, Maurice B. Ferraris, Joan D. TI RNA-Seq analysis of high NaCl-induced gene expression SO PHYSIOLOGICAL GENOMICS LA English DT Article DE NFAT5; hypertonicity; GO analysis; osmotic; RNA ID TRANSCRIPTION FACTOR TONEBP/OREBP; PROTEIN-TYROSINE-PHOSPHATASE; OXYGEN SPECIES CONTRIBUTE; ELEMENT-BINDING PROTEIN; STIMULATES TRANSCRIPTION; INDUCED ACTIVATION; HYPERTONICITY; CELLS; STRESS; NFAT5 AB High extracellular NaCl is known to change expression of numerous genes, many of which are regulated by the osmoprotective transcription factor nuclear factor of activated T cells-5 (NFAT5). In the present study we employed RNA-Seq to provide a comprehensive, unbiased account of genes regulated by high NaCl in mouse embryonic fibroblast cells (MEFs). To identify genes regulated by NFAT5 we compared wild-type MEFs (WT-MEFs) to MEFs in which mutation of the NFAT5 gene inhibits its transcriptional activity (Null-MEFs). In WT-MEFs adding NaCl to raise osmolality from 300 to 500 mosmol/kg for 24 h increases expression of 167 genes and reduces expression of 412. Raising osmolality through multiple passages (adapted cells) increases expression of 196 genes and reduces expression of 528. In Null-MEFs, after 24 h of high NaCl, expression of 217 genes increase and 428 decrease, while in adapted Null-MEFs 143 increase and 622 decrease. Fewer than 10% of genes are regulated in common between WT- and null-MEFs, indicating a profound difference in regulation of high-NaCl induced genes induced by NFAT5 compared with those induced in the absence of NFAT5. Based on our findings we suggest a mechanism for this phenomenon, which had previously been unexplained. The NFAT5 DNA-binding motif (osmotic response element) is overrepresented in the vicinity of genes that NFAT5 upregulates, but not genes that it downregulates. We used Gene Ontology and manual curation to determine the function of the genes targeted by NFAT5, revealing many novel consequences of NFAT5 transcriptional activity. C1 [Izumi, Yuichiro; Yang, Wenjing; Zhu, Jun; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Rm 6N307, Bethesda, MD 20892 USA. EM Maurice_burg@nih.gov NR 41 TC 3 Z9 3 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD OCT 1 PY 2015 VL 47 IS 10 BP 500 EP 513 DI 10.1152/physiolgenomics.00057.2015 PG 14 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA CT1QJ UT WOS:000362575100008 PM 26220925 ER PT J AU Song, JH Cui, L An, LB Li, WT Fang, ZZ Zhang, YY Dong, PP Wu, X Wang, LX Gonzalez, FJ Sun, XY Zhao, DW AF Song, Jin-Hui Cui, Li An, Li-Bin Li, Wen-Tao Fang, Zhong-Ze Zhang, Yan-Yan Dong, Pei-Pei Wu, Xue Wang, Li-Xuan Gonzalez, Frank J. Sun, Xiao-Yu Zhao, De-Wei TI Inhibition of UDP-Glucuronosyltransferases (UGTs) Activity by constituents of Schisandra chinensis SO PHYTOTHERAPY RESEARCH LA English DT Article DE Schisandra chinensis; UDP-glucuronosyltransferases (UGTs); herb-drug interaction; in silico; in vitro ID HERB-DRUG INTERACTION; EXTRACT; IDENTIFICATION; SPHENANTHERA; LIGNANS AB Structure-activity relationship for the inhibition of Schisandra chinensis's ingredients toward (Uridine-Diphosphate) UDP-glucuronosyltransferases (UGTs) activity was performed in the present study. In vitro incubation system was employed to screen the inhibition capability of S.chinensis's ingredients, and in silico molecular docking method was carried out to explain possible mechanisms. At 100M of compounds, the activity of UGTs was inhibited by less than 90% by schisandrol A, schisandrol B, schisandrin, schisandrin C, schisantherin A, gomisin D, and gomisin G. Schisandrin A exerted strong inhibition toward UGT1A1 and UGT1A3, with the residual activity to be 7.9% and 0% of control activity. Schisanhenol exhibited strong inhibition toward UGT2B7, with the residual activity to be 7.9% of control activity. Gomisin J of 100M inhibited 91.8% and 93.1% of activity of UGT1A1 and UGT1A9, respectively. Molecular docking prediction indicated different hydrogen bonds interaction resulted in the different inhibition potential induced by subtle structure alteration among schisandrin A, schisandrin, and schisandrin C toward UGT1A1 and UGT1A3: schisandrin A>schisandrin>schisandrin C. The detailed inhibition kinetic evaluation showed the strong inhibition of gomisin J toward UGT1A9 with the inhibition kinetic parameter (K-i) to be 0.7M. Based on the concentrations of gomisin J in the plasma of the rats given with S.chinensis, high herb-drug interaction existed between S.chinensis and drugs mainly undergoing UGT1A9-mediated metabolism. In conclusion, in silico-in vitro method was used to give the inhibition information and possible inhibition mechanism for S.chinensis's components toward UGTs, which guide the clinical application of S.chinensis. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Song, Jin-Hui; Cui, Li; Zhao, De-Wei] Dalian Univ, Affiliated Zhongshan Hosp, Dalian 116001, Peoples R China. [An, Li-Bin; Li, Wen-Tao] Dalian Univ, Dalian 116622, Peoples R China. [Wu, Xue; Wang, Li-Xuan; Sun, Xiao-Yu] Personalized Treatment & Diag Ctr, Dalian 116001, Peoples R China. [Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin 300070, Peoples R China. [Zhang, Yan-Yan] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou, Liaoning, Peoples R China. [Dong, Pei-Pei] Dalian Med Univ, Inst Integrat Med, Coll Pharm, Dalian 116044, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhao, DW (reprint author), Dalian Univ, Affiliated Zhongshan Hosp, 6 Jiefang St, Dalian 116001, Peoples R China. EM zhaodewei2000@163.com FU National Natural Science Foundation of China [81202586, 81202587, 81202588, 81303146] FX This work was supported by the National Natural Science Foundation of China (no. 81202586, 81202587, 81202588, 81303146). NR 16 TC 4 Z9 4 U1 6 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-418X EI 1099-1573 J9 PHYTOTHER RES JI Phytother. Res. PD OCT PY 2015 VL 29 IS 10 BP 1658 EP 1664 DI 10.1002/ptr.5395 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CT4QX UT WOS:000362792900029 PM 26084208 ER PT J AU Nock, MK Ursano, RJ Heeringa, SG Stein, MB Jain, S Raman, R Sun, XY Chiu, WT Colpe, LJ Fullerton, CS Gilman, SE Hwang, I Naifeh, JA Rosellini, AJ Sampson, NA Schoenbaum, M Zaslavsky, AM Kessler, RC AF Nock, Matthew K. Ursano, Robert J. Heeringa, Steven G. Stein, Murray B. Jain, Sonia Raman, Rema Sun, Xiaoying Chiu, Wai Tat Colpe, Lisa J. Fullerton, Carol S. Gilman, Stephen E. Hwang, Irving Naifeh, James A. Rosellini, Anthony J. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Kessler, Ronald C. CA Army STARRS Collaborators TI Mental Disorders, Comorbidity, and Pre-enlistment Suicidal Behavior Among New Soldiers in the US Army: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID ADOLESCENT SUICIDE; PREVALENCE; DEPRESSION; ATTEMPTERS AB We examined the associations between mental disorders and suicidal behavior (ideation, plans, and attempts) among new soldiers using data from the New Soldier Study (NSS) component of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS; N=38,507). Most new soldiers with a pre-enlistment history of suicide attempt reported a prior mental disorder (59.0%). Each disorder examined was associated with increased odds of suicidal behavior (ORs=2.6-8.6). Only PTSD and disorders characterized by irritability and impulsive/aggressive behavior (i.e., bipolar disorder, conduct disorder, oppositional defiant disorder, and attention-deficit/hyperactivity disorder) predicted unplanned attempts among ideators. Mental disorders are important predictors of pre-enlistment suicidal behavior among new soldiers and should figure prominently in suicide screening and prevention efforts. C1 [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Ursano, Robert J.; Fullerton, Carol S.; Naifeh, James A.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Stein, Murray B.] Univ Calif San Diego, VA San Diego Healthcare Syst, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.; Jain, Sonia; Raman, Rema; Sun, Xiaoying] Univ Calif San Diego, VA San Diego Healthcare Syst, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Raman, Rema] Univ Calif San Diego, VA San Diego Healthcare Syst, Dept Neurosci, La Jolla, CA 92093 USA. [Chiu, Wai Tat; Hwang, Irving; Rosellini, Anthony J.; Sampson, Nancy A.; Zaslavsky, Alan M.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Gilman, Stephen E.; Hwang, Irving] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Nock, MK (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. EM nock@wjh.harvard.edu OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army [U01MH087981]; U.S. Department of Health and Human Services, National Institutes of Health, and 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, and 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, NIMH, the Department of the Army, or the Department of Defense. NR 39 TC 5 Z9 5 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD OCT PY 2015 VL 45 IS 5 BP 588 EP 599 DI 10.1111/sltb.12153 PG 12 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CT3FR UT WOS:000362693100006 ER PT J AU Norton, JA Krampitz, G Jensen, RT AF Norton, Jeffrey A. Krampitz, Geoffrey Jensen, Robert T. TI Multiple Endocrine Neoplasia Genetics and Clinical Management SO SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Endocrine neoplasia; Genetics; Clinical management; Multiple endocrine neoplasia ID ZOLLINGER-ELLISON-SYNDROME; PANCREATIC NEUROENDOCRINE TUMORS; MEDULLARY-THYROID CARCINOMA; DES-TUMEURS-ENDOCRINES; LONG-TERM-FOLLOW; SYNDROME TYPE-I; ENETS CONSENSUS GUIDELINES; IMPAIRED FASTING GLUCOSE; C-RET PROTOONCOGENE; GERM-LINE MUTATIONS AB Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be suspected. Genetic testing for germline alterations in both the MEN type 1 (MEN1) gene and RET proto-oncogene is crucial to identifying those at risk in affected kindreds and directing timely surveillance and surgical therapy to those at greatest risk of potentially life-threatening neoplasia. Pancreatic, thymic, and bronchial neuroendocrine tumors are the leading cause of death in patients with MEN1 and should be aggressively considered by at least biannual computed tomography imaging. C1 [Norton, Jeffrey A.; Krampitz, Geoffrey] Stanford Univ, Dept Surg, Sch Med, Stanford, CA 94305 USA. [Jensen, Robert T.] Natl Inst Arthrit Diabet Digest & Kidney Dis, Cell Biol Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Norton, JA (reprint author), Stanford Univ, Dept Surg, Sch Med, 300 Pasteur Dr,H3591, Stanford, CA 94305 USA. EM janorton@stanford.edu FU NCI NIH HHS [R01 CA096645] NR 240 TC 3 Z9 3 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 1055-3207 EI 1558-5042 J9 SURG ONCOL CLIN N AM JI Surg. Oncol. Clin. N. Am. PD OCT PY 2015 VL 24 IS 4 BP 795 EP + DI 10.1016/j.soc.2015.06.008 PG 39 WC Oncology; Surgery SC Oncology; Surgery GA CT3GA UT WOS:000362694000012 PM 26363542 ER PT J AU McLeod, DSA Jonklaas, J Brierley, JD Ain, KB Cooper, DS Fein, HG Haugen, BR Ladenson, PW Magner, J Ross, DS Skarulis, MC Steward, DL Xing, MZ Litofsky, DR Maxon, HR Sherman, SI AF McLeod, Donald S. A. Jonklaas, Jacqueline Brierley, James D. Ain, Kenneth B. Cooper, David S. Fein, Henry G. Haugen, Bryan R. Ladenson, Paul W. Magner, James Ross, Douglas S. Skarulis, Monica C. Steward, David L. Xing, Mingzhao Litofsky, Danielle R. Maxon, Harry R. Sherman, Steven I. TI Reassessing the NTCTCS Staging Systems for Differentiated Thyroid Cancer, Including Age at Diagnosis SO THYROID LA English DT Article ID TALL-CELL VARIANT; CARCINOMA; PAPILLARY; PROGNOSIS; SURVIVAL; THERAPY; THYROTROPIN; REGISTRY; RISK AB Background: Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned. Objective: This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer. Methods: A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R-2). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination. Results: The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p=0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p=0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p=0.197). Conclusions: No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation. C1 [McLeod, Donald S. A.] Royal Brisbane & Womens Hosp, Dept Endocrinol & Diabet, Herston, Qld, Australia. [McLeod, Donald S. A.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, Herston, Qld, Australia. [McLeod, Donald S. A.] Univ Queensland, Sch Med, Herston, Qld, Australia. [Jonklaas, Jacqueline] Georgetown Univ, Med Ctr, Dept Med, Div Endocrinol, Washington, DC 20007 USA. [Brierley, James D.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Ain, Kenneth B.] Vet Affairs Med Ctr, Dept Internal Med, Lexington, KY USA. [Ain, Kenneth B.] Univ Kentucky, Lexington, KY USA. [Cooper, David S.; Ladenson, Paul W.; Xing, Mingzhao] Johns Hopkins Univ, Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Fein, Henry G.] Sinai Hosp, Div Endocrinol & Metab, Baltimore, MD 21215 USA. [Haugen, Bryan R.] Univ Colorado, Sch Med, Div Endocrinol Metab & Diabet, Aurora, CO USA. [Magner, James] Genzyme, Cambridge, MA USA. [Ross, Douglas S.] Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. [Skarulis, Monica C.] NIH, Diabet, Endocrinol, Obes Branch, Bethesda, MD 20892 USA. [Steward, David L.] Univ Cincinnati, Med Ctr, Dept Head & Neck Surg, Cincinnati, OH 45267 USA. [Maxon, Harry R.] Univ Cincinnati, Med Ctr, Dept Nucl Med, Cincinnati, OH 45267 USA. [Litofsky, Danielle R.; Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. RP Sherman, SI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, 1400 Pressler,Unit 1461, Houston, TX 77030 USA. EM sisherma@mdanderson.org RI McLeod, Donald/C-4242-2014; OI McLeod, Donald/0000-0003-1131-020X; Sherman, Steven/0000-0002-3079-5153 FU Genzyme; Sanofi Company; Pfizer; University of Texas M.D. Anderson Cancer Center Support Grant (NCI) [P30 CA016672]; Cancer Council Queensland; National Health and Medical Research Council of Australia [APP1092153] FX The NTCTCS has been supported in part by research grants from Genzyme, a Sanofi Company, and Pfizer, and by the University of Texas M.D. Anderson Cancer Center Support Grant (NCI Grant P30 CA016672). The Cancer Council Queensland (PhD Scholarship) and the National Health and Medical Research Council of Australia (APP1092153) supported D.M. NR 35 TC 4 Z9 4 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD OCT 1 PY 2015 VL 25 IS 10 BP 1097 EP 1105 DI 10.1089/thy.2015.0148 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7LY UT WOS:000362266300005 PM 26203804 ER PT J AU Bahadori, A Miglioretti, D Kruger, R Flynn, M Weinmann, S Smith-Bindman, R Lee, C AF Bahadori, Amir Miglioretti, Diana Kruger, Randell Flynn, Michael Weinmann, Sheila Smith-Bindman, Rebecca Lee, Choonsik TI Calculation of Organ Doses for a Large Number of Patients Undergoing CT Examinations SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE CT; dosimetry; informatics; Monte Carlo simulations; phantom ID COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; PEDIATRIC CT; CANCER-RISK; DOSIMETRY; SCANS; POPULATION; PHANTOMS; CHILDREN; PROGRAM AB OBJECTIVE. The objective of our study was to develop an automated calculation method to provide organ dose assessment for a large cohort of pediatric and adult patients undergoing CT examinations. MATERIALS AND METHODS. We adopted two dose libraries that were previously published: the volume CT dose index-normalized organ dose library and the tube current-exposure time product (100 mAs)-normalized weighted CT dose index library. We developed an algorithm to calculate organ doses using the two dose libraries and the CT parameters available from DICOM data. We calculated organ doses for pediatric (n = 2499) and adult (n = 2043) CT examinations randomly selected from four health care systems in the United States and compared the adult organ doses with the values calculated from the ImPACT calculator. RESULTS. The median brain dose was 20 mGy (pediatric) and 24 mGy (adult), and the brain dose was greater than 40 mGy for 11% (pediatric) and 18% (adult) of the head CT studies. Both the National Cancer Institute (NCI) and ImPACT methods provided similar organ doses (median discrepancy < 20%) for all organs except the organs located close to the scanning boundaries. The visual comparisons of scanning coverage and phantom anatomies revealed that the NCI method, which is based on realistic computational phantoms, provides more accurate organ doses than the ImPACT method. CONCLUSION. The automated organ dose calculation method developed in this study reduces the time needed to calculate doses for a large number of patients. We have successfully used this method for a variety of CT-related studies including retrospective epidemiologic studies and CT dose trend analysis studies. C1 [Bahadori, Amir] NASA, Space Radiat Anal Grp, Johnson Space Ctr, Houston, TX USA. [Miglioretti, Diana] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Div Biostat, Davis, CA 95616 USA. [Kruger, Randell] Marshfield Clin & Res Fdn, Dept Radiol, Marshfield, WI USA. [Flynn, Michael] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI USA. [Flynn, Michael] Henry Ford Hlth Syst, Ctr Hlth Serv Res, Detroit, MI USA. [Weinmann, Sheila] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH, Rockville, MD 20850 USA. RP Lee, C (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM leechoonsik@mail.nih.gov RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 24 TC 0 Z9 0 U1 0 U2 1 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 OCT PY 2015 VL 205 IS 4 BP 827 EP 833 DI 10.2214/AJR.14.14135 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300034 PM 26397332 ER PT J AU Miettinen, M Wang, ZF Lasota, J Heery, C Schlom, J Palena, C AF Miettinen, Markku Wang, Zengfeng Lasota, Jerzy Heery, Christopher Schlom, Jeffrey Palena, Claudia TI Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas An Immunohistochemical Study of 5229 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE brachyury; chordoma; seminoma; germ cell tumor; small cell carcinoma ID TRANSCRIPTION FACTOR BRACHYURY; EPITHELIAL-MESENCHYMAL TRANSITION; MESODERM FORMATION; SOFT-TISSUE; T-GENE; CANCER; MOUSE AB Brachyury is a transcription factor of the T-box family typically expressed in notochord and chordoma. Some studies report brachyury as highly specific for chordoma, whereas others have concluded that brachyury is expressed in many types of common carcinomas by reverse transcription polymerase chain reaction and immunohistochemistry and could be involved in the epithelial-mesenchymal transition and metastatic process. In this study, we immunohistochemically evaluated 5229 different tumors for nuclear brachyury expression using a new rabbit monoclonal antibody and automated immunostaining (Leica Bond Max). Only nuclear labeling was scored, and antibody dilution of 1:2000 was used. In normal tissues, only rare cells in seminiferous tubules were labeled; all other organs were negative. All chordomas (75/76), except a sarcomatous one, were positive, whereas chondrosarcomas were negative. Among epithelial tumors, positivity was often detected in embryonal carcinoma (74%) and seminoma (45%). Pulmonary small cell carcinoma was often positive (41%), whereas pulmonary and pancreatic adenocarcinomas only rarely showed nuclear brachyury positivity (3% to 4%). Common carcinomas such as ductal carcinomas of the breast or adenocarcinomas of the prostate only exceptionally showed nuclear positivity (<1%). No colorectal, hepatocellular, renal cell, squamous cell, thyroid or urothelial carcinoma, or mesothelioma showed nuclear brachyury positivity. Among mesenchymal and neuroectodermal tumors, only isolated cases of melanoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and follicular lymphoma showed nuclear expression. However, as shown previously with lung carcinoma, experiments with lower antibody dilutions (1:200 to 1:500) showed weak cytoplasmic and nuclear labeling in breast cancers. In addition to chordoma, we show here for the first time that nuclear brachyury expression is prevalent in embryonal carcinoma, seminoma, and small cell carcinoma of the lung but very rare in common carcinomas, sarcomas, and melanoma. With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma. C1 [Miettinen, Markku; Wang, Zengfeng; Lasota, Jerzy] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Heery, Christopher; Schlom, Jeffrey; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Miettinen, M (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. C.P. and J.S. have submitted, as part of their official duties at NIH, an employee invention report concerning the monoclonal anti-brachyury antibody used in this study. The remaining authors declare no conflict of interest. NR 23 TC 9 Z9 9 U1 3 U2 5 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 OCT PY 2015 VL 39 IS 10 BP 1305 EP 1312 DI 10.1097/PAS.0000000000000462 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA CS5IU UT WOS:000362112400001 PM 26099010 ER PT J AU Yuan, J Wright, G Rosenwald, A Steidl, C Gascoyne, RD Connors, JM Mottok, A Weisenburger, DD Greiner, TC Fu, K Smith, L Rimsza, LM Jaffe, ES Campo, E Martinez, A Delabie, J Braziel, RM Cook, JR Ott, G Vose, JM Staudt, LM Chan, WC AF Yuan, Ji Wright, George Rosenwald, Andreas Steidl, Christian Gascoyne, Randy D. Connors, Joseph M. Mottok, Anja Weisenburger, Dennis D. Greiner, Timothy C. Fu, Kai Smith, Lynette Rimsza, Lisa M. Jaffe, Elaine S. Campo, Elias Martinez, Antonio Delabie, Jan Braziel, Rita M. Cook, James R. Ott, German Vose, Julie M. Staudt, Louis M. Chan, Wing C. CA Lymphoma Leukemia Mol Profiling Pr TI Identification of Primary Mediastinal Large B-cell Lymphoma at Nonmediastinal Sites by Gene Expression Profiling SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE primary mediastinal large B-cell lymphoma; gene expression profiling; CIITA; PDL1; 2 ID GRAY ZONE LYMPHOMA; HODGKIN LYMPHOMA; MOLECULAR PATHOGENESIS; AMPLIFICATION; FEATURES; CHEMOTHERAPY; INDUCTION; SIGNATURE; SUBGROUP; GAIN AB Mediastinal involvement is considered essential for the diagnosis of primary mediastinal large B-cell lymphoma (PMBL). However, we have observed cases of diffuse large B-cell lymphoma (DLBCL) with features of PMBL but without detectable mediastinal involvement. The goal was to assess our previously established gene expression profiling (GEP) signature for PMBL in classifying these cases. In a large series of DLBCL cases, we identified 24 cases with a GEP signature of PMBL, including 9 cases with a submission diagnosis of DLBCL consistent with PMBL (G-PMBL-P) and 15 cases with a submission diagnosis of DLBCL. The pathology reviewers agreed with the diagnosis in the 9 G-PMBL-P cases. Among the other 15 DLBCL cases, 11 were considered to be PMBL or DLBCL consistent with PMBL, 3 were considered to be DLBCL, and 1 case was a gray-zone lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. All 9 G-PMBL-P and 9 of the 15 DLBCL cases (G-PMBL-M) had demonstrated mediastinal involvement at presentation. Interestingly, 6 of the 15 DLBCL cases (G-PMBL-NM) had no clinical or radiologic evidence of mediastinal involvement. The 3 subgroups of PMBL had otherwise similar clinical characteristics, and there were no significant differences in overall survival. Genetic alterations of CIITA and PDL1/2 were detected in 26% and 40% of cases, respectively, including 1 G-PMBL-NM case with gain of PDL1/2. In conclusion, PMBL can present as a nonmediastinal tumor without evidence of mediastinal involvement, and GEP offers a more precise diagnosis of PMBL. C1 [Yuan, Ji; Greiner, Timothy C.; Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Smith, Lynette] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Biostat, Omaha, NE USA. [Vose, Julie M.] Univ Nebraska Med Ctr, Dept Hematol Oncol, Omaha, NE USA. [Wright, George; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weisenburger, Dennis D.; Chan, Wing C.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Clin Pathol, Portland, OR 97201 USA. [Cook, James R.] Cleveland Clin, Dept Mol Pathol & Lab Med, Cleveland, OH 44106 USA. [Rosenwald, Andreas] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Inst Pathol, D-97070 Wurzburg, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Steidl, Christian; Gascoyne, Randy D.; Connors, Joseph M.; Mottok, Anja] Univ British Columbia, British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1M9, Canada. [Campo, Elias; Martinez, Antonio] Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain. [Delabie, Jan] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. RP Chan, WC (reprint author), City Hope Natl Med Ctr, Dept Pathol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM jochan@coh.org RI Campo, elias/O-7192-2016 OI Campo, elias/0000-0001-9850-9793 FU National Institutes of Health [UO1CA157581] FX Partly supported by National Institutes of Health grant UO1CA157581 to W.C.C. NR 31 TC 8 Z9 8 U1 1 U2 6 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 OCT PY 2015 VL 39 IS 10 BP 1322 EP 1330 DI 10.1097/PAS.0000000000000473 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA CS5IU UT WOS:000362112400003 PM 26135560 ER PT J AU Waters, AM Zimmer-Gembeck, MJ Craske, MG Pine, DS Bradley, BP Mogg, K AF Waters, Allison M. Zimmer-Gembeck, Melanie J. Craske, Michelle G. Pine, Daniel S. Bradley, Brendan P. Mogg, Karin TI Look for good and never give up: A novel attention training treatment for childhood anxiety disorders SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Anxiety; Children; Attention; Modification ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; BIAS MODIFICATION TREATMENT; ASSESSMENT SCALE CGAS; SOCIAL PHOBIA; ANXIOUS CHILDREN; GLOBAL ASSESSMENT; EXPERIMENTAL MANIPULATION; DEPRESSIVE-DISORDERS; MODIFICATION PROGRAM AB Attention bias modification training (ABMT) is a promising treatment for anxiety disorders. Recent evidence suggests that attention training towards positive stimuli, using visual-search based ABMT, has beneficial effects on anxiety and attention biases in children. The present study extends this prior research using distinctive techniques designed to increase participant learning, memory consolidation, and treatment engagement. Fifty-nine clinically anxious children were randomly assigned to the active treatment condition (ATC) (N = 31) or waitlist control condition (WLC) (N = 28). In the ATC, children completed 12 treatment sessions at home on computer in which they searched matrices for a pleasant or calm target amongst unpleasant background pictures, while also engaging in techniques designed to consolidate learning and memory for these search strategies. No contact was made with children in the WLC during the wait period. Diagnostic, parent- and child-reports of anxiety and depressive symptoms, externalising behaviour problems and attention biases were assessed pre- and post-condition and six-months after treatment. Children in the ATC showed greater improvements on multiple clinical measures compared to children in the WLC. Post-treatment gains improved six-months after treatment. Attention biases for angry and happy faces did not change significantly from pre-to post-condition. However, larger pre-treatment attention bias towards threat was associated with greater reduction in anxiety at post-treatment. Also, children who showed greater consolidation of learning and memory strategies during treatment achieved greater improvement in global functioning at post-treatment. Attention training towards positive stimuli using enhanced visual-search procedures appears to be a promising treatment for childhood anxiety disorders. (c) 2015 Elsevier Ltd. All rights reserved. C1 [Waters, Allison M.; Zimmer-Gembeck, Melanie J.] Griffith Univ, Sch Appl Psychol, Nathan, Qld 4111, Australia. [Craske, Michelle G.