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 autism compared with children with typical development. Iron deficiency has been linked to specific sleep disorders. The goal of the current study was to evaluate periodic limb movements in sleep and iron status in a group of children with autism compared with typically developing children and children with nonautism developmental delay to determine if iron status correlated with polysomnographic measures of latency and continuity and periodic limb movements in sleep. METHODS: A total of 102 children (68 with autism, 18 typically developing, 16 with developmental delay) aged 2 to 7 years underwent a one-night modified polysomnography study and phlebotomy at the National Institutes of Health to measure serum markers of iron status (ferritin, iron, transferrin, percent transferrin saturation). RESULTS: No serum iron marker was associated with periodic limb movements of sleep or any other sleep parameter; this did not differ among the diagnostic groups. No significant differences among groups were observed on serum iron markers or most polysomnogram parameters: periodic limb movements in sleep, periodic limb movements index, wake after sleep onset, or sleep efficiency. Children in the autism group had significantly less total sleep time. Serum ferritin was uniformly low across groups. CONCLUSIONS: This study found no evidence that serum ferritin is associated with polysomnogram measures of latency or sleep continuity or that young children with autism are at increased risk for higher periodic limb movements index compared with typically developing and developmental delay peers. C1 [Lane, Rebecca] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Lane, Rebecca; Kessler, Riley; Buckley, Ashura Williams; Farmer, Cristan; Thurm, Audrey; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Rodriguez, Alcibiades] NYU, Dept Neurol, New York, NY 10016 USA. [Felt, Barbara] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. RP Buckley, AW (reprint author), 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM Shu.Buckleyl@nih.gov FU Intramural Program of the National Institute of Mental Health of the National Institutes of Health FX This work was supported by and performed at the Intramural Program of the National Institute of Mental Health of the National Institutes of Health. Dr. Lane, Ms. Kessler, Dr. Buckley, Dr. Farmer, Dr. Thurm, and Dr. Swedo make no disclosures. Dr. Rodriguez reports no conflicts of interest and has served as a paid speaker for Intermezzo and Nuvigil in the past 24 months. Dr. Felt reports no conflicts of interest and has served as a consultant for Pfizer in the past 12 months. NR 47 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD OCT PY 2015 VL 53 IS 4 BP 343 EP 349 DI 10.1016/j.pediatrneurol.2015.06.014 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA CS4OX UT WOS:000362056500011 PM 26231264 ER PT J AU King, HE Wakeford, A Taylor, W Wetzell, B Rice, KC Riley, AL AF King, Heather E. Wakeford, Alison Taylor, William Wetzell, Bradley Rice, Kenner C. Riley, Anthony L. TI Sex differences in 3,4-methylenedioxypyrovalerone (MDPV)-induced taste avoidance and place preferences SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Place preference; Taste avoidance; Sex differences; MDPV ID GENDER-DIFFERENCES; BATH SALTS; DRUG-ABUSE; APPARATUS BIAS; UNITED-STATES; AVERSION; COCAINE; RATS; MORPHINE; MICE AB Synthetic cathinones, otherwise known as "bath salts", have gained significant attention in the last few years as a result of increased use and abuse. One such compound, 3,4-methylenedioxypyrovalerone (MDPV), is pharmacologically and behaviorally similar to cocaine and has been shown to possess both aversive and rewarding effects. For a host of other drugs, each of these effects (and their relative balance) can be influenced by a variety of factors, including sex, which in turn impacts drug taking behavior. In this context, the present assessment sought to determine whether males and females differed in MDPV-induced CTA and CPP. Both male and female Sprague-Dawley rats underwent a combined CTA/CPP procedure, in which an injection of one of three doses of MDPV (1.0,1.8 or 32 mg/kg) was paired with both a novel saccharin solution and a novel environment and changes in preferences for these stimuli were examined. Taste avoidance was evident in both sexes, although this avoidance was weaker in females compared to males. MDPV also produced place preferences in all drug-treated animals, but these preferences did not vary as a function of sex. The fact that females showed a weaker avoidance response compared to males (despite comparable preferences) suggests that females may have a heightened susceptibility to use and abuse of MDPV, paralleling results seen with cocaine and other stimulants. The present findings extend the behavioral characterization of MDPV and the factors that may alter its aversive and rewarding effects. (C) 2015 Elsevier Inc. All rights reserved. C1 [King, Heather E.; Wakeford, Alison; Taylor, William; Wetzell, Bradley; Riley, Anthony L.] Amer Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. RP King, HE (reprint author), Amer Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. EM hk9905a@american.edu RI Wetzell, B Bradley/J-6802-2013 OI Wetzell, B Bradley/0000-0002-2723-5542 FU Mellon Foundation; Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services FX This research was supported by a grant from the Mellon Foundation to ALR. A portion of this research was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism, NIH, US Department of Health and Human Services. The authors have no conflicts of interest to declare. Requests for reprints should be sent to: Heather King, Psychopharmacology Laboratory, Department of Psychology, American University, Washington DC 20016. NR 55 TC 5 Z9 5 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD OCT PY 2015 VL 137 BP 16 EP 22 DI 10.1016/j.pbb.2015.07.013 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA CS5SB UT WOS:000362137200003 PM 26216834 ER PT J AU Dueck, AC Mitchell, SA Rogak, LJ Ginos, B Sargent, DJ Shi, Q Farma, JM Eng, C Crane, C Kennecke, H O'Mara, AM Minasian, LM Schrag, D Basch, E AF Dueck, Amylou C. Mitchell, Sandra A. Rogak, Lauren J. Ginos, Brenda Sargent, Daniel J. Shi, Qian Farma, Jeffrey M. Eng, Cathy Crane, Christopher Kennecke, Hagen O'Mara, Ann M. Minasian, Lori M. Schrag, Deborah Basch, Ethan TI A cluster-randomized study of clinician-patient shared vs standard reporting of symptomatic adverse events using PRO-CTCAE nested in a multicenter trial of multimodal therapy for rectal cancer (Alliance N1048 PROSPECT) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Dueck, Amylou C.; Ginos, Brenda] Mayo Clin, Scottsdale, AZ USA. [Mitchell, Sandra A.; O'Mara, Ann M.; Minasian, Lori M.] NCI, Rockville, MD USA. [Rogak, Lauren J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sargent, Daniel J.; Shi, Qian] Mayo Clin, Rochester, MN USA. [Farma, Jeffrey M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Eng, Cathy; Crane, Christopher] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kennecke, Hagen] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 2 BP 1 EP 2 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100003 ER PT J AU Kent, EE Yuan, GG Topor, MS Chawla, N Gaillot, S DeMichele, K AF Kent, Erin E. Yuan, Gigi Topor, Marie S. Chawla, Neetu Gaillot, Sarah DeMichele, Kimberly TI Cancer registry-linked data with patient-reported outcomes and patient experiences with care: an overview of findings from the centers for medicare & medicaid and national cancer institute SEER-MHOS and SEER-CAHPS data resources SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Kent, Erin E.] NCI, Rockville, MD USA. [Yuan, Gigi; Topor, Marie S.] Informat Management Serv Inc, Calverton, MD USA. [Chawla, Neetu] Kaiser Permanente No Calif, Oakland, CA USA. [Gaillot, Sarah; DeMichele, Kimberly] Ctr Medicare Serv, Baltimore, MD USA. [Gaillot, Sarah; DeMichele, Kimberly] Ctr Medicaid Serv, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 1095 BP 93 EP 94 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100210 ER PT J AU Baeksted, C Nissen, A Pappot, H Bidstrup, PE Mitchell, SA Basch, E Dalton, SO Johansen, C AF Baeksted, Christina Nissen, Aase Pappot, Helle Bidstrup, Pernille E. Mitchell, Sandra A. Basch, Ethan Dalton, Susanne O. Johansen, Christoffer TI Danish translation and linguistic validation of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Baeksted, Christina] Copenhagen Univ Hosp, Rigshosp, Publ Hlth, Copenhagen, Denmark. [Baeksted, Christina; Nissen, Aase] Danish Canc Soc, Copenhagen, Denmark. [Pappot, Helle] Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. [Bidstrup, Pernille E.; Dalton, Susanne O.] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Mitchell, Sandra A.] NCI, Rockville, MD USA. [Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. [Johansen, Christoffer] Copenhagen Univ Hosp, Rigshosp, Med Sci, Copenhagen, Denmark. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 2047 BP 121 EP 122 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100275 ER PT J AU Smith, T Troeschel, A Castro, K Arora, N Stein, K McCabe, RM Clauser, S Ward, E AF Smith, Tenbroeck Troeschel, Alyssa Castro, Kate Arora, Neeraj Stein, Kevin McCabe, Ryan M. Clauser, Steven Ward, Elizabeth TI A PRO surveillance feasibility pilot, the prevalence and correlates of symptoms-related PROs it collected and the quality improvement reports it produced SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Smith, Tenbroeck; Troeschel, Alyssa; Stein, Kevin; Ward, Elizabeth] Amer Canc Soc, Atlanta, GA 30329 USA. [Castro, Kate] NCI, Rockville, MD USA. [Arora, Neeraj; Clauser, Steven] Patient Centered Outcomes Res Inst, Washington, DC USA. [McCabe, Ryan M.] Amer Coll Surg, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 2028 BP 140 EP 141 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100311 ER PT J AU Haverman, L Schepers, S Zadeh, S Grootenhuis, M Lori, W AF Haverman, Lotte Schepers, Sasja Zadeh, Sima Grootenhuis, Martha Lori, Wiener TI PRO feedback in a clinical practice setting: What patient-reported information do pediatric oncology providers find helpful? SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Haverman, Lotte; Schepers, Sasja; Grootenhuis, Martha] Emma Childrens Hosp, Acad Med Ctr, Amsterdam, Netherlands. [Zadeh, Sima; Lori, Wiener] NIH, Int Canc Inst, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 3003 BP 155 EP 155 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100345 ER PT J AU Di Veroli, GY Fornari, C Goldlust, I Mills, G Koh, SB Bramhall, JL Richards, FM Jodrell, DI AF Di Veroli, Giovanni Y. Fornari, Chiara Goldlust, Ian Mills, Graham Koh, Siang Boon Bramhall, Jo L. Richards, Frances M. Jodrell, Duncan I. TI An automated fitting procedure and software for dose-response curves with multiphasic features SO SCIENTIFIC REPORTS LA English DT Article ID PANCREATIC-CANCER; DRUG-SENSITIVITY; MODEL SELECTION; RISK-ASSESSMENT; TOXICITY; IDENTIFICATION; KINETICS; THERAPY; POTENCY; CELLS AB In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose-dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge. net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data. C1 [Di Veroli, Giovanni Y.; Fornari, Chiara; Goldlust, Ian; Mills, Graham; Koh, Siang Boon; Bramhall, Jo L.; Richards, Frances M.; Jodrell, Duncan I.] Univ Cambridge, CRUK Cambridge Inst, Cambridge CB2 1TN, England. [Goldlust, Ian] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Di Veroli, GY (reprint author), Univ Cambridge, CRUK Cambridge Inst, Cambridge CB2 1TN, England. EM Giovanni.DiVeroli@cruk.cam.ac.uk OI Bramhall, Jo/0000-0002-0996-1583; Koh, Siang-Boon/0000-0002-5494-3800 FU Cancer Research UK [C14303/A17197] FX This work was funded by Cancer Research UK grant C14303/A17197. NR 55 TC 4 Z9 4 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 1 PY 2015 VL 5 AR 14701 DI 10.1038/srep14701 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS5CQ UT WOS:000362094100001 PM 26424192 ER PT J AU Gupta, K AF Gupta, Kailash TI Pay-to-Play Publishing SO SCIENTIST LA English DT Editorial Material C1 [Gupta, Kailash] Univ Alabama Birmingham, Birmingham, AL USA. [Gupta, Kailash] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Gupta, Kailash] Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. [Gupta, Kailash] NIAID, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LABX MEDIA GROUP PI MIDLAND PA PO BOX 216, 478 BAY ST, MIDLAND, ONTARIO L4R 1K9, CANADA SN 0890-3670 EI 1547-0806 J9 SCIENTIST JI Scientist PD OCT PY 2015 VL 29 IS 10 BP 29 EP 30 PG 2 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA CS8AY UT WOS:000362309300006 ER PT J AU Ishii, K Young, NS AF Ishii, Kazusa Young, Neal S. TI Anemia of Central Origin SO SEMINARS IN HEMATOLOGY LA English DT Article ID RED-CELL APLASIA; DIAMOND-BLACKFAN ANEMIA; BONE-MARROW FAILURE; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; COLLABORATIVE STUDY-GROUP; COLONY-STIMULATING FACTOR; PARVOVIRUS B19 INFECTION; ANTI-THYMOCYTE GLOBULIN; MATCHED SIBLING DONORS AB Hypoproliferative anemia results from the inability of bone marrow to produce adequate numbers of red blood cells. The list of conditions that cause hypoproliferative anemia is long, starting from common etiologies as iron deficiency to rarer diagnoses of constitutional bone marrow failure syndromes. There is no perfect diagnostic algorithm, and clinical data may not always clearly distinguish "normal" from "abnormal", yet it is important for practicing dinicians to recognize each condition so that treatment can be initiated promptly. This review describes diagnostic approaches to hypoproliferative anemia, with particular emphasis on bone marrow failure syndromes. Published by Elsevier Inc. C1 [Ishii, Kazusa; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Ishii, K (reprint author), NIH, Bldg 10,CRC-4-5140,MSC 1475, Bethesda, MD 20892 USA. EM kazusa.ishii@nih.gov FU Intramural Research Program, NHLBI FX Funded by the Intramural Research Program, NHLBI. NR 166 TC 2 Z9 2 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2015 VL 52 IS 4 BP 321 EP 338 DI 10.1053/j.seminhematol.2015.07.002 PG 18 WC Hematology SC Hematology GA CS4QS UT WOS:000362061600009 PM 26404444 ER PT J AU Saber, H Himali, JJ Shoamanesh, A Beiser, A Pikula, A Harris, TB Roubenoff, R Romero, JR Kase, CS Vasan, RS Seshadri, S AF Saber, Hamidreza Himali, Jayandra J. Shoamanesh, Ashkan Beiser, Alexa Pikula, Aleksandra Harris, Tamara B. Roubenoff, Ronenn Romero, Jose Rafael Kase, Carlos S. Vasan, Ramachandran S. Seshadri, Sudha TI Serum Leptin Levels and the Risk of Stroke The Framingham Study SO STROKE LA English DT Article DE adipokines; leptin; obesity; risk; stroke ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; ISCHEMIC-STROKE; PLASMA LEPTIN; OBESE MICE; MYOCARDIAL-INFARCTION; FAT DISTRIBUTION; BLOOD-PRESSURE; RESISTANCE AB Background and Purpose Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of incident stroke in an elderly community based sample. Methods Serum leptin levels were assayed in 757 stroke free individuals (mean age, 79 years; 62% women) from the Framingham Original Cohort at the 22nd examination cycle (1990-1994). Incidence of all -stroke and ischemic stroke were prospectively ascertained. Results During a mean follow up of 10 years, 119 individuals developed stroke (99 ischemic strokes). In multivariable Cox regression models, log leptin levels were not associated with incidence of all -stroke or ischemic stroke (hazard ratios per SD increment in log leptin 0.90 [0.73-1.09] and 0.89 [0.72-1.11], respectively). The results were suggestive for potential effect modification by waist/hip ratio for the association between leptin and stroke (P=0.03). Adjusting for age, sex, and established stroke risk factors, analysis stratified by waist/hip ratio quartiles revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among only subjects in the top waist/hip ratio quartile (hazard ratio, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25] for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke). Conclusions Leptin levels were not directly related to the risk of incident stroke overall but there was an inverse association with stroke in the top waist/hip ratio quartile. Further investigations are required to confirm these findings and explore possible mechanisms for the observed association. C1 [Saber, Hamidreza; Beiser, Alexa; Romero, Jose Rafael; Kase, Carlos S.; Vasan, Ramachandran S.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Shoamanesh, Ashkan] McMaster Univ, Dept Med, Div Neurol, Populat Hlth Res Inst, Hamilton, ON, Canada. [Pikula, Aleksandra] Univ Toronto, Dept Neurol, Toronto, ON, Canada. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. [Roubenoff, Ronenn] Tufts Univ, Sch Med, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Saber, Hamidreza; Himali, Jayandra J.; Beiser, Alexa; Romero, Jose Rafael; Kase, Carlos S.; Vasan, Ramachandran S.; Seshadri, Sudha] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02118 USA. RP Saber, H (reprint author), Boston Univ, Dept Neurol, Sch Med, 72 E Concord St,B602, Boston, MA 02118 USA. EM Hsaber@bu.edu OI Seshadri, Sudha/0000-0001-6135-2622; Ramachandran, Vasan/0000-0001-7357-5970; Beiser, Alexa/0000-0001-8551-7778; /0000-0003-1391-9481 FU Framingham Heart Study's National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) contract [N01 HC25195, N01 HHSN-268201500001]; National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS017950]; National Institute on Aging [R01 AG16495, AG 033040, AG008122, AG033193, AG031287, K23 AG038444]; American Heart Association [11CRP4930020] FX This work was supported by the Framingham Heart Study's National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) contract (N01 HC25195 and N01 HHSN-268201500001) and by grants from the National Institute of Neurological Disorders and Stroke (NINDS; R01 NS017950), the National Institute on Aging (R01 AG16495, AG 033040, AG008122, AG033193, AG031287, and K23 AG038444), and the American Heart Association (11CRP4930020). We also thank the Framingham study team, especially the Neurology team, both investigators and staff, for their contributions to data collection over the past 4 decades. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, the National Institute on Aging, or the NIH. NR 49 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD OCT PY 2015 VL 46 IS 10 BP 2881 EP 2885 DI 10.1161/STROKEAHA.115.009463 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CS3TT UT WOS:000361998600025 PM 26337973 ER PT J AU Sanossian, N Liebeskind, DS Eckstein, M Starkman, S Stratton, S Pratt, FD Koenig, W Hamilton, S Kim-Tenser, M Conwit, R Saver, JL AF Sanossian, Nerses Liebeskind, David S. Eckstein, Marc Starkman, Sidney Stratton, Samuel Pratt, Franklin D. Koenig, William Hamilton, Scott Kim-Tenser, May Conwit, Robin Saver, Jeffrey L. CA FAST-MAG Investigators Coordinator TI Routing Ambulances to Designated Centers Increases Access to Stroke Center Care and Enrollment in Prehospital Research SO STROKE LA English DT Article DE emergency medical services; emergency service, hospital; prehospital emergency care; stroke; triage ID EMERGENCY MEDICAL-SERVICES; FIELD; IMPLEMENTATION; ASSOCIATION; METHODOLOGY; STATEMENT; THERAPY; PROJECT AB Background and Purpose Emergency medical services routing of patients with acute stroke to designated centers may increase the proportion of patients receiving care at facilities meeting national standards and augment recruitment for prehospital stroke research. Methods We analyzed consecutive patients enrolled within 2 hours of symptom onset in a prehospital stroke trial, before and after regional Los Angeles County Emergency Medical Services implementation of preferentially routing patients with acute stroke to approved stroke centers (ASCs). From January 2005 to mid-November 2009, patients were transported to the nearest emergency department, whereas from mid-November 2009 to December 2012, patients were preferentially transported to first 9, and eventually 29, ASCs. Results There were 863 subjects enrolled before and 764 after emergency medical service preferential routing, with implementation leading to an increase in the proportion cared for at an ASC from 10% to 91% (P<0.0001), with a slight decrease in paramedic on-scene to emergency department arrival time (34.5 [SD, 9.1] minutes versus 33.5 [SD, 10.3] minutes; P=0.045). The effects of routing were immediate and included an increase in proportion of receiving ASC care (from 17% to 88%; P<0.001) and a greater number of enrollments (18.6% increase) when comparing 12 months before and after regional stroke system implementation. Conclusions The establishment of a regionalized emergency medical services system of acute stroke care dramatically increased the proportion of patients with acute stroke cared for at ASCs, from 1 in 10 to >9 in 10, with no clinically significant increase in prehospital care times and enhanced recruitment of patients into a prehospital treatment trial. C1 [Sanossian, Nerses; Kim-Tenser, May] Univ So Calif, Dept Neurol, Los Angeles, CA 90033 USA. [Eckstein, Marc] Univ So Calif, Dept Emergency Med, Los Angeles, CA 90033 USA. [Stratton, Samuel] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Pratt, Franklin D.] Los Angeles Cty Fire Dept, Los Angeles, CA USA. [Koenig, William] Los Angeles Cty Emergency Med Serv Agcy, Los Angeles, CA USA. [Hamilton, Scott] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. RP Sanossian, N (reprint author), Univ So Calif, Roxanna Todd Hodges Comprehens Stroke Clin, 1520 San Pablo St,STE 3000, Los Angeles, CA 90033 USA. EM sanossia@yahoo.com FU National Institutes of Health-National Institute of Neurological Disorders and Stroke [U01 NS 44364] FX This study was supported by National Institutes of Health-National Institute of Neurological Disorders and Stroke Award U01 NS 44364. NR 19 TC 5 Z9 5 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD OCT PY 2015 VL 46 IS 10 BP 2886 EP 2890 DI 10.1161/STROKEAHA.115.010264 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CS3TT UT WOS:000361998600026 PM 26265130 ER PT J AU Pinsky, PF AF Pinsky, Paul F. TI Principles of Cancer Screening SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Cancer screening; Overdiagnosis; Lead time; Targeted screening; Number needed to screen; Performance characteristics ID RANDOMIZED CONTROLLED-TRIAL; SERVICES TASK-FORCE; LUNG-CANCER; BREAST-CANCER; FOLLOW-UP; COLORECTAL-CANCER; PROSTATE-CANCER; MORTALITY; SIGMOIDOSCOPY; MAMMOGRAPHY AB Cancer screening has long been an important component of the struggle to reduce the burden of morbidity and mortality from cancer. Notwithstanding this history, many aspects of cancer screening remain poorly understood. This article presents a summary of basic principles of cancer screening that are relevant for researchers, clinicians, and public health officials alike. C1 NCI, Canc Prevent Div, Bethesda, MD 20910 USA. RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20910 USA. EM pp4f@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 34 TC 1 Z9 1 U1 2 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD OCT PY 2015 VL 95 IS 5 BP 953 EP + DI 10.1016/j.suc.2015.05.009 PG 15 WC Surgery SC Surgery GA CS4OM UT WOS:000362055300005 PM 26315516 ER PT J AU Barnes, AJ Spinelli, E Young, S Martin, TM Kleete, KL Huestis, MA AF Barnes, Allan J. Spinelli, Eliani Young, Sheena Martin, Thomas M. Kleete, Kevin L. Huestis, Marilyn A. TI Validation of an ELISA Synthetic Cannabinoids Urine Assay SO THERAPEUTIC DRUG MONITORING LA English DT Article DE synthetic cannabinoids; ELISA; immunoassay ID CHROMATOGRAPHY-MASS SPECTROMETRY; LC-MS/MS; QUANTITATIVE MEASUREMENT; SMOKING MIXTURES; CASE SERIES; METABOLITES; JWH-018; SPICE; INTOXICATION; IMMUNOASSAY AB Background:Synthetic cannabinoids are touted as legal alternatives to cannabis, at least when first released, and routine urine cannabinoid screening methods do not detect these novel psychoactive substances. Synthetic cannabinoids are widely available, are a major public health and safety problem, and a difficult challenge for drug-testing laboratories. We evaluated performance of the National Medical Services (NMS) JWH-018 direct enzyme-linked immunosorbent assay (ELISA) kit to sensitively, selectively, and rapidly screen urinary synthetic cannabinoids.Methods:The NMS ELISA kit targeting the JWH-018 N-(5-hydroxypentyl) metabolite was used to screen 2492 urine samples with 5 and 10 mcg/L cutoffs. A fully validated liquid chromatography-tandem mass spectrometry method for 29 synthetic cannabinoids markers confirmed all presumptive positive and negative results. Performance challenges at 25% and 50% of cutoffs determined intraplate and interplate imprecision around proposed cutoffs.Results:The immunoassay was linear from 1 to 500 mcg/L with intraplate and interplate imprecision of 8.2% and <14.0%, respectively. No interferences were present from 93 common drugs of abuse, metabolites, coadministered drugs, over-the-counter medications, or structurally similar compounds, and 19 of 73 individual synthetic cannabinoids (26%) exhibited moderate to high cross-reactivity to JWH-018 N-(5-hydroxypentyl) metabolite. Sensitivity, specificity, and efficiency results