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. [Bradley, Brendan P.; Mogg, Karin] Univ Southampton, Psychol, Southampton SO9 5NH, Hants, England. RP Waters, AM (reprint author), Griffith Univ, Sch Appl Psychol, Nathan, Qld 4111, Australia. EM a.waters@griffith.edu.au RI Mogg, Karin/C-1181-2008 OI Mogg, Karin/0000-0002-2738-7378 FU Australian Research Council [DP120101678] FX This research was supported by funding awarded to the authors by the Australian Research Council (DP120101678). Thanks are due to Ms Emily Seager, Mr Xuesong Le, and the team of clinicians who served as independent assessors during this project. This trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000988853). NR 97 TC 6 Z9 7 U1 10 U2 34 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD OCT PY 2015 VL 73 BP 111 EP 123 DI 10.1016/j.brat.2015.08.005 PG 13 WC Psychology, Clinical SC Psychology GA CS5QI UT WOS:000362132600016 PM 26310362 ER PT J AU Peretti, M Angelini, M Savalli, N Florio, T Yuspa, SH Mazzanti, M AF Peretti, Marta Angelini, Marina Savalli, Nicoletta Florio, Tullio Yuspa, Stuart H. Mazzanti, Michele TI Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE Chloride channels; Cancer cells; CLIC1; CLIC4 ID CONDUCTANCE REGULATOR CFTR; HUMAN GLIOMA-CELLS; NASOPHARYNGEAL CARCINOMA-CELLS; HUMAN-MALIGNANT GLIOMA; ION-CHANNEL; OVARIAN-CANCER; NUCLEAR TRANSLOCATION; HUMAN GLIOBLASTOMA; PROTEOMIC ANALYSIS; COLORECTAL-CANCER AB In recent decades, growing scientific evidence supports the role of ion channels in the development of different cancers. Both potassium selective pores and chloride permeabilities are considered the most active channels during tumorigenesis. High rate of proliferation, active migration, and invasiveness into non-neoplastic tissues are specific properties of neoplastic transformation. All these actions require partial or total involvement of chloride channel activity. In this context, this class of membrane proteins could represent valuable therapeutic targets for the treatment of resistant tumors. However, this encouraging premise has not so far produced any valid new channel-targeted antitumoral molecule for cancer treatment. Problematic for drug design targeting ion channels is their vital role in normal cells for essential physiological functions. By targeting these membrane proteins involved in pathological conditions, it is inevitable to cause relevant side effects in healthy organs. In light of this, a new protein family, the chloride intracellular channels (CLICs), could be a promising class of therapeutic targets for its intrinsic individualities: CLIC1 and CLIC4, in particular, not only are overexpressed in specific tumor types or their corresponding stroma but also change localization and function from hydrophilic cytosolic to integral transmembrane proteins as active ionic channels or signal transducers during cell cycle progression in certain cases. These changes in intracellular localization, tissue compartments, and channel function, uniquely associated with malignant transformation, may offer a unique target for cancer therapy, likely able to spare normal cells. This article is part of a special issue itled "Membrane Channels and Transporters in Cancers." (C) 2015 Elsevier B.V. All rights reserved. C1 [Peretti, Marta; Angelini, Marina; Mazzanti, Michele] Univ Milan, Dept Life Sci, I-20133 Milan, Italy. [Savalli, Nicoletta] Univ Calif Los Angeles, David Geffen Sch Med, Div Mol Med, Dept Anesthesiol, Los Angeles, CA 90075 USA. [Florio, Tullio] Univ Genoa, Dipartimento Med Interna, Sez Farmacol, Genoa, Italy. [Florio, Tullio] Univ Genoa, Ctr Eccellenza Ric Biomed CEBR, Genoa, Italy. [Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mazzanti, M (reprint author), Univ Milan, Dept Life Sci, Via Celoria 26, I-20133 Milan, Italy. EM michele.mazzanti@unimi.it RI Florio, Tullio/A-2211-2012; OI Florio, Tullio/0000-0002-2394-996X; Mazzanti, Michele/0000-0002-1819-3811 FU Italian Ministry for the Scientific Research (PRIN); Italian Association for Cancer Research (AIRC) [IG13563]; Center for Cancer Research, National Cancer Institute, USA FX This work is supported by the Italian Ministry for the Scientific Research (PRIN 2007) to MM, from Italian Association for Cancer Research (AIRC, IG13563) to TF and by the intramural program of the Center for Cancer Research, National Cancer Institute, USA to SHY. The Authors would like to thank Dr. Giuliana Pelicci and Dr. Matteo Setti (IEO, European Institute of Oncology, Milan, Italy) for providing the stem/progenitor cells from human gioblastomas. NR 117 TC 13 Z9 14 U1 2 U2 13 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 OCT PY 2015 VL 1848 IS 10 SI SI BP 2523 EP 2531 DI 10.1016/j.bbamem.2014.12.012 PN B PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CS5YH UT WOS:000362153700006 PM 25546839 ER PT J AU Golding, N Wilson, AL Moyes, CL Cano, J Pigott, DM Velayudhan, R Brooker, SJ Smith, DL Hay, SI Lindsay, SW AF Golding, Nick Wilson, Anne L. Moyes, Catherine L. Cano, Jorge Pigott, David M. Velayudhan, Raman Brooker, Simon J. Smith, David L. Hay, Simon I. Lindsay, Steve W. TI Integrating vector control across diseases SO BMC MEDICINE LA English DT Article DE Disease mapping; Public health; Vector-borne disease; Vector control ID INSECTICIDE-TREATED NETS; VISCERAL LEISHMANIASIS; LYMPHATIC FILARIASIS; CONTROLLED-TRIAL; MALARIA CONTROL; WESTERN KENYA; CURTAINS; BEDNETS; IMPLEMENTATION; METAANALYSIS AB Background: Vector-borne diseases cause a significant proportion of the overall burden of disease across the globe, accounting for over 10 % of the burden of infectious diseases. Despite the availability of effective interventions for many of these diseases, a lack of resources prevents their effective control. Many existing vector control interventions are known to be effective against multiple diseases, so combining vector control programmes to simultaneously tackle several diseases could offer more cost-effective and therefore sustainable disease reductions. Discussion: The highly successful cross-disease integration of vaccine and mass drug administration programmes in low-resource settings acts a precedent for cross-disease vector control. Whilst deliberate implementation of vector control programmes across multiple diseases has yet to be trialled on a large scale, a number of examples of 'accidental' cross-disease vector control suggest the potential of such an approach. Combining contemporary high-resolution global maps of the major vector-borne pathogens enables us to quantify overlap in their distributions and to estimate the populations jointly at risk of multiple diseases. Such an analysis shows that over 80 % of the global population live in regions of the world at risk from one vector-borne disease, and more than half the world's population live in areas where at least two different vector-borne diseases pose a threat to health. Combining information on co-endemicity with an assessment of the overlap of vector control methods effective against these diseases allows us to highlight opportunities for such integration. Summary: Malaria, leishmaniasis, lymphatic filariasis, and dengue are prime candidates for combined vector control. All four of these diseases overlap considerably in their distributions and there is a growing body of evidence for the effectiveness of insecticide-treated nets, screens, and curtains for controlling all of their vectors. The real-world effectiveness of cross-disease vector control programmes can only be evaluated by large-scale trials, but there is clear evidence of the potential of such an approach to enable greater overall health benefit using the limited funds available. C1 [Golding, Nick; Moyes, Catherine L.; Pigott, David M.; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Wilson, Anne L.; Lindsay, Steve W.] Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England. [Cano, Jorge; Brooker, Simon J.] Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England. [Velayudhan, Raman] WHO, Dept Control Neglected Trop Dis, CH-1211 Geneva, Switzerland. [Smith, David L.; Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Smith, David L.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Smith, David L.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Golding, N (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. EM nick.golding.research@gmail.com RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570; Moyes, Catherine/0000-0002-8028-4079 FU Bill & Melinda Gates Foundation [OPP1053338, OPP1093011, OPP1033751]; GlaxoSmithKline; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Sir Richard Southwood Graduate Scholarship; Wellcome Trust [098045, 095066] FX Authors received funding from the Bill & Melinda Gates Foundation (OPP1053338: NG, ALW, JC, RV, SJB, SIH, SWL; OPP1093011: CLM, SIH; OPP1033751: JC, SJB), GlaxoSmithKline (JC, SJB), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (DLS, SIH, SWL), a Sir Richard Southwood Graduate Scholarship (DMP), and Senior Research Fellowships from the Wellcome Trust (098045: SJB; 095066: SIH). NR 45 TC 5 Z9 5 U1 3 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 1 PY 2015 VL 13 AR 249 DI 10.1186/s12916-015-0491-4 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CS3AU UT WOS:000361944300001 PM 26423147 ER PT J AU Raju, T AF Raju, Tonse TI Breastfeeding Research Supported by the NICHD SO BREASTFEEDING MEDICINE LA English DT Editorial Material C1 Eunice Kennedy Shrive Natl Inst Child Hlth & Huma, NIH, Bethesda, MD 20892 USA. RP Raju, T (reprint author), Eunice Kennedy Shrive Natl Inst Child Hlth & Huma, NIH, Bethesda, MD 20892 USA. EM abm@bfmed.org NR 0 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1556-8253 EI 1556-8342 J9 BREASTFEED MED JI Breastfeed. Med. PD OCT 1 PY 2015 VL 10 IS 8 BP 389 EP 390 DI 10.1089/bfm.2015.0114 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CS6FO UT WOS:000362173500003 PM 26431221 ER PT J AU Frazer, JK Li, KJ Galardy, P Perkins, SL Auperin, A Anderson, JR Pinkerton, R Buxton, A Gross, TG Weinstein, H Harrison, L Shiramizu, B Barth, M Goldman, S Patte, C Cairo, MS AF Frazer, J. Kimble Li, Kevin J. Galardy, Paul Perkins, Sherrie L. Auperin, Anne Anderson, James R. Pinkerton, Ross Buxton, Allen Gross, Thomas G. Weinstein, Howard Harrison, Lauren Shiramizu, Bruce Barth, Matthew Goldman, Stanton Patte, Catherine Cairo, Mitchell S. TI Excellent outcomes in children and adolescents with central nervous system-positive (CNS+) Burkitt lymphoma/leukemia (BL) or other mature B-NHL using intrathecal and systemic chemotherapy without CNS irradiation: results from FAB/LMB96 and ANHL01P1 studies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Meeting Abstract CT 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma CY OCT 22, 2015 CL Varese, ITALY C1 [Frazer, J. Kimble; Li, Kevin J.] Univ Oklahoma, Hlth Sci Ctr, Pediat Hematol Oncol, Oklahoma City, OK USA. [Galardy, Paul] Mayo Clin, Pediat Hematol Oncol, Rochester, MN USA. [Perkins, Sherrie L.] Univ Utah, Pathol Labs, Salt Lake City, UT USA. [Perkins, Sherrie L.] Univ Utah, ARUP Labs, Salt Lake City, UT USA. [Auperin, Anne; Patte, Catherine] CLCC Inst Cancerol Gustave Roussy, Dept Cancerol Enfant & Adolescent, Villejuif, France. [Anderson, James R.] Frontier Sci & Technol Res Fdn Inc, Madison, WI USA. [Pinkerton, Ross] Univ Queensland, Brisbane, Qld, Australia. [Buxton, Allen] Childrens Oncol Grp, Monrovia, CA USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, Rockville, MD USA. [Weinstein, Howard] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Hematol Oncol, Boston, MA USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Pediat, Valhalla, NY 10595 USA. [Shiramizu, Bruce] Univ Hawaii, Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Barth, Matthew] Roswell Pk Canc Inst, Pediat, Buffalo, NY 14263 USA. [Goldman, Stanton] Med City Childrens Hosp, Pediat Hematol Oncol, Dallas, TX USA. [Cairo, Mitchell S.] New York Med Coll, Med Pathol Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Cell Biol & Anat, Valhalla, NY 10595 USA. 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 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2015 VL 171 SU 1 SI SI MA 10 BP 6 EP 7 PG 2 WC Hematology SC Hematology GA CS9QG UT WOS:000362425300009 ER PT J AU Gross, T AF Gross, Thomas TI Diagnosis and treatment of post-transplant lymphoproliferative disease: challenging cases SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Meeting Abstract CT 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma CY OCT 22, 2015 CL Varese, ITALY C1 [Gross, Thomas] NCI, Ctr Global Hlth, Rockville, 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 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2015 VL 171 SU 1 SI SI MA 26 BP 17 EP 17 PG 1 WC Hematology SC Hematology GA CS9QG UT WOS:000362425300024 ER PT J AU Salaverria, I Schmidt, JA Gong, SY Pittaluga, S Gonzalez-Farre, B Balague, O Maffioti, T Garcia, N Mozos, A Cabecadas, J Van der Walt, J Bonzheim, I Fend, F Campo, E Jaffe, ES Quintanilla-Martinez, L AF Salaverria, Itziar Schmidt, Janine-Alison Gong, Shunyou Pittaluga, Stefania Gonzalez-Farre, Blanca Balague, Olga Maffioti, Teresa Garcia, Noelia Mozos, Anna Cabecadas, Jose Van der Walt, Jon Bonzheim, Irina Fend, Falko Campo, Elias Jaffe, Elaine S. Quintanilla-Martinez, Leticia TI Genome-wide analysis of follicular lymphoma pediatric type SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Meeting Abstract CT 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma CY OCT 22, 2015 CL Varese, ITALY C1 [Salaverria, Itziar; Gonzalez-Farre, Blanca; Balague, Olga; Garcia, Noelia; Campo, Elias] Inst Invest Biomed August Pi ISunyer IDIBAPS, Hosp Clin, Hematopathol Unit, Barcelona, Spain. [Schmidt, Janine-Alison; Bonzheim, Irina; Fend, Falko; Quintanilla-Martinez, Leticia] Univ Tubingen, Inst Pathol, Tubingen, Germany. [Gong, Shunyou; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Van der Walt, Jon] Barts & London NHS Trust, Dept Cellular Pathol, London, England. [Mozos, Anna] Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain. [Cabecadas, Jose] Inst Portugues Oncol Francisco Gentil, Dept Pathol, Lisbon, Portugal. [Van der Walt, Jon] Guys & St Thomas Hosp, Dept Histopathol, London SE1 9RT, England. 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 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2015 VL 171 SU 1 SI SI MA 117 BP 60 EP 61 PG 2 WC Hematology SC Hematology GA CS9QG UT WOS:000362425300113 ER PT J AU Shiramizu, B Goldman, S Perkins, SL Harrison, L Barth, M Miles, R Cairo, MS Gross, TG Alexander, S AF Shiramizu, Bruce Goldman, Stanton Perkins, Sherrie L. Harrison, Lauren Barth, Matthew Miles, Rodney Cairo, Mitchell S. Gross, Thomas G. Alexander, Sarah TI Incorporating mitochondrial DNA (MtDNA) measurement to supplement minimal residual disease assessment in B-NHL/Leukemia treatment strategies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Meeting Abstract CT 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma CY OCT 22, 2015 CL Varese, ITALY C1 [Shiramizu, Bruce] Univ Hawaii, Dept Pediat, Honolulu, HI 96822 USA. [Goldman, Stanton] Med City Childrens Hosp, Dept Pediat Hematol Oncol, Dallas, TX USA. [Perkins, Sherrie L.; Miles, Rodney] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Barth, Matthew] Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, Bethesda, MD 20892 USA. [Alexander, Sarah] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. 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 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2015 VL 171 SU 1 SI SI MA 150 BP 74 EP 74 PG 1 WC Hematology SC Hematology GA CS9QG UT WOS:000362425300146 ER PT J AU Ordonez, AE Collins, PY AF Ordonez, Anna E. Collins, Pamela Y. TI Advancing Research to Action in Global Child Mental Health SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Global mental health research; Research capacity building; Children; Adolescents; Grand challenges; Child development ID MIDDLE-INCOME COUNTRIES; UNIVERSAL PREVENTION TRIAL; AGE-OF-ONSET; UNTREATED PSYCHOSIS; HIGH-RISK; GRAND CHALLENGES; SOCIOECONOMIC-STATUS; RESEARCH PRIORITIES; SYSTEMATIC ANALYSIS; RANDOMIZED-TRIAL AB Most mental and substance use disorders begin during childhood and adolescence and are the leading cause of disability in this population. Prenatal and postnatal genetic, familial, social, and environmental exposures interact to influence risk for mental disorders and trajectories of cognitive development. Efforts to advance prevention and implement early interventions to reduce the burden of mental disorders require a global research workforce, intersectoral cooperation, attention to environmental contexts, and the development and testing of evidence-based interventions. The authors describe challenges and resources for building mental health research capacity that stands to influence children's mental health outcomes around the globe. C1 [Ordonez, Anna E.] NIMH, Off Clin Res, NIH, Bethesda, MD 20892 USA. NIMH, Off Res Dispar & Global Mental Hlth, NIH, Bethesda, MD 20892 USA. RP Collins, PY (reprint author), NIMH, Off Res Dispar & Global Mental Hlth, NIH, 6001 Execut Blvd,Suite 6217, Bethesda, MD 20892 USA. EM pamela.collins@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 95 TC 1 Z9 1 U1 4 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 1056-4993 EI 1558-0490 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD OCT PY 2015 VL 24 IS 4 BP 679 EP + DI 10.1016/j.chc.2015.06.002 PG 20 WC Psychiatry SC Psychiatry GA CS5YV UT WOS:000362155100003 PM 26346383 ER PT J AU Wilkinson, L Steel, A Mooshagian, E Zimmermann, T Keisler, A Lewis, JD Wassermann, EM AF Wilkinson, Leonora Steel, Adam Mooshagian, Eric Zimmermann, Trelawny Keisler, Aysha Lewis, Jeffrey D. Wassermann, Eric M. TI Online feedback enhances early consolidation of motor sequence learning and reverses recall deficit from transcranial stimulation of motor cortex SO CORTEX LA English DT Article DE Theta burst stimulation; Consolidation; Motor cortex; Motor skill; Sequence learning; Serial reaction time task ID PARKINSONS-DISEASE; MAGNETIC STIMULATION; HUNTINGTONS-DISEASE; BASAL GANGLIA; HEAD-INJURY; IMPLICIT; MEMORY; REWARD; PLASTICITY; STRIATUM AB Feedback and monetary reward can enhance motor skill learning, suggesting reward system involvement. Continuous theta burst (cTBS) transcranial magnetic stimulation (TMS) of the primary motor area (M1) disrupts processing, reduces excitability and impairs motor learning. To see whether feedback and reward can overcome the learning impairment associated with M1 cTBS, we delivered real or sham stimulation to two groups of participants before they performed a motor sequence learning task with and without feedback. Participants were trained on two intermixed sequences, one occurring 85% of the time (the "probable" sequence) and the other 15% of the time (the "improbable" sequence). We measured sequence learning as the difference in reaction time (RT) and error rate between probable and improbable trials (RT and error difference scores). Participants were also tested for sequence recall with the same indices of learning 60 min after cTBS. Real stimulation impaired initial sequence learning and sequence knowledge recall as measured by error difference scores and impaired sequence knowledge recall as measured by RT difference score. Relative to non-feedback learning, the introduction of feedback during sequence learning improved subsequent sequence knowledge recall indexed by RT difference score, in both real and sham stimulation groups and feedback reversed the RT difference score based sequence knowledge recall impairment from real cTBS that we observed in the non-feedback learning condition. Only the real cTBS group in the nonfeedback condition showed no evidence of explicit sequence knowledge when tested at the end of the study. Feedback improves recall of implicit and explicit motor sequence knowledge and can protect sequence knowledge against the effect of M1 inhibition. Adding feedback and monetary reward/punishment to motor skill learning may help overcome retention impairments or accelerate training in clinical and other settings. Published by Elsevier Ltd. C1 [Wilkinson, Leonora; Steel, Adam; Mooshagian, Eric; Zimmermann, Trelawny; Keisler, Aysha; Lewis, Jeffrey D.; Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Mooshagian, Eric; Zimmermann, Trelawny] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Mooshagian, Eric; Zimmermann, Trelawny] Henry M Jackson Fdn, Bethesda, MD USA. RP Wilkinson, L (reprint author), NINDS, Behav Neurol Unit, NIH, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM Leonora.Wilkinson@nih.gov; adam.steel@nih.gov; mooshagiane@pcg.wustl.edu; trezimmermann@gmail.com; ayshakeisler@gmail.com; jeffrey.lewis.3@us.af.mil; wassermanne@ninds.nih.gov OI Steel, Adam/0000-0001-8876-933X FU Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke [1ZIANS002977-14]; Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, via the Henry Jackson Foundation [300605-10.01-60855] FX The authors declare no conflict of interest. Funding came from the Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke (1ZIANS002977-14) and the Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, via the Henry Jackson Foundation (300605-10.01-60855) (to Dr. Mooshagian & Mr. Zimmermann). NR 65 TC 2 Z9 2 U1 2 U2 12 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD OCT PY 2015 VL 71 BP 134 EP 147 DI 10.1016/j.cortex.2015.06.012 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CS5PV UT WOS:000362131300013 PM 26204232 ER PT J AU Kim, SYH AF Kim, Scott Y. H. TI 'Human subjects research' as stigmatized activity: Implications for oversight reform SO CORTEX LA English DT Editorial Material C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 8 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD OCT PY 2015 VL 71 BP 417 EP 419 DI 10.1016/j.cortex.2015.04.020 PG 3 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CS5PV UT WOS:000362131300041 PM 26051212 ER PT J AU Hoon, MA AF Hoon, Mark A. TI Molecular dissection of itch SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID GASTRIN-RELEASING-PEPTIDE; SPINOTHALAMIC TRACT NEURONS; SUPERFICIAL DORSAL-HORN; SPINAL-CORD; SENSORY NEURONS; BEHAVIORAL-RESPONSES; PAIN; RECEPTOR; EXPRESSION; INTERNEURONS AB There have been many exciting recent advances in our understanding of the molecular and cellular basis of itch. These discoveries cover diverse aspects of itch sensation, from the identification of new receptors to the characterization of spinal cord itch circuits. A common thread of these studies is that they demonstrate that itch sensory signals are segregated from input for other somatosensory modalities, such as pain, touch, and thermosensation. This specificity is achieved by the expression of dedicated receptors and transmitters in a select population of sensory neurons which detect pruritogens. Further, recent studies show that itch specificity is maintained in a spinal cord circuit by the utilization of specific neurotransmitters and cognate receptors to convey input along a distinct cellular pathway. C1 NIDCR, Mol Genet Unit, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Hoon, MA (reprint author), NIDCR, Mol Genet Unit, Lab Sensory Biol, NIH, Bldg 35,Room 3F145,35 Convent Dr, Bethesda, MD 20892 USA. EM mark.hoon@nih.gov FU NIH NIDCR FX I am grateful to Santosh Mishra and Hans Jurgen Solinski for their critical readings on this manuscript. This work was supported by the intramural program of the NIH NIDCR. NR 48 TC 5 Z9 6 U1 1 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 EI 1873-6882 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD OCT PY 2015 VL 34 BP 61 EP 66 DI 10.1016/j.conb.2015.01.017 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CS5SU UT WOS:000362139300010 PM 25700248 ER PT J AU Marzi, A Feldmann, F Hanley, PW Scott, DP Gunther, S Feldmann, H AF Marzi, Andrea Feldmann, Friederike Hanley, Patrick W. Scott, Dana P. Guenther, Stephan Feldmann, Heinz TI Delayed Disease Progression in Cynomolgus Macaques Infected with Ebola Virus Makona Strain SO EMERGING INFECTIOUS DISEASES LA English DT Article ID RHESUS MACAQUES AB In late 2013, the largest documented outbreak of Ebola hemorrhagic fever started in Guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. In March 2014, Ebola virus (EBOV) was identified as the causative agent. This study compares the pathogenesis of a new EBOV strain, Makona, which was isolated in Guinea in 2014 with the prototype strain from the 1976 EBOV outbreak in the former Zaire. Both strains cause lethal disease in cynomolgus macaques with similar pathologic changes and hallmark features of Ebola hemorrhagic fever. However, disease progression was delayed in EBOV-Makona infected animals, suggesting decreased rather than increased virulence of this most recent EBOV strain. C1 [Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W.; Scott, Dana P.; Feldmann, Heinz] NIH, Hamilton, MT USA. [Guenther, Stephan] Bernhard Nocht Inst Trop Med, D-20359 Hamburg, Germany. RP Feldmann, H (reprint author), Rocky Mt Labs, Virol Lab, 903 South 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI Hanley, Patrick/0000-0003-2300-1818 FU Rocky Mountain Veterinary Branch; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Shelly Robertson for assistance with cytokine analysis, Elaine Haddock and the Rocky Mountain Veterinary Branch for support of this study, and Yoshihiro Kawaoka for providing polyclonal rabbit serum against EBOV viral protein 40.; This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 13 TC 24 Z9 24 U1 0 U2 10 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD OCT PY 2015 VL 21 IS 10 BP 1777 EP 1783 DI 10.3201/eid2110.150259 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CS5ZY UT WOS:000362158000011 PM 26402165 ER PT J AU Birnbaum, LS Miller, MF AF Birnbaum, Linda S. Miller, Mark F. TI Prenatal Programming and Toxicity (PPTOX) Introduction SO ENDOCRINOLOGY LA English DT Editorial Material ID DEVELOPMENTAL ORIGINS; PUBLIC-HEALTH; DISEASE; INHERITANCE; MECHANISMS; NUTRITION; EXPOSURE; LIFE; LEAD AB The developmental origin of health and disease hypothesis posits that early-life exposures, including prenatal, can influence disease outcomes throughout the entire lifespan of an organism. Over the past 30 years, scientific researchers have compiled robust epidemiological and mechanistic data showing the effects of early-life nutrition, chemical exposures, and stress on prenatal programing and toxicity. Using novel techniques in genomics and epigenetics, science is now establishing strong links between low-level early-life environmental exposures and the later development of noncommunicable diseases, such as cardiovascular disease, obesity, diabetes, neurodevelopmental and neurodegenerative disease, reproductive effects, immune system function and cancer. Now scientists must engage with communities, industry, policy makers, and clinicians to leverage our newfound understanding of prenatal programing and toxicity into better health outcomes across the lifespan. C1 [Birnbaum, Linda S.; Miller, Mark F.