were 83.7%, 99.4%, and 97.6%, as well as 71.6%, 99.7%, and 96.4% with the 5 and 10 mcg/L urine cutoffs, respectively.Conclusions:This high throughput immunoassay exhibited good diagnostic efficiency and documented that the NMS JWH-018 direct ELISA is a viable method for screening synthetic cannabinoids in urine targeting the JWH-018 N-(5-hydroxypentyl) and related analytes. Optimal performance was achieved with a matrix-matched 5 mcg/L urine cutoff. C1 [Barnes, Allan J.; Spinelli, Eliani; Young, Sheena; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, IRP, NIH, Baltimore, MD 21224 USA. [Spinelli, Eliani] Univ Fed Fluminense, CAPES Fdn BEX 1534 12, Sch Pharm, Rio De Janeiro, Brazil. [Martin, Thomas M.; Kleete, Kevin L.] Off Secretary Def Operat Readiness & Safety, Drug Testing & Program Policy, Washington, DC 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 OI Spinelli, Eliani/0000-0001-5488-2545 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health; Department of Defense FX Supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health and the Department of Defense through an interagency agreement. NR 29 TC 2 Z9 2 U1 5 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD OCT PY 2015 VL 37 IS 5 BP 661 EP 669 DI 10.1097/FTD.0000000000000201 PG 9 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA CS0LB UT WOS:000361749500015 PM 25706046 ER PT J AU Dahiya, N Sarachana, T Vu, L Becker, KG Wood, WH Zhang, YQ Atreya, CD AF Dahiya, Neetu Sarachana, Tewarit Vu, Long Becker, Kevin G. Wood, William H., III Zhang, Yongqing Atreya, Chintamani D. TI Platelet MicroRNAs: An Overview SO TRANSFUSION MEDICINE REVIEWS LA English DT Review DE MicroRNA; Blood disorders; Platelets; Signaling pathways ID MEGAKARYOCYTIC DIFFERENTIATION; ACTIVATED PLATELETS; K562 CELLS; MICROPARTICLES; MEGAKARYOPOIESIS; EXPRESSION; APOPTOSIS; PATHWAY; STORAGE AB MicroRNAs (miRNAs) are short similar to 22-nucleotide noncoding RNA that have been found to influence the expression of many genes and cellular processes by either repressing translation or degrading messenger RNA transcripts. Platelet miRNA expression has been shown to be perturbed during ex vivo storage of platelets and in platelet-associated disorders. Although bioinformatics-based miRNA target predictions have been established, direct experimental validation of the role of miRNAs in platelet biology has been rather slow. Target prediction studies are, nonetheless, valuable in directing the design of appropriate experiments to test specific miRNA:messenger RNA interactions relevant to the underlying mechanisms of platelet function in general and in disease as well as in ex vivo storage-associated "storage lesions," a collective term used to include physiologic, biochemical, and morphologic changes that occur in stored platelets. This brief review will focus on emerging human platelet miRNA studies to emphasize their potential role relevant to transfusion medicine field in terms of regulating platelet signaling pathways, markers of platelet associated disorders, and remote impactors of gene expression (intercellular biomodulators) as well as potential platelet quality markers of storage and pathogen reduction treatments. Published by Elsevier Inc. C1 [Dahiya, Neetu; Vu, Long; Atreya, Chintamani D.] US FDA, Sect Cell Biol, Lab Cellular Hematol, Div Hematol Res & Review,Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Sarachana, Tewarit] Chulalongkorn Univ, Dept Clin Chem, Fac Allied Hlth Sci, Bangkok, Thailand. [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 71,Room 4236, Silver Spring, MD 20993 USA. EM chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research, US Food and Drug Administration; Center for Biologics Evaluation and Research; Intramural Research Program FX CDA received funding for this study from the Center for Biologics Evaluation and Research, US Food and Drug Administration. ND and LV are recipients of a postdoctoral fellowship at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the US Food and Drug Administration. The collaborative work performed by the coauthors KGB, WHW, and YZ at the National Institute on Aging, NIH, was supported by their Intramural Research Program. We would like to thank Dr Valerie W. Hu from the Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine and Health Sciences, for allowing us to use the Ingenuity Pathway Analysis software. NR 44 TC 1 Z9 2 U1 3 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-7963 EI 1532-9496 J9 TRANSFUS MED REV JI Transf. Med. Rev. PD OCT PY 2015 VL 29 IS 4 BP 215 EP 219 DI 10.1016/j.tmrv.2015.08.002 PG 5 WC Hematology SC Hematology GA CS4LT UT WOS:000362048000001 PM 26341586 ER PT J AU Duffy, AG Ulahannan, SV Cao, L Rahma, OE Makarova-Rusher, OV Kleiner, DE Fioravanti, S Walker, M Carey, S Yu, Y Venkatesan, AM Turkbey, B Choyke, P Trepel, J Bollen, KC Steinberg, SM Figg, WD Greten, TF AF Duffy, A. G. Ulahannan, S. V. Cao, L. Rahma, O. E. Makarova-Rusher, O. V. Kleiner, D. E. Fioravanti, S. Walker, M. Carey, S. Yu, Y. Venkatesan, A. M. Turkbey, B. Choyke, P. Trepel, J. Bollen, K. C. Steinberg, S. M. Figg, W. D. Greten, T. F. TI A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib SO UNITED EUROPEAN GASTROENTEROLOGY JOURNAL LA English DT Article DE Hepatocellular carcinoma; clinical trial; endoglin; angiogenesis; CD105 ID ANTI-ENDOGLIN ANTIBODY; ADVANCED CANCER; BEVACIZUMAB; THERAPY; ANGIOGENESIS; COMBINATION; BIOMARKERS; BRIVANIB; CD105 AB Background: Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors. Objective: The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib. Methods: Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105. Results: A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study. Conclusions: TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib. C1 [Duffy, A. G.; Ulahannan, S. V.; Rahma, O. E.; Makarova-Rusher, O. V.; Fioravanti, S.; Walker, M.; Carey, S.; Greten, T. F.] NCI, Gastrointestinal Malignancies Sect, Thorac GI Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Cao, L.; Yu, Y.] NIH, Ctr Canc Res, Genet Branch, Bethesda, MD USA. [Kleiner, D. E.] NIH, Pathol Lab, Ctr Canc Res, Bethesda, MD USA. [Venkatesan, A. M.] NIH, Radiol & Imaging Sci, Ctr Canc Res, Bethesda, MD USA. [Turkbey, B.; Choyke, P.] NIH, Mol Imaging Dept, Ctr Canc Res, Bethesda, MD USA. [Trepel, J.] NIH, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD USA. [Bollen, K. C.; Figg, W. D.] NIH, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD USA. [Steinberg, S. M.] NIH, Biostat & Data Management, Ctr Canc Res, Bethesda, MD USA. RP Greten, TF (reprint author), NCI, 9000 Rockville Pike,10-12N224, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Figg Sr, William/M-2411-2016; Ulahannan, Susanna/H-6525-2016 OI Ulahannan, Susanna/0000-0002-7234-2283 FU Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 27 TC 3 Z9 4 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2050-6406 EI 2050-6414 J9 UNITED EUR GASTROENT JI United European Gastroenterol. J. PD OCT PY 2015 VL 3 IS 5 BP 453 EP 461 DI 10.1177/2050640615583587 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS3LG UT WOS:000361975100007 PM 26535124 ER PT J AU Sankineni, S George, AK Brown, AM Rais-Bahrami, S Wood, BJ Merino, MJ Pinto, PA Choyke, PL Turkbey, B AF Sankineni, Sandeep George, Arvin K. Brown, Anna M. Rais-Bahrami, Soroush Wood, Bradford J. Merino, Maria J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Posterior subcapsular prostate cancer: identification with mpMRI and MRI/TRUS fusion-guided biopsy SO ABDOMINAL IMAGING LA English DT Article DE Prostate cancer; Subcapsular; MRI; Fusion guided biopsy ID MULTIPARAMETRIC MRI; SPECIMENS AB The posterior subcapsular region of the prostate is often undersampled by transrectal ultrasound (TRUS)-guided biopsy. The close proximity of these lesions to the posterior capsular wall of the prostate makes them difficult to localize while increasing the need for early detection because of their increased risk for extracapsular extension. We retrospectively evaluated the multiparametric MRI (mpMRI) features of subcapsular prostate cancers to make radiologists more aware of this condition. Between January 2010 and July 2014, all patients referred for 3T mpMRI and subsequent MR-US Fusion-guided biopsy (FgBx) and systematic 12-core sextant biopsy (SBx) under an IRB approved protocol, were reviewed, and imaging confirmed subcapsular prostate cancers were identified. Subcapsular lesions were defined as thin lesions that were just inside the prostate capsule. Matching patient demographics and clinical findings including age, PSA, PSA density, whole prostate volume, history of prostate cancer, Gleason score, and clinical management were tabulated. Of 992 eligible patients, 33 patients had subcapsular lesions in the prostate detected by mpMRI. Mean age, PSA, and prostate volume in this group were 63 years (range: 52-76 years), 8.4 ng/mL (range: 1.22-65.20), and 53 mL (range: 12-125 mL), respectively. The combination biopsy (SBx + FgBx) confirmed prostate cancer in 24 of 33 patients (72.7%) and in 9 patients the biopsy was negative. Of the 24 cancers, 19 were confirmed on both FgBx and conventional biopsy; however, 5 cancers were only detected on FgBx. In 4 of the 19 patients in which both biopsy methods were positive, the FgBx yielded a higher Gleason score. Subcapsular lesions on mpMRI are relatively infrequent but are usually malignant. Although the majority are confirmed on conventional 12-core biopsies, about 20% of these lesions require FgBx for diagnosis, and FgBx more accurately grades the lesions in another 20%. Thus, FgBx is of considerable benefit in confirming the diagnosis of subcapsular prostate cancer despite their proximity to the prostatic capsule. C1 [Sankineni, Sandeep; Brown, Anna M.; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [George, Arvin K.; Rais-Bahrami, Soroush; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 NR 16 TC 15 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD OCT PY 2015 VL 40 IS 7 BP 2557 EP 2565 DI 10.1007/s00261-015-0426-8 PG 9 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CS1OJ UT WOS:000361835700049 PM 25916869 ER PT J AU Tana, MM Shums, Z Milo, J Norman, GL Leung, PS Gershwin, ME Noureddin, M Kleiner, DE Zhao, XC Heller, T Hoofnagle, JH AF Tana, Michele M. Shums, Zakera Milo, Jay Norman, Gary L. Leung, Patrick S. Gershwin, M. Eric Noureddin, Mazen Kleiner, David E. Zhao, Xiongce Heller, Theo Hoofnagle, Jay H. TI The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Autoantibodies; Primary biliary cirrhosis; Prognosis; Autoimmune liver disease; Serum markers; Ursodiol ID SYSTEMIC LUPUS-ERYTHEMATOSUS; ANTINUCLEAR ANTIBODIES; DISEASE PROGRESSION; MYASTHENIA-GRAVIS; CORRELATE; ANTIGENS AB Objectives: In primary biliary cirrhosis (PBC), the antimitochondrial antibody is a cornerstone of diagnosis, but there have been conflicting reports about the correlation of autoantibodies with disease stage and prognosis. We studied whether autoantibody levels changed over time and sought correlations with clinical outcomes in a cohort of patients with PBC. Methods: We tested serial serum samples from patients with PBC at a research institution for several autoantibodies. Long-term clinical follow-up data were used to calculate the slopes (change over time) for autoantibodies, platelet count, Ishak fibrosis score, biopsy copper, and number of portal areas with bile ducts. An adverse clinical outcome was defined as hepatic decompensation, development of hepatocellular carcinoma, liver transplantation, or liver-related death. We performed linear or logistic regression or Fisher exact test as appropriate, adjusting for multiple comparisons. Results: Twenty-seven patients with PBC with 145 serum samples were studied. Of the cohort, 85% was white, 81% was female, and median follow-up time was 20 years. Of the autoantibodies tested, only sp100 changed significantly over time. The sp100 slope was inversely associated with the Ishak fibrosis slope (parameter estimate, -0.05; P=.0003). Conclusions: While changes in most autoantibodies over time do not seem to correlate with clinical outcomes in PBC, a change in the sp100 autoantibody level may have prognostic utility with respect to the development of fibrosis on liver biopsy. C1 [Tana, Michele M.; Noureddin, Mazen; Kleiner, David E.; Zhao, Xiongce; Heller, Theo; Hoofnagle, Jay H.] NIDDK, NIH, Bethesda, MD 20892 USA. [Shums, Zakera; Milo, Jay; Norman, Gary L.] Inova Diagnost, San Diego, CA USA. [Leung, Patrick S.; Gershwin, M. Eric] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. RP Tana, MM (reprint author), 1001 Potrero Ave,3D9, San Francisco, CA 94110 USA. EM michele.tana@ucsf.edu FU Intramural NIH HHS [, Z99 DK999999]; NIDDK NIH HHS [P30 DK026743] NR 31 TC 3 Z9 4 U1 1 U2 12 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD OCT PY 2015 VL 144 IS 4 BP 601 EP 606 DI 10.1309/AJCPQV4A7QAEEFEV PG 6 WC Pathology SC Pathology GA CR7XJ UT WOS:000361565000009 PM 26386081 ER PT J AU Nee, R Martinez-Osorio, J Yuan, CM Little, DJ Watson, MA Agodoa, L Abbott, KC AF Nee, Robert Martinez-Osorio, Jorge Yuan, Christina M. Little, Dustin J. Watson, Maura A. Agodoa, Lawrence Abbott, Kevin C. TI Survival Disparity of African American Versus Non-African American Patients With ESRD Due to SLE SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Racial disparity; survival disparity; systemic lupus erythematosus (SLE); lupus nephritis; end-stage renal disease (ESRD); dialysis; all-cause mortality; African American; US Renal Data System (USRDS); competing risk; kidney transplantation ID LUPUS NEPHRITIS; UNITED-STATES; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; DIALYSIS PATIENTS; KIDNEY-DISEASE; RENAL-FAILURE; RACE; TRANSPLANT; ETHNICITY AB Background: A recent study showed an increased risk of death in African Americans compared with whites with end-stage renal disease (ESRD) due to lupus nephritis (LN). We assessed the impact of age stratification, socioeconomic factors, and kidney transplantation on the disparity in patient survival among African American versus non-African American patients with LN-caused ESRD, compared with other causes. Study Design: Retrospective cohort study. Setting & Participants: Using the US Renal Data System database, we identified 12,352 patients with LN-caused ESRD among 1,132,202 patients who initiated maintenance dialysis therapy from January 1, 1995, through December 31, 2006, and were followed up until December 31, 2010. Predictors: Baseline demographics and comorbid conditions, Hispanic ethnicity, socioeconomic factors (employment status, Medicare/Medicaid insurance, and area-level median household income based on zip code as obtained from the 2000 US census), and kidney transplantation as a time-dependent variable. Outcome: All-cause mortality. Measurements: Multivariable Cox and competing-risk regressions. Results: Mean duration of follow-up in the LN-caused ESRD and other-cause ESRD cohorts were 6.24 +/- 4.20 (SD) and 4.06 +/- 3.61 years, respectively. 6,106 patients with LN-caused ESRD (49.43%) and 853,762 patients with other-cause ESRD (76.24%) died during the study period (P < 0.001). Patients with LN-caused ESRD were significantly younger (mean age, 39.92 years) and more likely women (81.65%) and African American (48.13%) than those with other-cause ESRD. In the fully adjusted multivariable Cox regression model, African American (vs non-African American) patients with LN-caused ESRD had significantly increased risk of death at age 18 to 30 years (adjusted HR, 1.43; 95% CI, 1.24-1.65) and at age 31 to 40 years (adjusted HR, 1.17; 95% CI, 1.02-1.34). Among patients with other-cause ESRD, African Americans were at significantly increased risk at age 18 to 30 years (adjusted HR, 1.17; 95% CI, 1.11-1.22). Limitations: We used zip code-based median household income as a surrogate for patient income. Residual socioeconomic confounders may exist. Conclusions: African Americans are at significantly increased risk of death compared with non-African Americans with LN-caused ESRD at age 18 to 40 years, a racial disparity risk that is 10 years longer than that in the general ESRD population. Accounting for area-level median household income and transplantation significantly attenuated the disparity in mortality of African American versus non-African American patients with LN-caused ESRD. Published by Elsevier Inc. C1 [Nee, Robert; Yuan, Christina M.; Little, Dustin J.; Watson, Maura A.; Abbott, Kevin C.] Walter Reed Natl Mil Med Ctr, Nephrol, Bethesda, MD 20889 USA. [Martinez-Osorio, Jorge] Tripler Army Med Ctr, Nephrol, Honolulu, HI 96859 USA. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD USA. RP Nee, R (reprint author), Walter Reed Natl Mil Med Ctr, Serv Nephrol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM robert.nee.civ@mail.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 28 TC 5 Z9 5 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD OCT PY 2015 VL 66 IS 4 BP 630 EP 637 DI 10.1053/j.ajkd.2015.04.011 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CS1JK UT WOS:000361820100019 PM 26002293 ER PT J AU Louis, GMB Grewal, J Albert, PS Sciscione, A Wing, DA Grobman, WA Newman, RB Wapner, R D'Alton, ME Skupski, D Nageotte, MP Ranzini, AC Owen, J Chien, EK Craigo, S Hediger, ML Kim, S Zhang, CL Grantz, KL AF Louis, Germaine M. Buck Grewal, Jagteshwar Albert, Paul S. Sciscione, Anthony Wing, Deborah A. Grobman, William A. Newman, Roger B. Wapner, Ronald D'Alton, Mary E. Skupski, Daniel Nageotte, Michael P. Ranzini, Angela C. Owen, John Chien, Edward K. Craigo, Sabrina Hediger, Mary L. Kim, Sungduk Zhang, Cuilin Grantz, Katherine L. TI Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE birthweight; epidemiology; estimated fetal growth; fetal growth; pregnancy ID BIRTH-WEIGHT REFERENCE; FOR-GESTATIONAL-AGE; UNITED-STATES; DISEASE; COHORT; BORN; ULTRASOUND; REGRESSION; SIZE AB OBJECTIVE: Fetal growth is associated with long-term health yet no appropriate standards exist for the early identification of undergrown or overgrown fetuses. We sought to develop contemporary fetal growth standards for 4 self-identified US racial/ethnic groups. STUDY DESIGN: We recruited for prospective follow-up 2334 healthy women with low-risk, singleton pregnancies from 12 community and perinatal centers from July 2009 through January 2013. The cohort comprised: 614 (26%) non-Hispanic whites, 611 (26%) non-Hispanic blacks, 649 (28%) Hispanics, and 460 (20%) Asians. Women were screened at 8w0d to 13w6d for maternal health status associated with presumably normal fetal growth (aged 18-40 years; body mass index 19.0-29.9 kg/m(2); healthy lifestyles and living conditions; low-risk medical and obstetrical history); 92% of recruited women completed the protocol. Women were randomized among 4 ultrasonography schedules for longitudinal fetal measurement using the Voluson E8 (GE Healthcare, Milwaukee, WI). In-person interviews and anthropometric assessments were conducted at each visit; medical records were abstracted. The fetuses of 1737 (74%) women continued to be low risk (uncomplicated pregnancy, absent anomalies) at birth, and their measurements were included in the standards. Racial/ethnic-specific fetal growth curves were estimated using linear mixed models with cubic splines. Estimated fetal weight (EFW) and biometric parameter percentiles (5th, 50th, 95th) were determined for each gestational week and comparisons made by race/ethnicity, with and without adjustment for maternal and sociodemographic factors. RESULTS: EFW differed significantly by race/ethnicity > 20 weeks. Specifically at 39 weeks, the 5th, 50th, and 95th percentiles were 2790, 3505, and 4402 g for white; 2633, 3336, and 4226 g for Hispanic; 2621, 3270, and 4078 g for Asian; and 2622, 3260, and 4053 g for black women (adjusted global P<. 001). For individual parameters, racial/ethnic differences by order of detection were: humerus and femur lengths (10 weeks), abdominal circumference (16 weeks), head circumference (21 weeks), and biparietal diameter (27 weeks). The study-derived standard based solely on the white group erroneously classifies as much as 15% of non-white fetuses as growth restricted (EFW < 5th percentile). CONCLUSION: Significant differences in fetal growth were found among the 4 groups. Racial/ethnic-specific standards improve the precision in evaluating fetal growth. C1 [Louis, Germaine M. Buck; Grewal, Jagteshwar; Albert, Paul S.; Hediger, Mary L.; Kim, Sungduk; Zhang, Cuilin; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Sciscione, Anthony] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Wing, Deborah A.] Univ Calif Irvine, Sch Med, Dept Obstet Gynecol, Div Maternal Fetal Med, Irvine, CA 92717 USA. [Wing, Deborah A.] Fountain Valley Reg Hosp & Med Ctr, Fountain Valley, CA USA. [Nageotte, Michael P.] Miller Childrens Hosp, Long Beach Mem Med Ctr, Dept Obstet & Gynecol, Long Beach, CA USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Newman, Roger B.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Wapner, Ronald; D'Alton, Mary E.] Cornell Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY 10021 USA. [Skupski, Daniel] New York Hosp Queens, Dept Obstet & Gynecol, Queens, NY USA. [Ranzini, Angela C.] St Peters Univ Hosp, Dept Obstet & Gynecol, Div Maternal & Fetal Med, New Brunswick, NJ USA. [Owen, John] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Maternal Fetal Med, Sch Med, Birmingham, AL 35294 USA. [Chien, Edward K.] Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, Div Maternal Fetal Med, Providence, RI 02908 USA. [Craigo, Sabrina] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. EM louisg@mail.nih.gov OI Grewal, Jagteshwar/0000-0002-0141-4876; Buck Louis, Germaine/0000-0002-1774-4490; Grantz, Katherine/0000-0003-0276-8534 NR 38 TC 19 Z9 20 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2015 VL 213 IS 4 AR 449.e1 DI 10.1016/j.ajog.2015.08.032 PG 41 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CS2EA UT WOS:000361879400004 ER PT J AU Palatnik, A Mele, L Landon, MB Reddy, UM Ramin, SM Carpenter, MW Wapner, RJ Varner, MW Rouse, DJ Thorp, JM Sciscione, A Catalano, P Saade, GR Caritis, SN Sorokin, Y AF Palatnik, Anna Mele, Lisa Landon, Mark B. Reddy, Uma M. Ramin, Susan M. Carpenter, Marshall W. Wapner, Ronald J. Varner, Michael W. Rouse, Dwight J. Thorp, John M., Jr. Sciscione, Anthony Catalano, Patrick Saade, George R. Caritis, Steve N. Sorokin, Yoram CA Eunice Kennedy Shriver Natl Inst TI Timing of treatment initiation for mild gestational diabetes mellitus and perinatal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) CY FEB 02-07, 2015 CL San Diego, CA SP Soc Maternal Fetal Med DE gestational age; gestational diabetes mellitus; outcome ID PREGNANCY OUTCOMES; RECOMMENDATIONS; HYPERGLYCEMIA AB OBJECTIVE: The purpose of this study was to examine the association between gestational age (GA) at the time of treatment initiation for gestational diabetes mellitus (GDM) and maternal and perinatal outcomes. STUDY DESIGN: We conducted a secondary analysis of a multicenter randomized treatment trial of mild GDM in which women with mild GDM were assigned randomly to treatment vs usual care. The primary outcome of the original trial, as well as this analysis, was a composite perinatal adverse outcome that included neonatal hypoglycemia, hyperbilirubinemia, hyperinsulinemia, and perinatal death. Other outcomes that were examined included the frequency of large for GA, birthweight, neonatal intensive care unit admission, gestational hypertension/preeclampsia, and cesarean delivery. The interaction between GA at treatment initiation (stratified as 24-26, 27, 28, 29, and >= 30 weeks of gestation) and treatment group (treated vs routine care), with the outcomes of interest, was used to determine whether GA at treatment initiation was associated with outcome differences. RESULTS: Of 958 women whose cases were analyzed, those who initiated treatment at an earlier GA did not gain an additional treatment benefit compared with those who initiated treatment at a later GA (probability value for interaction with the primary outcome, .44). Similarly, there was no evidence that other outcomes were improved significantly by earlier initiation of GDM treatment (large for GA, P =.76; neonatal intensive care unit admission, P =.8; cesarean delivery, P =.82). The only outcome that had a significant interaction between GA and treatment was gestational hypertension/preeclampsia (P =.04), although there was not a clear cut GA trend where this outcome improved with treatment. CONCLUSION: Earlier initiation of treatment of mild GDM was not associated with stronger effect of treatment on perinatal outcomes. C1 [Palatnik, Anna] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Landon, Mark B.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Carpenter, Marshall W.] Brown Univ, Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY USA. [Varner, Michael W.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Thorp, John M., Jr.