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, 111 TW Alexander Dr,Bldg 101,Room B242, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 27 TC 4 Z9 4 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3405 EP 3407 DI 10.1210/en.2015-1458 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300002 PM 26241073 ER PT J AU Grandjean, P Barouki, R Bellinger, DC Casteleyn, L Chadwick, LH Cordier, S Etzel, RA Gray, KA Ha, EH Junien, C Karagas, M Kawamoto, T Lawrence, BP Perera, FP Prins, GS Puga, A Rosenfeld, CS Sherr, DH Sly, PD Suk, W Sun, Q Toppari, J van den Hazel, P Walker, CL Heindel, JJ AF Grandjean, Philippe Barouki, Robert Bellinger, David C. Casteleyn, Ludwine Chadwick, Lisa H. Cordier, Sylvaine Etzel, Ruth A. Gray, Kimberly A. Ha, Eun-Hee Junien, Claudine Karagas, Margaret Kawamoto, Toshihiro Lawrence, B. Paige Perera, Frederica P. Prins, Gail S. Puga, Alvaro Rosenfeld, Cheryl S. Sherr, David H. Sly, Peter D. Suk, William Sun, Qi Toppari, Jorma van den Hazel, Peter Walker, Cheryl L. Heindel, Jerrold J. TI Life-Long Implications of Developmental Exposure to Environmental Stressors: New Perspectives SO ENDOCRINOLOGY LA English DT Article ID EPIGENETIC TRANSGENERATIONAL INHERITANCE; HEALTH; ORIGINS; RISK; ESTROGENS; CHEMICALS AB The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for effects that may last a lifetime. Current testing paradigms do not allow proper characterization of risk factors and their interactions. Thus, relevant exposure levels and combinations for testing must be identified from human exposure situations and outcome assessments. Testing of potential underpinning mechanisms and biomarker development require laboratory animal models and in vitro approaches. Only few large-scale birth cohorts exist, and collaboration between birth cohorts on a global scale should be facilitated. DOHaD-based research has a crucial role in establishing factors leading to detrimental outcomes and developing early preventative/remediation strategies to combat these risks. C1 [Grandjean, Philippe; Bellinger, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Sun, Qi] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sun, Qi] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Grandjean, Philippe] Univ Southern Denmark, Inst Publ Hlth, Dept Environm Med, DK-5000 Odense, Denmark. [Barouki, Robert] Univ Paris 05, Hop Necker Enfants Malad, AP HP, INSERM Unit 1124, F-75015 Paris, France. [Casteleyn, Ludwine] Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium. [Chadwick, Lisa H.; Gray, Kimberly A.; Suk, William; Heindel, Jerrold J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. [Cordier, Sylvaine] Univ Rennes 1, INSERM, Unit 1085, F-35000 Rennes, France. [Etzel, Ruth A.] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. [Ha, Eun-Hee] Ewha Womans Univ, Sch Med, Dept Prevent Med, Seoul 158710, South Korea. [Junien, Claudine] INRA, MR Unite Mixte Rech Biol Dev & Reprod 1198, F-78350 Jouy En Josas, France. [Junien, Claudine] Univ Versailles St Quentin, F-78000 Versailles, France. [Karagas, Margaret] Geisel Sch Med Dartmouth, Childrens Environm Hlth & Dis Prevent Res Ctr, Hanover, NH 03766 USA. [Karagas, Margaret] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH 03766 USA. Univ Occupat & Environm Hlth, Dept Environm Hlth, Kitakyushu, Fukuoka 8078555, Japan. [Lawrence, B. Paige] Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. [Perera, Frederica P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY 10032 USA. [Perera, Frederica P.] Columbia Univ, Mailman Sch Publ Hlth, Columbia Ctr Childrens Environm Hlth, New York, NY 10032 USA. [Prins, Gail S.] Univ Illinois, Dept Urol, Chicago, IL 60612 USA. [Puga, Alvaro] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Rosenfeld, Cheryl S.] Univ Missouri, Thompson Ctr Autism & Neurobehav Disorders, Bond Life Sci Ctr, Genet Area Program,Biomed Sci, Columbia, MO 65211 USA. [Sherr, David H.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [Sly, Peter D.] Univ Queensland, Royal Childrens Hosp, Queensland Childrens Med Res Inst, Brisbane, Qld 4006, Australia. [Toppari, Jorma] Univ Turku, Dept Physiol, Turku 20014, Finland. [Toppari, Jorma] Univ Turku, Dept Pediat, Turku 20014, Finland. [Toppari, Jorma] Turku Univ Hosp, Turku 20014, Finland. [van den Hazel, Peter] Int Network Childrens Hlth Environm & Safety, NL-6955 Ellecom, Netherlands. [Walker, Cheryl L.] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA. RP Grandjean, P (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Landmark Ctr 3E-110,401 Pk Dr, Boston, MA 02115 USA. EM pgrand@hsph.harvard.edu RI Cordier, Sylvaine/F-7919-2013; OI Sly, Peter/0000-0001-6305-2201; Grandjean, Philippe/0000-0003-4046-9658 FU European Commission; National Institute of Environmental Health Sciences (NIEHS/National Institutes of Health); United States Environmental Protection Agency; Boston University Superfund Research Program; Geisel School of Medicine at Dartmouth; Harvard T.H. Chan School of Public Health; International Network on Children's Health, Environment and Safety; International Society for Children's Health and the Environment; International Society for Environmental Epidemiology; World Health Organization FX The PPTOX IV conference was supported by the European Commission, the National Institute of Environmental Health Sciences (NIEHS/National Institutes of Health), the United States Environmental Protection Agency, the Boston University Superfund Research Program, Geisel School of Medicine at Dartmouth, and Harvard T.H. Chan School of Public Health.; The PPTOX IV conference was sponsored by the International Network on Children's Health, Environment and Safety, the International Society for Children's Health and the Environment, the International Society for Environmental Epidemiology, and the World Health Organization. NR 31 TC 17 Z9 19 U1 3 U2 19 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3408 EP 3415 DI 10.1210/EN.2015-1350 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300003 PM 26241067 ER PT J AU Heindel, JJ Balbus, J Birnbaum, L Brune-Drisse, MN Grandjean, P Gray, K Landrigan, PJ Sly, PD Suk, W Slechta, DC Thompson, C Hanson, M AF Heindel, Jerrold J. Balbus, John Birnbaum, Linda Brune-Drisse, Marie Noel Grandjean, Philippe Gray, Kimberly Landrigan, Philip J. Sly, Peter D. Suk, William Slechta, Deborah Cory Thompson, Claudia Hanson, Mark TI Developmental Origins of Health and Disease: Integrating Environmental Influences SO ENDOCRINOLOGY LA English DT Review ID ENDOCRINE-DISRUPTING CHEMICALS; PUBLIC-HEALTH; PRENATAL STRESS; EXPOSURE; STATEMENT; SOCIETY; DIETHYLSTILBESTROL; CONSEQUENCES; EPIGENETICS; PHYSIOLOGY AB There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span but potentially across several generations; and second, to initiate the discussion of how adoption of DOHaD can promote a more realistic, accurate, and integrative approach to understanding environmental disruption of developmental programming and better inform clinical and policy interventions. C1 [Heindel, Jerrold J.; Balbus, John; Birnbaum, Linda; Gray, Kimberly; Suk, William; Thompson, Claudia] NIEHS, Res Triangle Pk, NC 27709 USA. [Brune-Drisse, Marie Noel] WHO, Dept Publ Hlth, Environm & Social Determinants Hlth, CH-1211 Geneva 27, Switzerland. [Grandjean, Philippe] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Landrigan, Philip J.] Mt Sinai Hosp, Dept Preventat Med, New York, NY 10029 USA. [Sly, Peter D.] Univ Queensland, Queensland Childrens Med Res Inst, Herston, Qld 4006, Australia. [Slechta, Deborah Cory] Univ Rochester, Sch Med, Dept Environm Med, Rochester, NY 14642 USA. [Hanson, Mark] Univ Southampton, Inst Dev Sci, Southampton SO17 1BJ, Hants, England. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov OI Sly, Peter/0000-0001-6305-2201 FU National Institute of Environmental Health Sciences Division of Extramural Research and Training FX This work was supported by the National Institute of Environmental Health Sciences Division of Extramural Research and Training. NR 26 TC 28 Z9 28 U1 4 U2 21 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3416 EP 3421 DI 10.1210/EN.2015-1394 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300004 PM 26241070 ER PT J AU Wahid, HH Dorian, CL Chin, PY Hutchinson, MR Rice, KC Olson, DM Moldenhauer, LM Robertson, SA AF Wahid, Hanan H. Dorian, Camilla L. Chin, Peck Yin Hutchinson, Mark R. Rice, Kenner C. Olson, David M. Moldenhauer, Lachlan M. Robertson, Sarah A. TI Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice SO ENDOCRINOLOGY LA English DT Article ID INDUCED PRETERM LABOR; NF-KAPPA-B; SMOOTH-MUSCLE-CELLS; FETAL MEMBRANES; DELAYED PARTURITION; SIGNALING PATHWAY; OXYTOCIN RECEPTOR; BLOOD MONOCYTES; MYELOID CELLS; MOUSE MODEL AB An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4-/-) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4-/- mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4-/- pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy. C1 [Wahid, Hanan H.; Dorian, Camilla L.; Chin, Peck Yin; Hutchinson, Mark R.; Moldenhauer, Lachlan M.; Robertson, Sarah A.] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. [Wahid, Hanan H.; Dorian, Camilla L.; Chin, Peck Yin; Hutchinson, Mark R.; Moldenhauer, Lachlan M.; Robertson, Sarah A.] Univ Adelaide, Sch Med, Adelaide, SA 5005, Australia. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, NIH, Rockville, MD 20892 USA. NIAAA, NIH, Rockville, MD 20892 USA. [Olson, David M.] Univ Alberta, Dept Obstet & Gynecol, Edmonton, AB TG6 2S2, Canada. [Olson, David M.] Univ Alberta, Dept Pediat, Edmonton, AB TG6 2S2, Canada. [Olson, David M.] Univ Alberta, Dept Physiol, Edmonton, AB TG6 2S2, Canada. RP Robertson, SA (reprint author), Univ Adelaide, Robinson Res Inst, Adelaide, SA 5005, Australia. EM sarah.robertson@adelaide.edu.au RI Robertson, Sarah/C-8182-2009; OI Robertson, Sarah/0000-0002-9967-0084; Hutchinson, Mark/0000-0003-2154-5950 FU National Health and Medical Research Council of Australia [APP1026178, APP465423]; Canadian Institutes of Health Research Grant [2011-09-15]; Australian Research Council [DP110100297]; National Institutes of Health Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism FX This work was supported by National Health and Medical Research Council of Australia Grants APP1026178 and APP465423, the Canadian Institutes of Health Research Grant 2011-09-15, and the Australian Research Council Grant DP110100297. A portion of this work was supported by the National Institutes of Health Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. NR 72 TC 2 Z9 2 U1 2 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3828 EP 3841 DI 10.1210/en.2015-1089 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300046 PM 26151355 ER PT J AU Ng, L Cordas, E Wu, XF Vella, KR Hollenberg, AN Forrest, D AF Ng, Lily Cordas, Emily Wu, Xuefeng Vella, Kristen R. Hollenberg, Anthony N. Forrest, Douglas TI Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor beta 1 SO ENDOCRINOLOGY LA English DT Article ID TR-BETA; CONE PHOTORECEPTORS; DEFICIENCY DISORDER; TECTORIAL MEMBRANE; TARGETED MUTATION; AUDITORY FUNCTION; GENE-EXPRESSION; IN-VIVO; RESISTANCE; ALPHA AB A key function of the thyroid hormone receptor beta (Thrb) gene is in the development of auditory function. However, the roles of the 2 receptor isoforms, TR beta 1 and TR beta 2, expressed by the Thrb gene are unclear, and it is unknown whether these isoforms promote the maintenance as well as development of hearing. We investigated the function of TR beta 1 in mice with a Thrb(b1) reporter allele that expresses beta-galactosidase instead of TR beta 1. In the immature cochlea, beta-galactosidase was detected in the greater epithelial ridge, sensory hair cells, spiral ligament, and spiral ganglion and in adulthood, at low levels in the hair cells, support cells and root cells of the outer sulcus. Although deletion of all TR beta isoforms causes severe, early-onset deafness, deletion of TR beta 1 or TR beta 2 individually caused no obvious hearing loss in juvenile mice. However, over subsequent months, TR beta 1 deficiency resulted in progressive loss of hearing and loss of hair cells. TR beta 1-deficient mice had minimal changes in serum thyroid hormone and thyrotropin levels, indicating that hormonal imbalances were unlikely to cause hearing loss. The results suggest mutually shared roles for TR beta 1 and TR beta 2 in cochlear development and an unexpected requirement for TR beta 1 in the maintenance of hearing in adulthood. C1 [Ng, Lily; Cordas, Emily; Wu, Xuefeng; Forrest, Douglas] NIDDK, NIH, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Vella, Kristen R.; Hollenberg, Anthony N.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. RP Forrest, D (reprint author), NIDDK, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU Intramural Research Program at National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health; National Institutes of Health [DK078090, DK056123] FX This work was supported by the Intramural Research Program at National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (D.F.) and National Institutes of Health Grants DK078090 and DK056123 (to A.N.H.). NR 59 TC 0 Z9 0 U1 2 U2 10 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3853 EP 3865 DI 10.1210/en.2015-1468 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300048 PM 26241124 ER PT J AU Abuhatzira, L Xu, HY Tahhan, G Boulougoura, A Schaffer, AA Notkins, AL AF Abuhatzira, Liron Xu, Huanyu Tahhan, Georges Boulougoura, Afroditi Schaeffer, Alejandro A. Notkins, Abner L. TI Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2 beta, and GAD65 SO FASEB JOURNAL LA English DT Article DE autoimmune diabetes; miRNA; miR-342; glucose-sensitive ID PANCREATIC BETA-CELLS; INSULIN-SECRETION; RIP-CHIP; ISLETS; EXPRESSION; MIRNAS; IDENTIFICATION; DECARBOXYLASE; AUTOIMMUNITY; COEXPRESSION AB Islet antigen (IA)-2, IA-2b, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA-2b, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens. C1 [Abuhatzira, Liron; Xu, Huanyu; Tahhan, Georges; Boulougoura, Afroditi; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Abuhatzira, L (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. EM abuhatzira@mail.nih.gov FU National Institute of Dental and Craniofacial Research; National Library of Medicine, U.S. National Institutes of Health (Bethesda, MD, USA) FX The authors thank Dr. John Tsang for advice and meaningful discussions. This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, and by the Intramural Research Program of the National Library of Medicine, U.S. National Institutes of Health (Bethesda, MD, USA). L.A. and A.L.N. conceived of the project, designed and performed experiments, and wrote the manuscript. H.X., G.T., and A.B. performed experiments, participated in the discussions and reviewed the manuscript. A.A.S. performed the simulation, advised on other aspects of the bioinformatics and reviewed the manuscript. The authors declare no conflicts of interest. NR 47 TC 3 Z9 3 U1 2 U2 9 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 OCT PY 2015 VL 29 IS 10 BP 4374 EP 4383 DI 10.1096/fj.15-273649 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA CR5FY UT WOS:000361367300025 PM 26148972 ER PT J AU Aravalli, RN Greten, TF AF Aravalli, Rajagopal N. Greten, Tim F. TI FoxC1: Novel Regulator of Inflammation-Induced Metastasis in Hepatocellular Carcinoma SO GASTROENTEROLOGY LA English DT Editorial Material ID INTERLEUKIN-8; CELLS C1 [Aravalli, Rajagopal N.] Univ Minnesota, Sch Med, Dept Radiol, Minneapolis, MN 55455 USA. [Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Aravalli, RN (reprint author), Univ Minnesota, Sch Med, Dept Radiol, MMC 292,420 Delaware St SE, Minneapolis, MN 55455 USA. EM aravalli@umn.edu NR 13 TC 1 Z9 1 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD OCT PY 2015 VL 149 IS 4 BP 861 EP 863 DI 10.1053/j.gastro.2015.08.032 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS3LX UT WOS:000361976900016 PM 26302490 ER PT J AU Xu, MJ Cai, Y Wang, H Altamirano, J Chang, BX Bertola, A Odena, G Lu, J Tanaka, N Matsusue, K Matsubara, T Mukhopadhyay, P Kimura, S Pacher, P Gonzalez, FJ Bataller, R Gao, B AF Xu, Ming-Jiang Cai, Yan Wang, Hua Altamirano, Jose Chang, Binxia Bertola, Adeline Odena, Gemma Lu, Jim Tanaka, Naoki Matsusue, Kimihiko Matsubara, Tsutomu Mukhopadhyay, Partha Kimura, Shioko Pacher, Pal Gonzalez, Frank J. Bataller, Ramon Gao, Bin TI Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans SO GASTROENTEROLOGY LA English DT Article DE Lipid Metabolism; Endoplasmic Reticulum; Inflammation; Translational Research ID LIVER-DISEASE PATHOGENESIS; LEPTIN-DEFICIENT MICE; THERAPEUTIC TARGETS; HEPATIC STEATOSIS; PPAR-GAMMA; CIDE PROTEINS; HEPATOSTEATOSIS; INJURY; FSP27; MODEL AB BACKGROUND & AIMS: Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression and focused on the mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets. METHODS: C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 (Fsp27(Hep-/-) mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor (GW9662) of peroxisome proliferator-activated receptor gamma (PPARG). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanolfed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed histologically and immunohistochemically and by transcriptome, immunoblotting, and real-time PCR analyses. RESULTS: Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including up-regulation of mouse Fsp27 (also called Cidec) and human CIDEC. Fsp27(Hep-/-) mice and mice given injections of adenovirus-Fsp27shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP-responsive element binding protein H (CREBH) prevented the increases in Fsp27 alpha and FSP27 beta mRNAs, respectively, and reduced liver injury in this chronic-plusbinge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of mitochondrial reactive oxygen species and damage to hepatocytes in mice. Hepatic CIDEC mRNA expression was increased in patients with AH and correlated with the degree of hepatic steatosis and disease severity including mortality. CONCLUSIONS: In mice, chronic-plus-binge ethanol feeding induces ASH that mimics some histological and molecular features observed in patients with AH. Hepatic expression of FSP27/CIDEC is highly up-regulated in mice following chronic-plus-binge ethanol feeding and in patients with AH; this up-regulation contributes to alcohol-induced liver damage. C1 [Xu, Ming-Jiang; Cai, Yan; Wang, Hua; Chang, Binxia; Bertola, Adeline; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Xu, Ming-Jiang] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100871, Peoples R China. [Cai, Yan; Tanaka, Naoki; Matsubara, Tsutomu; Kimura, Shioko; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Wang, Hua] Anhui Med Univ, Affiliated Hosp 1, Dept Oncol, Hefei, Peoples R China. [Altamirano, Jose; Bataller, Ramon] Vall dHebron Hosp, Vali dHebron Inst Recerca, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Altamirano, Jose; Bataller, Ramon] Vall dHebron Hosp, Vali dHebron Inst Recerca, Internal Med Dept, Liver Unit, Barcelona, Spain. [Odena, Gemma; Bataller, Ramon] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Lu, Jim] GoPath Diagnost LLC, Chicago, IL USA. [Matsusue, Kimihiko] Fukuoka Univ, Fac Pharmaceut Sci, Fukuoka 81401, Japan. [Mukhopadhyay, Partha; Pacher, Pal] NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Bataller, Ramon] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI Cai, Yan/P-4383-2015; OI Odena, Gemma/0000-0002-9317-4725; Bertola, Adeline/0000-0002-4885-8423 FU Intramural NIH HHS [Z01 AA000369-06, Z99 AA999999]; NIAAA NIH HHS [1U01AA021908-01, U01 AA020821, U01 AA021908] NR 42 TC 10 Z9 10 U1 3 U2 20 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 OCT PY 2015 VL 149 IS 4 BP 1030 EP U367 DI 10.1053/j.gastro.2015.06.009 PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS3LX UT WOS:000361976900038 PM 26099526 ER PT J AU Takamatsu, Y Tanaka, Y Kohgo, S Murakami, S Singh, K Das, D Venzon, DJ Amano, M Higashi-Kuwata, N Aoki, M Delino, NS Hayashi, S Takahashi, S Sukenaga, Y Haraguchi, K Sarafianos, SG Maeda, K Mitsuya, H AF Takamatsu, Yuki Tanaka, Yasuhito Kohgo, Satoru Murakami, Shuko Singh, Kamalendra Das, Debananda Venzon, David J. Amano, Masayuki Higashi-Kuwata, Nobuyo Aoki, Manabu Delino, Nicole S. Hayashi, Sanae Takahashi, Satoru Sukenaga, Yoshikazu Haraguchi, Kazuhiro Sarafianos, Stefan G. Maeda, Kenji Mitsuya, Hiroaki TI 4-modified nucleoside analogs: Potent inhibitors active against entecavir-resistant hepatitis B virus SO HEPATOLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITOR; ANTI-HIV ACTIVITY; IMMUNODEFICIENCY-VIRUS; IN-VITRO; UNITED-STATES; 4'-ETHYNYL-2-FLUORO-2'-DEOXYADENOSINE; LAMIVUDINE; INFECTION; THERAPY; TYPE-1 AB Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more-potent agents that offer profound viral suppression. Here, we report that 4-C-cyano-2-amino-2-deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC50]=0.4 nM) and HIV-1 (IC50=0.4 nM). In contrast, the approved anti-HBV NRTI, entecavir (ETV), potently inhibits HBV (IC50=0.7 nM), but is much less active against HIV-1 (IC50=1,000 nM). Similarly, the highly potent HIV-1 inhibitor, 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; IC50=0.3 nM) is less active against HBV (IC50=160 nM). Southern analysis using Huh-7 cells transfected with HBV-containing plasmids demonstrated that CAdA was potent against both wild-type (IC50=7.2 nM) and ETV-resistant HBV (IC50=69.6 nM for HBVETV-RL180M/S202G/M204V), whereas ETV failed to reduce (HBVETV-RV)-V-L180M/S202G/M204 DNA even at 1 mu M. Once-daily peroral administration of CAdA reduced HBVETV-RL180M/S202G/M204V viremia (P=0.0005) in human-liver-chimeric/HBVETV-RL180M/S202G/M204V-infected mice, whereas ETV completely failed to reduce HBVETV-RL80M/S202G/M204V viremia. None of the mice had significant drug-related body-weight or serum human-albumin concentration changes. Molecular modeling suggests that a shallower HBV-RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4-cyano of CAdA-triphosphate (TP), but not the longer 4-ethynyl of EFdA-TP. In contrast, the deeper HIV-1-RT pocket can efficiently accommodate the 4-substitutions of both NRTIs. The ETV-TP's cyclopentyl ring can bind more efficiently at the shallow HBV-RT binding pocket. Conclusion: These data provide insights on the structural and functional associations of HBV- and HIV-1-RTs and show that CAdA may offer new therapeutic options for HBV patients. (Hepatology 2015;62:1024-1036) C1 [Takamatsu, Yuki; Das, Debananda; Aoki, Manabu; Delino, Nicole S.; Maeda, Kenji; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Tanaka, Yasuhito; Murakami, Shuko; Hayashi, Sanae] Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Nagoya, Aichi, Japan. [Tanaka, Yasuhito; Hayashi, Sanae] Nagoya City Univ, Grad Sch Med Sci, Liver Unit, Nagoya, Aichi, Japan. [Kohgo, Satoru; Higashi-Kuwata, Nobuyo; Sukenaga, Yoshikazu; Maeda, Kenji; Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Res Inst, Tokyo 1628655, Japan. [Kohgo, Satoru; Higashi-Kuwata, Nobuyo; Sukenaga, Yoshikazu; Maeda, Kenji; Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Tokyo 1628655, Japan. [Kohgo, Satoru] Nihon Pharmaceut Univ, Dept Pharmaceut Sci, Saitama, Japan. [Singh, Kamalendra] Univ Missouri, Sch Med, Mol Microbiol & Immunol Biochem, Columbia, MO USA. [Singh, Kamalendra] Univ Missouri, Bond Life Sci Ctr, Columbia, MO USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Amano, Masayuki; Higashi-Kuwata, Nobuyo; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Hematol, Dept Rheumatol & Clin Immunol, Kumamoto, Japan. [Amano, Masayuki; Higashi-Kuwata, Nobuyo; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Infect Dis, Kumamoto, Japan. [Aoki, Manabu] Kumamoto Hlth Sci Univ, Dept Med Technol, Kumamoto, Japan. [Takahashi, Satoru] Nagoya City Univ, Grad Sch Med Sci, Dept Expt Pathol & Tumor Biol, Nagoya, Aichi, Japan. RP Maeda, K (reprint author), Natl Ctr Global Hlth & Med, Ctr Clin Sci, Shinjuku Ku, 1-21-1 Toyama, Tokyo 1628655, Japan. EM kmaeda@ri.ncgm.go.jp RI Amano, Masayuki/N-7407-2016; OI Amano, Masayuki/0000-0003-0516-9502; Sarafianos, Stefan G/0000-0002-5840-154X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; Health and Labor Sciences Research Grant (Practical Research on Hepatitis [Research on the innovative development and the practical application of new drugs for hepatitis B; International Research Center Aiming at the Control of AIDS, Kumamoto University; [R01AI112417]; [R01AI076119] FX This work was supported, in part, by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health (H.M.), in part by a Health and Labor Sciences Research Grant (Practical Research on Hepatitis [Research on the innovative development and the practical application of new drugs for hepatitis B [H.M., Ya.T., K.H.]), and in part by a Grant from International Research Center Aiming at the Control of AIDS, Kumamoto University (H.M.). S.G.S. was supported by R01AI112417 and R01AI076119. NR 38 TC 2 Z9 2 U1 0 U2 10 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 OCT PY 2015 VL 62 IS 4 BP 1024 EP 1036 DI 10.1002/hep.27962 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800009 PM 26122273 ER PT J AU Chang, BX Xu, MJ Zhou, Z Cai, Y Li, M Wang, W Feng, DC Bertola, A Wang, H Kunos, G Gao, B AF Chang, Binxia Xu, Ming-Jiang Zhou, Zhou Cai, Yan Li, Man Wang, Wei Feng, Dechun Bertola, Adeline Wang, Hua Kunos, George Gao, Bin TI Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: An important role for CXCL1 SO HEPATOLOGY LA English DT Article ID INDUCED NEUTROPHIL CHEMOATTRACTANT; INDUCED INSULIN-RESISTANCE; GENETICALLY-OBESE MICE; BODY-MASS INDEX; ACETAMINOPHEN HEPATOTOXICITY; ALCOHOL-CONSUMPTION; ADIPOSE-TISSUE; RISK-FACTORS; RAT-LIVER; DISEASE AB Obesity and alcohol consumption often coexist and work synergistically to promote steatohepatitis; however, the underlying mechanisms remain obscure. Here, we demonstrate that feeding mice a high-fat diet (HFD) for as little as 3 days markedly exacerbated acute ethanol binge-induced liver neutrophil infiltration and injury. Feeding mice with an HFD for 3 months plus a single binge of ethanol induced much more severe steatohepatitis. Moreover, 3-day or 3-month HFD-plus-ethanol binge (3d-HFD+ethanol or 3m-HFD+ethanol) treatment markedly up-regulated the hepatic expression of several chemokines, including chemokine (C-X-C motif) ligand 1 (Cxcl1), which showed the highest fold (approximately 20-fold and 35-fold, respectively) induction. Serum CXCL1 protein levels were also markedly elevated after the HFD+ethanol treatment. Blockade of CXCL1 with a CXCL1 neutralizing antibody or genetic deletion of the Cxcl1 gene reduced the HFD+ethanol-induced hepatic neutrophil infiltration and injury, whereas overexpression of Cxcl1 exacerbated steatohepatitis in HFD-fed mice. Furthermore, expression of Cxcl1 messenger RNA was up-regulated in hepatocytes, hepatic stellate cells, and endothelial cells isolated from HFD+ethanol-fed mice compared to mice that were only given the HFD, with the highest fold induction observed in hepatocytes. In vitro stimulation of hepatocytes with palmitic acid up-regulated the expression of Cxcl1 messenger RNA, and this up-regulation was attenuated after treatment with an inhibitor of extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, or nuclear factor B. In addition, hepatic or serum levels of free fatty acids were higher in HFD+ethanol-fed mice than in the control groups. Conclusion: An HFD combined with acute ethanol consumption synergistically induces acute liver inflammation and injury through the elevation of hepatic or serum free fatty acids and subsequent up-regulation of hepatic CXCL1 expression and promotion of hepatic neutrophil infiltration. (Hepatology 2015;62:1070-1085) C1 [Chang, Binxia; Xu, Ming-Jiang; Zhou, Zhou; Cai, Yan; Li, Man; Wang, Wei; Feng, Dechun; Bertola, Adeline; Wang, Hua; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Chang, Binxia] Beijing 302 Hosp, Inst Alcohol Liver Dis, Diag & Treatment Ctr Noninfect Liver Dis, Beijing, Peoples R China. RP Gao, B (reprint author), NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM xum4@mail.nih.gov; bgao@mail.nih.gov RI Cai, Yan/P-4383-2015; Feng, Dechun/Q-5962-2016; Zhou, Zhou/R-7788-2016; OI Bertola, Adeline/0000-0002-4885-8423 FU National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health); Beijing 302 Hospital FX Supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) and by Beijing 302 Hospital (B.C.). NR 50 TC 10 Z9 11 U1 0 U2 15 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 OCT PY 2015 VL 62 IS 4 BP 1070 EP 1085 DI 10.1002/hep.27921 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800013 PM 26033752 ER PT J AU Lu, YY Xu, WP Ji, JF Feng, DC Sourbier, C Yang, YF Qu, JH Zeng, Z Wang, CP Chang, XJ Chen, Y Mishra, A Xu, M Lee, MJ Lee, SM Trepel, J Linehan, WM Wang, XW Yang, YP Neckers, L AF Lu, Yinying Xu, Wanping Ji, Junfang Feng, Dechun Sourbier, Carole Yang, Youfeng Qu, Jianhui Zeng, Zhen Wang, Chunping Chang, Xiujuan Chen, Yan Mishra, Alok Xu, Max Lee, Min-Jung Lee, Sunmin Trepel, Jane Linehan, W. Marston Wang, Xinwei Yang, Yongping Neckers, Len TI Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID CANCER; DIFFERENTIATION; PROLIFERATION; CHAPERONE AB The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline-rich region (PRRL) compared to the other with a short PRR (PRRS). Recently, PRRL was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRRL expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRRL generally promotes and PRRS suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRRS leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRRS knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA-binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein-specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRRL, while SRPK2 knockdown causes accumulation of PRRS. The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRRS. Finally, HCC cell lines that predominantly express PRRL are differentially sensitive to heat shock protein 90 inhibition. Conclusion: Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable. (Hepatology 2015;62:1122-1131) C1 [Lu, Yinying; Qu, Jianhui; Zeng, Zhen; Wang, Chunping; Chang, Xiujuan; Chen, Yan; Yang, Yongping] Beijing 302 Hosp, Ctr Therapeut Res Hepatocarcinoma, Beijing, Peoples R China. [Lu, Yinying; Xu, Wanping; Sourbier, Carole; Yang, Youfeng; Mishra, Alok; Xu, Max; Linehan, W. Marston; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ji, Junfang; Wang, Xinwei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Feng, Dechun] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Lee, Min-Jung; Lee, Sunmin; Trepel, Jane] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 10-CRC,Room 1-5940, Bethesda, MD 20892 USA. EM neckers@nih.gov RI Wang, Xin/B-6162-2009; Feng, Dechun/Q-5962-2016 FU National Natural Science Foundation of China [81302154]; US National Cancer Institute, Center for Cancer Research [ZIA SC 010074, Z01-BC010876]; National Cancer Institute FX Supported by the National Natural Science Foundation of China (grant 81302154); by funds from the Intramural Research Program of the US National Cancer Institute, Center for Cancer Research (grant ZIA SC 010074 to Y.Y.L., W.X., and L.N.; grant Z01-BC010876 to J.J. and X.W.W.); and by a National Cancer Institute Career Development Award (to W.X.). NR 20 TC 5 Z9 5 U1 0 U2 7 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 OCT PY 2015 VL 62 IS 4 BP 1122 EP 1131 DI 10.1002/hep.27923 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800017 PM 26058814 ER PT J AU Won, C Kim, BH Yi, EH Choi, KJ Kim, EK Jeong, JM Lee, JH Jang, JJ Yoon, JH Jeong, WI Park, IC Kim, TW Bae, SS Factor, VM Ma, S Thorgeirsson, SS Lee, YH Ye, SK AF Won, Cheolhee Kim, Byung-Hak Yi, Eun Hee Choi, Kyung-Ju Kim, Eun-Kyung Jeong, Jong-Min Lee, Jae-Ho Jang, Ja-June Yoon, Jung-Hwan Jeong, Won-Il Park, In-Chul Kim, Tae Woo Bae, Sun Sik Factor, Valentina M. Ma, Stephanie Thorgeirsson, Snorri S. Lee, Yun-Han Ye, Sang-Kyu TI Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID KAPPA-B ACTIVITY; SELF-RENEWAL; CANCER-CELLS; LIVER-CANCER; STEM-CELLS; MOLECULAR TARGETS; STAT3 ACTIVATION; BREAST-CANCER; HYPOXIA; SORAFENIB AB Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1) expression. Active STAT3 interacted with nuclear factor kappa B (NF-B) p65 subunit to positively regulate the transcription of HIF-1 providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1 and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1 proteins. Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-B and HIF-1 during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment. (Hepatology 2015;62:1160-1173) C1 [Won, Cheolhee; Kim, Byung-Hak; Yi, Eun Hee; Ye, Sang-Kyu] Seoul Natl Univ, Coll Med, Dept Pharmacol & Biomed Sci, Seoul 110799, South Korea. [Won, Cheolhee; Ye, Sang-Kyu] Seoul Natl Univ, Coll Med, Neuroimmune Informat Storage Network Res Ctr, Seoul 110799, South Korea. [Kim, Byung-Hak] Seoul Natl Univ, Coll Med, Biomed Sci Project PLUS BK21, Seoul 110799, South Korea. [Choi, Kyung-Ju; Lee, Yun-Han] Yonsei Univ, Coll Med, Dept Radiat Oncol, Brain Korea PLUS Project Med Sci 21, Seoul 120749, South Korea. [Kim, Eun-Kyung; Bae, Sun Sik] Pusan Natl Univ, Sch Med, Dept Pharmacol, Yangsan, South Korea. [Jeong, Jong-Min; Jeong, Won-Il] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Lab Liver Res, Daejeon 305701, South Korea. [Lee, Jae-Ho] Kwandong Univ, Cheil Gen Hosp, Coll Med, Mol Oncol Lab, Seoul, South Korea. [Lee, Jae-Ho] Kwandong Univ, Coll Med, Womens Healthcare Ctr, Seoul, South Korea. [Jang, Ja-June] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 110799, South Korea. [Yoon, Jung-Hwan] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110799, South Korea. [Yoon, Jung-Hwan] Seoul Natl Univ, Coll Med, Liver Res Inst, Seoul 110799, South Korea. [Park, In-Chul] Korea Inst Radiol & Med Sci, Div Radiat Canc Res, Seoul, South Korea. [Kim, Tae Woo] Korea Univ, Grad Sch Med, Lab Infect & Immunol, Seoul, South Korea. [Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ma, Stephanie] Univ Hong Kong, Fac Med, Dept Anat, State Key Lab Liver Res, Hong Kong, Hong Kong, Peoples R China. [Ye, Sang-Kyu] Seoul Natl Univ, Coll Med, Ischem Hypox Dis Inst, Seoul 110799, South Korea. RP Ye, SK (reprint author), Seoul Natl Univ, Coll Med, Dept Pharmacol, 103 Daehangno, Seoul 110799, South Korea. EM yhlee87@yuhs.ac; sangkyu@snu.ac.kr RI JEONG, WON IL/B-6615-2011; OI Ma, Stephanie Kwai Yee/0000-0002-2029-7943 FU National R&D program for Cancer Control, Ministry of Health Welfare [0720540]; National Research Foundation of Korea (NRF) - Korea government (MESF) [2012R1A2A2A01012897, 2014R1A2A1A11053203]; National Research Foundation of Korea (NRF) - Korea government (MSIP) [2012R1A5A2A44671346]; Bio & Medical Technology Development Program, Ministry of Science, ICT & Future Planning [NRF-2012-M3A9C7050149]; Korean Health Technology R&D Project, Ministry of Health & Welfare, South Korea [A121982] FX Supported by grants from the National R&D program for Cancer Control, Ministry of Health & Welfare (0720540) and the National Research Foundation of Korea (NRF) funded by the Korea government (MESF; 2012R1A2A2A01012897 and 2014R1A2A1A11053203 and MSIP; 2012R1A5A2A44671346). This project was also supported by the Bio & Medical Technology Development Program, Ministry of Science, ICT & Future Planning (NRF-2012-M3A9C7050149), and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare (A121982), South Korea. [Funding information added September 11, after first online publication.] NR 39 TC 20 Z9 21 U1 4 U2 15 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 OCT PY 2015 VL 62 IS 4 BP 1160 EP 1173 DI 10.1002/hep.27968 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800020 PM 26154152 ER PT J AU Lee, YK Jee, BA Kwon, SM Yoon, YS Xu, WG Wang, HJ Wang, XW Thorgeirsson, SS Lee, JS Woo, HG Yoon, G AF Lee, Young-Kyoung Jee, Byul A. Kwon, So Mee Yoon, Young-Sil Xu, Wei Guang Wang, Hee-Jung Wang, Xin Wei Thorgeirsson, Snorri S. Lee, Jae-Seon Woo, Hyun Goo Yoon, Gyesoon TI Identification of a mitochondrial defect gene signature reveals NUPR1 as a key regulator of liver cancer progression SO HEPATOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; TRANSCRIPTION FACTORS; RETROGRADE RESPONSE; MESSENGER-RNA; CELL GROWTH; PROTEIN P8; DYSFUNCTION; EXPRESSION; NUCLEAR; DNA AB Many cancer cells require more glycolytic adenosine triphosphate production due to a mitochondrial respiratory defect. However, the roles of mitochondrial defects in cancer development and progression remain unclear. To address the role of transcriptomic regulation by mitochondrial defects in liver cancer cells, we performed gene expression profiling for three different cell models of mitochondrial defects: cells with chemical respiratory inhibition (rotenone, thenoyltrifluoroacetone, antimycin A, and oligomycin), cells with mitochondrial DNA depletion (Rho0), and liver cancer cells harboring mitochondrial defects (SNU354 and SNU423). By comparing gene expression in the three models, we identified 10 common mitochondrial defect-related genes that may be responsible for retrograde signaling from cancer cell mitochondria to the intracellular transcriptome. The concomitant expression of the 10 common mitochondrial defect genes is significantly associated with poor prognostic outcomes in liver cancers, suggesting their functional and clinical relevance. Among the common mitochondrial defect genes, we found that nuclear protein 1 (NUPR1) is one of the key transcription regulators. Knockdown of NUPR1 suppressed liver cancer cell invasion, which was mediated in a Ca2+ signaling-dependent manner. In addition, by performing an NUPR1-centric network analysis and promoter binding assay, granulin was identified as a key downstream effector of NUPR1. We also report association of the NUPR1-granulin pathway with mitochondrial defect-derived glycolytic activation in human liver cancer. Conclusion: Mitochondrial respiratory defects and subsequent retrograde signaling, particularly the NUPR1-granulin pathway, play pivotal roles in liver cancer progression. (Hepatology 2015;62:1174-1189) C1 [Lee, Young-Kyoung; Yoon, Young-Sil; Yoon, Gyesoon] Ajou Univ, Sch Med, Dept Biochem, Suwon 443380, South Korea. [Jee, Byul A.; Kwon, So Mee; Woo, Hyun Goo] Ajou Univ, Sch Med, Dept Physiol, Suwon 443380, South Korea. [Xu, Wei Guang; Wang, Hee-Jung] Ajou Univ, Sch Med, Dept Surg, Suwon 443380, South Korea. [Lee, Young-Kyoung; Jee, Byul A.; Kwon, So Mee; Woo, Hyun Goo; Yoon, Gyesoon] Ajou Univ, Grad Sch, Dept Biomed Sci, Suwon 443380, South Korea. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Jae-Seon] Inha Univ, Coll Med, Dept Biomed Sci, Inchon, South Korea. [Lee, Jae-Seon] Inha Univ, Coll Med, Hypoxia Related Dis Res Ctr, Inchon, South Korea. RP Yoon, G (reprint author), Ajou Univ, Sch Med, Dept Biochem, Suwon 443380, South Korea. EM hg@ajou.ac.kr; ypeace@aumc.ac.kr RI Wang, Xin/B-6162-2009 FU National Research Foundation of Korea - Korean government [NRF-2012R1A5A2048183] FX Supported by a National Research Foundation of Korea grant funded by the Korean government (NRF-2012R1A5A2048183). NR 47 TC 0 Z9 0 U1 1 U2 5 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 OCT PY 2015 VL 62 IS 4 BP 1174 EP 1189 DI 10.1002/hep.27976 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6TJ UT WOS:000362214800021 PM 26173068 ER PT J AU Melander, MC Jurgensen, HJ Madsen, DH Engelholm, LH Behrendt, N AF Melander, Maria C. Juergensen, Henrik J. Madsen, Daniel H. Engelholm, Lars H. Behrendt, Niels TI The collagen receptor uPARAP/Endo180 in tissue degradation and cancer SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Review DE cancer invasion; collagen; extracellular matrix; matrix degradation; CD280; MRC2 ID PLASMINOGEN-ACTIVATOR-RECEPTOR; MACROPHAGE MANNOSE RECEPTOR; HEPATIC STELLATE CELLS; TRANSMEMBRANE GLYCOPROTEIN; ARTICULAR-CARTILAGE; ENDOCYTIC RECEPTOR; DENATURED COLLAGEN; ENDOTHELIAL-CELLS; MATRIX TURNOVER; LECTIN RECEPTOR AB The collagen receptor uPARAP/Endo180, the product of the MRC2 gene, is a central component in the collagen turnover process governed by various mesenchymal cells. Through the endocytosis of collagen or large collagen fragments, this recycling receptor serves to direct basement membrane collagen as well as interstitial collagen to lysosomal degradation. This capacity, shared only with the mannose receptor from the same protein family, endows uPARAP/Endo180 with a critical role in development and homeostasis, as well as in pathological disruptions of the extracellular matrix structure. Important pathological functions of uPARAP/Endo180 have been identified in various cancers and in several fibrotic conditions. With a particular focus on matrix turnover in cancer, this review presents the necessary background for understanding the function of uPARAP/Endo180 at the molecular and cellular level, followed by an in-depth survey of the available knowledge of the expression and role of this receptor in various types of cancer and other degenerative diseases. C1 [Melander, Maria C.; Engelholm, Lars H.; Behrendt, Niels] Univ Copenhagen, Finsen Lab, Rigshosp, BRIC, DK-2200 Copenhagen N, Denmark. [Juergensen, Henrik J.; Madsen, Daniel H.] NIDCR, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Behrendt, N (reprint author), Univ Copenhagen, Finsen Lab, Rigshosp, BRIC, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark. EM niels.behrendt@finsenlab.dk FU Danish Cancer Society; Danish Medical Research Council; Danish Cancer Research Foundation; Lundbeck Foundation; Novo Nordisk Foundation; Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer); European Community's Seventh Framework Programme FP7 [201279] FX This study was supported by the Danish Cancer Society, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, the Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer) and the European Community's Seventh Framework Programme FP7/2007-2011 under grant agreement no. 201279. NR 85 TC 4 Z9 4 U1 0 U2 4 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 OCT PY 2015 VL 47 IS 4 BP 1177 EP 1188 DI 10.3892/ijo.2015.3120 PG 12 WC Oncology SC Oncology GA CS4PN UT WOS:000362058300001 PM 26316068 ER PT J AU Bradley, MM Costa, VD Lang, PJ AF Bradley, Margaret M. Costa, Vincent D. Lang, Peter J. TI Selective looking at natural scenes: Hedonic content and gender SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Emotion; Scene; Eye movements; Selective looking; Pupil ID ATTENTIONAL BIAS; SEX-DIFFERENCES; EYE-MOVEMENTS; AROUSAL; AVOIDANCE; STIMULI; EMOTION; THREAT; FEAR; MODULATION AB Choice viewing behavior when looking at affective scenes was assessed to examine differences due to hedonic content and gender by monitoring eye movements in a selective looking paradigm. On each trial, participants viewed a pair of pictures that included a neutral picture together with an affective scene depicting either contamination, mutilation, threat, food, nude males, or nude females. The duration of time that gaze was directed to each picture in the pair was determined from eye fixations. Results indicated that viewing choices varied with both hedonic content and gender. Initially, gaze duration for both men and women was heightened when viewing all affective contents, but was subsequently followed by significant avoidance of scenes depicting contamination or nude males. Gender differences were most pronounced when viewing pictures of nude females, with men continuing to devote longer gaze time to pictures of nude females throughout viewing, whereas women avoided scenes of nude people, whether male or female, later in the viewing interval. For women, reported disgust of sexual activity was also inversely related to gaze duration for nude scenes. Taken together, selective looking as indexed by eye movements reveals differential perceptual intake as a function of specific content, gender, and individual differences. (C) 2015 Elsevier B.V. All rights reserved. C1 [Bradley, Margaret M.; Lang, Peter J.] Univ Florida, Gainesville, FL 32611 USA. [Costa, Vincent D.] NIMH, Bethesda, MD 20892 USA. RP Bradley, MM (reprint author), Univ Florida, Gainesville, FL 32611 USA. EM bradley@ufl.edu OI Costa, Vincent/0000-0002-5412-8945 FU [MH072850] FX This research was supported in part by research grant MH072850 to Margaret M. Bradley. Thanks to Bob Sivinski for assistance with data collection and initial reduction. Correspondence concerning this manuscript can be sent to the Margaret M. Bradley at the Center for the Study of Emotion and Attention, Box 112766, University of Florida, Gainesville, Florida, 32611. NR 36 TC 6 Z9 6 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2015 VL 98 IS 1 BP 54 EP 58 DI 10.1016/j.ijpsycho.2015.06.008 PG 5 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA CS5QT UT WOS:000362133700007 PM 26156939 ER PT J AU Chow, K Kellman, P Spottiswoode, BS Nielles-Vallespin, S Arai, AE Salerno, M Thompson, RB AF Chow, Kelvin Kellman, Peter Spottiswoode, Bruce S. Nielles-Vallespin, Sonia Arai, Andrew E. Salerno, Michael Thompson, Richard B. TI Saturation pulse design for quantitative myocardial T-1 mapping SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Saturation pulses; Adiabatic pulses; B-0 inhomogeneity; B-1 inhomogeneity; T-1 mapping; Saturation recovery; SASHA ID HEART; PRECISION; PERFUSION; TESLA; TRAIN; COIL AB Background: Quantitative saturation-recovery based T-1 mapping sequences are less sensitive to systematic errors than the Modified Look-Locker Inversion recovery (MOLLI) technique but require high performance saturation pulses. We propose to optimize adiabatic and pulse train saturation pulses for quantitative T1 mapping to have <1 % absolute residual longitudinal magnetization (vertical bar M-Z/M-0 vertical bar) over ranges of B-0 and <(B)over cap>(1) (B-1 scale factor) inhomogeneity found at 1.5 T and 3 T. Methods: Design parameters for an adiabatic BIR4-90 pulse were optimized for improved performance within 1.5 T B-0 (+/- 120 Hz) and (B) over cap (1) (0.7-1.0) ranges. Flip angles in hard pulse trains of 3-6 pulses were optimized for 1.5 T and 3 T, with consideration of T-1 values, field inhomogeneities (B-0=+/- 240 H-z and (B) over cap (1)=0.4-1.2 at 3 T), and maximum achievable B-1 field strength. Residual M-Z/M-0 was simulated and measured experimentally for current standard and optimized saturation pulses in phantoms and in-vivo human studies. T-1 maps were acquired at 3 T in human subjects and a swine using a SAturation recovery single-SHot Acquisition (SASHA) technique with a standard 90 degrees-90 degrees-90 degrees and an optimized 6-pulse train. Results: Measured residual M-Z/M-0 in phantoms had excellent agreement with simulations over a wide range of B-0 and (B) over cap (1). The optimized BIR4-90 reduced the maximum residual vertical bar M-Z/M-0 vertical bar to <1 %, a 5.8x reduction compared to a reference BIR4-90. An optimized 3-pulse train achieved a maximum residual vertical bar M-Z/M-0 vertical bar <1 % for the 1.5 T optimization range compared to 11.3 % for a standard 90 degrees-90 degrees-90 degrees pulse train, while a 6-pulse train met this target for the wider 3 T ranges of B0 and (B) over cap (1). The 6-pulse train demonstrated more uniform saturation across both the myocardium and entire field of view than other saturation pulses in human studies. T1 maps were more spatially homogeneous with 6-pulse train SASHA than the reference 90 degrees-90 degrees-90 degrees SASHA in both human and animal studies. Conclusions: Adiabatic and pulse train saturation pulses optimized for different constraints found at 1.5 T and 3 T achieved <1 % residual vertical bar M-Z/M-0 vertical bar in phantom experiments, enabling greater accuracy in quantitative saturation recovery T-1 imaging. C1 [Chow, Kelvin; Thompson, Richard B.] Univ Alberta, Fac Med & Dent, Dept Biomed Engn, Res Transit Facil 1082, Edmonton, AB T6G 2V2, Canada. [Kellman, Peter; Nielles-Vallespin, Sonia; Arai, Andrew E.] NHLBI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Spottiswoode, Bruce S.] Siemens Med Solut USA Inc, Cardiovasc MR R&D, Chicago, IL USA. [Salerno, Michael] Univ Virginia Hlth Syst, Dept Med, Div Cardiovasc, Charlottesville, VA USA. [Salerno, Michael] Univ Virginia Hlth Syst, Dept Radiol, Charlottesville, VA USA. [Salerno, Michael] Univ Virginia Hlth Syst, Dept Med Imaging, Charlottesville, VA USA. [Salerno, Michael] Univ Virginia Hlth Syst, Biomed Engn, Charlottesville, VA USA. RP Thompson, RB (reprint author), Univ Alberta, Fac Med & Dent, Dept Biomed Engn, Res Transit Facil 1082, Edmonton, AB T6G 2V2, Canada. EM richard.thompson@ualberta.ca FU Canadian Institutes of Health Research; Alberta Innovates - Health Solutions; National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB] FX This work was supported by the Canadian Institutes of Health Research, Alberta Innovates - Health Solutions, and National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 21 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 1 PY 2015 VL 17 AR 84 DI 10.1186/s12968-015-0187-0 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CS6CB UT WOS:000362163700001 PM 26428468 ER PT J AU Guo, YH Fan, YB Zhang, JF Lomberk, GA Zhou, Z Sun, LJ Mathison, AJ Garcia-Barrio, MT Zhang, J Zeng, LX Li, L Pennathur, S Willer, CJ Rader, DJ Urrutia, R Chen, YE AF Guo, Yanhong Fan, Yanbo Zhang, Jifeng Lomberk, Gwen A. Zhou, Zhou Sun, Lijie Mathison, Angela J. Garcia-Barrio, Minerva T. Zhang, Ji Zeng, Lixia Li, Lei Pennathur, Subramaniam Willer, Cristen J. Rader, Daniel J. Urrutia, Raul Chen, Y. Eugene TI Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; RANDOMIZED CONTROLLED-TRIAL; REVERSE CHOLESTEROL TRANSPORT; ACUTE CORONARY SYNDROMES; GENOME-WIDE ASSOCIATION; STATIN-TREATED PATIENTS; OF-FUNCTION MUTATIONS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Kruppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific KIf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E-deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis. C1 [Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Sun, Lijie; Zhang, Ji; Willer, Cristen J.; Chen, Y. Eugene] Univ Michigan, Dept Internal Med, Cardiovasc Ctr, Med Ctr, Ann Arbor, MI 48105 USA. [Lomberk, Gwen A.; Mathison, Angela J.; Urrutia, Raul] Mayo Clin, Gastroenterol Res Unit, Lab Epigenet & Chromatin Dynam, Epigen Translat Program,Dept Biochem & Mol Biol, Rochester, MN USA. [Lomberk, Gwen A.; Mathison, Angela J.; Urrutia, Raul] Mayo Clin, Gastroenterol Res Unit, Lab Epigenet & Chromatin Dynam, Epigen Translat Program,Dept Biophys, Rochester, MN USA. [Lomberk, Gwen A.; Mathison, Angela J.; Urrutia, Raul] Mayo Clin, Gastroenterol Res Unit, Lab Epigenet & Chromatin Dynam, Epigen Translat Program,Dept Med, Rochester, MN USA. [Zhou, Zhou] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Sun, Lijie; Li, Lei] Peking Univ, Dept Cardiol, Hosp 3, Beijing 100871, Peoples R China. [Sun, Lijie; Li, Lei] Minist Hlth, Key Lab Cardiovasc Mol Biol & Regulatory Peptides, Beijing, Peoples R China. [Garcia-Barrio, Minerva T.] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Zeng, Lixia; Li, Lei; Pennathur, Subramaniam] Univ Michigan, Sch Med, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48105 USA. [Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Chen, YE (reprint author), Univ Michigan, Dept Internal Med, Cardiovasc Ctr, Med Ctr, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. EM echenum@umich.edu RI Zhou, Zhou/R-7788-2016 FU NIH [HL068878, HL105114, HL088391, DK89503, DK097153, DK52913, CA178627]; American Heart Association National Scientist Development [15SDG24470155, 14SDG19880014] FX This work was supported in whole or in part by NIH grants HL068878, HL105114, and HL088391 (to Y.E. Chen), DK89503 and DK097153 (to S. Pennathur), DK52913 (to R. Urrutia), and CA178627 (to G.A. Lomberk) and by American Heart Association National Scientist Development grants 15SDG24470155 (to Y. Guo) and 14SDG19880014 (to Y. Fan). NR 59 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2015 VL 125 IS 10 BP 3819 EP 3830 DI 10.1172/JCI79048 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS8BW UT WOS:000362311700014 PM 26368306 ER PT J AU Pala, F Morbach, H Castle, MC Schickel, JN Scaramuzza, S Chamberlain, N Cassani, B Glauzy, S Romberg, N Candotti, F Aiuti, A Bosticardo, M Villa, A Meffre, E AF Pala, Francesca Morbach, Henner Castle, Maria Carmina Schickel, Jean-Nicolas Scaramuzza, Samantha Chamberlain, Nicolas Cassani, Barbara Glauzy, Salome Romberg, Neil Candotti, Fabio Aiuti, Alessandro Bosticardo, Marita Villa, Anna Meffre, Eric TI Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID REGULATORY T-CELLS; SYNDROME PROTEIN; ACTIN CYTOSKELETON; ACTIVATION; WASP; AUTOIMMUNITY; HUMANS; COMPARTMENT; HOMEOSTASIS; DEFICIENCY AB Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients. C1 [Pala, Francesca; Castle, Maria Carmina; Scaramuzza, Samantha; Aiuti, Alessandro; Bosticardo, Marita; Villa, Anna] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy TIGET, I-20132 Milan, Italy. [Pala, Francesca; Morbach, Henner; Schickel, Jean-Nicolas; Chamberlain, Nicolas; Glauzy, Salome; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Cassani, Barbara] Humanitas Clin & Res Ctr, Rozzano, Italy. [Cassani, Barbara; Villa, Anna] CNR, IRGB, Milan Unit, I-20133 Milan, Italy. [Romberg, Neil] Yale Univ, Sch Med, Dept Pediat, Div Allergy & Clin Immunol, New Haven, CT 06510 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Aiuti, Alessandro] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy. RP Villa, A (reprint author), IRCCS San Raffaele Sci Inst, San Raffaele TIGET, Via Olgettina 58, I-20132 Milan, Italy. EM villa.anna@hsr.it; eric.meffre@yale.edu RI Cassani, Barbara/K-3871-2016; AIUTI, ALESSANDRO/K-3918-2016; OI Cassani, Barbara/0000-0002-4115-8109; AIUTI, ALESSANDRO/0000-0002-5398-1717; Villa, Anna/0000-0003-4428-9013 FU Italian Telethon Foundation (TIGET Core grant) [A2]; Ministero della Salute [GR-2009-1579814]; EU [261387]; NIH-NIAID [AI061093, A1071087, AI082713, AI095848, AI115001-01]; German Research Foundation (DFG) [MO 2160/2-1]; GlaxoSmithKline FX We thank L. Devine and C. Wang for cell sorting, and R. Sokolic and E. Garabedian for help enrolling patients. This work was supported by Italian Telethon Foundation (TIGET Core grant A2) (to A. Villa), Ministero della Salute (GR-2009-1579814) (to M. Bosticardo), EU project CELL PID (FP7 project 261387) (to A. Aiuti and A. Villa), and grants AI061093, A1071087, AI082713, and AI095848 from NIH-NIAID (to E. Meffre). H. Morbach received support from the German Research Foundation (DFG, MO 2160/2-1). N. Romberg received support from the NIH-NIAID (AI115001-01). Since January 2014, GlaxoSmithKline has in-licensed the WAS gene therapy program and has become the financial sponsor of the clinical trial conducted at TIGET. We thank all the medical staff of the HSR-TIGET Pediatric Clinical Research Unit, Pediatric Immunohematology, and BM Transplant Unit. We are indebted to the patients and their families for their commitment and cooperation. NR 44 TC 5 Z9 5 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2015 VL 125 IS 10 BP 3941 EP 3951 DI 10.1172/JCI82249 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS8BW UT WOS:000362311700023 PM 26368308 ER PT J AU Cohen, CJ Gartner, JJ Horovitz-Fried, M Shamalov, K Trebska-McGowan, K Bliskovsky, VV Parkhurst, MR Ankri, C Prickett, TD Crystal, JS Li, YF El-Gamil, M Rosenberg, SA Robbins, PF AF Cohen, Cyrille J. Gartner, Jared J. Horovitz-Fried, Miryam Shamalov, Katerina Trebska-McGowan, Kasia Bliskovsky, Valery V. Parkhurst, Maria R. Ankri, Chen Prickett, Todd. D. Crystal, Jessica S. Li, Yong F. El-Gamil, Mona Rosenberg, Steven A. Robbins, Paul F. TI Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; MUTATIONAL LANDSCAPE; GENE-THERAPY; CD4+T CELLS; ANTIGENS; TCR; RECOGNITION; CD4(+); BLOCKADE AB Adoptively transferred tumor-infiltrating T lymphocytes (TILs) that mediate complete regression of metastatic melanoma have been shown to recognize mutated epitopes expressed by autologous tumors. Here, in an attempt to develop a strategy for facilitating the isolation, expansion, and study of mutated antigen-specific T cells, we performed whole-exome sequencing on matched tumor and normal DNA isolated from 8 patients with metastatic melanoma. Candidate mutated epitopes were identified using a peptide-MHC-binding algorithm, and these epitopes were synthesized and used to generate panels of MHC tetramers that were evaluated for binding to tumor digests and cultured TILs used for the treatment of patients. This strategy resulted in the identification of 9 mutated epitopes from 5 of the 8 patients tested. Cells reactive with 8 of the 9 epitopes could be isolated from autologous peripheral blood, where they were detected at frequencies that were estimated to range between 0.4% and 0.002%. To the best of our knowledge, this represents the first demonstration of the successful isolation of mutation-reactive T cells from patients' peripheral blood prior to immune therapy, potentially providing the basis for designing personalized immunotherapies to treat patients with advanced cancer. C1 [Cohen, Cyrille J.; Horovitz-Fried, Miryam; Shamalov, Katerina; Ankri, Chen] Bar Ilan Univ, Goodman Fac Life Sci, Lab Tumor Immunol & Immunotherapy, IL-5290002 Ramat Gan, Israel. [Cohen, Cyrille J.; Gartner, Jared J.; Trebska-McGowan, Kasia; Parkhurst, Maria R.; Prickett, Todd. D.; Crystal, Jessica S.; Li, Yong F.; El-Gamil, Mona; Rosenberg, Steven A.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Bliskovsky, Valery V.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Cohen, CJ (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Lab Tumor Immunol & Immunotherapy, Gonda Bldg 204,Room 105, IL-5290002 Ramat Gan, Israel. EM Cyrille.Cohen@biu.ac.il FU Adelson Medical Research Foundation (AMRF); NIH Tetramer Core Facility [HHSN272201300006C] FX We thank Arnold Mixon and Shawn Farid for their excellent technical assistance during the cell-sorting procedures; the Adelson Medical Research Foundation (AMRF) for their generous support; and the NIH Tetramer Core Facility (contract HHSN272201300006C) for the provision of MHC tetramers. NR 50 TC 44 Z9 45 U1 4 U2 20 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 OCT PY 2015 VL 125 IS 10 BP 3981 EP 3991 DI 10.1172/JCI82416 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS8BW UT WOS:000362311700026 PM 26389673 ER PT J AU Okoro, C George, AK Siddiqui, MM Rais-Bahrami, S Walton-Diaz, A Shakir, NA Rothwax, JT Raskolnikov, D Stamatakis, L Su, D Turkbey, B Choyke, PL Merino, MJ Parnes, HL Wood, BJ Pinto, PA AF Okoro, Chinonyerem George, Arvin K. Siddiqui, M. Minhaj Rais-Bahrami, Soroush Walton-Diaz, Annerleim Shakir, Nabeel A. Rothwax, Jason T. Raskolnikov, Dima Stamatakis, Lambros Su, Daniel Turkbey, Baris Choyke, Peter L. Merino, Maria J. Parnes, Howard L. Wood, Bradford J. Pinto, Peter A. TI Magnetic Resonance Imaging/Transrectal Ultrasonography Fusion Prostate Biopsy Significantly Outperforms Systematic 12-Core Biopsy for Prediction of Total Magnetic Resonance Imaging Tumor Volume in Active Surveillance Patients SO JOURNAL OF ENDOUROLOGY LA English DT Article ID TRANSRECTAL ULTRASOUND BIOPSY; RADICAL PROSTATECTOMY; NEEDLE-BIOPSY; GUIDED BIOPSY; BIOCHEMICAL FAILURE; CANCER VOLUME; SPECIMENS; CORES; PERCENTAGE; ANTIGEN AB Objective: To correlate the highest percentage core involvement (HPCI) and corresponding tumor length (CTL) on systematic 12-core biopsy (SBx) and targeted magnetic resonance imaging/transrectal ultrasonography (MRI/TRUS) fusion biopsy (TBx), with total MRI prostate cancer (PCa) tumor volume (TV). Patients and Methods: Fifty patients meeting criteria for active surveillance (AS) based on outside SBx, who underwent 3.0T multiparametric prostate MRI (MP-MRI), followed by SBx and TBx during the same session at our institution were examined. PCa TVs were calculated using MP-MRI and then correlated using bivariate analysis with the HPCI and CTL for SBx and TBx. Results: For TBx, HPCI and CTL showed a positive correlation (R-2=0.31, P<0.0001 and R-2=0.37, P<0.0001, respectively) with total MRI PCa TV, whereas for SBx, these parameters showed a poor correlation (R-2=0.00006, P=0.96 and R-2=0.0004, P=0.89, respectively). For detection of patients with clinically significant MRI derived tumor burden greater than 500mm(3), SBx was 25% sensitive, 90.9% specific (falsely elevated because of missed tumors and extremely low sensitivity), and 54% accurate in comparison with TBx, which was 53.6% sensitive, 86.4% specific, and 68% accurate. Conclusions: HPCI and CTL on TBx positively correlates with total MRI PCa TV, whereas there was no correlation seen with SBx. TBx is superior to SBx for detecting tumor burden greater than 500mm(3). When using biopsy positive MRI derived TVs, TBx better reflects overall disease burden, improving risk stratification among candidates for active surveillance. C1 [Okoro, Chinonyerem; George, Arvin K.; Siddiqui, M. Minhaj; Rais-Bahrami, Soroush; Walton-Diaz, Annerleim; Shakir, Nabeel A.; Rothwax, Jason T.; Raskolnikov, Dima; Stamatakis, Lambros; Su, Daniel; Wood, Bradford J.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, CRC, Bldg 10,Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Shakir, Nabeel/0000-0002-9066-3670; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU NIH, NCI, Center for Cancer Research; NIH FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field.; This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 36 TC 12 Z9 12 U1 2 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD OCT 1 PY 2015 VL 29 IS 10 BP 1115 EP 1121 DI 10.1089/end.2015.0027 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CS6VB UT WOS:000362219900004 PM 25897467 ER PT J AU Huntoon, K Oldfield, EH Lonser, RR AF Huntoon, Kristin Oldfield, Edward H. Lonser, Russell R. TI Dr. Arvid Lindau and discovery of von Hippel-Lindau disease SO JOURNAL OF NEUROSURGERY LA English DT Editorial Material DE von Hippel-Lindau disease; Arvid Lindau; Harvey Cushing; hemangioblastoma; history ID HEMANGIOBLASTOMAS AB Arvid Lindau, MD, PhD, consolidated the disparate array of benign and malignant visceral and nervous system lesions into the neoplastic syndrome known as von Hippel-Lindau (VHL) disease. Based on this pioneering work, Dr. Lindau was awarded both a Rockefeller fellowship to work in Dr. Harvey Cushing's laboratory in Boston, Massachusetts, and the Lennmalm Prize. While working in Dr. Cushing's laboratory, Dr. Lindau continued his study of CNS hemangioblastomas. His work with Dr. Cushing led to their lifelong friendship and scientific collaboration. In this paper the authors describe Arvid Lindau's pioneering work in nervous system tumor pathology, his relationship to Dr. Cushing, and his role in advancing neurological surgery and research in Europe. C1 [Huntoon, Kristin; Oldfield, Edward H.; Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Huntoon, Kristin; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA. RP Huntoon, K (reprint author), Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. EM kristin.huntoon@osumc.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2015 VL 123 IS 4 BP 1093 EP 1097 DI 10.3171/2015.1.JNS131963 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CS1XV UT WOS:000361863100038 PM 25748307 ER PT J AU Mehta, GU Oldfield, EH AF Mehta, Gautam U. Oldfield, Edward H. TI CSF leak in transsphenoidal surgery Response SO JOURNAL OF NEUROSURGERY LA English DT Letter C1 [Mehta, Gautam U.] NINDS, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Charlottesville, VA USA. RP Mehta, GU (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD OCT PY 2015 VL 123 IS 4 BP 1109 EP 1110 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CS1XV UT WOS:000361863100041 PM 26697604 ER PT J AU Zanos, P Piantadosi, SC Wu, HQ Pribut, HJ Dell, MJ Can, A Snodgrass, HR Zarate, CA Schwarcz, R Gould, TD AF Zanos, Panos Piantadosi, Sean C. Wu, Hui-Qiu Pribut, Heather J. Dell, Matthew J. Can, Adem Snodgrass, H. Ralph Zarate, Carlos A., Jr. Schwarcz, Robert Gould, Todd D. TI The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine(B)-Site Inhibition SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MAJOR DEPRESSIVE DISORDER; FORCED SWIM TEST; NMDA RECEPTOR; 7-CHLOROKYNURENIC ACID; GLYCINE-SITE; IN-VIVO; ANTAGONIST; MICE; RAT; COMPLEX AB Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycine(B) co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists. C1 [Zanos, Panos; Piantadosi, Sean C.; Wu, Hui-Qiu; Pribut, Heather J.; Dell, Matthew J.; Can, Adem; Schwarcz, Robert; Gould, Todd D.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Wu, Hui-Qiu; Schwarcz, Robert] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Schwarcz, Robert; Gould, Todd D.] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. [Gould, Todd D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Snodgrass, H. Ralph] VistaGen Therapeut Inc, San Francisco, CA USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Rm 936 MSTF,685 W Baltimore St, Baltimore, MD 21201 USA. EM gouldlab@me.com FU NIMH Psychoactive Drug Screening Program [HHSN-271-2008-025C] FX 4-Cl-KYN was provided by VistaGen Therapeutics, Inc. Receptor binding profiles and Ki determinations were generously provided by the NIMH Psychoactive Drug Screening Program, Contract No. HHSN-271-2008-025C, directed by Dr. Bryan Roth (University of North Carolina, Chapel Hill, NC) in conjunction with Ms. Jamie Driscoll (NIMH, Bethesda, MD). NR 51 TC 11 Z9 12 U1 2 U2 10 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 OCT PY 2015 VL 355 IS 1 BP 76 EP 85 DI 10.1124/jpet.115.225664 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CS6WY UT WOS:000362225400008 PM 26265321 ER PT J AU Lee, SY Chen, SL Chang, YH Chen, PS Huang, SY Tzeng, NS Wang, LJ Lee, IH Wang, TY Chen, KC Yang, YK Hong, JS Lu, RB AF Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Chen, Po-See Huang, San-Yuan Tzeng, Nian-Sheng Wang, Liang-Jen Lee, I-Hui Wang, Tzu-Yun Chen, Kao-Chin Yang, Yen-Kuang Hong, Jau-Shyong Lu, Ru-Band TI ALDH2 polymorphism, associated with attenuating negative symptoms in patients with schizophrenia treated with add-on dextromethorphan SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Schizophrenia; Dextromethorphan; ALDH2 polymorphism ID NECROSIS-FACTOR-ALPHA; ALDEHYDE DEHYDROGENASE; PARKINSONS-DISEASE; ALCOHOL-METABOLISM; COMMON VARIANTS; FETAL EXPOSURE; RISK-FACTOR; CELLS; BRAIN; PHARMACOGENETICS AB Objective: Increasing the evidence of inflammation's contribution to schizophrenia; using anti-inflammatory or neurotrophic therapeutic agents to see whether they improve schizophrenia treatment. Dextromethorphan (DM), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, might protect monoamine neurons. Whether treating schizophrenia with risperidone plus add-on DM is more effective than risperidone (RISP) alone, and the association between the ALDH2 polymorphism and treatment response were investigated. Methods: A double-blind study in which patients with schizophrenia were randomly assigned to the RISP + DM (60 mg/day; n = 74) or the RISP + Placebo (n = 75) group. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) scores were used to evaluate clinical response during weeks 0, 1, 2, 4, 6, 8, and 11. The genotypes of the ALDH2 polymorphism were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A generalized estimating equation was used to analyze the effects of ALDH2 polymorphism on the clinical performance of DM. Results: PANSS and SANS scores were significantly lower in both groups after 11 weeks of treatment. SANS total scores were significantly lower in the RISP + DM group in patients with the ALDH2*2*2 genotype. onclusions: RISP plus add-on DM treatment reduced negative schizophrenia symptoms in patients with the ALDH2 polymorphism. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Po-See; Lee, I-Hui; Wang, Tzu-Yun; Chen, Kao-Chin; Yang, Yen-Kuang; Lu, Ru-Band] Natl Chang Kung Univ, Coll Med & Hosp, Dept Psychiat, Tainan 70428, Taiwan. [Yang, Yen-Kuang; Lu, Ru-Band] Natl Chang Kung Univ, Coll Med & Hosp, Inst Behav Med, Tainan 70428, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Chang Kung Univ, Coll Med & Hosp, Inst Allied Hlth Sci, Tainan 70428, Taiwan. [Chen, Po-See; Yang, Yen-Kuang; Lu, Ru-Band] Natl Chang Kung Univ, Addict Res Ctr, Tainan 70428, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Sch Med, Dept Neurol, Kaohsiung, Taiwan. [Chang, Yun-Hsuan] Asia Univ, Dept Psychol, Taichung, Taiwan. [Chen, Po-See; Lee, I-Hui; Wang, Tzu-Yun; Chen, Kao-Chin; Yang, Yen-Kuang; Lu, Ru-Band] Natl Cheng Kung Univ Hosp, Dept Psychiat, Tainan 70428, Yunlin, Taiwan. [Lee, I-Hui] Natl Cheng Kung Univ Hosp, Dept Psychiat, Dou Liou Branch, Tainan 70428, Yunlin, Taiwan. [Huang, San-Yuan; Tzeng, Nian-Sheng] Tri Serv Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. [Wang, Liang-Jen] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Taipei, Taiwan. [Hong, Jau-Shyong] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Inst Behav Med, Dept Psychiat, Coll Med & Hosp, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University FX This work was supported in part by grant NSC98-2314-B-006-022-MY3 (to RBL) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (to RBL) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (to RBL) from the Taiwan National Health Research Institute, and the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers. NR 59 TC 0 Z9 0 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2015 VL 69 BP 50 EP 56 DI 10.1016/j.jpsychires.2015.07.027 PG 7 WC Psychiatry SC Psychiatry GA CS2UP UT WOS:000361927800008 PM 26343594 ER PT J AU Diep, CS Hingle, M Chen, TA Dadabhoy, HR Beltran, A Baranowski, J Subar, AF Baranowski, T AF Diep, Cassandra S. Hingle, Melanie Chen, Tzu-An Dadabhoy, Hafza R. Beltran, Alicia Baranowski, Janice Subar, Amy F. Baranowski, Tom TI The Automated Self-Administered 24-Hour Dietary Recall for Children, 2012 Version, for Youth Aged 9 to 11 Years: A Validation Study SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE 24-hour recall; Children; Computer; Diet assessment; Web-based ID BODY-MASS INDEX; RECORDING SOFTWARE SYSTEM; MULTIPLE-PASS METHOD; RETENTION INTERVAL; SCHOOL-LUNCH; REPORTING ACCURACY; FOOD-INTAKE; 4TH-GRADE CHILDREN; 13-YEAR-OLD CHILDREN; PHYSICAL-ACTIVITY AB Background Valid methods of diet assessment are important for nutrition research and practice, but can be difficult with children. Objective To validate the 2012 version of the Automated Self-Administered 24-Hour Dietary Recall for Children (ASA24-Kids-2012), a self-administered web-based 24-hour dietary recall (24hDR) instrument, among children aged 9 to 11 years, in two sites. Design Quasiexperimental. Participants/setting In one site, trained staff members observed and recorded foods and drinks consumed by children (n=38) during school lunch. The next day, the observed children completed both ASA24-Kids-2012 and an interviewer-administered 24hDR in a randomized order. Procedures in a second site (n=31) were similar, except observations occurred during dinner in a community location. Statistical analyses Foods were classified as matches (reported and consumed), intrusions (reported, but not consumed), or omissions (not reported, but consumed) for each participant. Rates of matches, intrusions, and omissions were calculated. Rates were compared between each recall method using repeated measures analysis of covariance. For matched foods, the authors determined correlation coefficients between observed and reported serving sizes. Results Match, intrusion, and omission rates between ASA24-Kids-2012 and observed intakes in Site 1 were 37%, 27%, and 35%, respectively. Comparable rates for interviewer-administered 24hDRs were 57%, 20%, and 23%, respectively. In Site 2, match, intrusion, and omission rates between ASA24-Kids-2012 and observed intakes were 53%, 12%, and 36%, respectively, vs 76% matches, 9% intrusions, and 15% omissions for interviewer-administered 24hDRs. The relationship strength between reported and observed serving sizes for matched foods was 0.18 in Site 1 and 0.09 in Site 2 for ASA24-Kids-2012, and 0.46 in Site 1 and 0.11 in Site 2 for interviewer-administered 24hDRs. Conclusions ASA24-Kids-2012 was less accurate than interviewer-administered 24hDRs when compared with observed intakes, but both performed poorly. Additional research should assess the age at which children can complete recalls without the help of a parent or guardian, as well as elucidate under which circumstances recalls can reasonably be used among children. C1 [Diep, Cassandra S.; Chen, Tzu-An; Dadabhoy, Hafza R.; Beltran, Alicia; Baranowski, Janice; Baranowski, Tom] Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, USDA ARS, Houston, TX 77030 USA. [Hingle, Melanie] Univ Arizona, Coll Agr & Life Sci, Dept Nutr Sci, Tucson, AZ USA. [Subar, Amy F.] Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Diep, CS (reprint author), Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, USDA ARS, 1100 Bates St, Houston, TX 77030 USA. EM cdiep@bcm.edu OI Baranowski, Tom/0000-0002-0653-2222 FU National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK091254]; US Department of Agriculture/Agricultural Research Service [58-6250-0-008]; Primary Care Research Training Grant from National Research Service Award [T32 HP10031] FX This research was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (no. R01 DK091254) and by institutional support from the US Department of Agriculture/Agricultural Research Service under Cooperative Agreement no. 58-6250-0-008. C. S. Diep was supported fully by a Primary Care Research Training Grant from National Research Service Award (no. T32 HP10031). NR 58 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD OCT PY 2015 VL 115 IS 10 BP 1591 EP 1598 DI 10.1016/j.jand.2015.02.021 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CS5YL UT WOS:000362154100004 PM 25887784 ER PT J AU Isakova, T Ix, JH Sprague, SM Raphael, KL Fried, L Gassman, JJ Raj, D Cheung, AK Kusek, JW Flessner, MF Wolf, M Block, GA AF Isakova, Tamara Ix, Joachim H. Sprague, Stuart M. Raphael, Kalani L. Fried, Linda Gassman, Jennifer J. Raj, Dominic Cheung, Alfred K. Kusek, John W. Flessner, Michael F. Wolf, Myles Block, Geoffrey A. TI Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; DIETARY PHOSPHORUS RESTRICTION; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; LEFT-VENTRICULAR MASS; VITAMIN-D METABOLISM; HEMODIALYSIS-PATIENTS; PARATHYROID-HORMONE; CARDIOVASCULAR EVENTS AB Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With Binders and NicotinannidE study. C1 [Isakova, Tamara; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Div Nephrol & Hypertens, Dept Med, Chicago, IL 60611 USA. [Isakova, Tamara; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Ctr Translat Metab & Hlth, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Ix, Joachim H.] Univ Calif San Diego, Nephrol Sect, Vet Affairs San Diego Healthcare Syst, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Prevent Med, San Diego, CA 92103 USA. [Sprague, Stuart M.] Univ Chicago, Pritzker Sch Med, NprthShore Univ Hlth Syst, Evanston, IL USA. [Raphael, Kalani L.; Cheung, Alfred K.] Univ Utah, Salt Lake City Vet Affairs Healthcare Syst, Salt Lake City, UT USA. [Raphael, Kalani L.; Cheung, Alfred K.] Univ Utah, Div Nephrol & Hypertens, Salt Lake City, UT USA. [Fried, Linda] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Gassman, Jennifer J.] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Raj, Dominic] George Washington Univ, Div Renal Dis & Hypertens, Washington, DC USA. [Kusek, John W.; Flessner, Michael F.] NIDDK, Bethesda, MD USA. [Block, Geoffrey A.] Denver Nephrol, Denver, CO USA. RP Isakova, T (reprint author), 633 N St Clair St,Suite 18-083, Chicago, IL 60611 USA. EM tamara.isakova@northwestern.edu OI Raphael, Kalani/0000-0002-1378-2609 FU National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK081673, R01-DK102438, U01-DK099877, U01-DK097093, U01-DK099930, U01-DK099933, U01-DK099924]; Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research; VA Career Development Award [IK2CX000537]; Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation FX T.I. is supported by grants K23-DK081673 and R01-DK102438 from the National Institute of Diabetes and Digestive and Kidney Diseases and by the Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research.; K.L.R. is supported by the VA Career Development Award (IK2CX000537) and the Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation.; The COMBINE study is supported by grants U01-DK099877, U01-DK097093, U01-DK099930, U01-DK099933, U01-DK099924, and R01-DK102438 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 102 TC 20 Z9 22 U1 0 U2 11 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 OCT PY 2015 VL 26 IS 10 BP 2328 EP 2339 DI 10.1681/ASN.2015020117 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CS5ZL UT WOS:000362156700007 PM 25967123 ER PT J AU Limou, S Nelson, GW Lecordier, L An, P O'hUigin, CS David, VA Binns-Roemer, EA Guiblet, WM Oleksyk, TK Pays, E Kopp, JB Winkler, CA AF Limou, Sophie Nelson, George W. Lecordier, Laurence An, Ping O'hUigin, Colm S. David, Victor A. Binns-Roemer, Elizabeth A. Guiblet, Wilfried M. Oleksyk, Taras K. Pays, Etienne Kopp, Jeffrey B. Winkler, Cheryl A. TI Sequencing rare and common APOL1 coding variants to determine kidney disease risk SO KIDNEY INTERNATIONAL LA English DT Article DE APOL1; FSGS; HIVAN; personalized medicine; selection; trypanolysis ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIV-ASSOCIATED NEPHROPATHY; AFRICAN-AMERICANS; HAPLOTYPE STRUCTURE; HUMAN-POPULATIONS; PROTEIN FUNCTION; UNITED-STATES; CELL-DEATH; SELECTION; GENOME AB A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN. Testing for association with 33 common and rare variants with FSGS/HIVAN revealed no association independent of strong recessive G1 and G2 effects. Seeking additional variants that might have been under selection by pathogens and could represent candidates for kidney disease risk, we also sequenced an additional 1112 individuals representing 53 global populations. Except for G1 and G2, none of the 7 common codon-altering variants showed evidence of selection or could restore lysis against trypanosomes causing human African trypanosomiasis. Thus, only APOL1 G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN in the US population. Hence, in most potential clinical or screening applications, our study suggests that sequencing APOL1 exons is unlikely to bring additional information compared to genotyping only APOL1 G1 and G2 risk alleles. C1 [Limou, Sophie; An, Ping; Binns-Roemer, Elizabeth A.; Winkler, Cheryl A.] NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program,Frederick Natl Lab,Leidos Biome, Frederick, MD 21702 USA. [Nelson, George W.] Frederick Natl Lab, Leidos Biomed Res, Ctr Canc Res Informat Core, Frederick, MD USA. [Lecordier, Laurence; Pays, Etienne] Univ Libre Bruxelles, IBMM, Lab Mol Parasitol, Gosselies, Belgium. [O'hUigin, Colm S.] NCI, Lab Expt Immunol, Canc & Inflammat Program, Leidos Biomed Res,Frederick Natl Lab, Frederick, MD 21702 USA. [David, Victor A.] NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program,Frederick Natl Lab, Frederick, MD 21702 USA. [Guiblet, Wilfried M.; Oleksyk, Taras K.] Univ Puerto Rico Mayaguez, Dept Biol, Caribbean Genome Ctr, Mayaguez, PR USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. RP Winkler, CA (reprint author), NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Basic Sci Program, 1050 Boyles St,Bldg 560,Room 21-19, Frederick, MD 21702 USA. EM winklerc@mail.nih.gov FU Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN26120080001E]; Intramural Research Programs of Frederick National Lab; Center for Cancer Research; NIDDK, NIH; WELBIO (Walloon Excellence in Life Science and Biotechnology) FX We thank the reviewers and editorial board for their comments, as we believe they have substantially improved our manuscript. This work has been presented as a poster (FR-PO198) at the American Society of Nephrology annual meeting, Philadelphia PA, 2014. This work has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN26120080001E, and by the Intramural Research Programs of Frederick National Lab, Center for Cancer Research, and NIDDK, NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The work of the Brussels team was financed by WELBIO (Walloon Excellence in Life Science and Biotechnology). NR 43 TC 5 Z9 5 U1 0 U2 2 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 OCT PY 2015 VL 88 IS 4 BP 754 EP 763 DI 10.1038/ki.2015.151 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CS6UY UT WOS:000362219600016 PM 25993319 ER PT J AU Agarwal, R Kusek, JW Pappas, MK AF Agarwal, Rajiv Kusek, John W. Pappas, Maria K. TI A randomized trial of intravenous and oral iron in chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE adverse effects; anemia; chronic kidney disease; iron; randomized controlled trial ID STAGE RENAL-DISEASE; HEMODIALYSIS-PATIENTS; PARENTERAL IRON; OXIDATIVE STRESS; FERRIC CARBOXYMALTOSE; ANEMIA MANAGEMENT; NATIONAL-HEALTH; INJURY; THERAPY; SERUM AB Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6ml/min per 1.73m(2), intravenous -4.0ml/min per 1.73m(2), between-group difference -0.35 ml/min per 1.73m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases. C1 [Agarwal, Rajiv; Pappas, Maria K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Agarwal, Rajiv; Pappas, Maria K.] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Kusek, John W.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. RP Agarwal, R (reprint author), Indiana Univ, 1481 W 10th St, Indianapolis, IN 46202 USA. EM ragarwal@iu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK71633]; Indiana Institute for Medical Research FX This study was supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK71633) and Indiana Institute for Medical Research. NR 34 TC 29 Z9 31 U1 3 U2 6 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 OCT PY 2015 VL 88 IS 4 BP 905 EP 914 DI 10.1038/ki.2015.163 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CS6UY UT WOS:000362219600032 PM 26083656 ER PT J AU Souza, ACP Yuen, PST Star, RA AF Souza, Ana Carolina P. Yuen, Peter S. T. Star, Robert A. TI Re: Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI Reply SO KIDNEY INTERNATIONAL LA English DT Letter C1 [Souza, Ana Carolina P.; Yuen, Peter S. T.; Star, Robert A.] Natl Inst Diabet & Digest & Kidney Dis, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. RP Star, RA (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Div Kidney Urol & Hematol Dis, Renal Diagnost & Therapeut Unit, NIH, 6707 Democracy Blvd,Room 625, Bethesda, MD 20892 USA. EM starr@niddk.nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural NIH HHS [ZIA DK043403-15, ZIA DK043400-15, Z99 DK999999] NR 4 TC 0 Z9 0 U1 0 U2 1 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 OCT PY 2015 VL 88 IS 4 BP 915 EP 917 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA CS6UY UT WOS:000362219600034 PM 26422627 ER PT J AU Uyoga, S Ndila, CM Macharia, AW Nyutu, G Shah, S Peshu, N Clarke, GM Kwiatkowski, DP Rockett, KA Williams, TN AF Uyoga, Sophie Ndila, Carolyne M. Macharia, Alex W. Nyutu, Gideon Shah, Shivang Peshu, Norbert Clarke, Geraldine M. Kwiatkowski, Dominic P. Rockett, Kirk A. Williams, Thomas N. CA MalariaGEN Consortium TI Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study SO LANCET HAEMATOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; SICKLE-CELL TRAIT; G6PD DEFICIENCY; DEHYDROGENASE-DEFICIENCY; NATURAL-SELECTION; RESISTANCE; POPULATION; AFRICA; SUSCEPTIBILITY; HETEROZYGOTES AB Background The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated the relationships between G6PD deficiency and both malaria and non-malarial illnesses among children in Kenya. Methods We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only significant cause of G6PD deficiency. We tested the associations between G6PD deficiency and severe and complicated Plasmodium falciparum malaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than 14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998, and Feb 28, 2010. Controls were children aged between 3-12 months who were born within the same study area between August 2006, and September 2010. We assessed the association between G6PD deficiency and both uncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than 10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya and Chonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the casec-ontrol study was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while for the cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed by Poisson regression), by G6PD deficiency category. Findings 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normal genotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%) children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD deficiency, we found significant protection from severe malaria (odds ratio [OR] 0.82, 95% CI 0.70-0.97; p=0.020) among G6PD c.202T heterozygous girls but no evidence for protection among G6PD c.202T hemizygous boys and homozygous girls (OR 1.18, 0.99-1.40; p=0.056). Median follow-up for the mild disease cohort study was 2.24 years (IQR 2.22-2.85). G6PD c.202T had no effect on other common diseases of childhood in heterozygous girls (incidence rate ratio 0.98, 95% CI 0.86-1.11; p=0.82) or homozygous girls or hemizygous boys (0.93, 0.82-1.04; p=0.25), with the sole exception of a marginally significant increase in the incidence of helminth infections among heterozygous girls. Interpretation Heterozygous girls might be the driving force for the positive selection of G6PD deficiency alleles. Further studies are needed to definitively establish the mechanisms by which G6PD deficiency confers an advantage against malaria in heterozygous individuals. Such studies could lead to the development of new treatments. Copyright (C) Uyoga et al. Open Access article distributed under the terms of CC BY. C1 [Uyoga, Sophie; Ndila, Carolyne M.; Macharia, Alex W.; Nyutu, Gideon; Peshu, Norbert; Williams, Thomas N.] KEMRI Wellcome Trust Res Programme, Dept Epidemiol & Demog, Kilifi 80108, Kenya. [Ndila, Carolyne M.; Shah, Shivang; Clarke, Geraldine M.; Kwiatkowski, Dominic P.; Rockett, Kirk A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Shah, Shivang] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Kwiatkowski, Dominic P.] Wellcome Trust Sanger Inst, Cambridge, England. [Williams, Thomas N.] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Dept Med, London, England. RP Williams, TN (reprint author), KEMRI Wellcome Trust Res Programme, Ctr Geog Med Res Coast, POB 230, Kilifi 80108, Kenya. EM tom.williams@imperial.ac.uk RI Deloukas, Panos/B-2922-2013; OI Deloukas, Panos/0000-0001-9251-070X; Mangano, Valentina D/0000-0002-2021-6162; Kivinen, Katja/0000-0002-1135-7625; Auburn, Sarah/0000-0002-4638-536X; Small, Kerrin/0000-0003-4566-0005; Kwiatkowski, Dominic/0000-0002-5023-0176; Mead, Daniel/0000-0001-7717-4330; Manske, Magnus/0000-0001-5916-0947 FU Wellcome Trust [091758, 077383, 090770, 084535]; UK Medical Research Council [G19/9, G0600718]; Medical Scientist Training Program at the US National Institutes of Health; Wolfson College, Oxford; Oxford University Exploration Club; European Community's Seventh Framework Programme [242095]; Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative [566]; Wellcome Trust Centre for Human Genetics, Oxford, UK [090532] FX We thank Johnstone Makale, Emily Nyatichi, and Metrine Tendwa for laboratory support, the staff of Kilifi County Hospital and the KEMRI-Wellcome Trust Research Programme, Kilifi, for their help with data and sample collection, and the study participants and their parents for participating in this study. The genotyping of samples was undertaken at both the KEMRI-Wellcome Trust Research Programme in Kilifi and at the MalariaGEN Resource Centre in Oxford, UK. TNW is funded by the Wellcome Trust (091758) and DPK receives support from the UK Medical Research Council (G19/9). SS is supported by the Medical Scientist Training Program at the US National Institutes of Health and received travel funds from Wolfson College, Oxford, and from the Oxford University Exploration Club. This research received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095 and from the UK Medical Research Council (G0600718). The MalariaGEN Project is supported by the Wellcome Trust (077383) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative and through a Wellcome Trust Strategic Award (090770). The Wellcome Trust provides core support to The KEMRI-Wellcome Trust Research Programme in Kilifi (084535) and the Wellcome Trust Centre for Human Genetics (090532), Oxford, UK. This paper is published with permission from the Director of the Kenya Medical Research Institute. NR 42 TC 5 Z9 5 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2352-3026 J9 LANCET HAEMATOL JI Lancet Haematol. PD OCT PY 2015 VL 2 IS 10 BP E437 EP E444 DI 10.1016/S2352-3026(15)00152-0 PG 8 WC Hematology SC Hematology GA CS4VY UT WOS:000362075400014 PM 26686045 ER PT J AU Ledgerwood, JE AF Ledgerwood, Julie E. TI Use of low dose rVSV-ZEBOV: safety issues in a Swiss cohort SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID I CLINICAL-TRIAL; EBOLA-VIRUS; VACCINE C1 NIAID, Vaccine Res Ctr, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ledgerwood, JE (reprint author), NIAID, Vaccine Res Ctr, NIH, US Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ledgerwood@mail.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2015 VL 15 IS 10 BP 1117 EP 1119 DI 10.1016/S1473-3099(15)00222-4 PG 3 WC Infectious Diseases SC Infectious Diseases GA CS1UQ UT WOS:000361854300003 PM 26248511 ER PT J AU Koh, C Canini, L Dahari, H Zhao, XC Uprichard, SL Haynes-Williams, V Winters, MA Subramanya, G Cooper, SL Pinto, P Wolff, EF Bishop, R Han, MAT Cotler, SJ Kleiner, DE Keskin, O Idilman, R Yurdaydin, C Glenn, JS Heller, T AF Koh, Christopher Canini, Laetitia Dahari, Hare Zhao, Xiongce Uprichard, Susan L. Haynes-Williams, Vanessa Winters, Mark A. Subramanya, Gitanjali Cooper, Stewart L. Pinto, Peter Wolff, Erin F. Bishop, Rachel Han, Ma Ai Thanda Cotler, Scott J. Kleiner, David E. Keskin, Onur Idilman, Ramazan Yurdaydin, Cihan Glenn, Jeffrey S. Heller, Theo TI Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial SO LANCET INFECTIOUS DISEASES LA English DT Article ID CHRONIC DELTA-HEPATITIS; MYELODYSPLASTIC SYNDROME; B VIRUS; INTERFERON; PREVALENCE; LEUKEMIA; EFFICACY; ANTIBODY; CARRIERS; THERAPY AB Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis.' Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group land 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014,14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were 0.73 log IU/mL in group 1 (95% CI 0.17-1.31; p=0.03) and -1.54 log IU/mL in group 2 (1-21-1.93; p<0.0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0.78, p<0.0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0.75 days [SE 0.24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0.952 [SE 0.06] vs 0.739 [0.05], p<0.001), and the HDV half-life was 1-62 days (0.07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. C1 [Koh, Christopher; Haynes-Williams, Vanessa; Han, Ma Ai Thanda; Heller, Theo] NIDDKD, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDKD, Off Director, NIH, Bethesda, MD 20892 USA. [Canini, Laetitia; Dahari, Hare; Uprichard, Susan L.; Subramanya, Gitanjali; Cotler, Scott J.] Loyola Univ, Med Ctr, Program Expt & Theoret Modeling, Div Hepatol, Maywood, IL 60153 USA. [Canini, Laetitia] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. [Dahari, Hare] Los Alamos Natl Lab, Theoret Biol & Biophys Grp, Los Alamos, NM USA. [Winters, Mark A.; Glenn, Jeffrey S.] Stanford Sch Med, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA USA. [Winters, Mark A.; Glenn, Jeffrey S.] Stanford Sch Med, Dept Microbiol & Immunol, Stanford, CA USA. [Cooper, Stewart L.] Calif Pacific Med Ctr, Div Hepatol, San Francisco, CA USA. [Pinto, Peter] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wolff, Erin F.] NICHHD, Unit Reprod & Regenerat Med, NIH, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, Consult Serv Sect, NIH, Bethesda, MD 20892 USA. [Keskin, Onur; Idilman, Ramazan; Yurdaydin, Cihan] Ankara Univ, Sch Med, Dept Gastroenterol, TR-06100 Ankara, Turkey. RP Koh, C (reprint author), NIDDKD, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM Christopher.Koh@nih.gov; TheoH@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health; Eiger Biopharmaceuticals Inc. FX National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc. NR 27 TC 23 Z9 23 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD OCT PY 2015 VL 15 IS 10 BP 1167 EP 1174 DI 10.1016/S1473-3099(15)00074-2 PG 8 WC Infectious Diseases SC Infectious Diseases GA CS1UQ UT WOS:000361854300027 PM 26189433 ER PT J AU Wiestner, A AF Wiestner, Adrian TI PROLONGing remissions in patients with CLL SO LANCET ONCOLOGY LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; RITUXIMAB MAINTENANCE; PHASE-3 TRIAL; OPEN-LABEL; OFATUMUMAB; IBRUTINIB; PRIMA C1 NHLBI, NIH, Bethesda, MD 20817 USA. RP Wiestner, A (reprint author), NHLBI, NIH, Bethesda, MD 20817 USA. EM wiestnera@mail.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2015 VL 16 IS 13 BP 1282 EP 1284 DI 10.1016/S1470-2045(15)00219-3 PG 4 WC Oncology SC Oncology GA CS3BO UT WOS:000361946300028 PM 26377301 ER PT J AU Carle, AC Riley, W Hays, RD Cella, D AF Carle, Adam C. Riley, William Hays, Ron D. Cella, David TI Confirmatory Factor Analysis of the Patient Reported Outcomes Measurement Information System (PROMIS) Adult Domain Framework Using Item Response Theory Scores SO MEDICAL CARE LA English DT Article DE construct validity; conceptual framework; domain definition; confirmatory factor analysis; item response theory; Patient reported Outcomes Measurement Information System; PROMIS ID FIT INDEXES; HEALTH; ISSUES; SF-36; BANKS AB Background:To guide measure development, National Institutes of Health-supported Patient reported Outcomes Measurement Information System (PROMIS) investigators developed a hierarchical domain framework. The framework specifies health domains at multiple levels. The initial PROMIS domain framework specified that physical function and symptoms such as Pain and Fatigue indicate Physical Health (PH); Depression, Anxiety, and Anger indicate Mental Health (MH); and Social Role Performance and Social Satisfaction indicate Social Health (SH). We used confirmatory factor analyses to evaluate the fit of the hypothesized framework to data collected from a large sample.Methods:We used data (n=14,098) from PROMIS's wave 1 field test and estimated domain scores using the PROMIS item response theory parameters. We then used confirmatory factor analyses to test whether the domains corresponded to the PROMIS domain framework as expected.Results:A model corresponding to the domain framework did not provide ideal fit [root mean square error of approximation (RMSEA)=0.13; comparative fit index (CFI)=0.92; Tucker Lewis Index (TLI)=0.88; standardized root mean square residual (SRMR)=0.09]. On the basis of modification indices and exploratory factor analyses, we allowed Fatigue to load on both PH and MH. This model fit the data acceptably (RMSEA=0.08; CFI=0.97; TLI=0.96; SRMR=0.03).Discussion:Our findings generally support the PROMIS domain framework. Allowing Fatigue to load on both PH and MH improved fit considerably. C1 [Carle, Adam C.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Carle, Adam C.] Univ Cincinnati, Dept Psychol, Coll Arts & Sci, Cincinnati, OH 45221 USA. [Riley, William] NCI, Sci Res & Technol Branch, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med, Los Angeles, CA 90024 USA. [Hays, Ron D.] Univ Calif Los Angeles, Hlth Serv Res, Los Angeles, CA 90024 USA. [Cella, David] Northwestern Univ, Dept Med Social Sci, Evanston, IL USA. [Cella, David] Northwestern Univ, Inst Publ Hlth & Med, Ctr Patient Centered Outcomes, Evanston, IL USA. RP Carle, AC (reprint author), James M Anderson Ctr Hlth Syst Excellence, 3333 Burnett,ML 7014, Cincinnati, OH 45229 USA. EM adam.carle.cchmc@gmail.com FU NCI NIH HHS [P30 CA060553]; NIAMS NIH HHS [U01 AR057940] NR 23 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2015 VL 53 IS 10 BP 894 EP 900 DI 10.1097/MLR.0000000000000413 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS5IL UT WOS:000362111500009 PM 26366521 ER PT J AU Eisenberg, IW Wallace, GL Kenworthy, L Gotts, SJ Martin, A AF Eisenberg, Ian W. Wallace, Gregory L. Kenworthy, Lauren Gotts, Stephen J. Martin, Alex TI Insistence on sameness relates to increased covariance of gray matter structure in autism spectrum disorder SO MOLECULAR AUTISM LA English DT Article DE Autism; Insistence on sameness; Repetitive behavior; MRI; Structural covariance; Subcortex ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; REPETITIVE BEHAVIORS; DIAGNOSTIC INTERVIEW; DEVELOPMENTAL TRAJECTORIES; FUNCTIONAL CONNECTIVITY; AMYGDALA; CHILDREN; STRIATUM; INDIVIDUALS AB Background: Autism spectrum disorder (ASD) is characterized by atypical development of cortical and subcortical gray matter volume. Subcortical structural changes have been associated with restricted and repetitive behavior (RRB), a core component of ASD. Behavioral studies have identified insistence on sameness (IS) as a separable RRB dimension prominent in high-functioning ASD, though no simple brain-behavior relationship has emerged. Structural covariance, a measure of morphological coupling among brain regions using magnetic resonance imaging (MRI), has proven an informative measure of anatomical relationships in typical development and neurodevelopmental disorders. In this study, we use this measure to characterize the relationship between brain structure and IS. Methods: We quantified the structural covariance of cortical and subcortical gray matter volume in 55 individuals with high-functioning ASD using 3T MRI. We then related these structural metrics to individual IS scores, as assessed by the Repetitive Behavior Scale-Revised (RBS-R). Results: We found that increased coupling among subcortical regions and between subcortical and cortical regions related to greater IS symptom severity. Most pronounced, the striatum and amygdala participated in a plurality of identified relationships, indicating a central role for these structures in IS symptomatology. These structural associations were specific to IS and did not relate to any of the other RRB subcomponents measured by the RBS-R. Conclusions: This study indicates that behavioral dimensions in ASD can relate to the coordination of development across multiple brain regions, which might be otherwise obscured using typical brain-behavior correlations. It also expands the structures traditionally related to RRB in ASD and provides neuroanatomical evidence supportive of IS as a separate RRB dimension. C1 [Eisenberg, Ian W.; Wallace, Gregory L.; Gotts, Stephen J.; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC USA. [Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Rockville, MD USA. RP Eisenberg, IW (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM ianeisenberg90@gmail.com OI Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program at NIMH, NIH [1-ZIA-MH002920-05] FX This work was supported by the Intramural Research Program at NIMH, NIH under grant number 1-ZIA-MH002920-05, and it was conducted under National Institutes of Health Clinical Study Protocol 10-M-0027 (ClinicalTrials.gov ID NCT01031407). We would also like to thank the children/adults and their families who gave their time and energy to assist in completing this research and Bako Orionzi for the aid in data collection. NR 66 TC 2 Z9 2 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD OCT 1 PY 2015 VL 6 AR 54 DI 10.1186/s13229-015-0047-7 PG 12 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA CS4WC UT WOS:000362075800001 PM 26435832 ER PT J AU Davis, BW Seabury, CM Brashear, WA Li, G Roelke-Parker, M Murphy, WJ AF Davis, Brian W. Seabury, Christopher M. Brashear, Wesley A. Li, Gang Roelke-Parker, Melody Murphy, William J. TI Mechanisms Underlying Mammalian Hybrid Sterility in Two Feline Interspecies Models SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE hybrid sterility; Haldane's rule; large X-effect; speciation; feline ID GENOME-WIDE ASSOCIATION; Y-CHROMOSOME; HOUSE MICE; IMMUNOGLOBULIN SUPERFAMILY; REPRODUCTIVE ISOLATION; MALE-INFERTILITY; GENETIC-ANALYSIS; SEX-CHROMOSOMES; SPECIATION GENE; DOMESTIC CAT AB The phenomenon of male sterility in interspecies hybrids has been observed for over a century, however, few genes influencing this recurrent phenotype have been identified. Genetic investigations have been primarily limited to a small number of model organisms, thus limiting our understanding of the underlying molecular basis of this well-documented "rule of speciation." We utilized two interspecies hybrid cat breeds in a genome-wide association study employing the Illumina 63 K single-nucleotide polymorphism array. Collectively, we identified eight autosomal genes/gene regions underlying associations with hybrid male sterility (HMS) involved in the function of the blood-testis barrier, gamete structural development, and transcriptional regulation. We also identified several candidate hybrid sterility regions on the X chromosome, with most residing in close proximity to complex duplicated regions. Differential gene expression analyses revealed significant chromosome-wide upregulation of X chromosome transcripts in testes of sterile hybrids, which were enriched for genes involved in chromatin regulation of gene expression. Our expression results parallel those reported in Mus hybrids, supporting the "Large X-Effect" in mammalian HMS and the potential epigenetic basis for this phenomenon. These results support the value of the interspecies feline model as a powerful tool for comparison to rodent models of HMS, demonstrating unique aspects and potential commonalities that underpin mammalian reproductive isolation. C1 [Davis, Brian W.; Seabury, Christopher M.; Brashear, Wesley A.; Li, Gang; Roelke-Parker, Melody; Murphy, William J.] Texas A&M Univ, Coll Vet Med, College Stn, TX 77843 USA. [Davis, Brian W.; Seabury, Christopher M.; Brashear, Wesley A.; Murphy, William J.] Texas A&M Univ, Interdisciplinary Program Genet, College Stn, TX 77843 USA. [Roelke-Parker, Melody] NCI, NIH, Bethesda, MD 20892 USA. RP Murphy, WJ (reprint author), Texas A&M Univ, Coll Vet Med, College Stn, TX 77843 USA. EM wmurphy@cvm.tamu.edu RI li, gang/E-5640-2014 FU Morris Animal Foundation (MAF) [D12FE-019]; Cat Health Network/MAF [D12FE-502]; Winn Feline Foundation [07-034]; NIH LRP from the NICHD [1L50HD070410-01]; Texas AAMP;M College of Veterinary Medicine AMP; Biomedical Sciences; Texas AgriLife Research FX We would like to thank Marilyn Raymond, Eduardo Eizirik, Lynn Colenda, and Buhdan Pukazhenthi for assistance with the generation of early generation Bengal hybrids at NIH. We thank Alison Pearks Wilkerson, Breanne Harty, and Nicholas Kennedy for technical assistance. We thank Lynn Bustamante, TAMU Veterinary Histopathology Laboratory, for testis slide preparations, Dr Brad Weeks for slide scanning and imaging, and Dr Beverly Purswell for savannah histopathology reports. We also thank the numerous Bengal and Savannah cat breeders for generously contributing samples, pedigrees, and breeding data for this project, especially Dr Kristin Filseth and Kathrin Stucki. This work was supported, in part, by Morris Animal Foundation (MAF) Grant D12FE-019 to W.J.M., Cat Health Network/MAF grant D12FE-502 to W.J.M. and C.M.S., and Winn Feline Foundation Grant 07-034 to W.J.M. B.W.D. acknowledges the support of NIH LRP award 1L50HD070410-01 from the NICHD and the Texas A&M College of Veterinary Medicine & Biomedical Sciences. C.M.S. acknowledges support from the Texas A&M College of Veterinary Medicine & Biomedical Sciences and Texas AgriLife Research. B.W.D., C.M.S., M.R.-P., and W.J.M. designed research; B.W.D., C.M.S., W.B., G.L., M.R.-P., and W.J.M. performed research; C.M.S. and M.R.-P. contributed new reagents or analytic tools; B.W.D., C.M.S., W.B., G.L., and W.J.M. analyzed data; and B.W.D., C.M.S., and W.J.M. wrote the paper with input from all authors. NR 92 TC 6 Z9 6 U1 5 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD OCT PY 2015 VL 32 IS 10 BP 2534 EP 2546 DI 10.1093/molbev/msv124 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA CS3PQ UT WOS:000361987100003 PM 26006188 ER PT J AU Manes, NP Angermann, BR Koppenol-Raab, M An, E Sjoelund, VH Sun, J Ishii, M Germain, RN Meier-Schellersheim, M Nita-Lazar, A AF Manes, Nathan P. Angermann, Bastian R. Koppenol-Raab, Marijke An, Eunkyung Sjoelund, Virginie H. Sun, Jing Ishii, Masaru Germain, Ronald N. Meier-Schellersheim, Martin Nita-Lazar, Aleksandra TI Targeted Proteomics-Driven Computational Modeling of Macrophage S1P Chemosensing SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID RNA-SEQ EXPERIMENTS; MASS-SPECTROMETRY; CELL-MIGRATION; QUANTITATIVE PROTEOMICS; PROTEIN IDENTIFICATION; ACTIN CYTOSKELETON; BONE HOMEOSTASIS; SYSTEMS BIOLOGY; LIVING CELLS; IN-VIVO AB Osteoclasts are monocyte-derived multinuclear cells that directly attach to and resorb bone. Sphingosine-1-phosphate (S1P)(1) regulates bone resorption by functioning as both a chemoattractant and chemorepellent of osteoclast precursors through two G-protein coupled receptors that antagonize each other in an S1P-concentration-dependent manner. To quantitatively explore the behavior of this chemosensing pathway, we applied targeted proteomics, transcriptomics, and rule-based pathway modeling using the Simmune toolset. RAW264.7 cells (a mouse monocyte/macrophage cell line) were used as model osteoclast precursors, RNA-seq was used to identify expressed target proteins, and selected reaction monitoring (SRM) mass spectrometry using internal peptide standards was used to perform absolute abundance measurements of pathway proteins. The resulting transcript and protein abundance values were strongly correlated. Measured protein abundance values, used as simulation input parameters, led to in silico pathway behavior matching in vitro measurements. Moreover, once model parameters were established, even simulated responses toward stimuli that were not used for parameterization were consistent with experimental findings. These findings demonstrate the feasibility and value of combining targeted mass spectrometry with pathway modeling for advancing biological insight. C1 [Manes, Nathan P.; Angermann, Bastian R.; Koppenol-Raab, Marijke; An, Eunkyung; Sjoelund, Virginie H.; Sun, Jing; Germain, Ronald N.; Meier-Schellersheim, Martin; Nita-Lazar, Aleksandra] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Ishii, Masaru] Osaka Univ, Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan. RP Nita-Lazar, A (reprint author), NIAID, LSB, Cellular Net Works Prote Unit, NIH, 9000 Rockville Pike,4-101, Bethesda, MD 20892 USA. EM nitalazarau@niaid.nih.gov RI Manes, Nathan/E-2817-2012 OI Manes, Nathan/0000-0001-6701-3314 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study used the Office of Cyber Infrastructure and Computational Biology (OCICB) High Performance Computing (HPC) cluster at the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 94 TC 2 Z9 2 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2015 VL 14 IS 10 BP 2661 EP 2681 DI 10.1074/mcp.M115.048918 PG 21 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CS6KA UT WOS:000362186200008 PM 26199343 ER PT J AU Katebi, A Gholami, E Taheri, T Zahedifard, F Habibzadeh, S Taslimi, Y Shokri, F Papadopoulou, B Kamhawi, S Valenzuela, JG Rafati, S AF Katebi, A. Gholami, E. Taheri, T. Zahedifard, F. Habibzadeh, S. Taslimi, Y. Shokri, F. Papadopoulou, B. Kamhawi, S. Valenzuela, J. G. Rafati, S. TI Leishmania tarentolae secreting the sand fly salivary antigen PpSP15 confers protection against Leishmania major infection in a susceptible BALB/c mice model SO MOLECULAR IMMUNOLOGY LA English DT Article DE L. tarentolae-PpSP15; Sand fly; Saliva; L. major; BALB/c mice CpG; Vaccine ID CPG MOTIFS; CUTANEOUS LEISHMANIASIS; VISCERAL LEISHMANIASIS; VACCINE; OLIGODEOXYNUCLEOTIDES; IMMUNITY; VECTOR; IL-17; GENE; DNA AB Cutaneous leishmaniasis is a zoonotic, vector-borne disease causing a major health problem in several countries. No vaccine is available and there are limitations associated with the current therapeutic regimens. Immune responses to sand fly saliva have been shown to protect against Leishmania infection. A cellular immune response to PpSP15, a protein from the sand fly Phlebotomus papatasi, was sufficient to control Leishmania major infection in mice. This work presents data supporting the vaccine potency of recombinant live non-pathogenic Leishmania (L.) tarentolae secreting PpSP15 in mice and its potential as a new vaccine strategy against L major. We generated a recombinant L. tarentolae-PpSP15 strain delivered in the presence of CpG ODN and evaluated its immunogenicity and protective immunity against L. major infection in BALB/c mice. In parallel, different vaccination modalities using PpSP15 as the target antigen were compared. Humoral and cellular immune responses were evaluated before and at three and eight weeks after challenge. Footpad swelling and parasite load were assessed at eight and eleven weeks post-challenge. Our results show that vaccination with L tarentolae-PpSP15 in combination with CpG as a prime-boost modality confers strong protection against L. major infection that was superior to other vaccination modalities used in this study. This approach represents a novel and promising vaccination strategy against Old World cutaneous leishmaniasis. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Katebi, A.; Gholami, E.; Taheri, T.; Zahedifard, F.; Habibzadeh, S.; Taslimi, Y.; Rafati, S.] Pasteur Inst Iran, Dept Immunotherapy & Leishmania Vaccine Res, Tehran, Iran. [Katebi, A.; Shokri, F.] Univ Tehran Med Sci, Sch Publ Hlth, Dept Immunol, Tehran, Iran. [Papadopoulou, B.] Univ Laval, CHU Quebec Res Ctr, Res Ctr Infect Dis, Quebec City, PQ, Canada. [Papadopoulou, B.] Univ Laval, Dept Microbiol Infect Dis & Immunol, Quebec City, PQ, Canada. [Papadopoulou, B.] Canada Univ, Quebec City, PQ, Canada. NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Rafati, S (reprint author), Pasteur Inst Iran, Dept Immunotherapy & Leishmania Vaccine Res, Tehran, Iran. EM s_rafati@yahoo.com FU Pasteur Institute of Iran [ID 719] FX Special thanks to Amir Mizbani for English editing. The authors wish to thank A. Javadi (Pasteur Institute of Iran, Department of Immunology) and Mr. Sh. Alizadeh for their technical assistance. This work was supported by a grant from Pasteur Institute of Iran (ID 719). NR 31 TC 4 Z9 4 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD OCT PY 2015 VL 67 IS 2 BP 501 EP 511 DI 10.1016/j.molimm.2015.08.001 PN B PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA CS2SQ UT WOS:000361922400035 PM 26298575 ER PT J AU Nikpay, M Goel, A Won, HH Hall, LM Willenborg, C Kanoni, S Saleheen, D Kyriakou, T Nelson, CP Hopewell, JC Webb, TR Zeng, L Dehghan, A Alver, M Armasu, SM Auro, K Bjonnes, A Chasman, DI Chen, SF Ford, I Franceschini, N Gieger, C Grace, C Gustafsson, S Huang, J Hwang, SJ Kim, YK Kleber, ME Lau, KW Lu, XF Lu, YC Lyytikainen, LP Mihailov, E Morrison, AC Pervjakova, N Qu, LM Rose, LM Salfati, E Saxena, R Scholz, M Smith, AV Tikkanen, E Uitterlinden, A Yang, XL Zhang, WH Zhao, W de Andrade, M de Vries, PS van Zuydam, NR Anand, SS Bertram, L Beutner, F Dedoussis, G Frossard, P Gauguier, D Goodall, AH Gottesman, O Haber, M Han, BG Huang, J Jalilzadeh, S Kessler, T Konig, IR Lannfelt, L Lieb, W Lind, L Lindgren, CM Lokki, ML Magnusson, PK Mallick, NH Mehra, N Meitinger, T Memon, FUR Morris, AP Nieminen, MS Pedersen, NL Peters, A Rallidis, LS Rasheed, A Samuel, M Shah, SH Sinisalo, J Stirrups, KE Trompet, S Wang, LY Zaman, KS Ardissino, D Boerwinkle, E Borecki, IB Bottinger, EP Buring, JE Chambers, JC Collins, R Cupples, LA Danesh, J Demuth, I Elosua, R Epstein, SE Esko, T Feitosa, MF Franco, OH Franzosi, MG Granger, CB Gu, DF Gudnason, V Hall, AS Hamsten, A Harris, TB Hazen, SL Hengstenberg, C Hofman, A Ingelsson, E Iribarren, C Jukema, JW Karhunen, PJ Kim, BJ Kooner, JS Kullo, IJ Lehtimaki, T Loos, RJF Melander, O Metspalu, A Marz, W Palmer, CN Perola, M Quertermous, T Rader, DJ Ridker, PM Ripatti, S Roberts, R Salomaa, V Sanghera, DK Schwartz, SM Seedorf, U Stewart, AF Stott, DJ Thiery, J Zalloua, PA O'Donnell, CJ Reilly, MP Assimes, TL Thompson, JR Erdmann, J Clarke, R Watkins, H Kathiresan, S McPherson, R Deloukas, P Schunkert, H Samani, NJ Farrall, M AF Nikpay, Majid Goel, Anuj Won, Hong-Hee Hall, Leanne M. Willenborg, Christina Kanoni, Stavroula Saleheen, Danish Kyriakou, Theodosios Nelson, Christopher P. Hopewell, Jemma C. Webb, Thomas R. Zeng, Lingyao Dehghan, Abbas Alver, Maris Armasu, Sebastian M. Auro, Kirsi Bjonnes, Andrew Chasman, Daniel I. Chen, Shufeng Ford, Ian Franceschini, Nora Gieger, Christian Grace, Christopher Gustafsson, Stefan Huang, Jie Hwang, Shih-Jen Kim, Yun Kyoung Kleber, Marcus E. Lau, King Wai Lu, Xiangfeng Lu, Yingchang Lyytikainen, Leo-Pekka Mihailov, Evelin Morrison, Alanna C. Pervjakova, Natalia Qu, Liming Rose, Lynda M. Salfati, Elias Saxena, Richa Scholz, Markus Smith, Albert V. Tikkanen, Emmi Uitterlinden, Andre Yang, Xueli Zhang, Weihua Zhao, Wei de Andrade, Mariza de Vries, Paul S. van Zuydam, Natalie R. Anand, Sonia S. Bertram, Lars Beutner, Frank Dedoussis, George Frossard, Philippe Gauguier, Dominique Goodall, Alison H. Gottesman, Omri Haber, Marc Han, Bok-Ghee Huang, Jianfeng Jalilzadeh, Shapour Kessler, Thorsten Koenig, Inke R. Lannfelt, Lars Lieb, Wolfgang Lind, Lars Lindgren, Cecilia M. Lokki, Marja-Liisa Magnusson, Patrik K. Mallick, Nadeem H. Mehra, Narinder Meitinger, Thomas Memon, Fazal-ur-Rehman Morris, Andrew P. Nieminen, Markku S. Pedersen, Nancy L. Peters, Annette Rallidis, Loukianos S. Rasheed, Asif Samuel, Maria Shah, Svati H. Sinisalo, Juha Stirrups, Kathleen E. Trompet, Stella Wang, Laiyuan Zaman, Khan S. Ardissino, Diego Boerwinkle, Eric Borecki, Ingrid B. Bottinger, Erwin P. Buring, Julie E. Chambers, John C. Collins, Rory Cupples, L. Adrienne Danesh, John Demuth, Ilja Elosua, Roberto Epstein, Stephen E. Esko, Tonu Feitosa, Mary F. Franco, Oscar H. Franzosi, Maria Grazia Granger, Christopher B. Gu, Dongfeng Gudnason, Vilmundur Hall, Alistair S. Hamsten, Anders Harris, Tamara B. Hazen, Stanley L. Hengstenberg, Christian Hofman, Albert Ingelsson, Erik Iribarren, Carlos Jukema, J. Wouter Karhunen, Pekka J. Kim, Bong-Jo Kooner, Jaspal S. Kullo, Iftikhar J. Lehtimaki, Terho Loos, Ruth J. F. Melander, Olle Metspalu, Andres Maerz, Winfried Palmer, Colin N. Perola, Markus Quertermous, Thomas Rader, Daniel J. Ridker, Paul M. Ripatti, Samuli Roberts, Robert Salomaa, Veikko Sanghera, Dharambir K. Schwartz, Stephen M. Seedorf, Udo Stewart, Alexandre F. Stott, David J. Thiery, Joachim Zalloua, Pierre A. O'Donnell, Christopher J. Reilly, Muredach P. Assimes, Themistocles L. Thompson, John R. Erdmann, Jeanette Clarke, Robert Watkins, Hugh Kathiresan, Sekar McPherson, Ruth Deloukas, Panos Schunkert, Heribert Samani, Nilesh J. Farrall, Martin CA CARDIoGRAMplusC4D Consortium TI A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease SO NATURE GENETICS LA English DT Article ID HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCUS; GENETIC-VARIANTS; CELL-MIGRATION; IDENTIFIES 13; MICE LACKING; EXPRESSION; RISK AB Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. C1 [Nikpay, Majid; Stewart, Alexandre F.; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada. [Goel, Anuj; Kyriakou, Theodosios; Grace, Christopher; Jalilzadeh, Shapour; Watkins, Hugh; Farrall, Martin] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Goel, Anuj; Kyriakou, Theodosios; Grace, Christopher; van Zuydam, Natalie R.; Jalilzadeh, Shapour; Lindgren, Cecilia M.; Morris, Andrew P.; Ingelsson, Erik; Watkins, Hugh; Farrall, Martin] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Won, Hong-Hee; Bjonnes, Andrew; Saxena, Richa; Lindgren, Cecilia M.; Esko, Tonu; Kathiresan, Sekar] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Won, Hong-Hee; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Won, Hong-Hee; Bjonnes, Andrew; Saxena, Richa; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Won, Hong-Hee; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hall, Leanne M.; Nelson, Christopher P.; Webb, Thomas R.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Willenborg, Christina; Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Willenborg, Christina; Koenig, Inke R.; Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Kanoni, Stavroula; Stirrups, Kathleen E.; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Saleheen, Danish; Zhao, Wei] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Saleheen, Danish; Frossard, Philippe; Rasheed, Asif; Samuel, Maria] Ctr Noncommunicable Dis, Karachi, Pakistan. [Nelson, Christopher P.; Webb, Thomas R.; Goodall, Alison H.; Samani, Nilesh J.] Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Hopewell, Jemma C.; Lau, King Wai; Collins, Rory; Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Hopewell, Jemma C.; Lau, King Wai; Collins, Rory; Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England. [Zeng, Lingyao; Kessler, Thorsten; Hengstenberg, Christian; Schunkert, Heribert] Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany. [Zeng, Lingyao; Gieger, Christian; Meitinger, Thomas; Peters, Annette; Hengstenberg, Christian; Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Munich, Germany. [Dehghan, Abbas; Uitterlinden, Andre; de Vries, Paul S.; Franco, Oscar H.; Hofman, Albert] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Alver, Maris; Mihailov, Evelin; Pervjakova, Natalia; Esko, Tonu; Metspalu, Andres; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Alver, Maris; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Armasu, Sebastian M.; de Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Auro, Kirsi; Pervjakova, Natalia; Perola, Markus] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Auro, Kirsi; Pervjakova, Natalia; Tikkanen, Emmi; Perola, Markus; Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Auro, Kirsi; Pervjakova, Natalia; Perola, Markus] Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland. [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.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Shufeng; Lu, Xiangfeng; Yang, Xueli; Wang, Laiyuan; Gu, Dongfeng] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China. [Chen, Shufeng; Lu, Xiangfeng; Yang, Xueli; Huang, Jianfeng; Wang, Laiyuan; Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Gieger, Christian; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol, Uppsala, Sweden. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Huang, Jie; Danesh, John; Ripatti, Samuli] Wellcome Trust Sanger Inst, Hinxton, England. [Hwang, Shih-Jen; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hwang, Shih-Jen; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kim, Yun Kyoung; Han, Bok-Ghee; Kim, Bong-Jo] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Lyytikainen, Leo-Pekka; Karhunen, Pekka J.; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Qu, Liming] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Salfati, Elias; Ingelsson, Erik; Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Saxena, Richa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Scholz, Markus] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Scholz, Markus; Beutner, Frank; Thiery, Joachim] LIFE Res Ctr Civilizat Dis, Leipzig, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Tikkanen, Emmi; Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England. [van Zuydam, Natalie R.; Palmer, Colin N.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Anand, Sonia S.] McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada. [Bertram, Lars] Univ Lubeck, Inst Neurogenet & Integrat, Platform Genome Analyt, Lubeck, Germany. [Bertram, Lars] Univ Lubeck, Inst Expt Gen, Platform Genome Analyt, Lubeck, Germany. [Bertram, Lars] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, England. [Beutner, Frank] Univ Leipzig, Heart Ctr Leipzig, Cardiol, D-04109 Leipzig, Germany. [Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Gauguier, Dominique] INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France. [Goodall, Alison H.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Haber, Marc; Zalloua, Pierre A.] Lebanese Amer Univ, Sch Med, Beirut, Lebanon. [Huang, Jianfeng] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Hypertens Div, Beijing 100730, Peoples R China. [Kessler, Thorsten] Klinikum Rechts Der Isar, Munich, Germany. [Koenig, Inke R.] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Lind, Lars] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden. [Lokki, Marja-Liisa] Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland. [Magnusson, Patrik K.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Mallick, Nadeem H.] Punjab Inst Cardiol, Lahore, Pakistan. [Mehra, Narinder] All India Inst Med Sci, New Delhi, India. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Humangenet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Memon, Fazal-ur-Rehman; Rasheed, Asif] Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Nieminen, Markku S.; Sinisalo, Juha] Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland. [Rallidis, Loukianos S.] Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, GR-11527 Athens, Greece. [Shah, Svati H.; Granger, Christopher B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Stirrups, Kathleen E.] Univ Cambridge, Dept Haematol, Cambridge, England. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Wang, Laiyuan] Natl Human Genome Ctr Beijing, Beijing, Peoples R China. [Zaman, Khan S.] Natl Inst Cardiovasc Dis, Karachi, Pakistan. [Ardissino, Diego] Univ Parma, Azienda Osped, Div Cardiol, I-43100 Parma, Italy. [Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Borecki, Ingrid B.; Feitosa, Mary F.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Demuth, Ilja] Berlin Aging Study 2, Berlin, Germany. [Demuth, Ilja] Charite, Res Grp Geriatr, D-13353 Berlin, Germany. [Demuth, Ilja] Charite, Inst Med & Human Genet, D-13353 Berlin, Germany. [Elosua, Roberto] Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain. [Epstein, Stephen E.] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC USA. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol & Basic & Translat Obes Res, Boston, MA USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Franzosi, Maria Grazia] IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Hamsten, Anders] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hazen, Stanley L.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Iribarren, Carlos] Kaiser Permanente Div Res, Oakland, CA USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interunivers Cardiol Inst Netherlands, Utrecht, Netherlands. [Karhunen, Pekka J.] Univ Tampere, Sch Med, Dept Forens Med, FIN-33101 Tampere, Finland. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Cardiovasc Sci, London, England. [Kullo, Iftikhar J.] Mayo Clin, Dept Med, Cardiovasc Dis, Rochester, MN USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Melander, Olle] Lund Univ, Univ Hosp Malmo, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden. [Maerz, Winfried] Synlab Acad, Synlab Serv, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Roberts, Robert] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Coll Med, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Oklahoma Ctr Neurosci, Oklahoma City, OK USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA. [Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Seedorf, Udo] Univ Med Ctr Hamburg Eppendorf, Ctr Dent & Oral Med, Dept Prosthet Dent, Hamburg, Germany. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Thiery, Joachim] Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany. [Zalloua, Pierre A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02114 USA. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. RP Watkins, H (reprint author), Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. EM hugh.watkins@rdm.ox.ac.uk; sekar@broadinstitute.org; rmcpherson@ottawaheart.ca; martin.farrall@well.ox.ac.uk RI Gudnason, Vilmundur/K-6885-2015; Erdmann, Jeanette/P-7513-2014; Konig, Inke/A-4544-2009; Magnusson, Patrik/C-4458-2017; Lieb, Wolfgang/C-1990-2012; Feitosa, Mary/K-8044-2012; Meitinger, Thomas/O-1318-2015; Kessler, Thorsten/O-7426-2015; Webb, Tom/C-6237-2011; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Bertram, Lars/K-3889-2015; Smith, Albert/K-5150-2015; Deloukas, Panos/B-2922-2013; Study, GoDARTS/K-9448-2016; OI Won, Hong-Hee/0000-0001-5719-0552; Gudnason, Vilmundur/0000-0001-5696-0084; ELOSUA, ROBERTO/0000-0001-8235-0095; Palmer, Colin/0000-0002-6415-6560; Stewart, Alexandre/0000-0003-2673-9164; Gieger, Christian/0000-0001-6986-9554; Erdmann, Jeanette/0000-0002-4486-6231; Zhao, Wei/0000-0002-8301-9297; zalloua, pierre/0000-0002-8494-5081; Watkins, Hugh/0000-0002-5287-9016; Feitosa, Mary/0000-0002-0933-2410; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bertram, Lars/0000-0002-0108-124X; Smith, Albert/0000-0003-1942-5845; Deloukas, Panos/0000-0001-9251-070X; Assimes, Themistocles/0000-0003-2349-0009; Sinisalo, Juha/0000-0002-0169-5137; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Peters, Annette/0000-0001-6645-0985 FU British Heart Foundation [RE/13/1/30181, FS/14/55/30806, RG/08/014/24067, RG/14/5/30893]; Medical Research Council [MR/L003120/1, MR/L01629X/1]; NCI NIH HHS [UM1 CA182913]; NHLBI NIH HHS [R01 HL117078, R01 HL127564, R33 HL120757]; NIDDK NIH HHS [R01 DK089256] NR 83 TC 110 Z9 111 U1 12 U2 39 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 OCT PY 2015 VL 47 IS 10 BP 1121 EP + DI 10.1038/ng.3396 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900007 PM 26343387 ER PT J AU Dina, C Bouatia-Naji, N Tucker, N Delling, FN Toomer, K Durst, R Perrocheau, M Fernandez-Friera, L Solis, J Le Tourneau, T Chen, MH Probst, V Bosse, Y Pibarot, P Zelenika, D Lathrop, M Hercberg, S Roussel, R Benjamin, EJ Bonnet, F Lo, SH Dolmatova, E Simonet, F Lecointe, S Kyndt, F Redon, R Le Marec, H Froguel, P Ellinor, PT Vasan, RS Bruneval, P Markwald, RR Norris, RA Milan, DJ Slaugenhaupt, SA Levine, RA Schott, JJ Hagege, AA Jeunemaitre, X AF Dina, Christian Bouatia-Naji, Nabila Tucker, Nathan Delling, Francesca N. Toomer, Katelynn Durst, Ronen Perrocheau, Maelle Fernandez-Friera, Leticia Solis, Jorge Le Tourneau, Thierry Chen, Ming-Huei Probst, Vincent Bosse, Yohan Pibarot, Philippe Zelenika, Diana Lathrop, Mark Hercberg, Serge Roussel, Ronan Benjamin, Emelia J. Bonnet, Fabrice Lo, Su Hao Dolmatova, Elena Simonet, Floriane Lecointe, Simon Kyndt, Florence Redon, Richard Le Marec, Herve Froguel, Philippe Ellinor, Patrick T. Vasan, Ramachandran S. Bruneval, Patrick Markwald, Roger R. Norris, Russell A. Milan, David J. Slaugenhaupt, Susan A. Levine, Robert A. Schott, Jean-Jacques Hagege, Albert A. Jeunemaitre, Xavier CA PROMESA Investigators MVP-France Leducq Transatlantic MITRAL Networ TI Genetic association analyses highlight biological pathways underlying mitral valve prolapse SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CARDIAC VALVULAR DYSTROPHY; FILAMIN-A; NATURAL-HISTORY; MARFAN-SYNDROME; CELL-MIGRATION; EXPRESSION; LOCUS; PATHOGENESIS; METAANALYSIS AB Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death(1). Previous family and pathophysiological studies suggest a complex pattern of inheritance(2-5). We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor(6) and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns(1-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair(7). C1 [Dina, Christian; Le Tourneau, Thierry; Probst, Vincent; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Herve; Schott, Jean-Jacques] CNRS, INSERM, Inst Thorax, UMR 1087,UMR 6291, Nantes, France. [Dina, Christian; Le Tourneau, Thierry; Probst, Vincent; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Herve; Schott, Jean-Jacques] Univ Nantes, CHU Nantes, Nantes, France. [Bouatia-Naji, Nabila; Perrocheau, Maelle; Bruneval, Patrick; Hagege, Albert A.; Jeunemaitre, Xavier] Paris Cardiovasc Res Ctr, INSERM, UMR 970, Paris, France. [Bouatia-Naji, Nabila; Perrocheau, Maelle; Hercberg, Serge; Bruneval, Patrick; Jeunemaitre, Xavier] Paris Descartes Univ, Paris Sorbonne Cite, Paris, France. [Tucker, Nathan; Dolmatova, Elena; Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Delling, Francesca N.; Chen, Ming-Huei; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res,US Natl Inst Hlth, Framingham, MA USA. [Delling, Francesca N.; Benjamin, Emelia J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Cardiovasc Div, Boston, MA 02215 USA. [Toomer, Katelynn; Markwald, Roger R.; Norris, Russell A.] Med Univ S Carolina, Childrens Res Inst, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Durst, Ronen] Hadassah Hebrew Univ Med Ctr, Dept Cardiol, Jerusalem, Israel. [Fernandez-Friera, Leticia; Solis, Jorge] Univ Ctr Estudios Univ CEU, Hosp Univ Monteprincipe, Madrid, Spain. [Fernandez-Friera, Leticia; Solis, Jorge; Leducq Transatlantic MITRAL Networ] Carlos III CNIC, Ctr Nacl Invest Cardiovasc, Madrid, Spain. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Bosse, Yohan; Pibarot, Philippe] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Zelenika, Diana; Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] Genome Quebec, Montreal, PQ, Canada. [Hercberg, Serge] Univ Paris 13, Sorbonne Paris Cite, Bobigny, France. [Hercberg, Serge] INRA, INSERM, U1153, U1125,Nutr Epidemiol Res Unit,Epidemiol & Biostat, Bobigny, France. [Hercberg, Serge] Avicenne Hosp, AP HP, Dept Publ Hlth, Bobigny, France. [Hercberg, Serge; Roussel, Ronan] Paris Diderot Univ, Paris, France. [Roussel, Ronan] Ctr Rech Cordeliers, INSERM, UMRS 1138, Paris, France. [Roussel, Ronan] Hop Xavier Bichat, AP HP, Fibrosis Inflammat Remodeling Cardiovasc Resp & R, Dept Endocrinol Diabet & Nutr, Paris, France. [Bonnet, Fabrice] Univ Hosp Pontchaillou, INSERM, CIC 0203, Rennes, France. [Bonnet, Fabrice] Univ Hosp, Dept Endocrinol, Rennes, France. [Lo, Su Hao] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Froguel, Philippe] Univ Lille 2, CNRS, Lille Pasteur Inst, UMR 8199,EGID, Lille, France. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Ellinor, Patrick T.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bruneval, Patrick] Hop Europeen Georges Pompidou, AP HP, Dept Pathol, Paris, France. [Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Slaugenhaupt, Susan A.; Levine, Robert A.] Harvard Univ, Sch Med, Boston, MA USA. [Levine, Robert A.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Hagege, Albert A.] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France. [Jeunemaitre, Xavier] Hop Europeen Georges Pompidou, AP HP, Dept Genet, Paris, France. RP Dina, C (reprint author), CNRS, INSERM, Inst Thorax, UMR 1087,UMR 6291, Nantes, France. EM christian.dina@univ-nantes.fr; nabila.bouatia-naji@inserm.fr; xavier.jeunemaitre@inserm.fr RI probst, vincent/D-4996-2015; BOUATIA-NAJI, NABILA/D-5863-2013; Redon, Richard/F-3303-2014; OI Benjamin, Emelia/0000-0003-4076-2336; Redon, Richard/0000-0001-7751-2280; Bouatia-Naji, Nabila/0000-0001-5424-2134 FU Nantes Hospital (CHU Nantes); US National Institutes of Health (NIH) [K24 HL67434, R01 HL72265, HL109506]; French young investigator fund [ANR-13-ISV1-0006-0]; Hassenfeld Scholar Program; NIH [HL092577, HL104156, K24HL105780, HL065962]; American Heart Association [13EIA14220013, 15GRNT25080052]; Fondation Leducq [14CVD01]; Canadian Institutes of Health Research (CIHR) [MOP-102737, MOP-114997, MOP-126072]; Fonds de recherche Quebec-Sante (FRQS); CIHR [MOP-102481, MOP-137058]; Spanish Society of Cardiology; fund for medical discovery of the Massachusetts General Hospital; European Commission; US National Institutes of Health [C06 RR018823]; Extramural Research Facilities Program of the Heart, Lung, and Blood Institute [R01-HL33756, COBRE 1P30 GM103342, 8P20 GM103444-07, R01-HL127692]; INSERM; French Society of Cardiology FX We acknowledge the major contribution of the Leducq Foundation, Paris for supporting a transatlantic consortium investigating the physiopathology of mitral valve disease, for which this genome-wide association study was a major project (coordinators: R.A.L. and A.A.H.). We thank J. Leyton-Mange, X.-X. Nguyen and M. McLellan for help with the zebrafish experiments and P. Mathieu as one of the main investigators of the PROGRAM (Determinants of the Progression and Outcomes of Organic Mitral Regurgitation) study, from which was ascertained the Canadian MVP case control study. C.D., T.L.T. and J.-J.S. acknowledge a translational research grant on genetics of mitral valve funded by the Nantes Hospital (CHU Nantes). R.A.L. acknowledges grant support from the US National Institutes of Health (NIH; grants K24 HL67434, R01 HL72265 and HL109506). N.B.-N. is recipient of a French young investigator fund (ANR-13-ISV1-0006-0). D.J.M. acknowledges the support of the Hassenfeld Scholar Program and a gift from Michael Zak. P.T.E. is supported by grants from the NIH (HL092577, HL104156, K24HL105780, HL065962), an Established Investigator Award from the American Heart Association (13EIA14220013) and support from the Fondation Leducq (14CVD01). P.P. holds the Canada Research Chair in Valvular Heart Diseases and is supported by grants from the Canadian Institutes of Health Research (CIHR; grants MOP-102737, MOP-114997 and MOP-126072). Y.B. is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec-Sante (FRQS) and is supported by the CIHR (MOP-102481 and MOP-137058). L.F.-F. and J.S. received financial support from the Spanish Society of Cardiology. R.D. was supported by fellowships from the fund for medical discovery of the Massachusetts General Hospital and by a Marie Curie reintegration award from the European Commission R.R.M. and R.A.N. performed their work in a facility constructed with support from the US National Institutes of Health, grant C06 RR018823, from the Extramural Research Facilities Program of the Heart, Lung, and Blood Institute: R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M. and R.A.N.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL127692 (D.J.M., S.A.S. and R.A.N.) and American Heart Association 15GRNT25080052 (R.A.N.). A.A.H., N.B.-N. and X.J. acknowledge funds from INSERM and the French Society of Cardiology. NR 38 TC 11 Z9 11 U1 4 U2 23 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 OCT PY 2015 VL 47 IS 10 BP 1206 EP + DI 10.1038/ng.3383 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900017 PM 26301497 ER PT J AU Hernandez, SF Vahidi, NA Park, S Weitzel, RP Tisdale, J Rueda, BR Wolff, EF AF Hernandez, Silvia F. Vahidi, Nima A. Park, Solji Weitzel, R. Patrick Tisdale, John Rueda, Bo R. Wolff, Erin F. TI Characterization of extracellular DDX4-or Ddx4-positive ovarian cells SO NATURE MEDICINE LA English DT Letter ID ACTIVE GERM-CELLS; LINE; MOUSE C1 [Hernandez, Silvia F.; Rueda, Bo R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Hernandez, Silvia F.; Rueda, Bo R.] Harvard Univ, Sch Med, Boston, MA USA. [Rueda, Bo R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. [Vahidi, Nima A.; Park, Solji; Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Weitzel, R. Patrick; Tisdale, John; Wolff, Erin F.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Wolff, EF (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM erin.wolff@nih.gov FU Intramural NIH HHS NR 6 TC 8 Z9 8 U1 2 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 OCT PY 2015 VL 21 IS 10 BP 1114 EP 1116 DI 10.1038/nm.3966 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400006 PM 26444630 ER PT J AU Zhang, JY Dominguez-Sola, D Hussein, S Lee, JE Holmes, AB Bansal, M Vlasevska, S Mo, TW Tang, HY Basso, K Ge, K Dalla-Favera, R Pasqualucci, L AF Zhang, Jiyuan Dominguez-Sola, David Hussein, Shafinaz Lee, Ji-Eun Holmes, Antony B. Bansal, Mukesh Vlasevska, Sofija Mo, Tongwei Tang, Hongyan Basso, Katia Ge, Kai Dalla-Favera, Riccardo Pasqualucci, Laura TI Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis SO NATURE MEDICINE LA English DT Article ID FOLLICULAR LYMPHOMA; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; SOMATIC MUTATIONS; SUPER-ENHANCERS; COMPASS FAMILY; TRANSCRIPTION; CHROMATIN; SELECTION; MICE AB Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL-and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events. C1 [Zhang, Jiyuan; Dominguez-Sola, David; Hussein, Shafinaz; Holmes, Antony B.; Vlasevska, Sofija; Mo, Tongwei; Tang, Hongyan; Basso, Katia; Dalla-Favera, Riccardo; Pasqualucci, Laura] Columbia Univ, Inst Canc Genet, New York, NY 10027 USA. [Dominguez-Sola, David] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Dominguez-Sola, David] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Lee, Ji-Eun; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Bansal, Mukesh] Columbia Univ, Dept Syst Biol, New York, NY USA. [Basso, Katia; Dalla-Favera, Riccardo; Pasqualucci, Laura] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Dalla-Favera, Riccardo] Columbia Univ, Dept Genet & Dev, New York, NY USA. [Dalla-Favera, Riccardo] Columbia Univ, Dept Microbiol & Immunol, New York, NY USA. [Dalla-Favera, Riccardo; Pasqualucci, Laura] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY USA. RP Pasqualucci, L (reprint author), Columbia Univ, Inst Canc Genet, New York, NY 10027 USA. EM lp171@columbia.edu FU US National Institutes of Health [RO1-CA172492, RO1-CA37295]; Lymphoma Research Foundation FX We would like to thank U. Klein and S. Zha for discussions, S. Nataraj, L. Belver, C. Scuoppo and N. De Silva for help and suggestions on various experimental procedures, E. McIntush (Bethyl Laboratories, Inc.) for help in generating several antibodies to KMT2D, the Flow Cytometry Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University for assistance with cell-sorting procedures, the Molecular Pathology lab for the preparation of mouse FFPE tissue samples and the Genomic Technologies Shared Resource for sequencing the ChIP-DNA libraries. We also thank S. Cory (Walter and Eliza Hall Institute of Medical Research, Parkville, Australia) for the VavP-Bcl2 mice and K. Rajewsky (Max Delbruck Center for Molecular Medicine, Berlin, Germany) for the CD19-Cre and C gamma 1-Cre mice. The indicated DLBCL cell lines in Supplementary Table 5 were a kind gift of L. Staudt, M.A. Shipp and T. Gilmore. This work was supported by US National Institutes of Health grants RO1-CA172492 (L.P.) and RO1-CA37295 (R.D.-F.), and J.Z. is supported by a Lymphoma Research Foundation postdoctoral fellowship. L.P. is on leave from the University of Perugia. NR 75 TC 27 Z9 27 U1 3 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 OCT PY 2015 VL 21 IS 10 BP 1190 EP + PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400021 PM 26366712 ER PT J AU Ortega-Molina, A Boss, IW Canela, A Pan, H Jiang, YW Zhao, CY Jiang, M Hu, DQ Agirre, X Niesvizky, I Lee, JE Chen, HT Ennishi, D Scott, DW Mottok, A Hother, C Liu, SC Cao, XJ Tam, W Shaknovich, R Garcia, BA Gascoyne, RD Ge, K Shilatifard, A Elemento, O Nussenzweig, A Melnick, AM Wendel, HG AF Ortega-Molina, Ana Boss, Isaac W. Canela, Andres Pan, Heng Jiang, Yanwen Zhao, Chunying Jiang, Man Hu, Deqing Agirre, Xabier Niesvizky, Itamar Lee, Ji-Eun Chen, Hua-Tang Ennishi, Daisuke Scott, David W. Mottok, Anja Hother, Christoffer Liu, Shichong Cao, Xing-Jun Tam, Wayne Shaknovich, Rita Garcia, Benjamin A. Gascoyne, Randy D. Ge, Kai Shilatifard, Ali Elemento, Olivier Nussenzweig, Andre Melnick, Ari M. Wendel, Hans-Guido TI The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development SO NATURE MEDICINE LA English DT Article ID FOLLICULAR LYMPHOMA; CANCER-THERAPY; KAPPA-B; MUTATIONS; ACTIVATION; MONOMETHYLATION; LYMPHOCYTES; MICROARRAY; MLL3/MLL4; PROTEIN AB The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways. C1 [Ortega-Molina, Ana; Zhao, Chunying; Jiang, Man; Wendel, Hans-Guido] MSKCC, Canc Biol & Genet Program, New York, NY 10021 USA. [Ortega-Molina, Ana; Boss, Isaac W.; Jiang, Yanwen; Agirre, Xabier; Niesvizky, Itamar; Shaknovich, Rita; Melnick, Ari M.] Weill Cornell Med Coll, Dept Med, Div Hematol Oncol, New York, NY USA. [Boss, Isaac W.; Niesvizky, Itamar; Melnick, Ari M.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA. [Canela, Andres; Chen, Hua-Tang; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Pan, Heng; Jiang, Yanwen; Elemento, Olivier] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY USA. [Hu, Deqing; Shilatifard, Ali] Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA. [Agirre, Xabier] Univ Navarra, CIMA, Area Oncol, E-31080 Pamplona, Spain. [Lee, Ji-Eun; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Ennishi, Daisuke; Scott, David W.; Mottok, Anja; Hother, Christoffer; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Liu, Shichong; Cao, Xing-Jun; Garcia, Benjamin A.] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Epigenet Program, Philadelphia, PA 19104 USA. [Tam, Wayne] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. RP Wendel, HG (reprint author), MSKCC, Canc Biol & Genet Program, New York, NY 10021 USA. EM amm2014@med.cornell.edu; Wendelh@mskcc.org FU Leukemia & Lymphoma Society; American Cancer Society [RSG-13-048-01-LIB]; Lymphoma Research Foundation; Cycle for Survival; W.H. Goodwin and A. Goodwin; Commonwealth Foundation for Cancer Research; Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center; US National Institutes of Health (NIH) [RO1CA183876-01, 1R01CA19038-01, P30 CA008748]; NIH [R01CA187109, R01GM110174, R01CA150265]; Chemotherapy Foundation; Sass Foundation; NIH from the Office of the Director [DP2OD007447]; NIDDK, NIH; NIH; National Cancer Institute; Center for Cancer Research; Department of Defense [11557134]; Alex Lemonade Stand Foundation FX We thank E. Oricchio (MSKCC), V. Sanghvi (MSKCC), M. Boice (MSKCC), W. Beguelin and M. del Pilar Dominguez Rodriguez (Weill Cornell Medical College) for advice and reagents. Thanks to E. de Stanchina and all of the members of the MSK Antitumor assessment core for technical assistance with mice, the MSK Laboratory of Comparative Pathology, the MSK Flow Cytometry and MSK Molecular Cytology cores, H. Hagenau for Southern blot analysis and B. Sleckman for Ig kappa III probe. A.O.-M. is supported by funding from The Leukemia & Lymphoma Society. H.G.W. is supported by the American Cancer Society grant RSG-13-048-01-LIB, the Lymphoma Research Foundation, Cycle for Survival, W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center, US National Institutes of Health (NIH) grants RO1CA183876-01 and 1R01CA19038-01 and Core Grant P30 CA008748. H.G.W. is a Scholar of the Leukemia and Lymphoma Society. A.M.M. is supported by NIH grant R01CA187109, the Chemotherapy Foundation and is a Scholar of the Burroughs Wellcome Foundation. I.W.B. is supported by a Sass Foundation Post-doctoral Fellowship award. B.A.G. acknowledges funding from an NIH Innovator grant (DP2OD007447) from the Office of the Director and NIH grant R01GM110174. A.S.H. is supported by NIH grant R01CA150265. The work in the K.G. laboratory was supported by the Intramural Research Program of the NIDDK, NIH. The work in the A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research, a Department of Defense grant (BCRP DOD Idea Expansion Award, grant 11557134) and the Alex Lemonade Stand Foundation Award. NR 48 TC 25 Z9 25 U1 2 U2 15 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 OCT PY 2015 VL 21 IS 10 BP 1199 EP + DI 10.1038/nm.3943 PG 15 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400022 PM 26366710 ER PT J AU Prideaux, B Via, LE Zimmerman, MD Eum, S Sarathy, J O'Brien, P Chen, C Kaya, F Weiner, DM Chen, PY Song, T Lee, M Shim, TS Cho, JS Kim, W Cho, SN Olivier, KN Barry, CE Dartois, V AF Prideaux, Brendan Via, Laura E. Zimmerman, Matthew D. Eum, Seokyong Sarathy, Jansy O'Brien, Paul Chen, Chao Kaya, Firat Weiner, Danielle M. Chen, Pei-Yu Song, Taeksun Lee, Myungsun Shim, Tae Sun Cho, Jeong Su Kim, Wooshik Cho, Sang Nae Olivier, Kenneth N. Barry, Clifton E., III Dartois, Veronique TI The association between sterilizing activity and drug distribution into tuberculosis lesions SO NATURE MEDICINE LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; ANTITUBERCULOSIS DRUGS; PULMONARY TUBERCULOSIS; MURINE TUBERCULOSIS; COMPUTED-TOMOGRAPHY; MOXIFLOXACIN; CHEMOTHERAPY; GRANULOMAS; RESISTANCE; MODEL AB Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB. C1 [Prideaux, Brendan; Zimmerman, Matthew D.; Sarathy, Jansy; O'Brien, Paul; Chen, Chao; Kaya, Firat; Chen, Pei-Yu; Dartois, Veronique] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 07102 USA. [Via, Laura E.; Weiner, Danielle M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Eum, Seokyong; Song, Taeksun; Lee, Myungsun] Int TB Res Ctr, Chang Won, South Korea. [Shim, Tae Sun] Asan Med Ctr, Seoul, South Korea. [Cho, Jeong Su] Pusan Natl Univ Hosp, Pusan, South Korea. [Kim, Wooshik] Natl Med Ctr, Seoul, South Korea. [Cho, Sang Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Cho, Sang Nae] Yonsei Univ, Coll Med, Inst Immunol & Immunol Dis, Seoul, South Korea. [Olivier, Kenneth N.] NHLBI, Pulm Clin Med, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Barry, Clifton E., III] Univ Cape Town, Inst Infect Dis & Mol Med, Dept Clin Lab Sci, ZA-7925 Cape Town, South Africa. RP Barry, CE (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov; veronique.dartois@rutgers.edu RI Barry, III, Clifton/H-3839-2012; Chen, Chao/J-7879-2015 FU US National Institutes of Health (NIH) [1R01AI106398-01, OPP1066499]; Bill and Melinda Gates Foundation; NIH National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute; Korean Centers for Disease Control of the Korean Ministry of Health and Welfare; Grand Challenge for Global Health (GCGH 11) consortium FX We thank D. Young and the funders of the Grand Challenge for Global Health (GCGH 11) consortium for their faith and support. We are grateful to the subjects who enrolled in the study; Y. Kim, M.S. Kong, Y. Cai, J. Gonzales and L. Goldfeder; and the clinical teams at the three Korean centers (Asan Medical Centre, Pusan National University Hospital, and the National Medical Center) for their efforts in making the study a success. We thank S. Dorman, D. Alland and H. Boshoff for sharing clinical MIC and in vitro MAC data sets, M. Stoeckli and D. Staab for providing access to the MALDI imaging platform at the Novartis Institutes for Biomedical Research, E. Eugenin, J. Flynn and J. Mattila for sharing images of M. tuberculosis in nonhuman primate lesions, and T. Dick for discussions and advice. This work was carried out with funding from US National Institutes of Health (NIH) grant 1R01AI106398-01 (V.D.), grant OPP1066499 (V.D.) from the Bill and Melinda Gates Foundation, the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases (C.E.B.) and the National Heart, Lung and Blood Institute (K.N.O.), as well as funding from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare to the International Tuberculosis Research Center. NR 42 TC 49 Z9 49 U1 5 U2 26 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 OCT PY 2015 VL 21 IS 10 BP 1223 EP + DI 10.1038/nm.3937 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400025 PM 26343800 ER PT J AU Hariri, AR Holmes, A AF Hariri, Ahmad R. Holmes, Andrew TI Finding translation in stress research SO NATURE NEUROSCIENCE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DEEP BRAIN-STIMULATION; FEAR EXTINCTION; CONDITIONED FEAR; INDIVIDUAL-DIFFERENCES; SEROTONIN TRANSPORTER; GENETIC-VARIATION; MENTAL-DISORDERS; AMYGDALA VOLUME; REMOTE MEMORIES AB In our ongoing efforts to advance understanding of human diseases, translational research across rodents and humans on stress-related mental disorders stands out as a field that is producing discoveries that illuminate mechanisms of risk and pathophysiology at a brisk rate. Here we offer a Perspective on how a productive translational research dialog between preclinical models and clinical studies of these disorders is being powered by an ever-developing appreciation of the shared neural circuits and genetic architecture that moderate the response to stress across species. Working from these deep foundations, we discuss the approaches, both traditional and innovative, that have the potential to deliver a new generation of risk biomarkers and therapeutic strategies for stress-related disorders. C1 [Hariri, Ahmad R.] Duke Univ, Dept Psychol & Neurosci, Lab NeuroGenet, Durham, NC 27708 USA. [Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Rockville, MD 20852 USA. RP Hariri, AR (reprint author), Duke Univ, Dept Psychol & Neurosci, Lab NeuroGenet, Durham, NC 27708 USA. EM ahmad.hariri@duke.edu FU Duke University; US National Institutes of Health [R01DA033369, R01AG049789]; National Institute on Alcohol Abuse and Alcoholism Intramural Research Program; Henry Jackson Foundation for Advancement of Military Medicine; Department of Defense in Center for Neuroscience and Regenerative Medicine FX Acknowledgments A.R.H. is supported by Duke University and by US National Institutes of Health grants R01DA033369 and R01AG049789. A.H. is supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program, the Henry Jackson Foundation for the Advancement of Military Medicine, and the Department of Defense in the Center for Neuroscience and Regenerative Medicine. NR 70 TC 4 Z9 4 U1 3 U2 17 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 OCT PY 2015 VL 18 IS 10 BP 1347 EP 1352 DI 10.1038/nn.4111 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CS2OK UT WOS:000361910600003 PM 26404709 ER PT J AU Mayse, JD Nelson, GM Avila, I Gallagher, M Lin, SC AF Mayse, Jeffrey D. Nelson, Geoffrey M. Avila, Irene Gallagher, Michela Lin, Shih-Chieh TI Basal forebrain neuronal inhibition enables rapid behavioral stopping SO NATURE NEUROSCIENCE LA English DT Article ID RESPONSE-INHIBITION; PREFRONTAL CORTEX; RAT NEOCORTEX; GANGLIA; PERFORMANCE; NUCLEUS; SIGNALS; TASK; MICROSTIMULATION; SALIENCE AB Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. Although most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, we found that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were nearly completely inhibited by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a previously unknown subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. C1 [Mayse, Jeffrey D.; Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. [Mayse, Jeffrey D.; Nelson, Geoffrey M.; Avila, Irene; Lin, Shih-Chieh] NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. RP Lin, SC (reprint author), NIA, Neural Circuits & Cognit Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. EM shih-chieh.lin@nih.gov OI Lin, Shih-Chieh/0000-0003-3693-5476; Nelson, Geoffrey/0000-0001-9825-4241 FU National Institute on Aging; NARSAD Young Investigator Award; US National Institutes of Health [P01 AG09973, F31 AG045039] FX We thank P.R. Rapp, J. Long, S.M. Raver and V. Stuphorn for critical discussions and reading of the manuscript, and H.M.V. Manzur and B. Brock for technical support. This research was funded by the intramural Research Program of the National Institute on Aging and by a NARSAD Young Investigator Award to S.-C.L., and grants from the US National Institutes of Health (P01 AG09973 M.G. and F31 AG045039 to J.D.M.). NR 38 TC 3 Z9 3 U1 6 U2 11 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 OCT PY 2015 VL 18 IS 10 BP 1501 EP + DI 10.1038/nn.4110 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CS2OK UT WOS:000361910600022 PM 26368943 ER PT J AU Lane, R Kessler, R Buckley, AW Rodriguez, A Farmer, C Thurm, A Swedo, S Felt, B AF Lane, Rebecca Kessler, Riley Buckley, Ashura Williams Rodriguez, Alcibiades Farmer, Cristan Thurm, Audrey Swedo, Susan Felt, Barbara TI Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children With Autism SO PEDIATRIC NEUROLOGY LA English DT Article DE autism; ferritin; iron; periodic limb movements ID RESTLESS LEGS SYNDROME; DEFICIENCY ANEMIA; PSYCHIATRIC-DISORDERS; SPECTRUM DISORDERS; MOTOR-ACTIVITY; AGED CHILDREN; FERRITIN; VARIABILITY; POPULATION; PREVALENCE AB OBJECTIVE: Recent data suggest that both disordered sleep and low serum iron occur more frequently in children with