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Sciscione, Anthony] Drexel Univ, Sch Med, Philadelphia, PA 19104 USA. [Catalano, Patrick] Case Western Reserve Univ, Dept Obstet & Gynecol, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Mele, Lisa] George Washington Univ, Ctr Biostat, Dept Obstet & Gynecol, Washington, DC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Palatnik, A (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. EM anna.palatnik@northwestern.edu RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; palatnik, anna/0000-0001-6568-0201 FU NCATS NIH HHS [UL1 TR000439]; NCRR NIH HHS [C06 RR011234, M01 RR000034, M01 RR000080, M01-RR00034, M01-RR00080, UL1 RR024989, UL1 RR025764, UL1-RR024989, UL1-RR025764]; NICHD NIH HHS [HD40544, HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40545, HD40560, HD53097, HD53118, U01 HD036801, U10 HD021410, U10 HD027860, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, U10 HD053097, U10 HD053118, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD053097]; NIDDK NIH HHS [P30 DK079626] NR 17 TC 0 Z9 0 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2015 VL 213 IS 4 AR 560.e1 DI 10.1016/j.ajog.2015.06.022 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CS2EA UT WOS:000361879400033 PM 26071920 ER PT J AU Reddy, UM Rice, MM Grobman, WA Bailit, JL Wapner, RJ Varner, MW Thorp, JM Leveno, KJ Caritis, SN Prasad, M Tita, ATN Saade, GR Sorokin, Y Rouse, DJ Blackwell, SC Tolosa, JE AF Reddy, Uma M. Rice, Madeline Murguia Grobman, William A. Bailit, Jennifer L. Wapner, Ronald J. Varner, Michael W. Thorp, John M., Jr. Leveno, Kenneth J. Caritis, Steve N. Prasad, Mona Tita, Alan T. N. Saade, George R. Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst TI Serious maternal complications after early preterm delivery (24-33 weeks' gestation) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE classic cesarean delivery; early preterm delivery; hemorrhage; infection; intensive care unit admission; maternal morbidity ID CLASSICAL CESAREAN-SECTION; UTERINE INCISION; TRANSVERSE; OUTCOMES AB OBJECTIVE: We sought to describe the prevalence of serious maternal complications following early preterm birth by gestational age (GA), delivery route, and type of cesarean incision. STUDY DESIGN: Trained personnel abstracted data from maternal and neonatal charts for all deliveries on randomly selected days representing one third of deliveries across 25 US hospitals over 3 years (n = 115,502). All women delivering nonanomalous singletons between 23-33 weeks' gestation were included. Women were excluded for antepartum stillbirth and highly morbid conditions for which route of delivery would not likely impact morbidity including nonreassuring fetal status, cord prolapse, placenta previa, placenta accreta, placental abruption, and severe and unstable maternal conditions (cardiopulmonary collapse, acute respiratory distress syndrome, seizures). Serious maternal complications were defined as: hemorrhage (blood loss >= 1500 mL, blood transfusion, or hysterectomy for hemorrhage), infection (endometritis, wound dehiscence, or wound infection requiring antibiotics, reopening, or unexpected procedure), intensive care unit admission, or death. Delivery route was categorized as classic cesarean delivery (CCD), low transverse cesarean delivery (LTCD), low vertical cesarean delivery (LVCD), and vaginal delivery. Association of delivery route with complications was estimated using multivariable regression models yielding adjusted relative risks (aRR) controlling for maternal age, race, body mass index, hypertension, diabetes, preterm premature rupture of membranes, preterm labor, GA, and hospital of delivery. RESULTS: Of 2659 women who met criteria for inclusion in this analysis, 8.6% of women experienced serious maternal complications. Complications were associated with GA and were highest between 23-27 weeks of gestation. The frequency of complications was associated with delivery route; compared with 3.5% of vaginal delivery, 23.0% of CCD (aRR, 3.54; 95% confidence interval (CI), 2.29-5.48), 12.1% of LTCD (aRR, 2.59; 95% CI, 1.77-3.77), and 10.3% of LVCD (aRR, 2.27; 95% CI, 0.68-7.55) experienced complications. There was no significant difference in complication rates between CCD and LTCD (aRR, 1.37; 95% CI, 0.95-1.97) or between CCD and LVCD (aRR, 1.56; 95% CI, 0.48-5.07). CONCLUSION: The risk of maternal complications after early preterm delivery is substantial, particularly in women who undergo cesarean delivery. Obstetricians need to be prepared to manage potential hemorrhage, infection, and intensive care unit admission for early preterm births requiring cesarean delivery. C1 [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Washington, DC USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Prasad, Mona] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Wapner, Ronald J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, John M., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Blackwell, Sean C.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Tita, Alan T. N.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Rouse, Dwight J.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Intramural NIH HHS [Z99 HD999999]; NCATS NIH HHS [UL1 TR000439]; NCRR NIH HHS [5UL1 RR025764, UL1 RR024989, UL1 RR025764]; NICHD NIH HHS [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, U01 HD036801, U10 HD021410, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, U10 HD053097, U10 HD053118, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD053097] NR 14 TC 7 Z9 7 U1 3 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2015 VL 213 IS 4 AR 538.e1 DI 10.1016/j.ajog.2015.06.064 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CS2EA UT WOS:000361879400024 PM 26164696 ER PT J AU Rich-Edwards, JW Klungsoyr, K Wilcox, AJ Skjaerven, R AF Rich-Edwards, Janet W. Klungsoyr, Kari Wilcox, Allen J. Skjaerven, Rolv TI Duration of pregnancy, even at term, predicts long-term risk of coronary heart disease and stroke mortality in women: a population-based study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cardiovascular diseases; epidemiology; pregnancy; prevention; risk factors ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; PRETERM DELIVERY; BIRTH-WEIGHT; RETROSPECTIVE COHORT; CIGARETTE-SMOKING; GESTATIONAL-AGE; MATERNAL RISK; INFLAMMATION; METAANALYSIS AB OBJECTIVE: Preterm delivery may predict an increased risk of cardiovascular disease in mothers, providing opportunities for prevention. No study had examined whether gestation length within the term period predicts future CVD, and there are few data segregating spontaneous from medically indicated deliveries. STUDY DESIGN: We used proportional hazards models to predict CVD death by gestation length, adjusted for age, education, and delivery year among 688,662 women with births from 1967 through 1998 in the Medical Birth Registry of Norway. Mothers were traced in the National Cause of Death Registry through 2009; there were 2324 CVD deaths. RESULTS: Compared with women who delivered spontaneously at 39-41 weeks' gestation, women who spontaneously delivered earlier had higher risks of CVD death. Hazard ratios were 1.9 at 22-31 weeks, 2.2 at 32-34 weeks, 1.6 at 35-36 weeks, and 1.4 at 37-38 weeks. Risks were higher among women with medically indicated deliveries (hazard ratio, 4.8 at 22-31 weeks, 2.7 at 32-34 weeks, 4.3 at 35-36 weeks, and 1.6 at 37-38 weeks compared with spontaneous deliveries at 39-41 weeks). Neither spontaneous nor indicated delivery after 41 weeks was associated with CVD mortality. Risks were highest with recurrent preterm pregnancies, and for women who delivered only one child, especially if that delivery was preterm. CONCLUSION: Women who deliver spontaneously before 37 weeks had a 2-fold increased risk of CVD mortality compared with women who had delivered after 38 weeks. Even women with spontaneous deliveries at early term (37-38 weeks) had a 41% elevated risk of CVD death compared with women delivering at 39-41 weeks. C1 [Rich-Edwards, Janet W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Rich-Edwards, Janet W.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rich-Edwards, Janet W.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Klungsoyr, Kari; Skjaerven, Rolv] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Klungsoyr, Kari; Skjaerven, Rolv] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. [Wilcox, Allen J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Rich-Edwards, JW (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. EM jr33@partners.org OI Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 43 TC 3 Z9 4 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2015 VL 213 IS 4 AR 518.e1 DI 10.1016/j.ajog.2015.06.001 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CS2EA UT WOS:000361879400017 PM 26070706 ER PT J AU Ghosh, S Sengupta, A Chandra, K AF Ghosh, Soumita Sengupta, Arjun Chandra, Kousik TI Quantitative metabolic profiling of NMR spectral signatures of branched chain amino acids in blood serum SO AMINO ACIDS LA English DT Article DE BCAA; NMR; Metabolites; COSY; CPMG ID QUANTIFICATION; SPECTROSCOPY; DISEASE AB Branched Chain Amino Acids (BCAAs) are related to different aspects of diseases like pathogenesis, diagnosis and even prognosis. While in some diseases, levels of all the BCAAs are perturbed; in some cases, perturbation occurs in one or two while the rest remain unaltered. In case of ischemic heart disease, there is an enhanced level of plasma leucine and isoleucine but valine level remains unaltered. In 'Hypervalinemia', valine is elevated in serum and urine, but not leucine and isoleucine. Therefore, identification of these metabolites and profiling of individual BCAA in a quantitative manner in body-fluid like blood plasma/serum have long been in demand. H-1 NMR resonances of the BCAAs overlap with each other which complicates quantification of individual BCAAs. Further, the situation is limited by the overlap of broad resonances of lipoprotein with the resonances of BCAAs. The widely used commercially available kits cannot differentially estimate the BCAAs. Here, we have achieved proper identification and characterization of these BCAAs in serum in a quantitative manner employing a Nuclear Magnetic Resonance-based technique namely T-2-edited Correlation Spectroscopy (COSY). This approach can easily be extended to other body fluids like bile, follicular fluids, saliva, etc. C1 [Ghosh, Soumita; Sengupta, Arjun; Chandra, Kousik] Tata Inst Fundamental Res, Dept Chem Sci, Bombay 400005, Maharashtra, India. [Ghosh, Soumita] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Sengupta, Arjun] Univ Penn, Dept Syst Pharmacol & Translat Sci, Philadelphia, PA 19104 USA. [Chandra, Kousik] Indian Inst Sci, Bangalore 560012, Karnataka, India. RP Chandra, K (reprint author), Johannes Kepler Univ Linz, Inst Organ Chem, TNF Turm, Altenberger Str 69,3rd Floor, A-4040 Linz, Austria. EM kousikchandra@gmail.com FU DST; TIFR; Council of Scientific and Industrial Research, Government of India; DST Inspire Faculty fellowship FX The financial support by DST and TIFR is gratefully acknowledged. KC acknowledges DST Inspire Faculty fellowship for providing financial support. AS acknowledges Council of Scientific and Industrial Research, Government of India for providing SPM Fellowship. KC acknowledges the NMR facility provided by TIFR, Mumbai and JKU, Linz. NR 19 TC 1 Z9 1 U1 3 U2 11 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD OCT PY 2015 VL 47 IS 10 BP 2229 EP 2236 DI 10.1007/s00726-015-1994-1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS1AA UT WOS:000361792600016 PM 25991390 ER PT J AU van Doremalen, N Munster, VJ AF van Doremalen, Neeltje Munster, Vincent J. TI Animal models of Middle East respiratory syndrome coronavirus infection SO ANTIVIRAL RESEARCH LA English DT Review DE MERS-CoV; Animal models; Coronavirus; Middle East respiratory syndrome coronavirus; Emerging viruses; Public health ID RECEPTOR-BINDING DOMAIN; DIPEPTIDYL PEPTIDASE 4; MERS-COV; RHESUS MACAQUES; MOUSE MODEL; NEUTRALIZING ANTIBODIES; FUNCTIONAL RECEPTOR; CLINICAL-FEATURES; IMMUNE-RESPONSES; DROMEDARY CAMELS AB The emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second time that a new, highly pathogenic coronavirus has emerged in the human population in the 21st century. In this review, we discuss the current state of knowledge of animal models of MERS-CoV infection. Commonly used laboratory animal species such as Syrian hamsters, mice and ferrets are not susceptible to MERS-CoV, due to differences in the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4). The initially developed animal models comprise two nonhuman primate species, the rhesus macaque and the common marmoset. Rhesus macaques develop a mild to moderate respiratory disease upon inoculation, reminiscent of milder MERS cases, whereas marmosets develop a moderate to severe respiratory disease, recapitulating the severe disease observed in some patients. Dromedary camels, considered to be the reservoir for MERS-CoV, develop a mild upper respiratory tract infection with abundant viral shedding. Although normal mice are not susceptible to MERS-CoV, expression of the human DPP4 (hDPP4) overcomes the lack of susceptibility. Transgenic hDPP4 mice develop severe and lethal respiratory disease upon inoculation with MERS-CoV. These hDPP4 transgenic mice are potentially the ideal first line animal model for efficacy testing of therapeutic and prophylactic countermeasures. Further characterization of identified countermeasures would ideally be performed in the common marmoset model, due to the more severe disease outcome. This article forms part of a symposium in Antiviral Research on "From SARS to MERS: research on highly pathogenic human coronaviruses." Published by Elsevier B.V. C1 [van Doremalen, Neeltje; Munster, Vincent J.] NIAID, NIH, Virol Lab, Div Intramural Res, Hamilton, MT USA. RP Munster, VJ (reprint author), NIAID, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM Vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX The authors would like to thank Dana Scott and Ryan Kissinger for excellent assistance with the design of the figures. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 71 TC 10 Z9 10 U1 3 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD OCT PY 2015 VL 122 BP 28 EP 38 DI 10.1016/j.antiviral.2015.07.005 PG 11 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA CR8CH UT WOS:000361578200004 PM 26192750 ER PT J AU Trevino, S Waalkes, MP Hernandez, JAF Leon-Chavez, BA Aguilar-Alonso, P Brambila, E AF Trevino, Samuel Waalkes, Michael P. Flores Hernandez, Jose Angel Alicia Leon-Chavez, Bertha Aguilar-Alonso, Patricia Brambila, Eduardo TI Chronic cadmium exposure in rats produces pancreatic impairment and insulin resistance in multiple peripheral tissues SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Cadmium; Hyperglycemia; Hyperinsulinemia; Insulin resistance; Insulin sensitivity; Insulin indexes ID BETA-CELL FUNCTION; MAGNETIC-RESONANCE-SPECTROSCOPY; HEPATIC GLUCOSE-PRODUCTION; TYPE-2 DIABETES-MELLITUS; LOW-DENSITY-LIPOPROTEIN; FATTY LIVER-DISEASE; FASTING GLUCOSE; CARDIOVASCULAR-DISEASE; GLUCONEOGENIC ENZYMES; ATHEROGENIC INDEX AB Previous studies have linked cadmium exposure to disturbances in carbohydrate and lipid metabolism. In this study we investigate the effects in Wistar rats of an oral cadmium exposure in drinking water on carbohydrates, lipids and insulin release. Also, using mathematical models we studied the effect of cadmium on insulin resistance and sensitivity in liver, muscle, adipose and cardiovascular tissue. Cadmium exposure induced hyperglycemia, increased insulin release after a glucose load, and caused increases in serum triglycerides, cholesterol, LDL-C and VLDL-C, and a decrease of HDL-C. In addition, there was an accumulation of cadmium in pancreas and an increase of insulin. After exposure, HOMA-IR was increased, while the HOMA-5%, QUICKI and Matsuda-DeFronzo indexes showed decreases. A decrease of insulin sensitivity was shown in muscle and liver. Additionally, cadmium increases insulin resistance in the liver, adipose tissue and cardiovascular system. Finally, beta-cell functioning was evaluated by HOMA-B% index and insulin disposition index, which were decreased, while insulin generation index increased. In conclusion, cadmium increases insulin release, induces hyperglycemia and alters lipid metabolism. These changes likely occur as a consequence of reduced sensitivity and increased insulin resistance in multiple insulin-dependent and non-dependent tissues, producing a biochemical phenotype similar to metabolic syndrome and diabetes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Trevino, Samuel; Alicia Leon-Chavez, Bertha; Aguilar-Alonso, Patricia; Brambila, Eduardo] Benemerita Univ Autonoma Puebla, Fac Ciencias Quim, Lab Invest Quim Clin, Puebla, Mexico. [Waalkes, Michael P.] NIEHS, Stem Cell Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program,NIH, Res Triangle Pk, NC 27709 USA. [Flores Hernandez, Jose Angel] Benemerita Univ Autonoma Puebla, Fac Ciencias Quim, Dept Anal Clin, Puebla, Mexico. RP Brambila, E (reprint author), 14 Sur Esq Av San Claudio,Edif CQ1,Ciudad Univ, Puebla 72570, Pue, Mexico. EM eduardobrambilal@yahoo.com.mx FU VIEP, BUAP [BRME-NAT143-G]; CONACYT [297337] FX This work was supported by the grant BRME-NAT143-G from VIEP, BUAP and Samuel Tevino Mora was recipient of a scholarship (297337) from CONACYT. We thanks Dr. Carlos Escamilla W. (Bioterio Calude Bernard, BUAP) for his assistance and the donation of the animals used in this work. NR 80 TC 2 Z9 2 U1 7 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD OCT 1 PY 2015 VL 583 BP 27 EP 35 DI 10.1016/j.abb.2015.07.010 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CR9AA UT WOS:000361644400004 PM 26253262 ER PT J AU Groseth, A Vine, V Weisend, C Ebihara, H AF Groseth, Allison Vine, Veronica Weisend, Carla Ebihara, Hideki TI Complete genome sequence of trivittatus virus SO ARCHIVES OF VIROLOGY LA English DT Article ID CALIFORNIA ENCEPHALITIS; SEROGROUP AB Trivittatus virus (family Bunyaviridae, genus Orthobunyavirus) represents an important genetic intermediate between the California encephalitis group and the Bwamba/Pongola and Nyando groups. Here, we report the first complete genome sequence of the prototype (Eklund) strain, isolated in 1948, which, interestingly, shows only a few differences when compared to partial sequences of modern strains. C1 [Groseth, Allison; Vine, Veronica; Weisend, Carla; Ebihara, Hideki] NIAID, Virol Lab, Mol Virol & Host Pathogen Interact Unit, Div Intramural Res,NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Ebihara, H (reprint author), NIAID, Virol Lab, Mol Virol & Host Pathogen Interact Unit, Div Intramural Res,NIH,Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov FU Intramural Research Program of NIH FX The authors are very grateful to Robert. B. Tesh (UTMB, WRCEVA) for providing us with the virus. We are also grateful to the members of the Rocky Mountain Laboratories (RML) Genomics Unit for their services. This work was supported by the Intramural Research Program of the NIH. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the NIH. NR 11 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD OCT PY 2015 VL 160 IS 10 BP 2637 EP 2639 DI 10.1007/s00705-015-2532-x PG 3 WC Virology SC Virology GA CS1IN UT WOS:000361817600030 PM 26212363 ER PT J AU Braenne, I Civelek, M Vilne, B Di Narzo, A Johnson, AD Zhao, YQ Reiz, B Codoni, V Webb, TR Asl, HF Hamby, SE Zeng, LY Tregouet, DA Hao, K Topol, EJ Schadt, EE Yang, X Samani, NJ Bjorkegren, JLM Erdmann, J Schunkert, H Lusis, AJ AF Braenne, Ingrid Civelek, Mete Vilne, Baiba Di Narzo, Antonio Johnson, Andrew D. Zhao, Yuqi Reiz, Benedikt Codoni, Veronica Webb, Thomas R. Asl, Hassan Foroughi Hamby, Stephen E. Zeng, Lingyao Tregouet, David-Alexandre Hao, Ke Topol, Eric J. Schadt, Eric E. Yang, Xia Samani, Nilesh J. Bjorkegren, Johan L. M. Erdmann, Jeanette Schunkert, Heribert Lusis, Aldons J. CA Leducq Consortium CAD Genomics TI Prediction of Causal Candidate Genes in Coronary Artery Disease Loci SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary artery disease; genome-wide association study; microRNAs; single-nucleotide polymorphism; systems biology ID GENOME-WIDE ASSOCIATION; EXPRESSION; VARIANTS; GENETICS; DATABASE; OBESITY; UPDATE; TOOL; IDENTIFICATION; ANNOTATION AB Objective Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. Approach and Results All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously. Conclusions Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses. C1 [Braenne, Ingrid; Reiz, Benedikt; Erdmann, Jeanette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Braenne, Ingrid; Reiz, Benedikt; Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Braenne, Ingrid; Reiz, Benedikt; Erdmann, Jeanette] Univ Heart Ctr Lubeck, Lubeck, Germany. [Civelek, Mete; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Zhao, Yuqi; Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Vilne, Baiba; Zeng, Lingyao; Schunkert, Heribert] Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Di Narzo, Antonio; Hao, Ke; Schadt, Eric E.; Bjorkegren, Johan L. M.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Di Narzo, Antonio; Hao, Ke; Schadt, Eric E.; Bjorkegren, Johan L. M.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA USA. [Codoni, Veronica; Tregouet, David-Alexandre] INSERM, UMR S 1166, Paris, France. [Codoni, Veronica; Tregouet, David-Alexandre] Univ Paris 06, Sorbonne Univ, Team Genom & Pathophysiol Cardiovasc Dis, UMR S 1166, Paris, France. [Codoni, Veronica; Tregouet, David-Alexandre] ICAN, Paris, France. [Webb, Thomas R.; Hamby, Stephen E.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Webb, Thomas R.; Hamby, Stephen E.; Samani, Nilesh J.] NIHR Leicester Cardiovasc Biomed Res Unit, BHF Cardiovasc Res Ctr, Leicester, Leics, England. [Asl, Hassan Foroughi; Bjorkegren, Johan L. M.] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden. [Topol, Eric J.] Scripps Translat Sci Inst, Dept Mol & Expt Med, La Jolla, CA USA. RP Lusis, AJ (reprint author), Univ Calif Los Angeles, Dept Med, Div Cardiol, 650 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM jlusis@mednet.ucla.edu RI Webb, Tom/C-6237-2011; Tregouet, David-Alexandre/E-3961-2016; Zhao, Yuqi/L-5639-2016; Johnson, Andrew/G-6520-2013; Erdmann, Jeanette/P-7513-2014; OI Zhao, Yuqi/0000-0003-0730-5854; Erdmann, Jeanette/0000-0002-4486-6231; Civelek, Mete/0000-0002-8141-0284 FU Transatlantic Networks of Excellence Award from Foundation Leducq [12CVD02]; US National Institutes of Health [HL28481, HL114437, HL30568, HL123295]; German Federal Ministry of Education and Research; FP7 European Union project; CVgenes@target [261123]; Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces; National Institutes of Health Pathway to Independence Award [HL121172]; American Heart Association Scientist Development Grant [13SDG17290032]; British Heart Foundation; NIHR Leicester Cardiovascular Biomedical Research Unit; Astra-Zeneca Translational Science Centre-Karolinska Institutet; University of Tartu (SP1GVARENG) FX This work was supported by Transatlantic Networks of Excellence Award (12CVD02) from Foundation Leducq (all authors), US National Institutes of Health grants HL28481, HL114437, HL30568, and HL123295 (A.J. Lusis). Funding is provided by the German Federal Ministry of Education and Research in the context of the e:Med program (e:AtheroSysMed and sysINFLAME), the FP7 European Union project and CVgenes@target (261123). Further grants were received by the Universitat zu Lubeck. This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces. M. Civelek is supported by an National Institutes of Health Pathway to Independence Award (HL121172). Y. Zhao and X. Yang are supported by an American Heart Association Scientist Development Grant (13SDG17290032). N.J. Samani and T.R. Webb are funded by the British Heart Foundation. N.J. Samani is a UK National Institute for Health Research (NIHR) Senior Investigator. S.E. Hamby is funded by the NIHR Leicester Cardiovascular Biomedical Research Unit. J.L.M. Bjorkegren is supported by grants from Astra-Zeneca Translational Science Centre-Karolinska Institutet and by the University of Tartu (SP1GVARENG). NR 57 TC 15 Z9 15 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2015 VL 35 IS 10 BP 2207 EP 2217 DI 10.1161/ATVBAHA.115.306108 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CR8NL UT WOS:000361610700017 ER PT J AU Durda, P Sabourin, J Lange, EM Nalls, MA Mychaleckyj, JC Jenny, NS Li, J Walston, J Harris, TB Psaty, BM Valdar, W Liu, YM Cushman, M Reiner, AP Tracy, RP Lange, LA AF Durda, Peter Sabourin, Jeremy Lange, Ethan M. Nalls, Mike A. Mychaleckyj, Josyf C. Jenny, Nancy Swords Li, Jin Walston, Jeremy Harris, Tamara B. Psaty, Bruce M. Valdar, William Liu, Yongmei Cushman, Mary Reiner, Alex P. Tracy, Russell P. Lange, Leslie A. TI Plasma Levels of Soluble Interleukin-2 Receptor a Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; genome-wide association study; inflammation; interleukin-2 receptor subunit; heart failure ID CORONARY-ARTERY-DISEASE; SUSCEPTIBILITY LOCI; T-CELLS; RECEPTOR; VARIANT AB Objective Interleukin (IL) -2 receptor subunit regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2R (sIL-2R) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2R levels. Approach and Results We measured baseline levels of sIL-2R in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2R in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2R was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5x10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31x10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs. Conclusions These results support a role for sIL-2R in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14. C1 [Durda, Peter; Jenny, Nancy Swords; Cushman, Mary; Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Cushman, Mary] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Sabourin, Jeremy; Lange, Ethan M.; Li, Jin; Valdar, William; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lange, Ethan M.; Valdar, William] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Sabourin, Jeremy; Lange, Ethan M.; Valdar, William] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Mychaleckyj, Josyf C.] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Walston, Jeremy] Johns Hopkins Univ, Dept Geriatr Med, Johns Hopkins Med Inst, Baltimore, MD USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.; Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Div Cardiol, Grp Hlth Res Inst, Seattle, WA USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. RP Tracy, RP (reprint author), Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. EM russell.tracy@med.uvm.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295]; National Institute of Neurological Disorders and Stroke; National Institute on Aging (NIA) [R01AG023629]; NHLBI; MESA investigators; NHLBI [N02-HL-64278]; US Environmental Protection Agency (EPA) [RD831697]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, AG-15928, AG-20098, AG-027058]; NIA Intramural Research Program; National Institutes of Health [HHSN268200782096C]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [UL1-TR-001079]; [UL1-TR-000040] FX The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant U01HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Multiethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, and UL1-TR-000040. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. This publication was developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the US Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. The Health ABC Study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106 and, in part, by the NIA Intramural Research Program. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). The research reported in this article was supported through AG-15928, AG-20098, and AG-027058 from the NIA. NR 25 TC 4 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2015 VL 35 IS 10 BP 2246 EP 2253 DI 10.1161/ATVBAHA.115.305289 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CR8NL UT WOS:000361610700022 PM 26293465 ER PT J AU Coyne, SP Lindell, SG Clemente, J Barr, CS Parker, KJ Maestripieri, D AF Coyne, Sean P. Lindell, Stephen G. Clemente, Jessica Barr, Christina S. Parker, Karen J. Maestripieri, Dario TI Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE DRD4; Rhesus macaque; Juvenile; Social behavior; Impulsivity ID NOVELTY SEEKING; GENE LOCUS; EXON-III; DRD4; COMMUNICATION; SELECTION AB A polymorphism in the dopamine receptor D4 (DRD4) gene has been associated with significant variation in behavioral impulsivity, novelty-seeking, and risk-taking in humans and other animals. Rhesus macaques are an excellent animal model for research on the genetic basis of behavior using the candidate gene approach. Little is known, however, about allelic variation in DRD4 in large free-ranging populations of rhesus macaques and how this allelic variation relates to emotion regulation and behavior. In this study, we genotyped for the DRD4 polymorphism 178 individuals of different age and sex categories in the free-ranging rhesus macaque population on the island of Cayo Santiago, PR. Moreover, we examined the possible association between DRD4 allelic variation and three measures of juvenile behavior (time spent in proximity to the mother, avoidance of other individuals, and behavioral restlessness). Five different DRD4 alleles (5R, 5.5R, 6R, 6.5R, and 7R) were identified in the subject population. The most common allele was the 5R allele (78.5%), followed by the 7R allele (16.1%). Juveniles carrying the long form of the DRD4 allele (7R) spent less time in proximity to their mothers, avoided other individuals more often, and scored higher on behavioral restlessness than juveniles carrying the shorter alleles. Behavioral restlessness was also influenced by maternal DRD4 genotype. These results highlight both similarities and differences in the relative occurrence of DRD4 alleles and their association with behavior in this rhesus macaque population, other nonhuman primate species or populations, and humans. (C) 2015 Elsevier B.V. All rights reserved. C1 [Coyne, Sean P.; Maestripieri, Dario] Univ Chicago, Inst Mind & Biol, Chicago, IL 60637 USA. [Coyne, Sean P.; Maestripieri, Dario] Univ Chicago, Dept Comparat Human Dev, Chicago, IL 60637 USA. [Lindell, Stephen G.; Clemente, Jessica; Barr, Christina S.] NIAAA, Sect Comparat Behav Genom, NIH, Bethesda, MD 20892 USA. [Parker, Karen J.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Coyne, SP (reprint author), Univ Chicago, Inst Mind & Biol, 940 E 57th St, Chicago, IL 60637 USA. EM spcoyne@uchicago.edu; lindells@mail.nih.gov; jgclemente@mix.wvu.edu; cbarr@mail.nih.gov; kjparker@stanford.edu; dario@uchicago.edu FU NIH [R01-HD067175]; Hinds Fund of the University of Chicago; National Center for Research Resources (NCRR) [P40-OD012217-25]; Office of Research Infrastructure Programs of the NIH FX We would like to thank Christine Fleener, Aneila Hogan, and Michelle Evans for help in the field, John Addicott and James Higham for creating the Access database and queries, and the Caribbean Primate Research Center staff for logistical assistance. We are also grateful to Alex Georgiev and Tara Mandalaywala for thoughtful discussion of analyses. This research was supported by NIH grant R01-HD067175 to D. Maestripieri and K. J. Parker, the Hinds Fund of the University of Chicago to S.P. Coyne, and grant P40-OD012217-25 from the National Center for Research Resources (NCRR) and the Office of Research Infrastructure Programs of the NIH to the Caribbean Primate Research Center of the University of Puerto Rico. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. NR 23 TC 3 Z9 3 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD OCT 1 PY 2015 VL 292 BP 50 EP 55 DI 10.1016/j.bbr.2015.06.014 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CR8EI UT WOS:000361583500007 PM 26073765 ER PT J AU Katayama, K Kapoor, K Ohnuma, S Patel, A Swaim, W Ambudkar, IS Ambudkar, SV AF Katayama, Kazuhiro Kapoor, Khyati Ohnuma, Shinobu Patel, Atish Swaim, William Ambudkar, Indu S. Ambudkar, Suresh V. TI Revealing the fate of cell surface human P-glycoprotein (ABCB1): The lysosomal degradation pathway SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE P-glycoprotein; Endosome; Degradation; Half-life; Proteasome; Lysosome ID ACUTE MYELOID-LEUKEMIA; MDR1 GENE-EXPRESSION; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; MEMBRANE-GLYCOPROTEINS; SIMULTANEOUS BINDING; IN-VITRO; TRANSPORTERS; CANCER; GLYCOSYLATION AB P-glycoprotein (P-gp) transports a variety of chemically dissimilar amphipathic compounds including anticancer drugs. Although mechanisms of P-gp drug transport are widely studied, the pathways involving its internalization are poorly understood. The present study is aimed at elucidating the pathways involved in degradation of cell surface P-gp. The fate of P-gp at the cell surface was determined by biotinylating cell surface proteins followed by flow cytometry and Western blotting. Our data shows that the half-life of endogenously expressed P-gp is 26.7 +/- 1.1 h in human colorectal cancer HCT-15 cells. Treatment of cells with Bafilomycin A1 (BafA1) a vacuolar ATPase inhibitor increased the half-life of P-gp at the cell surface to 36.1 +/- 0.5 h. Interestingly, treatment with the proteasomal inhibitors MG132, MG115 or lactacystin alone did not alter the-half-life of the protein. When cells were treated with both lysosomal and proteasomal inhibitors (BafA1 and MG132), the half-life was further prolonged to 39-50 h. Functional assays done with rhodamine 123 or cakein-AM, fluorescent substrates of P-gp, indicated that the transport function of P-gp was not affected by either biotinylation or treatment with BafA1 or proteasomal inhibitors. Immunofluorescence studies done with the antibody against lysosomal marker LAMP1 and the P-gp-specific antibody UIC2 in permeabilized cells indicated that intracellular P-gp is primarily localized in the lysosomal compartment Our results suggest that the lysosomal degradation system could be targeted to increase the sensitivity of P-gp- expressing cancer cells towards chemotherapeutic drugs. Published by Elsevier B.V. C1 [Katayama, Kazuhiro; Kapoor, Khyati; Ohnuma, Shinobu; Patel, Atish; Ambudkar, Suresh V.] NCI, Ctr Canc Res, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Swaim, William; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Ctr Canc Res, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and National Institute of Dental and Craniofacial Research FX We thank Dr. Hwei Ling Ong for the help with confocal microscopy experiments and George Leiman for the editorial assistance. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and National Institute of Dental and Craniofacial Research. NR 46 TC 2 Z9 3 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD OCT PY 2015 VL 1853 IS 10 BP 2361 EP 2370 DI 10.1016/j.bbamcr.2015.06.001 PN A PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS0TM UT WOS:000361775100016 PM 26057472 ER PT J AU Nuche-Berenguer, B Jensen, RT AF Nuche-Berenguer, Bernardo Jensen, R. T. TI Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE PAK2 activation; Pancreatic acini; CCK; Signaling; Pancreatic growth factor; PKC ID STIMULATED TYROSINE PHOSPHORYLATION; EPITHELIAL-MESENCHYMAL TRANSITION; SIGNAL-REGULATED KINASE; C-DEPENDENT MECHANISM; FOCAL ADHESION KINASE; SMOOTH-MUSCLE-CELLS; SRC FAMILY KINASE; P21-ACTIVATED KINASE; CANCER CELLS; GLUCOSE-HOMEOSTASIS AB P-21-activated kinases (PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I (PAK1-3)/group-II (PAK4-6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI-hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors [EGF, PDGF, bFGF], by secretagogues activating phospholipase-C (PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC [TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors (wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAR, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAIC2 via small GTPases (CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC- and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show that PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis. (C) 2015 Published by Elsevier B.V. C1 [Nuche-Berenguer, Bernardo; Jensen, R. T.] NIDDK, NIH, DDB, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU Intramural Research Program of the NIDDK, NIH [Zoi DK053100-20, DK053101-19] FX This work is partially supported by the Intramural Research Program of the NIDDK, NIH (Zoi DK053100-20, DK053101-19). NR 114 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD OCT PY 2015 VL 1853 IS 10 BP 2371 EP 2382 DI 10.1016/j.bbamcr.2015.05.011 PN A PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS0TM UT WOS:000361775100017 PM 25979836 ER PT J AU de Souza, LB Ong, HL Liu, XB Ambudkar, IS AF de Souza, Lorena Brito Ong, Hwei Ling Liu, Xibao Ambudkar, Indu S. TI Fast endocytic recycling determines TRPC1-STIM1 clustering in ER-PM junctions and plasma membrane function of the channel SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE TRPC1; Orai1; STIM1; Store-operated calcium entry; Endocytic recycling; Surface expression ID STROMAL INTERACTION MOLECULE-1; OPERATED CALCIUM-CHANNELS; CAPACITATIVE CA2+ ENTRY; ACTIVATES CRAC CHANNELS; SALIVARY-GLAND CELLS; TRPC CHANNELS; STORE DEPLETION; STIM1; ORAI1; RELEASE AB Stromal interaction molecule 1 (STIM1) senses depletion of ER-Ca2+ store and clusters in ER-PM junctions where it associates with and gates Ca2+ influx channels, Orai1 and TRPC1. Clustering of TRPC1 with STIM1 and Orai1 in these junctions is critical since Orai1-mediated Ca2+ entry triggers surface expression of TRPC1 while STIM1 gates the channel. Thus, plasma membrane function of TRPC1 depends on the delivery of the channel to the sites where STIM1 puncta are formed. This study examines intracellular trafficking mechanism(s) that determine plasma membrane expression and function of TRPC1 in cells where Orai1 and TRPC1 are endogenously expressed and contribute to Ca2+ entry. We report that TRPC1 is internalized by Arf6-dependent pathway, sorted to Rab5-containing early endosomes, and trafficked to ER-PM junctions by Rab4-dependent fast recycling. Overexpression of Arf6, or Rab5, but not the respective dominant negative mutants, induced retention of TRPC1 in early endosomes and suppressed TRPC1 function. Notably, cells expressing Arf6 or Rab5 displayed an inwardly rectifying I-CRAC current that is mediated by Orai1 instead of TRPC1-associated I-SOC, demonstrating that Orai1 function was not altered. Importantly, expression of Rab4, but not STIM1, with Rab5 rescued surface expression and function of TRPC1, restoring generation of I-SOC. Together, these data demonstrate that trafficking via fast recycling endosomes determines TRPC1-STIM1 clustering within ER-PM junctions following ER-Ca2+ store depletion which is critical for the surface expression and function of the channel. Ca2+ influx mediated by TRPC1 modifies Ca2+-dependent physiological response of cells. Published by Elsevier B.V. C1 [de Souza, Lorena Brito; Ong, Hwei Ling; Liu, Xibao; Ambudkar, Indu S.] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, NIH, Bldg 10,Room 1N-113, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov RI Brito de Souza, Lorena/N-3385-2014 OI Brito de Souza, Lorena/0000-0002-2462-6759 FU NIDCR-DIR FX We would like to thank Julie Donaldson (NHLBI, NIH, Bethesda, MD, USA), Robert Lodge (Universite Laval, Quebec City, Canada), Tamas Balla (NICHD, NIH, Bethesda, MD, USA) and Richard Lewis (Stanford University, Stanford, CA, USA) for kindly sharing constructs that were used in this study. We also acknowledge funding from the NIDCR-DIR for ISA. NR 55 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD OCT PY 2015 VL 1853 IS 10 BP 2709 EP 2721 DI 10.1016/j.bbamcr.2015.07.019 PN A PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS0TM UT WOS:000361775100047 PM 26232624 ER PT J AU Yoon, JH Kim, J Gorospe, M AF Yoon, Je-Hyun Kim, Jiyoung Gorospe, Myriam TI Long noncoding RNA turnover SO BIOCHIMIE LA English DT Review DE Ribonucleoprotein complex; RNA-binding protein; Long noncoding RNA ID CIRCULAR RNAS; TRIPLE-HELIX; TUMOR-SUPPRESSOR; HUMAN GENOME; PROTEIN HUR; HUMAN-CELLS; DECAY; TARGET; MICRORNAS; STABILITY AB Most RNAs transcribed in mammalian cells lack protein-coding sequences. Among them is a vast family of long (>200 nt) noncoding (lnc)RNAs. LncRNAs can modulate cellular protein expression patterns by influencing the transcription of many genes, the post-transcriptional fate of mRNAs and ncRNAs, and the turnover and localization of proteins. Given the broad impact of lncRNAs on gene regulation, there is escalating interest in elucidating the mechanisms that govern the steady-state levels of lncRNAs. In this review, we summarize our current knowledge of the factors and methanisms that modulate mammalian lncRNA stability. (C) Published by Elsevier B.V. C1 [Yoon, Je-Hyun; Kim, Jiyoung; Gorospe, Myriam] NIA, LG, IRP, NIH, Baltimore, MD 21224 USA. RP Yoon, JH (reprint author), NIA, LG, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yoonjehyun@gmail.com; myriam-gorospe@nih.gov FU National Institute on Aging Intramural Research Program, National Institutes of Health FX JHY, JK, and MG were supported by the National Institute on Aging Intramural Research Program, National Institutes of Health. NR 77 TC 9 Z9 9 U1 5 U2 25 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 EI 1638-6183 J9 BIOCHIMIE JI Biochimie PD OCT PY 2015 VL 117 BP 15 EP 21 DI 10.1016/j.biochi.2015.03.001 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS1YN UT WOS:000361864900003 PM 25769416 ER PT J AU Urbano-Ispizua, A Pavletic, SZ Flowers, ME Klein, JP Zhang, MJ Carreras, J Montoto, S Perales, MA Aljurf, MD Akpek, G Bredeson, CN Costa, LJ Dandoy, C Freytes, CO Fung, HC Gale, RP Gibson, J Hamadani, M Hayashi, RJ Inamoto, Y Inwards, DJ Lazarus, HM Maloney, DG Martino, R Munker, R Nishihori, T Olsson, RF Rizzieri, DA Reshef, R Saad, A Savani, BN Schouten, HC Smith, SM Socie, G Wirk, B Yu, LC Saber, W AF Urbano-Ispizua, Alvaro Pavletic, Steven Z. Flowers, Mary E. Klein, John P. Zhang, Mei-Jie Carreras, Jeanette Montoto, Silvia Perales, Miguel-Angel Aljurf, Mahmoud D. Akpek, Goerguen Bredeson, Christopher N. Costa, Luciano J. Dandoy, Christopher Freytes, Cesar O. Fung, Henry C. Gale, Robert Peter Gibson, John Hamadani, Mehdi Hayashi, Robert J. Inamoto, Yoshihiro Inwards, David J. Lazarus, Hillard M. Maloney, David G. Martino, Rodrigo Munker, Reinhold Nishihori, Taiga Olsson, Richard F. Rizzieri, David A. Reshef, Ran Saad, Ayman Savani, Bipin N. Schouten, Harry C. Smith, Sonali M. Socie, Gerard Wirk, Baldeep Yu, Lolie C. Saber, Wael TI The Impact of Graft-versus-Host Disease on the Relapse Rate in Patients with Lymphoma Depends on the Histological Subtype and the Intensity of the Conditioning Regimen SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Graft-versus-host disease; Lymphoma ID STEM-CELL TRANSPLANTATION; BONE-MARROW TRANSPLANT; NON-HODGKIN-LYMPHOMA; ALLOGENEIC TRANSPLANTATION; FOLLICULAR LYMPHOMA; AUTOLOGOUS TRANSPLANTATION; EUROPEAN GROUP; BLOOD; INFUSIONS; REMISSIONS AB The purpose of this study was to analyze the impact of graft-versus-host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients with a diagnosis of Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma (FL), peripheral T cell lymphoma, or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor hematopoietic cell transplantation between 1997 and 2009 were included. Two thousand six hundred eleven cases were included. A reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplantations. In a multivariate analysis of myeloablative cases (n = 970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n = 1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (risk ratio [RR],.51; P = 3.049) and in MCL (RR,.41; P = .019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR,.14; P = .007; and RR,.15; P = .0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment-related mortality and overall survival (OS) in FL cases but did not affect treatment-related mortality, OS or PFS in MCL. This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Urbano-Ispizua, Alvaro] Univ Barcelona, Hosp Clin, IDIBAPS, Dept Hematol, Barcelona, Spain. [Urbano-Ispizua, Alvaro] Inst Res Josep Carreras, Barcelona, Spain. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Flowers, Mary E.; Inamoto, Yoshihiro; Maloney, David G.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Klein, John P.; Zhang, Mei-Jie; Carreras, Jeanette; Hamadani, Mehdi; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Klein, John P.; Zhang, Mei-Jie] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Montoto, Silvia] Barts Hlth NHS Trust, St Bartholomews Hosp, Dept Haematooncol, London, England. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplant Serv, New York, NY 10021 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Hematol Oncol Sect, Gilbert, AZ USA. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher N.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Costa, Luciano J.; Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Dandoy, Christopher] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fung, Henry C.] Temple Hlth, Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Gibson, John] Royal Prince Alfred Hosp, Inst Haematol, Camperdown, NSW 2050, Australia. [Hayashi, Robert J.] Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Inwards, David J.] Mayo Clin, Div Hematol, Rochester, MN USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Martino, Rodrigo] Hosp Santa Creu & Sant Pau, Div Hematol, Barcelona, Spain. [Munker, Reinhold] Louisiana State Univ Hlth, Dept Internal Med, Div Hematol Oncol, Shreveport, LA USA. [Nishihori, Taiga] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Med Oncol, Tampa, FL 33612 USA. [Olsson, Richard F.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Rizzieri, David A.] Duke Univ, Div Hematol Malignancies & Cellular Therapy, Durham, NC USA. [Reshef, Ran] Univ Penn, Dept Med, Abramson Canc Ctr, Med Ctr, Philadelphia, PA 19104 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Schouten, Harry C.] Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands. [Smith, Sonali M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Socie, Gerard] Hop St Louis, Dept Hematol, Paris, France. [Wirk, Baldeep] SUNY Stony Brook, Med Ctr, Dept Internal Med, Stony Brook, NY 11794 USA. [Yu, Lolie C.] Louisiana State Univ, Med Ctr, Childrens Hosp, Div Hematol Oncol,Ctr Canc & Blood Disorders, New Orleans, LA USA. RP Urbano-Ispizua, A (reprint author), Hosp Clin Barcelona, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain. EM aurbano@clinic.ub.es OI Saad, Ayman /0000-0003-0003-0130 FU National Cancer Institute [U24-CA076518]; National Heart, Lung, and Blood Institute [5U10HL069294]; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; grant/cooperative agreement 5U10HL069294 from the National Heart, Lung, and Blood Institute and National Cancer Institute; contract HHSH250201200016C with Health Resources and Services Administration; 2 grants from the Office of Naval Research (N00014-12-1-0142 and N00014-13-1-0039); and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen; an anonymous donation to the Medical College of Wisconsin; Ariad; Be The Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; Histo-Genetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; 'Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Therakos; University of Minnesota; University of Utah; and *WellPoint. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. NR 27 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1746 EP 1753 DI 10.1016/j.bbmt.2015.05.010 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100009 PM 25981509 ER PT J AU Verneris, MR Lee, SJ Ahn, KW Wang, HL Battiwalla, M Inamoto, Y Fernandez-Vina, MA Gajewski, J Pidala, J Munker, R Aljurf, M Saber, W Spellman, S Koreth, J AF Verneris, Michael R. Lee, Stephanie J. Ahn, Kwang Woo Wang, Hai-Lin Battiwalla, Minoo Inamoto, Yoshihiro Fernandez-Vina, Marcelo A. Gajewski, James Pidala, Joseph Munker, Reinhold Aljurf, Mahmoud Saber, Wael Spellman, Stephen Koreth, John TI HLA Mismatch Is Associated with Worse Outcomes after Unrelated Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation: An Analysis from the Center for International Blood and Marrow Transplant Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Bone marrow transplantation; Leukemia; Hematologic malignancies; Pediatric oncology ID CLASS-I; CLINICAL-SIGNIFICANCE; HLA-DPB1; GRAFT; SURVIVAL; RECIPIENTS; LEUKEMIA; REGISTRY; IMPACT AB Over the past 2 decades, reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC HCT) has increased substantially. Many patients do not have fully HLA-matched donors, and the impact of HLA mismatch on RIC HCT has not been examined in large cohorts. We analyzed 2588 recipients of 8/8 HLA-high resolution matched (n = 2025) or single-locus mismatched (n = 563) unrelated donor (URD) RIC HCT from 1999 to 2011. Overall survival (OS) was the primary outcome. Secondary endpoints included treatment-related mortality (TRM), relapse, disease-free survival (DFS), and acute/chronic graft-versus-host disease (GVHD). Adjusted 1- and 3-year OS was better in 8/8- versus 7/8-matched recipients (54.7% versus 48.8%, P = .01, and 37.4% versus 30.9%, P = .005, respectively). In multivariate models 7/8 URD RIC HCT recipients had more grades II to IV acute GVHD (RR = 1.29, P = .0034), higher TRM (RR = 1.52, P < .0001), and lower DFS (RR = 1.12, P = .0015) and OS (RR = 1.25, P = .0001), with no difference in relapse or chronic GVHD. In subgroup analysis, inferior transplant outcomes were noted regardless of the HLA allele mismatched. Previously reported permissive mismatches at HLA-C (C*03:03/C*03:04) and HLA-DPI (based on T cell epitope matching) were not associated with better outcomes. Although feasible, single-locus mismatch in RIC URD HCT is associated with inferior outcomes. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Verneris, Michael R.] Univ Minnesota, Dept Pediat BMT, Minneapolis, MN 55455 USA. [Lee, Stephanie J.; Inamoto, Yoshihiro] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Wang, Hai-Lin; Saber, Wael] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Fernandez-Vina, Marcelo A.] Stanford Univ, Dept Pathol, Palo Alto, CA 94304 USA. [Gajewski, James] Oregon Hlth & Sci Univ, Dept Hematol, Portland, OR 97201 USA. [Pidala, Joseph] Univ S Florida, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Munker, Reinhold] Louisiana State Univ, Hlth Sci Ctr, Dept Hematol Oncol, Shreveport, LA 71105 USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp & Res Ctr, Pediat HSCT, Adult HSCT, Riyadh 11211, Saudi Arabia. [Spellman, Stephen] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Koreth, John] Dana Farber Canc Inst, Dept Hematol Oncol, Boston, MA 02115 USA. RP Verneris, MR (reprint author), Univ Minnesota, Dept Pediat BMT, 425 E River Rd,CCRB 654, Minneapolis, MN 55455 USA. EM verneris@umn.edu OI Verneris, Michael/0000-0002-7097-5917 FU NCI NIH HHS [U24 CA076518]; NHLBI NIH HHS [U01 HL069294] NR 26 TC 10 Z9 11 U1 4 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1783 EP 1789 DI 10.1016/j.bbmt.2015.05.028 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100014 PM 26055300 ER PT J AU Ayas, M Eapen, M Le-Rademacher, J Carreras, J Abdel-Azim, H Alter, BP Anderlini, P Battiwalla, M Bierings, M Buchbinder, DK Bonfim, C Camitta, BM Fasth, AL Gale, RP Lee, MA Lund, TC Myers, KC Olsson, RF Page, KM Prestidge, TD Radhi, M Shah, AJ Schultz, KR Wirk, B Wagner, JE Deeg, HJ AF Ayas, Mouhab Eapen, Mary Le-Rademacher, Jennifer Carreras, Jeanette Abdel-Azim, Hisham Alter, Blanche P. Anderlini, Paolo Battiwalla, Minoo Bierings, Marc Buchbinder, David K. Bonfim, Carmem Camitta, Bruce M. Fasth, Anders L. Gale, Robert Peter Lee, Michelle A. Lund, Troy C. Myers, Kasiani C. Olsson, Richard F. Page, Kristin M. Prestidge, Tim D. Radhi, Mohamed Shah, Ami J. Schultz, Kirk R. Wirk, Baldeep Wagner, John E. Deeg, H. Joachim TI Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Fanconi anemia; Graft failure; Second transplantation ID LOW-DOSE CYCLOPHOSPHAMIDE; SIBLING DONOR; ANTITHYMOCYTE GLOBULIN; CONDITIONING REGIMENS; STEM-CELLS; FLUDARABINE; EXPERIENCE; RADIATION; GRAFT; IRRADIATION AB A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Ayas, Mouhab] King Faisal Specialist Hosp & Res Ctr, Dept Pediat Hematol Oncol, Riyadh 11211, Saudi Arabia. [Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Le-Rademacher, Jennifer] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Abdel-Azim, Hisham] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bierings, Marc] Univ Med Ctr Utrecht, Dept Pediat Hematol, Utrecht, Netherlands. [Buchbinder, David K.] Childrens Hosp Orange Cty, Div Pediat Hematol, Orange, CA 92668 USA. [Bonfim, Carmem] Univ Fed Parana, Hosp Clin, BR-80060000 Curitiba, Parana, Brazil. [Camitta, Bruce M.] Med Coll Wisconsin, Midwest Ctr Canc & Blood Disorders, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Fasth, Anders L.] Univ Gothenburg, Dept Pediat, Gothenburg, Sweden. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Hematol Res Ctr, Div Expt Med, Dept Med, London, England. [Lee, Michelle A.] Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Boston, MA USA. [Lund, Troy C.; Wagner, John E.] Univ Minnesota, Dept Pediat, Med Ctr, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Myers, Kasiani C.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Bone Marrow Transplant & Immune Deficiency, Cincinnati, OH 45229 USA. [Olsson, Richard F.] Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Page, Kristin M.] Duke Univ, Med Ctr, Pediat Blood & Marrow Transplant, Durham, NC USA. [Prestidge, Tim D.] Starship Childrens Hosp, Blood & Canc Ctr, Auckland, New Zealand. [Radhi, Mohamed] Childrens Mercy Hosp, Pediat Hematol Oncol Stem Cell Transplantat, Kansas City, MO 64108 USA. [Shah, Ami J.] Univ Calif Los Angeles, Dept Pediat, Mattel Childrens Hosp, Div Hematol Oncol, Los Angeles, CA 90024 USA. [Schultz, Kirk R.] Univ British Columbia, British Columbias Childrens Hosp, Dept Pediat Hematol Oncol & Bone Marrow Transplan, Vancouver, BC V5Z 1M9, Canada. [Wirk, Baldeep] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Deeg, H. Joachim] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RP Ayas, M (reprint author), King Faisal Specialist Hosp & Res Ctr, MBC 53,POB 3354, Riyadh 11211, Saudi Arabia. FU Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI), NHLBI [U24-CA076518]; National Institute of Allergy and Infectious Diseases; NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc; Amgen FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), NHLBI, and National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; Contract HHSH250201200016C with the Health Resources and Services Administration; Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Actinium Pharmaceuticals*; Allos Therapeutics, Inc; Amgen*; Anonymous donation to the Medical College of Wisconsin; Ariad; Be The Match Foundation; Blue Cross and Blue Shield Association*; Celgene*; Chimerix, Inc; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc; Gamida Cell Teva Joint Venture Ltd*; Genentech; Gentium SpA*; Genzyme; GlaxoSmithKline; Health Research, Inc, Roswell Park Cancer Institute; Histo-Genetics; Incyte Corp; Jeff Gordon Children's Foundation; Kiadis Pharma; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co; Milliman USA, Inc*; Miltenyi Biotec*; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc; PerkinElmer, Inc; Remedy Informatics*; Sanofi US*; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc; St. Baldrick's Foundation; StemCyte, a Global Cord Blood Therapeutics Co; Stemsoft Software, Inc; Swedish Orphan Biovitrum; Tarix Pharmaceuticals*; Terumo BCT*; Teva Neuroscience, Inc*; Therakos*; University of Minnesota; University of Utah; and WellPoint*. The views expressed in this article do not reflect the official policy or position of the NIH, the Department of the Navy, the Department of Defense, the Health Resources and Services Administration, or any other agency of the US Government. This research was supported in part by the Intramural Research Program of the NIH and the NCI (B.A.). NR 30 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1790 EP 1795 DI 10.1016/j.bbmt.2015.06.012 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100015 PM 26116087 ER PT J AU Khan, NE Rosenberg, PS Lehmann, HP Alter, BR AF Khan, Nicholas E. Rosenberg, Philip S. Lehmann, Harold P. Alter, Blanche R. TI Preemptive Bone Marrow Transplantation for FANCD1/BRCA2 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Preemptive transplantation; Fanconi anemia; BRCA2; Markov model; Decision analysis ID HEMATOPOIETIC-CELL TRANSPLANTATION; QUALITY-OF-LIFE; FANCONI-ANEMIA; MYELODYSPLASTIC SYNDROME; ACUTE-LEUKEMIA; BRCA2; RISK; FAILURE; CANCER; IRRADIATION AB Children with biallelic mutations in FANCD1/BRCA2 are at uniquely high risks of leukemia and solid tumors. Preemptive bone marrow transplantation (PE-BMT) has been proposed to avoid the development of leukemia, but empirical study of PE-BMT is unlikely because of the rarity of these children and the unknown benefit of PE-BMT. We used survival analysis to estimate the risks of leukemia and the expected survival if leukemia could be eliminated by curative PE-BMT. We used the results in a decision analysis model to explore the plausibility of PE-BMT for children with variable ages at diagnosis and risks of transplantation-related mortality. For example, PE-BMT at 1 year of age with a 10% risk of transplantation-related mortality increased the mean survival by 1.7 years. The greatest benefit was for patients diagnosed between 1 and 3 years of age, after which the benefit of PE-BMT decreased with age at diagnosis, and the risk of death froth solid tumors constituted a relatively greater burden of mortality. Our methods may be used to model survival for other hematologic disorders with limited empirical data and a pressing need for clinical guidance. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Khan, Nicholas E.; Alter, Blanche R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lehmann, Harold P.] Johns Hopkins Sch Med, Hlth Sci Informat, Baltimore, MD USA. RP Alter, BR (reprint author), 9609 Med Ctr Dr,Room 6E452, Rockville, MD 20850 USA. EM alterb@mail.nih.gov FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 33 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1796 EP 1801 DI 10.1016/j.bbmt.2015.07.006 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100016 PM 26183081 ER PT J AU Shaw, BE Logan, BR Kiefer, DM Chitphakdithai, P Pedersen, TL Abdel-Azim, H Abidi, MH Akpek, G Diaz, MA Artz, AS Dandoy, C Gajewski, JL Hematti, P Kamble, RT Kasow, KA Lazarus, HM Liesveld, JL Majhail, NS O'Donne, PV Olsson, RF Savani, BN Schears, RM Stroncek, DF Switzer, GE Williams, EP Wingard, JR Wirk, BM Confer, DL Pulsipher, MA AF Shaw, Bronwen E. Logan, Brent R. Kiefer, Deidre M. Chitphakdithai, Pintip Pedersen, Tanya L. Abdel-Azim, Hisham Abidi, Muneer H. Akpek, Gorgun Diaz, Miguel A. Artz, Andrew S. Dandoy, Christopher Gajewski, James L. Hematti, Peiman Kamble, Rammurti T. Kasow, Kimberley A. Lazarus, Hillard M. Liesveld, Jane L. Majhail, Navneet S. O'Donne, Paul V. Olsson, Richard F. Savani, Bipin N. Schears, Raquel M. Stroncek, David F. Switzer, Galen E. Williams, Eric P. Wingard, John R. Wirk, Baldeep M. Confer, Dennis L. Pulsipher, Michael A. TI Analysis of the Effect of Race, Socioeconomic Status, and Center Size on Unrelated National Marrow Donor Program Donor Outcomes: Donor Toxicities Are More Common at Low-Volume Bone Marrow Collection Centers SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Race; Socioeconomic status; Donor center; Unrelated donor; Donor toxicities; Bone marrow; PBSC ID BLOOD STEM-CELLS; ADVERSE EVENTS; PROSPECTIVE TRIAL; AUTOLOGOUS BLOOD; EXPERIENCE; DONATION; APHERESIS; RECOVERY; QUALITY; HARVEST AB Previous studies have shown that risks of collection-related pain and symptoms are associated with sex, body mass index, and age in unrelated donors undergoing collection at National Marrow Donor Program centers. We hypothesized that other important factors (race, socioeconomic status [SES], and number of procedures at the collection center) might affect symptoms in donors. We assessed outcomes in 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors collected between 2004 and 2009. Pain/symptoms are reported as maximum levels over mobilization and collection (PBSC) or within 2 days of collection (BM) and at 1 week after collection. For PBSC donors, race and center volumes were not associated with differences in pain/symptoms at any time. PBSC donors with high SES levels reported higher maximum symptom levels 1 week after donation (P = .017). For BM donors, black males reported significantly higher levels of pain (OR, 1.90; CI, 1.14 to 3.19; P = .015). No differences were noted by SES group. BM donors from low-volume centers reported more toxicity (OR, 2.09; CI, 1.26 to 3.46; P = .006). In conclusion, race and SES have a minimal effect on donation-associated symptoms. However, donors from centers performing <= 1 BM collection every 2 months have more symptoms after BM donation. Approaches should be developed by registries and low-volume centers to address this issue. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Shaw, Bronwen E.; Logan, Brent R.] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Logan, Brent R.; Kiefer, Deidre M.; Chitphakdithai, Pintip] CIBMTR, Natl Marrow Donor Program Be Match, Minneapolis, MN USA. [Pedersen, Tanya L.] Allina Hlth, Minneapolis, MN USA. [Abdel-Azim, Hisham] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA. [Abidi, Muneer H.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Div BMT, Detroit, MI USA. [Akpek, Gorgun] Banner MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy Program, Gilbert, AZ USA. [Diaz, Miguel A.] Hosp Infantil Univ Nino Jesus, Dept Hematol Oncol, Madrid, Spain. [Dandoy, Christopher] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Dandoy, Christopher] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Gajewski, James L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Hematti, Peiman] Univ Wisconsin Hosp & Clin, Div Hematol Oncol Bone Marrow Transplantat, Madison, WI 53792 USA. [Kamble, Rammurti T.] Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA. [Kasow, Kimberley A.] Univ N Carolina, Dept Pediat, Div Hematol Oncol, Chapel Hill, NC USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Liesveld, Jane L.] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Majhail, Navneet S.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [O'Donne, Paul V.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Olsson, Richard F.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Schears, Raquel M.] Mayo Clin, Rochester, MN USA. [Stroncek, David F.] NIH, Dept Transfus Med, Clin Ctr, Bethesda, MD 20892 USA. [Switzer, Galen E.] Univ Pittsburgh, Pittsburgh, PA USA. [Williams, Eric P.; Confer, Dennis L.] BeTheMatch Natl Marrow Donor Program, Minneapolis, MN USA. [Wingard, John R.] Univ Florida, Dept Med, Div Hematol & Oncol, Gainesville, FL USA. [Wirk, Baldeep M.] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Pulsipher, Michael A.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA. RP Shaw, BE (reprint author), CIBMTR Froedtert, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM bshaw@doctors.org.uk OI Abidi, Muneer/0000-0002-9936-6031 FU Public Health Service from the National Cancer Institute (NCI) [5U24-CA076518]; National Heart, Lung and Blood Institute (NHLBI) [5U10HL069294, R01 HL085707]; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U10HL069294 from the NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration; 2 grants (N00014-13-1-0039 and N00014-14-1-0028) from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; *Gilead Sciences, Inc.; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; *Mesoblast; *Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; *Strakan, Inc.; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. Asterisk (*) denotes corporate members. Dr. M. A. Pulsipher's contribution to this work is supported by R01 HL085707 from the NHLBI. NR 25 TC 2 Z9 2 U1 5 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1830 EP 1838 DI 10.1016/j.bbmt.2015.06.013 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100021 PM 26116089 ER PT J AU Raffa, D Maggio, B Plescia, F Cascioferro, S Raimondi, MV Cancemi, G D'Anneo, A Lauricella, M Cusimano, MG Bai, R Hamel, E Daidone, G AF Raffa, Demetrio Maggio, Benedetta Plescia, Fabiana Cascioferro, Stella Raimondi, Maria Valeria Cancemi, Gabriella D'Anneo, Antonella Lauricella, Marianna Cusimano, Maria Grazia Bai, Ruoli Hamel, Ernest Daidone, Giuseppe TI Synthesis, antiproliferative activity and possible mechanism of action of novel 2-acetamidobenzamides bearing the 2-phenoxy functionality SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 2-(2-Phenoxyacetamido)benzamides; Antiproliferative activity; G0/G1 arrest; Apoptosis; Pro-caspase 3 ID BIOLOGICAL EVALUATION; INHIBITORS; CELLS; CANCER; IDENTIFICATION; PARTHENOLIDE; DISCOVERY; AMIDES AB Several new 2-(2-phenoxyacetamido) benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R-1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Raffa, Demetrio; Maggio, Benedetta; Plescia, Fabiana; Cascioferro, Stella; Raimondi, Maria Valeria; Cancemi, Gabriella; Cusimano, Maria Grazia; Daidone, Giuseppe] Dipartimento Sci & Tecnol Biol Chim & Farmaceut, I-90123 Palermo, Italy. [D'Anneo, Antonella] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol, Biochem Lab, I-90123 Palermo, Italy. [Lauricella, Marianna] Univ Palermo, Dept Expt Biomed & Clin Neurosci, Biochem Lab, I-90123 Palermo, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Raffa, D (reprint author), Dipartimento Sci & Tecnol Biol Chim & Farmaceut, Via Archirafi 32, I-90123 Palermo, Italy. EM demetrio.raffa@unipa.it; benedetta.maggio@unipa.it OI Daidone, Giuseppe/0000-0002-9529-8449; D'ANNEO, Antonella/0000-0002-1785-8236 FU Fondo di Finanziamento della Ricerca di Ateneo FX Financial support from 'Fondo di Finanziamento della Ricerca di Ateneo (ex 60%)' is gratefully acknowledged. The authors wish to thank the Developmental Therapeutics Program of the National Cancer Institute of the United States of America for performing the antiproliferative screening of compounds. NR 32 TC 4 Z9 4 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 1 PY 2015 VL 23 IS 19 BP 6305 EP 6316 DI 10.1016/j.bmc.2015.08.027 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CR8XT UT WOS:000361638400008 PM 26344588 ER PT J AU Redwine, KM James, LP O'Riordan, M Sullivan, JE Blumer, JL AF Redwine, Karen M. James, Laura P. O'Riordan, MaryAnn Sullivan, Janice E. Blumer, Jeffrey L. CA Network Pediat Pharmacology Res TI Accuracy of the Spacelabs 90217 ambulatory blood pressure monitor in a pediatric population SO BLOOD PRESSURE MONITORING LA English DT Article DE adolescents; ambulatory blood pressure monitoring; children; validation ID CHILDREN; VALIDATION AB BackgroundAmbulatory blood pressure monitoring techniques provide unique advantages for diagnosing hypertension, although few devices have been independently validated in the pediatric population.MethodsWe sought to validate the accuracy of ambulatory blood pressure monitoring with the Spacelabs 90217 monitor in children using a modified British Hypertension Society protocol.ResultsA total of 112 children, aged between 6 and 17 years, completed the study at one of the three participating centers. Overall, the monitor earned an A' for systolic blood pressure and B' for diastolic blood pressure. It performed slightly better among 6-12 year olds (A/A) compared with 13-17 year olds (A/B).ConclusionsWe conclude that the Spacelabs 90217 monitor is an appropriate monitor for use in children who are 6 years of age or older. C1 [Redwine, Karen M.] Univ Arkansas Med Sci, Dept Pediat, Div Pediat Nephrol, Little Rock, AR 72202 USA. [James, Laura P.] Univ Arkansas Med Sci, Dept Pediat, Sect Clin Pharmacol & Toxicol, Little Rock, AR 72202 USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [O'Riordan, MaryAnn] Case Western Reserve Univ Hosp, Dept Pediat, Div Pediat Crit Care, Cleveland, OH 44106 USA. [Blumer, Jeffrey L.] Univ Toledo, Dept Pediat, Toledo, OH 43606 USA. [Sullivan, Janice E.] Univ Louisville, Dept Pediat, Louisville, KY 40292 USA. [Sullivan, Janice E.] Univ Louisville, Dept Pharmacol Toxicol, Div Pediat Crit Care, Louisville, KY 40292 USA. [Sullivan, Janice E.] Univ Louisville, Kosair Char Pediat Clin Res Unit, Louisville, KY USA. [Network Pediat Pharmacology Res] NICHHD, Rockville, MD USA. RP Redwine, KM (reprint author), Univ Arkansas Med Sci, Dept Pediat, Div Pediat Nephrol, 1 Childrens Way,Slot 512-14, Little Rock, AR 72202 USA. EM redwinekarenm@uams.edu FU Case Western Reserve University/Cleveland Clinic CTSA Core Award [3UL1RR024989-03S2]; National Institutes of Child Health and Human Development [5U10HD031324-15, 3U10 HD 021324-15S1, 5U10 HD 031323-15, U10 HD045934, U10 HD045986]; Translational Research Institute through the NIH National Center for Research Resources [UL1TR000039, KL2TR000063]; National Center for Advancing Translational Sciences; Arkansas Children's Hospital Research Institute; Arkansas Biosciences Institute FX The project described was funded by the Case Western Reserve University/Cleveland Clinic CTSA Core Award (3UL1RR024989-03S2). The Network of Pediatric Pharmacology Research Unit was funded by the National Institutes of Child Health and Human Development (5U10HD031324-15, 3U10 HD 021324-15S1, 5U10 HD 031323-15, U10 HD045934, U10 HD045986). Dr Redwine was also supported by the Translational Research Institute, grants UL1TR000039 and KL2TR000063, through the NIH National Center for Research Resources and the National Center for Advancing Translational Sciences, as well as by the Arkansas Children's Hospital Research Institute and the Arkansas Biosciences Institute, the major research component of the Tobacco Settlement Proceeds Act of 2000. NR 9 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1359-5237 EI 1473-5725 J9 BLOOD PRESS MONIT JI Blood Press. Monit. PD OCT PY 2015 VL 20 IS 5 BP 295 EP 298 DI 10.1097/MBP.0000000000000132 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CR6SN UT WOS:000361477800012 PM 26529437 ER PT J AU DeGrazia, D Beauchamp, TL AF DeGrazia, David Beauchamp, Tom L. TI Reassessing Animal Research Ethics SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Editorial Material C1 [DeGrazia, David] NIH, Dept Bioeth, Washington, DC 20894 USA. [DeGrazia, David] George Washington Univ, Dept Philosophy, Washington, DC USA. [Beauchamp, Tom L.] Georgetown Univ, Dept Philosophy, Washington, DC USA. [Beauchamp, Tom L.] Georgetown Univ, Kennedy Inst Eth, Washington, DC 20057 USA. RP DeGrazia, D (reprint author), NIH, Dept Bioeth, Washington, DC 20894 USA. FU National Institutes of Health (NIH) Clinical Center FX DeGrazia's work on this introduction was supported, in part, by intramural funds from the National Institutes of Health (NIH) Clinical Center. The views expressed are those of the two authors. They do not represent the position or policy of the NIH Department of Bioethics, the NIH, the U.S. Public Health Service, or the Department of Health and Human Services. NR 9 TC 0 Z9 0 U1 2 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD OCT PY 2015 VL 24 IS 4 BP 385 EP 389 DI 10.1017/S0963180115000055 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA CR7YX UT WOS:000361569300002 PM 26364774 ER PT J AU DeGrazia, D Sebo, J AF DeGrazia, David Sebo, Jeff TI Necessary Conditions for Morally Responsible Animal Research SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article DE animal research; animal ethics; moral status; harm to animals; expected benefit; unnecessary harm ID EXPERIMENTATION AB In this article, we present three necessary conditions for morally responsible animal research that we believe people on both sides of this debate can accept. Specifically, we argue that, even if human beings have higher moral status than nonhuman animals, animal research is morally permissible only if it satisfies (1) an expectation of sufficient net benefit, (2) a worthwhile-life condition, and (3) a no-unnecessary-harm/qualified-basic-needs condition. We then claim that, whether or not these necessary conditions are jointly sufficient for justified animal research, they are relatively demanding, with the consequence that many animal experiments may fail to satisfy them. C1 [DeGrazia, David] NIH, Dept Bioeth, Washington, DC 20894 USA. [DeGrazia, David] George Washington Univ, Dept Philosophy, Washington, DC USA. [Sebo, Jeff] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP DeGrazia, D (reprint author), NIH, Dept Bioeth, Washington, DC 20894 USA. FU NIH Clinical Center FX We thank colleagues in the Department of Bioethics at the NIH for invaluable feedback on a draft of this article, and Joe Millum and Tom Beauchamp for detailed written comments. This work was supported, in part, by intramural funds from the NIH Clinical Center. The views expressed are our own. They do not represent the position or policy of the NIH, the Public Health Service, or the Department of Health and Human Services. NR 19 TC 1 Z9 1 U1 16 U2 28 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD OCT PY 2015 VL 24 IS 4 BP 420 EP 430 DI 10.1017/S0963180115000080 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA CR7YX UT WOS:000361569300005 PM 26364777 ER PT J AU Kantin, H Wendler, D AF Kantin, Holly Wendler, David TI Is There a Role for Assent or Dissent in Animal Research? SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article DE animals used for research; assent or dissent in animal research; respecting preferences of animal research subjects ID GREAT APES; CHIMPANZEES; ETHICS AB Current regulations and widely accepted principles for animal research focus on minimizing the burdens and harms of research on animals. However, these regulations and principles do not consider a possible role for assent or dissent in animal research. Should investigators solicit the assent or respect the dissent of animals who are used in research, and, if so, under what circumstances? In this article we pursue this question and outline the relevant issues that bear on the answer. We distinguish two general reasons for respecting the preferences of research participants regarding whether they participate in research-welfare-based reasons and agency-based reasons. We argue that there are welfare-based reasons for researchers to consider, and in some cases respect, the dissent of all animals used in research. After providing a brief account of the nature of agency-based reasons, we argue that there is good reason to think that these reasons apply to at least chimpanzees. We argue that there is an additional reason for researchers to respect the dissent-and, when possible, solicit the assent-of any animal to whom agency-based reasons apply. C1 [Kantin, Holly] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Wendler, David] NIH, Sect Res Eth, Dept Bioeth, Bethesda, MD 20892 USA. RP Kantin, H (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. FU NIH Clinical Center FX Thanks to Tom Beauchamp for detailed written comments and Rahul Nayak for helpful discussion. Special thanks to David DeGrazia for helpful feedback and detailed written comments on multiple drafts. This work was supported, in part, by intramural funds from the NIH Clinical Center. The views expressed are our own. They do not represent the position or policy of the NIH, the NIH Department of Bioethics, the Public Health Service, or the Department of Health and Human Services. NR 32 TC 0 Z9 0 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD OCT PY 2015 VL 24 IS 4 BP 459 EP 472 DI 10.1017/S0963180115000110 PG 14 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA CR7YX UT WOS:000361569300008 PM 26364780 ER PT J AU Cao, X Choi, S Maleth, JJ Park, S Ahuja, M Muallem, S AF Cao, Xu Choi, Seok Maleth, Jozsef J. Park, Seonghee Ahuja, Malini Muallem, Shmuel TI The ER/PM microdomain, PI(4,5)P-2 and the regulation of STIM1-Orai1 channel function SO CELL CALCIUM LA English DT Review DE ER/PM microdomains; Calcium signaling; Stim1; Orai1 ID MEMBRANE CONTACT SITES; FAST CA2+-DEPENDENT INACTIVATION; SEPTIN DIFFUSION BARRIER; SALIVARY-GLAND CELLS; OPERATED CA2+ ENTRY; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; POLARIZED EXPRESSION; EXTENDED SYNAPTOTAGMINS; RECEPTOR-ACTIVITY AB All forms of cell signaling occur in discreet cellular microdomains in which the ER is the main participant and include microdomains formed by the ER with lysosomes, endosomes, the nucleus, mitochondria and the plasma membrane. In the microdomains the two opposing organelles transfer and exchange constituents including lipids and ions. As is the case for other forms of signaling pathways, many components of the receptor-evoked Ca2+ signal are clustered at the ER/PM microdomain, including the Orai1-STIM1 complex. This review discusses recent advances in understanding the molecular components that tether the ER and plasma membrane to form the ER/PM microdomains in which PI(4,5)P-2 is enriched, and how dynamic targeting of the Orai1-STIM1 complex to PI(4,5)P-2-poor and PI(4,5)P-2-rich microdomains controls the activity of Orai1 and its regulation by Ca2+ that is mediated by SARAF. Published by Elsevier Ltd. C1 [Cao, Xu; Ahuja, Malini; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Choi, Seok] Chosun Univ, Coll Med, Dept Physiol, Gwangju 501375, South Korea. [Maleth, Jozsef J.] Univ Szeged, Dept Med 1, H-6725 Szeged, Hungary. [Park, Seonghee] Ewha Womans Univ, Sch Med, Dept Physiol, Seoul 158710, South Korea. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov RI Cao, Xu/G-6209-2015 OI Cao, Xu/0000-0003-1796-2735 FU NIH/NIDCR [DE000735]; National Foundation of Korea Grant - Korean Government [NRF-2013S1A2A2035370] FX This work was supported by NIH/NIDCR intramural grant DE000735 and by the National Foundation of Korea Grant funded by the Korean Government (NRF-2013S1A2A2035370). NR 107 TC 16 Z9 17 U1 2 U2 11 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD OCT PY 2015 VL 58 IS 4 SI SI BP 342 EP 348 DI 10.1016/j.ceca.2015.03.003 PG 7 WC Cell Biology SC Cell Biology GA CS1TD UT WOS:000361849700003 PM 25843208 ER PT J AU Ong, HL Ambudkar, IS AF Ong, Hwei Ling Ambudkar, Indu S. TI Molecular determinants of TRPC1 regulation within ER-PM junctions SO CELL CALCIUM LA English DT Review DE TRPC; STIM1; Orai1; SOCE; ER-PM junctions; Lipid rafts; Caveolin ID OPERATED CA2+ ENTRY; PLASMA MEMBRANE JUNCTIONS; PULMONARY ARTERIAL-HYPERTENSION; RECEPTOR POTENTIAL CHANNELS; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; LIPID RAFT DOMAINS; CALCIUM-ENTRY; STORE DEPLETION; HUMAN PLATELETS; ENDOTHELIAL-CELLS AB Store-operated calcium entry (SOCE) is activated within the endoplasmic reticulum (ER)-plasma membrane (PM) junctions in the plasma membrane and involves assembly of the channels, Orai1 and TRPC1, with the regulatory protein, STIM1, in response to depletion of Ca2+ in the ER. The dynamic assembly of the channel complexes as well as regulation of channel activity and cell function is dependent on critical components that are either already localized in and/or recruited to the junctions following cell stimulation. These include proteins and lipids in the plasma membrane, ER, and cytosol. Together, these coordinated interactions lead to assembly and activation of Orai1/STIM1 and TRPC1/STIM1 channels. Recent studies demonstrate that Ca2+ signals generated by Orai1 are detected locally within the ER-PM junctions by various signaling proteins that trigger and regulate other Ca2+-dependent functions. One such function is the plasma membrane recruitment of TRPC1 channels where it is activated by STIM1. Activation of TRPC1 within the ER-PM junctions leads to generation of distinct [Ca2+], signals and regulation of cellular functions different from those regulated by Orai1. Thus, it has been suggested that Orai1 and TRPC1 channels are compartmentalized in distinct microdomains. Such compartmentalization involves organization of plasma membrane lipids as well as structural and scaffolding proteins, the nature of which is still poorly understood. Importantly, there appears to be dynamic reorganization of the micro domains within existing ER-PM junctions that allow segregated proteins to interact. Together, these highly specific and coordinated remodeling of protein complexes and membrane domains results in generation of spatially- and temporally-controlled Ca2+ signals that are critical for numerous downstream cellular functions. Published by Elsevier Ltd. C1 [Ong, Hwei Ling; Ambudkar, Indu S.] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ong, HL (reprint author), NIDCR, NIH, Bldg 10 Room 1N-113, Bethesda, MD 20892 USA. EM ongh@mail.nih.gov; indu.ambudkar@nih.gov FU Intramural Research Program of the NIH, NIDCR FX Work in ISA's laboratory is supported by the Intramural Research Program of the NIH, NIDCR. NR 145 TC 14 Z9 14 U1 1 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD OCT PY 2015 VL 58 IS 4 SI SI BP 376 EP 386 DI 10.1016/j.ceca.2015.03.008 PG 11 WC Cell Biology SC Cell Biology GA CS1TD UT WOS:000361849700007 PM 25922260 ER PT J AU Cecchi, F Lih, CJ Lee, YH Walsh, W Rabe, DC Williams, PM Bottaro, DP AF Cecchi, Fabiola Lih, Chih-Jian Lee, Young H. Walsh, William Rabe, Daniel C. Williams, Paul M. Bottaro, Donald P. TI Expression array analysis of the hepatocyte growth factor invasive program SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Hepatocyte growth factor; MET receptor tyrosine kinase; Signal transduction; Cell migration; Prostate cancer; Tumor metastasis ID PROSTATE-CANCER CELLS; HEAT-SHOCK PROTEINS; BREAST-CANCER; C-MET; ASPARAGINE SYNTHETASE; ANDROGEN RECEPTOR; IN-VIVO; FACTOR/SCATTER FACTOR; CRYSTAL-STRUCTURE; P-CADHERIN AB Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. Here we show that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival. C1 [Cecchi, Fabiola; Lee, Young H.; Rabe, Daniel C.; Bottaro, Donald P.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lih, Chih-Jian; Walsh, William; Williams, Paul M.] Leidos Biomed Res Inc, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD 21702 USA. [Lih, Chih-Jian; Walsh, William; Williams, Paul M.] Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. EM don.bottaro@nih.gov OI Bottaro, Donald/0000-0002-5057-5334 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute Division of Cancer Treatment and Diagnosis FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the National Cancer Institute Division of Cancer Treatment and Diagnosis. NR 137 TC 0 Z9 0 U1 1 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD OCT PY 2015 VL 32 IS 7 BP 659 EP 676 DI 10.1007/s10585-015-9735-0 PG 18 WC Oncology SC Oncology GA CR9ZF UT WOS:000361715300003 PM 26231668 ER PT J AU Smart, D Garcia-Glaessner, A Palmieri, D Wong-Goodrich, SJ Kramp, T Gril, B Shukla, S Lyle, T Hua, E Cameron, HA Camphausen, K Steeg, PS AF Smart, DeeDee Garcia-Glaessner, Alejandra Palmieri, Diane Wong-Goodrich, Sarah J. Kramp, Tamalee Gril, Brunilde Shukla, Sudhanshu Lyle, Tiffany Hua, Emily Cameron, Heather A. Camphausen, Kevin Steeg, Patricia S. TI Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE Metastasis; Brain; Radiation; Breast; Cancer; Radiosensitivity ID NEURAL PRECURSOR CELLS; DEPENDENT COGNITIVE IMPAIRMENT; TUMOR BARRIER PERMEABILITY; HIPPOCAMPAL NEUROGENESIS; IN-VIVO; ADULT NEUROGENESIS; MOUSE MODEL; IRRADIATION; MICE; RADIOTHERAPY AB Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy x 10 fractions (3 x 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy x 1 (15 x 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 x 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 x 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 x 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy. C1 [Smart, DeeDee; Garcia-Glaessner, Alejandra; Kramp, Tamalee; Shukla, Sudhanshu; Camphausen, Kevin] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Palmieri, Diane; Gril, Brunilde; Lyle, Tiffany; Hua, Emily; Steeg, Patricia S.] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wong-Goodrich, Sarah J.; Cameron, Heather A.] NIMH, Sect Neuroplast, NIH, Bethesda, MD 20892 USA. [Palmieri, Diane] NHLBI, Bethesda, MD 20892 USA. RP Smart, D (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM smartd@mail.nih.gov; steegp@mail.nih.gov RI Cameron, Heather/E-6221-2011; OI Cameron, Heather/0000-0002-3245-5777; Shukla, Sudhanshu/0000-0002-7091-7215 FU Intramural Research program of the National Cancer Institute; Department of Defense Center of Excellence Breast Cancer Research Program [W81XWH-06-0033] FX This work was supported by the Intramural Research program of the National Cancer Institute and by the Department of Defense Center of Excellence Breast Cancer Research Program Award W81XWH-06-0033. The authors thank Dr. Yong Qian for excellent animal procedures. NR 60 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 EI 1573-7276 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD OCT PY 2015 VL 32 IS 7 BP 717 EP 727 DI 10.1007/s10585-015-9739-9 PG 11 WC Oncology SC Oncology GA CR9ZF UT WOS:000361715300007 PM 26319493 ER PT J AU Michelle, EH Mammen, AL AF Michelle, E. Harlan Mammen, Andrew L. TI Myositis Mimics SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Autoimmune myopathies; Inclusion body myositis; Facioscapulohumeral muscular dystrophy; Dysferlinopathy; McArdle's disease; Acid maltase ID INCLUSION-BODY MYOSITIS; IDIOPATHIC INFLAMMATORY MYOPATHIES; COMPLEX CLASS-I; MUSCULAR-DYSTROPHIES; MCARDLE-DISEASE; DIAGNOSTIC-TOOL; POMPES-DISEASE; NATURAL COURSE; PILOT TRIAL; HYPOTHYROIDISM AB Patients with autoimmune myositis typically present with muscle weakness, elevated serum levels of muscle enzymes, and abnormal muscle biopsies. However, patients with other acquired myopathies or genetic muscle diseases may have remarkably similar presentations. Making the correct diagnosis of another muscle disease can prevent these patients from being exposed to the risks of immunosuppressive medications, which benefit those with myositis, but not those with other types of muscle disease. Here, we review some of the most common acquired and inherited muscle diseases that can mimic autoimmune myositis, including inclusion body myositis, limb girdle muscular dystrophies, metabolic myopathies, mitochondrial myopathies, and endocrine myopathies. We emphasize aspects of the medical history, physical exam, laboratory evaluation, and muscle biopsy analysis that can help clinicians distinguish myositis mimics from true autoimmune myositis. C1 [Michelle, E. Harlan] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Mammen, Andrew L.] NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, 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 andrew.mammen@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX Production of this article was supported [in part] by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 65 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD OCT PY 2015 VL 17 IS 10 AR 63 DI 10.1007/s11926-015-0541-0 PG 8 WC Rheumatology SC Rheumatology GA CR8MX UT WOS:000361608800003 PM 26290112 ER PT J AU Egwuagu, CE Yu, CR Sun, L Wang, RX AF Egwuagu, Charles E. Yu, Cheng-Rong Sun, Lin Wang, Renxi TI Interleukin 35: Critical regulator of immunity and lymphocyte-mediated diseases SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Interleukin 35; IL-12 family cytokines; Autoimmune diseases; Cytokine therapy; Regulatory B cells; Breg; i35-Breg; iTR35; Adoptive B cell therapy ID CD4(+) T-CELLS; B-CELLS; AUTOIMMUNE INFLAMMATION; IL-12 FAMILY; CYTOKINE; IL-27; DIFFERENTIATION; UVEITIS; RECEPTOR; BIOLOGY AB Cytokines coordinate the activities of innate and adaptive immune systems and the Interleukin 12 (IL-12) family of cytokines has emerged as critical regulators of immunity in infectious and autoimmune diseases. While some members (IL-12 and IL-23) are associated with the pathogenesis of chronic inflammatory diseases, others (IL-27 and IL-35) mitigate autoimmune diseases. Unlike IL-12, IL-23 and IL-27 that are produced mainly by antigen presenting cells, IL-35 is predominantly secreted by regulatory B (i35-Bregs) and T (iTR35) cells. The discovery that IL-35 can induce the conversion or expansion of lymphocytes to regulatory B and T cells has considerable implications for therapeutic use of autologous regulatory B and T cells in human diseases. Although our current understanding of the immunobiology of IL-35 or its subunits (p35 and Ebi3) is still rudimentary, our goal in this review is to summarize what we know about this enigmatic cytokine and its potential clinical use, particularly in the treatment of CNS autoimmune diseases. Published by Elsevier Ltd. C1 [Egwuagu, Charles E.; Yu, Cheng-Rong; Sun, Lin] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Renxi] Beijing Inst Basic Med Sci, Immunol Lab, Beijing 100850, Peoples R China. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bldg 10,Room 10N109A,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov RI Sun, Lin/I-3146-2016 FU Intramural NIH HHS [Z01 EY000262-13, ZIA EY000262-19, ZIA EY000315-21, ZIA EY000372-14] NR 51 TC 9 Z9 11 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD OCT PY 2015 VL 26 IS 5 SI SI BP 587 EP 593 DI 10.1016/j.cytogfr.2015.07.013 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS1ZS UT WOS:000361868200013 PM 26279360 ER PT J AU Gibbs, BB Gabriel, KP Reis, JP Jakicic, JM Carnethon, MR Sternfeld, B AF Gibbs, Bethany Barone Gabriel, Kelley Pettee Reis, Jared P. Jakicic, John M. Carnethon, Mercedes R. Sternfeld, Barbara TI Cross-sectional and Longitudinal Associations Between Objectively Measured Sedentary Time and Metabolic Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO DIABETES CARE LA English DT Article ID INTENSITY PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; POSTPRANDIAL GLUCOSE; CARDIOMETABOLIC RISK; BEHAVIOR; HEALTH; RESPONSES; OBESITY AB OBJECTIVEProlonged sedentary time (ST) might be contributing to the diabetes epidemic, but most studies have been cross-sectional and few have objectively measured ST. The purpose of this study was to evaluate cross-sectional and 5-year longitudinal relationships between ST and metabolic parameters and outcomes.RESEARCH DESIGN AND METHODSThis was an analysis of 2,027 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (aged 38-50 years, 57% female, and mean BMI of 29.0 7.0 kg/m(2)) with accelerometry data (4 days with 10 h/day) measured at the year 20 follow-up exam (2005-2006). Metabolic variables (fasting glucose, fasting insulin, 2-h postchallenge glucose, HOMA of insulin resistance [HOMA-IR], and HbA(1c)) and outcomes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], prediabetes by HbA(1c), and diabetes) were assessed concurrently and 5 years later.RESULTSAverage ST was 8.1 +/- 1.7 h/day or 55 +/- 10% of wear time. Each additional hour per day of ST was cross-sectionally associated with a 3% higher fasting insulin and HOMA-IR (both P < 0.01) but not 5-year changes in metabolic parameters. Having 10 h/day vs. <6 h/day of ST was associated with an odds ratio (OR) = 2.74 (95% CI 1.13, 6.62) for IGT and an OR = 3.80 (95% CI 1.39, 10.35) for diabetes. ST was not associated with prevalent IFG, prevalent prediabetes by HbA(1c), or 5-year incidence of any metabolic outcomes (all P > 0.05).CONCLUSIONSST was independently related to insulin, HOMA-IR, and prevalent diabetes and IGT but did not predict 5-year changes in metabolic parameters or incidence of metabolic outcomes. These results suggest that higher ST may not be a risk factor for future metabolic outcomes, but more research with repeated ST measurement and longer follow-up is needed. C1 [Gibbs, Bethany Barone; Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA 15260 USA. [Gabriel, Kelley Pettee] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Sternfeld, Barbara] Kaiser Permanente No Calif, Dept Res, Oakland, CA USA. RP Gibbs, BB (reprint author), Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA 15260 USA. EM bbarone@pitt.edu 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, P30 AG024827]; NHLBI [AG0005, R01-HL-078972, 1R01-HL53560-01A1] FX CARDIA is supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C, the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). The CARDIA Fitness Study was supported by NHLBI grant R01-HL-078972. The CARDIA Young Adults Longitudinal Trends in Antioxidants was supported by NHLBI grant 1R01-HL53560-01A1. B.B.G. was supported by NIA grant P30 AG024827. NR 30 TC 3 Z9 3 U1 1 U2 10 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 IS 10 BP 1835 EP 1843 DI 10.2337/dc15-0226 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS1PW UT WOS:000361840500018 ER PT J AU Wherrett, DK Chiang, JL Delamater, AM DiMeglio, LA Gitelman, SE Gottlieb, PA Herold, KC Lovell, DJ Orchard, TJ Ryan, CM Schatz, DA Wendler, DS Greenbaum, CJ AF Wherrett, Diane K. Chiang, Jane L. Delamater, Alan M. DiMeglio, Linda A. Gitelman, Stephen E. Gottlieb, Peter A. Herold, Kevan C. Lovell, Daniel J. Orchard, Trevor J. Ryan, Christopher M. Schatz, Desmond A. Wendler, David S. Greenbaum, Carla J. CA Type 1 Diabet TrialNet Study Grp TI Defining Pathways for Development of Disease-Modifying Therapies in Children With Type 1 Diabetes: A Consensus Report SO DIABETES CARE LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; BETA-CELL FUNCTION; JUVENILE IDIOPATHIC ARTHRITIS; PLACEBO-CONTROLLED TRIAL; POPULATION-BASED COHORT; PRESERVES C-PEPTIDE; PITTSBURGH EPIDEMIOLOGY; DOUBLE-BLIND; COMPLICATIONS TRIAL AB Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course. Therefore, the efficacy of disease-modifying therapies may be different in the two populations. Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care. This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies. C1 [Wherrett, Diane K.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. [Chiang, Jane L.] Amer Diabet Assoc, Alexandria, VA USA. [Delamater, Alan M.] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [DiMeglio, Linda A.] Indiana Univ, Dept Pediat, Indianapolis, IN 46204 USA. [Gitelman, Stephen E.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Gottlieb, Peter A.] Univ Colorado, Dept Med, Denver, CO USA. [Gottlieb, Peter A.] Univ Colorado, Dept Pediat, Denver, CO 80202 USA. [Herold, Kevan C.] Yale Univ, Dept Immunobiol, New Haven, CT USA. [Lovell, Daniel J.] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA. [Orchard, Trevor J.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Ryan, Christopher M.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Schatz, Desmond A.] Univ Florida, Dept Pediat, Gainesville, FL USA. [Wendler, David S.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Greenbaum, Carla J.] Benaroya Res Inst, Diabet Res Program, Seattle, WA 98101 USA. RP Greenbaum, CJ (reprint author), Benaroya Res Inst, Diabet Res Program, Seattle, WA 98101 USA. EM cjgreen@benaroyaresearch.org OI orchard, trevor/0000-0001-9552-3215 FU Sanofi; Novo Nordisk; Pfizer; JDRF; Novartis; NIH; Omni Bio Pharmaceutical; Bristol-Myers Squibb; National Institute of Diabetes and Digestive and Kidney Diseases; Profil Institute for Clinical Research; Eli Lilly; Abbott Laboratories; Gilead FX All authors have completed the Unified Competing Interest form at www.icmje.org/conflicts-of-interest (available upon request from J.L.C.) and declare the following conflicts of interest. L.A.D. reports personal fees from Sanofi and grants from Novo Nordisk, outside the submitted work. P.A.G. reports grants from Pfizer, JDRF, Novartis, the NIH, and Omni Bio Pharmaceutical and nonfinancial support from ViaCyte, Genentech, and Baxter, outside the submitted work. P.A.G. has a patent related to the use of AAT for the treatment of type 1 diabetes with royalties paid to Omni Bio Pharmaceutical. D.J.L. reports grants from Bristol-Myers Squibb and other support from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Laboratories, Horizon Pharma, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, and Celgene, outside the submitted work. T.J.O. reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases, during the conduct of the study; personal fees from the Profil Institute for Clinical Research, Eli Lilly, Abbott Laboratories, and Gilead; and other support from Bristol-Myers Squibb, outside the submitted work. C.M.R. reports personal fees from Novo Nordisk, outside the submitted work. C.J.G. reports grants from Novo Nordisk and Novartis, outside the submitted work. No other potential conflicts of interest relevant to this article were reported. NR 96 TC 6 Z9 6 U1 2 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2015 VL 38 IS 10 BP 1975 EP 1985 DI 10.2337/dc15-1429 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS1PW UT WOS:000361840500037 PM 26404927 ER PT J AU Xu, HY Abuhatzira, L Carmona, GN Vadrevu, S Satin, LS Notkins, AL AF Xu, Huanyu Abuhatzira, Liron Carmona, Gilberto N. Vadrevu, Suryakiran Satin, Leslie S. Notkins, Abner L. TI The Ia-2 beta intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice SO DIABETOLOGIA LA English DT Article DE Cav1.2; IA-2; Insulin secretion; Intronic miRNA; MicroRNAs ID VESICLE PROTEINS IA-2; DOWN-REGULATION; TARGETED DISRUPTION; GLUCOSE-TOLERANCE; LUNG-CANCER; HOST GENES; NULL MICE; EXPRESSION; CALCIUM; CELLS AB Aims/hypothesis miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2 beta (also known as PTPRN2). Islet antigen (IA)-2 and IA-2 beta are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The present experiments were initiated to decipher the regulatory network between miR-153 and its host gene Ia-2 beta (also known as Ptprn2). Methods Insulin secretion was determined by ELISA. Identification of miRNA targets was assessed using luciferase assays and by quantitative real-time PCR and western blots in vitro and in vivo. Target protector was also employed to evaluate miRNA target function. Results Functional studies revealed that miR-153 mimic suppresses both glucose- and potassium-induced insulin secretion (GSIS and PSIS, respectively), whereas miR-153 inhibitor enhances both GSIS and PSIS. A similar effect on dopamine secretion also was observed. Using miRNA target prediction software, we found that miR-153 is predicted to target the 3'UTR region of the calcium channel gene, Cacna1c. Further studies confirmed that Cacna1c mRNA and protein are downregulated by miR-153 mimics and upregulated by miR-153 inhibitors in insulin-secreting freshly isolated mouse islets, in the insulin-secreting mouse cell line MIN6 and in the dopamine-secreting cell line PC12. Conclusions/interpretation miR-153 is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, which suggests that IA-2 beta and miR-153 have opposite functional effects on the secretory pathway. C1 [Xu, Huanyu; Abuhatzira, Liron; Carmona, Gilberto N.; Notkins, Abner L.] Natl Inst Hlth, Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, Bethesda, MD 20892 USA. [Vadrevu, Suryakiran; Satin, Leslie S.] Univ Michigan, Sch Med, Brehm Diabet Res Ctr, Ann Arbor, MI 48109 USA. RP Notkins, AL (reprint author), Natl Inst Hlth, Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM anotkins@dir.nidcr.nih.gov FU Intramural Research Program of the NIDCR, NIH, Bethesda, MD, USA; [RO1DK46409] FX This work was supported by the Intramural Research Program of the NIDCR, NIH, Bethesda, MD, USA. Research in LSS's lab is funded by RO1DK46409. NR 40 TC 4 Z9 4 U1 3 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2015 VL 58 IS 10 BP 2298 EP 2306 DI 10.1007/s00125-015-3683-8 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR7NY UT WOS:000361538600013 PM 26141787 ER PT J AU Meni, ACS Swithers, SE Rother, KI AF Meni, Allison C. Sylvetsky Swithers, Susan E. Rother, Kristina I. TI Positive association between artificially sweetened beverage consumption and incidence of diabetes SO DIABETOLOGIA LA English DT Letter DE Artificial sweeteners; Artificially sweetened beverages; Diabetes; Diet soda; Non-nutritive sweeteners; Obesity; Soda; Sugar-sweetened beverages C1 [Meni, Allison C. Sylvetsky; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Meni, Allison C. Sylvetsky] George Washington Univ, Dept Exercise & Nutr Sci, Milken Inst Sch Publ Hlth, Washington, DC USA. [Swithers, Susan E.] Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab, NIH, 9000 Rockville Pike,Bldg 10,Room 8C432A, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov NR 8 TC 3 Z9 3 U1 11 U2 49 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2015 VL 58 IS 10 BP 2455 EP 2456 DI 10.1007/s00125-015-3694-5 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR7NY UT WOS:000361538600029 ER PT J AU Anderson, LA Tavilla, A Brenner, H Luttmann, S Navarro, C Gavin, AT Holleczek, B Johnston, BT Cook, MB Bannon, F Sant, M AF Anderson, L. A. Tavilla, A. Brenner, H. Luttmann, S. Navarro, C. Gavin, A. T. Holleczek, B. Johnston, B. T. Cook, M. B. Bannon, F. Sant, M. CA EUROCARE 5 Working Grp TI Survival for oesophageal, stomach and small intestine cancers in Europe 1999-2007: Results from EUROCARE-5 SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Oesophageal; Stomach; Small intestine; Survival; Europe ID SMALL-BOWEL CANCER; UNITED-STATES; BENCHMARKING PARTNERSHIP; TIME TRENDS; MORTALITY DATABASE; POPULATION; COUNTRIES; EPIDEMIOLOGY; PATTERNS; REGISTRATION AB Background: European regional variation in cancer survival was reported in the EUROCARE-4 study for patients diagnosed in 1995-1999. Relative survival (RS) estimates are here updated for patients diagnosed with cancer of the oesophagus, stomach and small intestine from 2000 to 2007. Trends in RS from 1999-2001 to 2005-2007 are presented to monitor and discuss improvements in patient survival in Europe. Materials and methods: EUROCARE-5 data from 29 countries (87 cancer registries) were used to investigate 1- and 5-year RS. Using registry-specific life-tables stratified by age, gender and calendar year, age-standardised 'complete analysis' RS estimates by country and region were calculated for Northern, Southern, Eastern and Central Europe, and for Ireland and United Kingdom (UK). Survival trends of patients in periods 1999-2001, 2002-2004 and 2005-2007 were investigated using the 'period' RS approach. We computed the 5-year RS conditional on surviving the first year (5-year conditional survival), as the ratio of age-standardised 5-year RS to 1-year RS. Results: Oesophageal cancer 1- and 5-year RS (40% and 12%, respectively) remained poor in Europe. Patient survival was worst in Eastern (8%), Northern (11%) and Southern Europe (10%). Europe-wide, there was a 3% improvement in oesophageal cancer 5-year survival by 2005-2007, with Ireland and the UK (3%), and Central Europe (4%) showing large improvements. Europe-wide, stomach cancer 5-year RS was 25%. Ireland and UK (17%) and Eastern Europe (19%) had the poorest 5-year patient survival. Southern Europe had the best 5-year survival (30%), though only showing an improvement of 2% by 2005-2007. Small intestine cancer 5-year RS for Europe was 48%, with Central Europe having the best (54%), and Ireland and UK the poorest (37%). Five-year patient survival improvement for Europe was 8% by 2005-2007, with Central, Southern and Eastern Europe showing the greatest increases (P9%). Conclusions: Survival for these cancer sites, particularly oesophageal cancer, remains poor in Europe with wide variation. Further investigation into the wide variation, including analysis by histology and anatomical sub-site, will yield insights to better monitor and explain the improvements in survival observed over time. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Anderson, L. A.; Gavin, A. T.; Bannon, F.] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland. [Tavilla, A.] Italian Natl Inst Hlth, Natl Ctr Epidemiol, Rome, Italy. [Brenner, H.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, H.] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, H.] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Luttmann, S.] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen Canc Registry, Bremen, Germany. [Navarro, C.] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Navarro, C.] CIBERESP, Madrid, Spain. [Navarro, C.] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain. [Gavin, A. T.] Queens Univ Belfast, Northern Ireland Canc Registry, Belfast BT12 6BJ, Antrim, North Ireland. [Holleczek, B.] Saarland Canc Registry, D-66119 Saarbrucken, Germany. [Johnston, B. T.] Belfast Hlth & Social Care Trust, Belfast, Antrim, North Ireland. [Cook, M. B.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sant, M.] Fdn IRCCS Ist Nazl Tumori, Analyt Epidemiol & Hlth Impact Unit, Dept Prevent & Predict Med, I-20133 Milan, Italy. RP Anderson, LA (reprint author), Queens Univ Belfast, Inst Clin Sci, Ctr Publ Hlth, Block B,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM l.anderson@qub.ac.uk RI Sant, Milena/D-2362-2017; Minicozzi, Pamela/J-6089-2016; Castro, Clara/M-4779-2013; Cook, Michael/A-5641-2009; Giorgi Rossi, Paolo/K-6367-2016; Brenner, Hermann/B-4627-2017 OI Sant, Milena/0000-0002-4148-8597; Minicozzi, Pamela/0000-0002-7273-7947; Castro, Clara/0000-0001-9653-4581; Cook, Michael/0000-0002-0533-7302; Giorgi Rossi, Paolo/0000-0001-9703-2460; Brenner, Hermann/0000-0002-6129-1572 NR 45 TC 4 Z9 4 U1 3 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2015 VL 51 IS 15 BP 2144 EP 2157 DI 10.1016/j.ejca.2015.07.026 PG 14 WC Oncology SC Oncology GA CS1QJ UT WOS:000361842200006 ER PT J AU Bakir-Gungor, B Remmers, EF Meguro, A Mizuki, N Kastner, DL Gul, A Sezerman, OU AF Bakir-Gungor, Burcu Remmers, Elaine F. Meguro, Akira Mizuki, Nobuhisa Kastner, Daniel L. Gul, Ahmet Sezerman, Osman Ugur TI 'Epistatic interactions between autoimmunity and genetic thrombophilia' Reply SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID BEHCETS-DISEASE C1 [Bakir-Gungor, Burcu] Abdullah Gul Univ, Fac Engn & Nat Sci, Dept Comp Engn, Kayseri, Turkey. [Remmers, Elaine F.; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Meguro, Akira; Mizuki, Nobuhisa] Yokohama City Univ, Sch Med, Dept Ophthalmol, Yokohama, Kanagawa 232, Japan. [Gul, Ahmet] Istanbul Univ, Dept Internal Med, Div Rheumatol, Istanbul, Turkey. [Sezerman, Osman Ugur] Sabanci Univ, Fac Engn & Nat Sci, Dept Biol Sci & Bioengn, Istanbul, Turkey. RP Bakir-Gungor, B (reprint author), Abdullah Gul Univ, Fac Engn & Nat Sci, Dept Comp Engn, Kayseri, Turkey. EM burcu.gungor@agu.edu.tr NR 5 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD OCT PY 2015 VL 23 IS 10 BP 1279 EP 1280 DI 10.1038/ejhg.2014.288 PG 3 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CS0KK UT WOS:000361747700003 ER PT J AU Bonilha, VL Bell, BA Rayborn, ME Yang, XP Kaul, C Grossman, GH Samuels, IS Hollyfield, JG Xie, CS Cai, HB Shadrach, KG AF Bonilha, Vera L. Bell, Brent A. Rayborn, Mary E. Yang, Xiaoping Kaul, Charlie Grossman, Gregory H. Samuels, Ivy S. Hollyfield, Joe G. Xie, Chengsong Cai, Huaibin Shadrach, Karen G. TI Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE DJ-1 knockout; Retina; Morphology; Physiology; Histology; Immunohistology; Biochemistry; Oxidation ID ONSET PARKINSONS-DISEASE; LIGHT-EVOKED RESPONSES; PIGMENT EPITHELIUM; MACULAR DEGENERATION; DROSOPHILA DJ-1; BRUCHS MEMBRANE; GEOGRAPHIC ATROPHY; CELL-DEATH; MITOCHONDRIAL LOCALIZATION; ANTIOXIDATIVE STRESS AB DJ-1/PARK7 mutations or deletions cause autosomal recessive early onset Parkinson's disease (PD). Thus, DJ-1 protein has been extensively studied in brain and neurons. PD patients display visual symptoms; however, the visual symptoms specifically attributed to PD patients carrying DJ-1/PARK7 mutations are not known. In this study, we analyzed the structure and physiology of retinas of 3- and 6-month-old DJ-1 knockout (KO) mice to determine how loss of function of DJ-1 specifically contributes to the phenotypes observed in PD patients. As compared to controls, the DJ-1 KO mice displayed an increase in the amplitude of the scotopic ERG b-wave and cone ERG, while the amplitude of a subset of the dc-ERG components was decreased. The main structural changes in the DJ-1 KO retinas were found in the outer plexiform layer (OPL), photoreceptors and retinal pigment epithelium (RPE), which were observed at 3 months and progressively increased at 6 months. RPE thinning and structural changes within the OPL were observed in the retinas in DJ-1 KO mice. DJ-1 KO retinas also exhibited disorganized outer segments, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased 7,8-dihydro-8-oxoguanine-labeled DNA oxidation. Accelerated outer retinal atrophy was observed in DJ-1 KO mice after selective oxidative damage induced by a single tail vein injection of NaIO3, exposing increased susceptibility to oxidative stress. Our data indicate that DJ-1-deficient retinas exhibit signs of morphological abnormalities and physiological dysfunction in association with increased oxidative stress. Degeneration of RPE cells in association with oxidative stress is a key hallmark of age-related macular degeneration (AMD). Therefore, in addition to detailing the visual defects that occur as a result of the absence of DJ-1, our data is also relevant to AMD pathogenesis. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Bonilha, Vera L.; Hollyfield, Joe G.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Ophthalmol, Cleveland, OH 44106 USA. [Bonilha, Vera L.; Bell, Brent A.; Rayborn, Mary E.; Yang, Xiaoping; Kaul, Charlie; Grossman, Gregory H.; Samuels, Ivy S.; Hollyfield, Joe G.; Shadrach, Karen G.] Cleveland Clin, Cole Eye Inst, Dept Ophthalm Res, Cleveland, OH 44106 USA. [Samuels, Ivy S.] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Xie, Chengsong; Cai, Huaibin] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Bonilha, VL (reprint author), Cleveland Clin, Cole Eye Inst, Dept Ophthalm Res, Cleveland, OH 44106 USA. EM bonilhav@ccf.org FU NIH [EY017153]; Department of Veteran's Affairs CDA-2; Research to Prevent Blindness; Wolf Family Foundation; Intramural Research Program of National Institute on Aging [Z01-AG000945] FX The authors thank Dr. Neal Peachey for comments on the manuscript. This work is a continuation of studies funded by the NIH grant EY017153 (VLB). This work was also supported by a Department of Veteran's Affairs CDA-2 (ISS), an unrestricted grant from the Research to Prevent Blindness, by the Wolf Family Foundation, and partially supported by the Intramural Research Program of National Institute on Aging (Z01-AG000945) (HC). NR 81 TC 1 Z9 2 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD OCT PY 2015 VL 139 BP 22 EP 36 DI 10.1016/j.exer.2015.07.014 PG 15 WC Ophthalmology SC Ophthalmology GA CS0VW UT WOS:000361781300003 PM 26215528 ER PT J AU Wang, J Mojumder, DK Yan, J Xie, A Standaert, RF Qian, HH Pepperberg, DR Frishman, LJ AF Wang, Jing Mojumder, Deb Kumar Yan, Jun Xie, An Standaert, Robert F. Qian, Haohua Pepperberg, David R. Frishman, Laura J. TI In vivo electroretinographic studies of the role of GABA(C) receptors in retinal signal processing SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Electroretinogram; GABA; GABA receptors; Retina; Retinal signaling ID DARK-ADAPTED ELECTRORETINOGRAM; ROD BIPOLAR CELLS; SCOTOPIC THRESHOLD RESPONSE; GAMMA-AMINOBUTYRIC-ACID; MOUSE RETINA; CAT RETINA; RAT RETINA; B-WAVE; HORIZONTAL CELLS; TRANSMITTER RELEASE AB All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Wang, Jing; Mojumder, Deb Kumar; Frishman, Laura J.] Univ Houston, Coll Optometry, Houston, TX 77204 USA. [Mojumder, Deb Kumar] Texas Tech Univ, Hlth Sci Ctr, Dept Neurol, Lubbock, TX 79430 USA. [Yan, Jun; Standaert, Robert F.] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. [Yan, Jun] Chengdu Kanghong Pharmaceut Co Ltd, Chengdu, Sichuan, Peoples R China. [Xie, An; Qian, Haohua; Pepperberg, David R.] Univ Illinois, Illinois Eye & Ear Infirm, Dept Ophthalmol & Visual Sci, Lions Illinois Eye Res Inst, Chicago, IL 60612 USA. [Xie, An] Brown Univ, Lifespan Cardiovasc Inst, Providence, RI 02906 USA. [Xie, An] Brown Univ, Warren Alpert Sch Med, Providence, RI 02906 USA. [Standaert, Robert F.] Univ Tennessee, Dept Biochem & Mol Cellular Biol, Knoxville, TN 37996 USA. [Qian, Haohua] NEI, NIH, Bethesda, MD 20892 USA. RP Frishman, LJ (reprint author), Univ Houston, Coll Optometry, 4901 Calhoun,505 J Davis Armistead, Houston, TX 77204 USA. RI Standaert, Robert/D-9467-2013; OI Standaert, Robert/0000-0002-5684-1322; Frishman, Laura/0000-0002-4226-5109 FU Daniel F. and Ada L. Rice Foundation (Skokie, IL) [NIH EY06671, EY07551, EY016094, EY001792]; Bright Focus Foundation (Clarksburg, MD); Research to Prevent Blindness (New York, NY); Hope for Vision (Washington, DC); University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) [UL1RR029879] FX NIH EY06671, EY07551, EY016094, EY001792 Daniel F. and Ada L. Rice Foundation (Skokie, IL); Bright Focus Foundation (formerly the American Health Assistance Foundation) (Clarksburg, MD); Research to Prevent Blindness (New York, NY); Hope for Vision (Washington, DC); and Award UL1RR029879 from the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS). NR 58 TC 2 Z9 2 U1 3 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD OCT PY 2015 VL 139 BP 48 EP 63 DI 10.1016/j.exer.2015.07.002 PG 16 WC Ophthalmology SC Ophthalmology GA CS0VW UT WOS:000361781300005 PM 26164072 ER PT J AU Santosh, KC Wendling, L AF Santosh, K. C. Wendling, Laurent TI Character recognition based on non-linear multi-projection profiles measure SO FRONTIERS OF COMPUTER SCIENCE LA English DT Article DE character recognition; the Radon features; dynamic programming; shape descriptors ID AUTOMATIC RECOGNITION; FOURIER DESCRIPTORS; SHAPES; RADON AB In this paper, we study a method for isolated handwritten or hand-printed character recognition using dynamic programming for matching the non-linear multi-projection profiles that are produced from the Radon transform. The idea is to use dynamic time warping (DTW) algorithm to match corresponding pairs of the Radon features for all possible projections. By using DTW, we can avoid compressing feature matrix into a single vector which may miss information. It can handle character images in different shapes and sizes that are usually happened in natural handwriting in addition to difficulties such as multi-class similarities, deformations and possible defects. Besides, a comprehensive study is made by taking a major set of state-of-the-art shape descriptors over several character and numeral datasets from different scripts such as Roman, Devanagari, Oriya, Bangla and Japanese-Katakana including symbol. For all scripts, the method shows a generic behaviour by providing optimal recognition rates but, with high computational cost. C1 [Santosh, K. C.] NIH, US Natl Lib Med NLM, Bethesda, MD 20894 USA. [Wendling, Laurent] Univ Paris Descartes Paris V, SIP LIPADE, F-75270 Paris 06, France. RP Santosh, KC (reprint author), NIH, US Natl Lib Med NLM, Bethesda, MD 20894 USA. EM santosh.kc@nih.gov OI Santosh, K.C./0000-0003-4176-0236 NR 43 TC 1 Z9 1 U1 0 U2 7 PU HIGHER EDUCATION PRESS PI BEIJING PA NO 4 DEWAI DAJIE, BEIJING 100120, PEOPLES R CHINA SN 2095-2228 EI 2095-2236 J9 FRONT COMPUT SCI-CHI JI Front.. Comput. Sci. PD OCT PY 2015 VL 9 IS 5 BP 678 EP 690 DI 10.1007/s11704-015-3400-2 PG 13 WC Computer Science, Information Systems; Computer Science, Software Engineering; Computer Science, Theory & Methods SC Computer Science GA CR8NP UT WOS:000361611300002 ER PT J AU Czajkowski, SM Powell, LH Adler, N Naar-King, S Reynolds, KD Hunter, CM Laraia, B Olster, DH Perna, FM Peterson, JC Epel, E Boyington, JE Charlson, ME AF Czajkowski, Susan M. Powell, Lynda H. Adler, Nancy Naar-King, Sylvie Reynolds, Kim D. Hunter, Christine M. Laraia, Barbara Olster, Deborah H. Perna, Frank M. Peterson, Janey C. Epel, Elissa Boyington, Josephine E. Charlson, Mary E. CA Obesity Related Behav Intervention TI From Ideas to Efficacy: The ORBIT Model for Developing Behavioral Treatments for Chronic Diseases SO HEALTH PSYCHOLOGY LA English DT Article DE health behavior; behavioral treatment development; translation of basic behavioral research into behavioral treatments; behavioral study designs and methods; prevention and management of chronic disease; lifestyle ID RANDOMIZED CONTROLLED-TRIALS; LIFE-STYLE INTERVENTION; CLINICAL-PRACTICE; OBESITY TREATMENT; UNITED-STATES; WEIGHT-LOSS; DESIGN; HEALTH; PREVENTION; DEATH AB Objective: Given the critical role of behavior in preventing and treating chronic diseases, it is important to accelerate the development of behavioral treatments that can improve chronic disease prevention and outcomes. Findings from basic behavioral and social sciences research hold great promise for addressing behaviorally based clinical health problems, yet there is currently no established pathway for translating fundamental behavioral science discoveries into health-related treatments ready for Phase III efficacy testing. This article provides a systematic framework for developing behavioral treatments for preventing and treating chronic diseases. Method: The Obesity-Related Behavioral Intervention Trials (ORBIT) model for behavioral treatment development features a flexible and progressive process, prespecified clinically significant milestones for forward movement, and return to earlier stages for refinement and optimization. Results: This article presents the background and rationale for the ORBIT model, a summary of key questions for each phase, a selection of study designs and methodologies well-suited to answering these questions, and prespecified milestones for forward or backward movement across phases. Conclusions: The ORBIT model provides a progressive, clinically relevant approach to increasing the number of evidence-based behavioral treatments available to prevent and treat chronic diseases. C1 [Czajkowski, Susan M.; Boyington, Josephine E.] NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Powell, Lynda H.] Rush Univ, Dept Prevent Med, Med Ctr, Chicago, IL 60612 USA. [Adler, Nancy; Epel, Elissa] Univ Calif San Francisco, Ctr Hlth & Community, Dept Psychiat, San Francisco, CA 94143 USA. [Adler, Nancy] Univ Calif San Francisco, Ctr Hlth & Community, Dept Pediat, San Francisco, CA 94143 USA. [Naar-King, Sylvie] Wayne State Univ, Pediat Prevent Res Ctr, Detroit, MI 48202 USA. [Reynolds, Kim D.] Claremont Grad Univ, Sch Community & Global Hlth, Claremont, CA 91711 USA. [Hunter, Christine M.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Laraia, Barbara] Univ Calif Berkeley, Sch Publ Hlth, Div Community Hlth & Human Dev, Berkeley, CA 94720 USA. [Olster, Deborah H.] NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. [Perna, Frank M.] NCI, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Peterson, Janey C.; Charlson, Mary E.] Weill Cornell Med Coll, Ctr Integrat Med, New York, NY USA. RP Czajkowski, SM (reprint author), MSC 7936,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM czajkows@mail.nih.gov FU National Institutes of Health; National Heart, Lung, and Blood Institute [U01 HL097843, U01 HL097894, U01 HL097973]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HL097889, U01 HL097839]; National Cancer Institute [U01 CA150387]; National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK088380]; NIH Office of Behavioral and Social Sciences Research; National Institute on Aging; American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies [K23AG042869] FX The Obesity-Related Behavioral Intervention Trials (ORBIT) consortium, consisting of seven research projects and a Resource and Coordination Unit (RCU), was supported by cooperative agreement grants from the National Institutes of Health. In particular, the National Heart, Lung, and Blood Institute funded Grants #U01 HL097843, #U01 HL097894, and #U01 HL097973. The National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development together cofunded Grants #U01 HL097889 and #U01 HL097839. The National Cancer Institute funded Grant #U01 CA150387. The National Institute of Diabetes and Digestive and Kidney Diseases funded Grant #U01 DK088380. The NIH Office of Behavioral and Social Sciences Research funded the RCU at Northwestern University to facilitate collaboration across the seven funded research projects. Preparation of this article was also supported by the National Institute on Aging, the American Federation for Aging Research, the John A. Hartford Foundation, and the Atlantic Philanthropies under Grant #K23AG042869. The authors would like to acknowledge key feedback and suggestions made by Peter Kaufmann, Rena Wing, and Leonard Epstein during earlier phases of this article's development. The views expressed in this article are those of the authors and do not necessarily reflect the view of the National Institutes of Health (NIH) or the U.S. Department of Health and Human Services. NR 51 TC 13 Z9 13 U1 3 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD OCT PY 2015 VL 34 IS 10 BP 971 EP 982 DI 10.1037/hea0000161 PG 12 WC Psychology, Clinical; Psychology SC Psychology GA CR8XC UT WOS:000361636600001 PM 25642841 ER PT J AU Hoeksema, M Tripathi, S White, M Qi, L Taubenberger, J van Eijk, M Haagsman, H Hartshorn, KL AF Hoeksema, Marloes Tripathi, Shweta White, Mitchell Qi, Li Taubenberger, Jeffery van Eijk, Martin Haagsman, Henk Hartshorn, Kevan L. TI Arginine-rich histones have strong antiviral activity for influenza A viruses SO INNATE IMMUNITY LA English DT Article DE Histones; innate immunity; influenza; pandemic; antimicrobial peptide ID SURFACTANT PROTEIN-D; NEUTROPHIL EXTRACELLULAR TRAPS; MANNOSE-BINDING LECTIN; ACUTE LUNG INJURY; ANTIMICROBIAL PEPTIDE; DIFFERENTIAL-MODE; PANDEMIC H1N1; LIVER-INJURY; INFECTION; DEFENSINS AB While histones are best known for DNA binding and transcription-regulating properties, they also have antimicrobial activity against a broad range of potentially pathogenic organisms. Histones are abundant in neutrophil extracellular traps, where they play an important role in NET-mediated antimicrobial killing. Here, we show anti-influenza activity of histones against both seasonal H3N2 and H1N1, but not pandemic H1N1. The arginine rich histones, H3 and H4, had greater neutralizing and viral aggregating activity than the lysine rich histones, H2A and H2B. Of all core histones, histone H4 is most potent in neutralizing IAV, and incubation with IAV with histone H4 results in a decrease in uptake and viral replication by epithelial cells when measured by qRT-PCR. The antiviral activity of histone H4 is mediated principally by direct effects on viral particles. Histone H4 binds to IAV as assessed by ELISA and co-sedimentation of H4 with IAV. H4 also induces aggregation, as assessed by confocal microscopy and light transmission assays. Despite strong antiviral activity against the seasonal IAV strains, H4 was inactive against pandemic H1N1. These findings indicate a possible role for histones in the innate immune response against IAV. C1 [Hoeksema, Marloes; Tripathi, Shweta; White, Mitchell; Hartshorn, Kevan L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Hoeksema, Marloes; van Eijk, Martin; Haagsman, Henk] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, NL-3508 TC Utrecht, Netherlands. [Qi, Li; Taubenberger, Jeffery] NIAID, Bethesda, MD 20892 USA. RP Hartshorn, KL (reprint author), Boston Univ, Sch Med, EBRC 414,650 Albany St, Boston, MA 02118 USA. EM khartsho@bu.edu FU NHLBI [R01 HL 069031] FX This work was supported by NHLBI grant number R01 HL 069031. NR 48 TC 6 Z9 6 U1 2 U2 10 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-4259 EI 1753-4267 J9 INNATE IMMUN-LONDON JI Innate Immun. PD OCT PY 2015 VL 21 IS 7 BP 736 EP 745 DI 10.1177/1753425915593794 PG 10 WC Biochemistry & Molecular Biology; Immunology; Medicine, Research & Experimental; Microbiology SC Biochemistry & Molecular Biology; Immunology; Research & Experimental Medicine; Microbiology GA CR7JU UT WOS:000361526600007 PM 26138524 ER PT J AU Rennert, O Lee, TL AF Rennert, Owen Lee, Tin-Lap TI Epigenetics dynamics in development and disease SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Editorial Material C1 [Rennert, Owen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Lee, Tin-Lap] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RP Lee, TL (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. EM leetl@cuhk.edu.hk RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 NR 0 TC 0 Z9 0 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD OCT PY 2015 VL 67 BP 44 EP 44 DI 10.1016/j.biocel.2015.07.004 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS0TI UT WOS:000361774700006 PM 26183655 ER PT J AU Ferrada, MA Xie, YD Nuermberger, E AF Ferrada, Marcela A. Xie, Yingda Nuermberger, Eric TI Primary HIV infection presenting as limbic encephalitis and rhabdomyolysis SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; AIDS; epidemiology; primary HIV infection; limbic encephalitis; rhabdomyolysis; seroconversion; North America ID IMMUNODEFICIENCY-VIRUS-INFECTION AB Recognising the initial clinical presentation of acute HIV infection could enable earlier initiation of antiretroviral therapy and appropriate counselling to reduce the risk of transmission to others. Herein, we describe an unusual case of acute HIV infection presenting as limbic encephalitis and rhabdomyolysis. C1 [Ferrada, Marcela A.; Nuermberger, Eric] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Ferrada, Marcela A.; Xie, Yingda] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Ferrada, MA (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM marcela.ferrada@nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD OCT PY 2015 VL 26 IS 11 BP 835 EP 836 DI 10.1177/0956462414560777 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CS0MM UT WOS:000361754500010 PM 25414090 ER PT J AU Koller, M Patel, K Chi, BH Wools-Kaloustian, K Dicko, F Chokephaibulkit, K Chimbetete, C Hazra, R Ayaya, S Leroy, V Trong, HK Egger, M Davies, MA AF Koller, Manuel Patel, Kunjal Chi, Benjamin H. Wools-Kaloustian, Kara Dicko, Fatoumata Chokephaibulkit, Kulkanya Chimbetete, Cleophas Hazra, Rohan Ayaya, Samual Leroy, Valeriane Huu Khanh Trong Egger, Matthias Davies, Mary-Ann CA IeDEA NISDI PHACS IMPAACT 219C Studies TI Authors' Reply: Early Initiation of Antiretroviral Therapy Among Young Children: A Long Way to Go SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter ID HIV; IMMUNODEFICIENCY C1 [Koller, Manuel; Egger, Matthias] Univ Bern, ISPM, CH-3012 Bern, Switzerland. [Patel, Kunjal] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chi, Benjamin H.] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Wools-Kaloustian, Kara] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Dicko, Fatoumata] Gabriel Toure Hosp, Dept Pediat, Bamako, Mali. [Chokephaibulkit, Kulkanya] Mahidol Univ, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. [Chimbetete, Cleophas] Newlands Clin, Harare, Zimbabwe. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Ayaya, Samual] Moi Univ, Dept Pediat, Coll Hlth Sci, Eldoret, Kenya. [Leroy, Valeriane] French Natl Inst Hlth & Med Res, INSERM, U897, Bordeaux, France. [Huu Khanh Trong] Childrens Hosp 1, Ho Chi Minh City, Vietnam. [Egger, Matthias; Davies, Mary-Ann] Univ Cape Town, Fac Hlth Sci, Sch Publ Hlth & Family Med, ZA-7700 Rondebosch, South Africa. RP Koller, M (reprint author), Univ Bern, ISPM, CH-3012 Bern, Switzerland. FU NIAID NIH HHS [5U01-AI069924-05, 1U01 AI069927, 5U01AI069919-04, U01 AI069911, U01 AI069919, U01 AI069924, U01AI069911-01] NR 11 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2015 VL 70 IS 2 BP E71 EP E72 DI 10.1097/QAI.0000000000000773 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CR8NY UT WOS:000361612200010 PM 26218412 ER PT J AU Lubega, M Tumwesigye, NM Kadobera, D Marrone, G Wabwire-Mangen, F Peterson, S Reynolds, SJ Ekstrom, AM AF Lubega, Muhamadi Tumwesigye, Nazarius Mbona Kadobera, Daniel Marrone, Gaetano Wabwire-Mangen, Fred Peterson, Stefan Reynolds, Steven J. Ekstrom, Anna Mia TI Effect of Community Support Agents on Retention of People Living With HIV in Pre-antiretroviral Care: A Randomized Controlled Trial in Eastern Uganda SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE community support agents; HIV care retention ID SUB-SAHARAN AFRICA; SOUTH-AFRICA; NORTHERN TANZANIA; FOLLOW-UP; THERAPY; ADHERENCE; ART; METAANALYSIS; PREVENTION; INITIATION AB Background:Over 50% of people living with HIV (PLHIV) in sub-Saharan Africa are lost to follow-up between diagnosis and initiation of antiretroviral treatment during pre-antiretroviral (pre-ARV) care. The effect of providing home counseling visits by community support agents on 2-year retention in pre-ARV care was evaluated through a randomized controlled trial in eastern Uganda.Methods:Four hundred newly screened HIV-positive patients were randomly assigned to receive posttest counseling alone (routine arm) or posttest counseling and monthly home counseling visits by community support agents to encourage them go back for routine pre-ARV care (intervention arm). The outcome measure was the proportion of new PLHIV in either arm who attended their scheduled pre-ARV care visits for at least 6 of the anticipated 8 visits in the first 24 months after HIV diagnosis. The difference between the 2 study arms was assessed using the (2) and T tests. Mantel-Haenszel Risk Ratios and multivariate logistic models were used to assess the adjusted effect of the intervention on the outcome.Results:In all models generated, participants receiving monthly home counseling visits were 2.5 times more likely to be retained in pre-ARV compared with those in standard care over a period of 24 months (adjusted risk ratio, 2.5; 95% confidence interval: 2.0 to 3.0).Conclusion:Monthly follow-up home visits by community workers more than doubled the retention of PLHIV in pre-ARV care in rural Uganda and can be applicable in similar resource-poor settings. C1 [Lubega, Muhamadi] Iganga Dist Adm, Dist Hlth Off, Iganga, Uganda. [Lubega, Muhamadi; Kadobera, Daniel] Makerere Univ, Iganga Mayuge Hlth & Demog Surveillance Syst, Kampala, Uganda. [Lubega, Muhamadi] Makerere Univ, Sch Publ Hlth, Dept Hlth Policy Planning & Management, Kampala, Uganda. [Lubega, Muhamadi] Busoga Univ, Inst Hlth Sci, Iganga, Uganda. [Lubega, Muhamadi; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Lubega, Muhamadi; Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Tumwesigye, Nazarius Mbona; Wabwire-Mangen, Fred] Makerere Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Kampala, Uganda. [Marrone, Gaetano; Peterson, Stefan; Ekstrom, Anna Mia] Karolinska Inst, Dept Publ Hlth Sci Global Hlth IHCAR, Solna, Sweden. [Peterson, Stefan] Uppsala Univ, IMCH, Dept Womens & Childrens Hlth, Uppsala, Sweden. [Ekstrom, Anna Mia] Karolinska Univ Hosp, Dept Infect Dis, Solna, Sweden. RP Lubega, M (reprint author), US Mission, Uganda POB 7007, Kampala, Uganda. EM dlmuhamadi@yahoo.co.uk FU Sida; European Commission through ARVMAC-INCO-DEV FP6 program; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health FX The trial received financial and logistical support in part from Sida and the European Commission through ARVMAC-INCO-DEV FP6 program and also in part (S.J.R.) from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and National Institutes of Health. The report has been compiled according to the CONSORT 2012 updated guidelines for reporting parallel group randomized trials and was registered by the current controlled trials CCT as ISRCTN94133652. NR 36 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2015 VL 70 IS 2 BP E36 EP E43 DI 10.1097/QAI.0000000000000723 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CR8NY UT WOS:000361612200001 PM 26079842 ER PT J AU El-Toukhy, S Choi, K AF El-Toukhy, Sherine Choi, Kelvin TI Smoking-Related Beliefs and Susceptibility Among United States Youth Nonsmokers SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; Racial/ethnic disparities; Smoking-related beliefs; Smoking susceptibility ID ADOLESCENTS; CIGARETTE AB Purpose: The purpose of the study was to examine racial/ethnic disparities in smoking beliefs and susceptibility in a nationally representative sample of United States youth nonsmokers (N = 21,931). Methods: Weighted regression models were used to examine smoking-related beliefs and susceptibility by race/ethnicity adjusting for demographics, exposure to pro-tobacco advertising and promotions, parental guidance against tobacco use, and peer norms. Results: Compared with non-Hispanic whites, racial/ethnic minority youth endorsed pro-smoking beliefs and were susceptible to smoking. Non-Hispanic blacks, non-Hispanic Asians, and Hispanics embraced social benefits of smoking (all p < .05). Hispanics had lower perceptions of tobacco-related risks (adjusted odds ratio = .87) and were more susceptible to smoking (adjusted odds ratio = 1.56). Disparities in smoking beliefs and susceptibility persisted between minority and non-Hispanic white youth after adjusting for exposure to pro-tobacco advertising and promotions, parental guidance against tobacco use, and peer norms. Conclusions: Smoking-related beliefs and susceptibility varied by race/ethnicity among youth nonsmokers after accounting for known predictors of youth smoking. Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine. C1 [El-Toukhy, Sherine; Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Choi, K (reprint author), Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bldg 3 Rm 5W05,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Kelvin.choi@nih.gov FU National Institutes of Health, National Institute on Minority Health and Health Disparities, Division of Intramural Research FX Funding for this research was provided by the National Institutes of Health, National Institute on Minority Health and Health Disparities, Division of Intramural Research. The funder did not play any role in this research. NR 10 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD OCT PY 2015 VL 57 IS 4 BP 448 EP 450 DI 10.1016/j.jadohealth.2015.06.016 PG 3 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA CS0NX UT WOS:000361759300016 PM 26271160 ER PT J AU McCann, DJ Petry, NM Bresell, A Isacsson, E Wilson, E Alexander, RC AF McCann, David J. Petry, Nancy M. Bresell, Anders Isacsson, Eva Wilson, Ellis Alexander, Robert C. TI Medication Nonadherence, "Professional Subjects," and Apparent Placebo Responders Overlapping Challenges for Medications Development SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Review DE medication adherence; professional subjects; reinforcement interventions ID MAJOR DEPRESSIVE DISORDER; CLINICAL-TRIALS; ANTIHYPERTENSIVE MEDICATIONS; SELF-REPORT; ANTIRETROVIRAL THERAPY; SCHIZOPHRENIA TRIALS; EXPLORATORY ANALYSES; DRUG APPLICATIONS; EFFICACY DATA; DOUBLE-BLIND AB Nonadherence is a major problem in clinical trials of new medications. To evaluate the extent of nonadherence, this study evaluated pharmacokinetic sampling from 1765 subjects receiving active therapy across 8 psychiatric trials conducted between 2001 and 2011. With nonadherence defined as greater than 50% of plasma samples below the limit of quantification for study drug, the percentage of nonadherent subjects ranged from 12.8% to 39.2%. There was a trend toward increased nonadherence in studies with greater numbers of subjects, but an association with nonadherence was not apparent for other study design parameters or subject characteristics. For 2 trials with multiple recruitment sites in geographical proximity, several subjects attempted to simultaneously enroll at separate site locations. The construct of professional subjects, those who enroll in trials only for financial gain, is gaining attention, and we therefore modeled the impact of professional subjects on medication efficacy trials. The results indicate that enrollment of professional subjects who are destined to succeed (those who will appear to achieve treatment success regardless of study drug assignment) can substantially increase both the apparent placebo response rate and the sample size requirement for statistical power, while decreasing the observed effect size. The overlapping nature of nonadherence, professional subjects, and placebo response suggests that these issues should be considered and addressed together. Following this approach, we describe a novel clinical trial design to minimize the adverse effects of professional subjects on trial outcomes and discuss methods to monitor adherence. C1 [McCann, David J.] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Petry, Nancy M.] Univ Connecticut, Sch Med, Calhoun Cardiol Ctr, Farmington, CT USA. [Petry, Nancy M.] Univ Connecticut, Sch Med, Dept Med, Farmington, CT USA. [Bresell, Anders; Isacsson, Eva; Wilson, Ellis; Alexander, Robert C.] AstraZeneca, Neurosci, Innovat Med, Cambridge, MA USA. RP McCann, DJ (reprint author), NIDA, 6001 Execut Blvd,Suite 4123, Bethesda, MD 20892 USA. EM dmccann@NIH.GOV FU AstraZeneca FX David J. McCann is an employee of the National Institutes of Health. Nancy M. Petry is an employee of the University of Connecticut. Robert C. Alexander, Anders Bresell, Eva Isacsson, and Ellis Wilson were employees of AstraZeneca at the time of this study. AstraZeneca sponsored all clinical trials analyzed in this study. The authors declare no other conflicts of interest. NR 65 TC 3 Z9 3 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2015 VL 35 IS 5 BP 566 EP 573 DI 10.1097/JCP.0000000000000372 PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA CR0TM UT WOS:000361036100011 PM 26244381 ER PT J AU Teff, KL Rickels, K Alshehabi, E Rickels, MR AF Teff, Karen L. Rickels, Karl Alshehabi, Erica Rickels, Michael R. TI Metabolic Impairments Precede Changes in Hunger and Food Intake Following Short-Term Administration of Second-Generation Antipsychotics SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE atypical antipsychotics; body weight; insulin sensitivity; glucagon-like peptide 1; second-generation antipsychotics ID WEIGHT-GAIN; ATYPICAL ANTIPSYCHOTICS; GLUCOSE-METABOLISM; INSULIN-RESISTANCE; HEALTHY-VOLUNTEERS; OLANZAPINE; SCHIZOPHRENIA; RISPERIDONE; TOLERANCE; SECRETION AB The second-generation antipsychotics (SGAs) are associated with weight gain and an increased incidence of metabolic diseases. The metabolic impairments are assumed a consequence of increased body adiposity secondary to central nervous system-associated increases in food intake. We have previously reported that, independent of weight gain, 9 days of olanzapine administration to control subjects is associated with insulin resistance and increases in postprandial levels of insulin and glucagon-like peptide 1 to a mixed meal challenge. This current report describes previously unpublished data on the effects of the SGAs olanzapine and aripiprazole compared with placebo on detailed hunger and satiety responses over the 12-day inpatient evaluation as well as postprandial ghrelin and leptin responses prior to and following administration of the 2 SGAs. We found no changes in hunger, fullness, or in the orexigenic hormone ghrelin or satiety hormone leptin, consistent with our previous report indicating no change in weight during this study. The results indicate that the SGAs are associated with metabolic changes prior to changes in hunger, satiety, and food intake, and this temporal separation suggests that there are differential mechanisms mediating SGA-associated changes in metabolism and food intake. C1 [Teff, Karen L.; Alshehabi, Erica] Univ Penn, Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Rickels, Karl] Univ Penn, Dept Psychiat, Mood & Anxiety Disorders Treatment & Res Program, Philadelphia, PA 19104 USA. [Rickels, Michael R.] Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. RP Teff, KL (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bldg 2DEM,Room 685,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM teffk@niddk.nih.gov FU National Institutes of Health (NIH) [DK084383]; NIH [DK19525] FX This study was supported by National Institutes of Health (NIH) grant DK084383 (to K.L.T.); core services were provided by the University of Pennsylvania Diabetes Research Center sponsored by NIH DK19525 and Clinical and Translational Research Center facilities from NIH UL1-RR-024134. NR 25 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2015 VL 35 IS 5 BP 579 EP 582 DI 10.1097/JCP.0000000000000393 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA CR0TM UT WOS:000361036100013 PM 26274045 ER PT J AU Wang, L Tran, AB Nociti, FH Thumbigere-Math, V Foster, BL Krieger, CC Kantovitz, KR Novince, CM Koh, AJ McCauley, LK Somerman, MJ AF Wang, L. Tran, A. B. Nociti, F. H., Jr. Thumbigere-Math, V. Foster, B. L. Krieger, C. C. Kantovitz, K. R. Novince, C. M. Koh, A. J. McCauley, L. K. Somerman, M. J. TI PTH and Vitamin D Repress DMP1 in Cementoblasts SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE parathyroid hormone; 1,25D; dentin matrix protein 1; mineral homeostasis; RNA sequencing; hormonal regulation ID DENTIN MATRIX PROTEIN-1; OSTEOCLASTIC BONE-RESORPTION; PARATHYROID-HORMONE; GENE-EXPRESSION; IN-VITRO; FEEDBACK LOOP; OSTEOCYTES; FGF23; DIFFERENTIATION; CELLS AB A complex feedback mechanism between parathyroid hormone (PTH), 1,25(OH)(2)D-3 (1,25D), and fibroblast growth factor 23 (FGF-23) maintains mineral homeostasis, in part by regulating calcium and phosphate absorption/reabsorption. Previously, we showed that 1,25D regulates mineral homeostasis by repressing dentin matrix protein 1 (DMP1) via the vitamin D receptor pathway. Similar to 1,25D, PTH may modulate DMP1, but the underlying mechanism remains unknown. Immortalized murine cementoblasts (OCCM.30), similar to osteoblasts and known to express DMP1, were treated with PTH (1-34). Real-time quantitative polymerase chain reaction (PCR) and Western blot revealed that PTH decreased DMP1 gene transcription (85%) and protein expression (30%), respectively. PTH mediated the downregulation of DMP1 via the cAMP/protein kinase A (PKA) pathway. Immunohistochemistry confirmed the decreased localization of DMP1 in vivo in cellular cementum and alveolar bone of mice treated with a single dose (50 mu g/kg) of PTH (1-34). RNA-seq was employed to further identify patterns of gene expression shared by PTH and 1,25D in regulating DMP1, as well as other factors involved in mineral homeostasis. PTH and 1,25D mutually upregulated 36 genes and mutually downregulated 27 genes by 2-fold expression (P 0.05). Many identified genes were linked with the regulation of bone/tooth homeostasis, cell growth and differentiation, calcium signaling, and DMP1 transcription. Validation of RNA-seq results via PCR array confirmed a similar gene expression pattern in response to PTH and 1,25D treatment. Collectively, these results suggest that PTH and 1,25D share complementary effects in maintaining mineral homeostasis by mutual regulation of genes/proteins associated with calcium and phosphate metabolism while also exerting distinct roles on factors modulating mineral metabolism. Furthermore, PTH may modulate phosphate homeostasis by downregulating DMP1 expression via the cAMP/PKA pathway. Targeting genes/proteins mutually governed by PTH and 1,25D may be a viable approach for designing new therapies for preserving mineralized tissue health. C1 [Wang, L.; Tran, A. B.; Nociti, F. H., Jr.; Thumbigere-Math, V.; Foster, B. L.; Kantovitz, K. R.; Somerman, M. J.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bethesda, MD 20892 USA. [Nociti, F. H., Jr.; Kantovitz, K. R.] Univ Estadual Campinas, Sch Dent, Div Periodont, Dept Prosthodont & Periodont, Piracicaba, SP, Brazil. [Krieger, C. C.] NIDDK, NIH, Bethesda, MD USA. [Novince, C. M.; Koh, A. J.; McCauley, L. K.] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Novince, C. M.] Med Univ S Carolina, Dept Oral Hlth Sci, Charleston, SC 29425 USA. RP Wang, L (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bldg 50 Room 4120, Bethesda, MD 20892 USA. EM le.wang@nih.gov RI Kantovitz, Kamila/J-4567-2013; OI Kantovitz, Kamila/0000-0003-2045-7924; Krieger, Christine/0000-0002-1856-415X FU Intramural Research Program of National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK53904] FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (MJS) and the National Institute of Diabetes and Digestive and Kidney Diseases R01DK53904 (LKM). The authors thank Dr. Chunlin Qin (Baylor College of Dentistry) for providing the DMP1 antibody, Gustavo Gutierrez-Cruz and Steve Brooks from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for RNA-seq analysis, and Mudita Patel (NIAMS) for technical assistance. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 37 TC 1 Z9 1 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2015 VL 94 IS 10 BP 1408 EP 1416 DI 10.1177/0022034515599726 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CS1JD UT WOS:000361819400012 PM 26276370 ER PT J AU Laiyemo, AO Doubeni, C Pinsky, PF Doria-Rose, VP Bresalier, R Hickey, T Riley, T Church, TR Weissfeld, J Schoen, RE Marcus, PM Prorok, PC AF Laiyemo, Adeyinka O. Doubeni, Chyke Pinsky, Paul F. Doria-Rose, V. Paul Bresalier, Robert Hickey, Thomas Riley, Thomas Church, Tim R. Weissfeld, Joel Schoen, Robert E. Marcus, Pamela M. Prorok, Philip C. TI Occurrence of Distal Colorectal Neoplasia Among Whites and Blacks Following Negative Flexible Sigmoidoscopy: An Analysis of PLCO Trial SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE PLCO; colorectal cancer disparities; adenomatous polyps; flexible sigmoidoscopy; screening ID CANCER SCREENING TRIAL; AVERAGE-RISK PERSONS; AMERICAN-COLLEGE; COLON POLYPS; COLONOSCOPY; PREVALENCE; YIELD; DISPARITIES; POPULATION; RECURRENCE AB It is unclear whether the higher rate of colorectal cancer (CRC) among non-Hispanic blacks (blacks) is due to lower rates of CRC screening or greater biologic risk. We aimed to evaluate whether blacks are more likely than non-Hispanic whites (whites) to develop distal colon neoplasia (adenoma and/or cancer) after negative flexible sigmoidoscopy (FSG). We analyzed data of participants with negative FSGs at baseline in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial who underwent repeat FSGs 3 or 5 years later. Subjects with polyps or masses were referred to their physicians for diagnostic colonoscopy. We collected and reviewed the records of diagnostic evaluations. Our analytic cohort consisted of 21,550 whites and 975 blacks. We did a comparison by race (whites vs. blacks) in the findings of polyps or masses at repeat FSG, the follow-up of abnormal test results and the detection of colorectal neoplasia at diagnostic colonoscopy. At the follow-up FSG examination, 304 blacks (31.2 %) and 4183 whites (19.4 %) had abnormal FSG, [adjusted relative risk (RR) = 1.00; 95 % confidence interval (CI), 0.90-1.10]. However, blacks were less likely to undergo diagnostic colonoscopy (76.6 % vs. 83.1 %; RR = 0.90; 95 % CI, 0.84-0.96). Among all included patients, blacks had similar risk of any distal adenoma (RR = 0.86; 95 % CI, 0.65-1.14) and distal advanced adenoma (RR = 1.01; 95 % CI, 0.60-1.68). Similar results were obtained when we restricted our analysis to compliant subjects who underwent diagnostic colonoscopy (RR = 1.01; 95 % CI, 0.80-1.29) for any distal adenoma and (RR = 1.18; 95 % CI, 0.73-1.92) for distal advanced adenoma. We did not find any differences between blacks and whites in the risk of distal colorectal adenoma 3-5 years after negative FSG. However, follow-up evaluations were lower among blacks. C1 [Laiyemo, Adeyinka O.] Howard Univ, Coll Med, Dept Med, Washington, DC 20060 USA. [Laiyemo, Adeyinka O.; Prorok, Philip C.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Doubeni, Chyke] Univ Penn, Leonard Davis Inst Hlth Econ, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Doubeni, Chyke] Univ Penn, Perelman Sch Med, Ctr Publ Hlth Initiat, Philadelphia, PA 19104 USA. [Pinsky, Paul F.] NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Doria-Rose, V. Paul; Marcus, Pamela M.] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Bresalier, Robert] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hickey, Thomas; Riley, Thomas] Informat Management Serv Inc, Rockville, MD USA. [Church, Tim R.] Univ Minnesota, Sch Publ Hlth, Dept Environm Hlth Sci, Minneapolis, MN USA. [Weissfeld, Joel; Schoen, Robert E.] Univ Pittsburgh, Dept Med & Epidemiol, Pittsburgh, PA USA. [Laiyemo, Adeyinka O.] Howard Univ, Coll Med, Dept Med, Div Gastroenterol, Washington, DC USA. RP Laiyemo, AO (reprint author), Howard Univ, Coll Med, Dept Med, Div Gastroenterol, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM adeyinka.laiyemo@howard.edu OI Doubeni, Chyke/0000-0001-7495-0285; Doria-Rose, Vincent/0000-0002-8802-5143 FU National Institutes of Health FX National Institutes of Health. NR 31 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2015 VL 30 IS 10 BP 1447 EP 1453 DI 10.1007/s11606-015-3297-3 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000019 PM 25835747 ER PT J AU Gissen, P Arias, IM AF Gissen, Paul Arias, Irwin M. TI Structural and functional hepatocyte polarity and liver disease SO JOURNAL OF HEPATOLOGY LA English DT Review DE Hepatocyte polarity; Inherited liver diseases; Hepatocyte biology; Cholestasis; Canalicular diseases ID HEPATITIS-C VIRUS; FAMILIAL INTRAHEPATIC CHOLESTASIS; SALT EXPORT PUMP; WIF-B CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; MICROVILLUS INCLUSION DISEASE; CANALICULAR MEMBRANE-VESICLES; ACTIVATED PROTEIN-KINASE; CANINE KIDNEY-CELLS; HEPATOCELLULAR-CARCINOMA AB Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Gissen, Paul] UCL, MRC Lab Mol Cell Biol, London, England. [Gissen, Paul] UCL Inst Child Hlth, London, England. [Gissen, Paul] Great Ormond St Hosp Sick Children, London, England. [Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. RP Gissen, P (reprint author), MRC Lab Mol Cell Biol, Gower St, London WC1E 6BT, England. EM p.gissen@ucl.ac.uk FU ERC [337057 CLOC]; Wellcome Trust [WT095662MA] FX P.G. is a Wellcome Trust Senior Research Fellow in Clinical Sciences (WT095662MA); P.G. is supported by the ERC Starter Grant 337057 CLOC. NR 158 TC 6 Z9 7 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD OCT PY 2015 VL 63 IS 4 BP 1023 EP 1037 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS0EG UT WOS:000361729900029 PM 26116792 ER PT J AU Evans, H Killoran, KE Mitre, BK Morris, CP Kim, SY Mitre, E AF Evans, Holly Killoran, Kristin E. Mitre, Blima K. Morris, C. Paul Kim, So-Young Mitre, Edward TI Ten Weeks of Infection with a Tissue-Invasive Helminth Protects against Local Immune Complex-Mediated Inflammation, but Not Cutaneous Type I Hypersensitivity, in Previously Sensitized Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGIC AIRWAY INFLAMMATION; REGULATORY T-CELLS; LITOMOSOIDES-SIGMODONTIS; MAST-CELLS; ASTHMA; EOSINOPHILS; MODEL; IGE; RECRUITMENT; CHEMOTAXIS AB In this study, we evaluated the effect chronic helminth infection has on allergic disease in mice previously sensitized to OVA. Ten weeks of infection with Litomosoides sigmodontis reduced immunological markers of type I hypersensitivity, including OVA-specific IgE, basophil activation, and mast cell degranulation. Despite these reductions, there was no protection against immediate clinical hypersensitivity following intradermal OVA challenge. However, late-phase ear swelling, due to type III hypersensitivity, was significantly reduced in chronically infected animals. Levels of total IgG2a, OVA-specific IgG2a, and OVA-specific IgG1 were reduced in the setting of infection. These reductions were most likely due to increased Ab catabolism as ELISPOT assays demonstrated that infected animals do not have suppressed Ab production. Ear histology 24 h after challenge showed infected animals have reduced cellular infiltration in the ear, with significant decreases in numbers of neutrophils and macrophages. Consistent with this, infected animals had less neutrophil-specific chemokines CXCL-1 and CXCL-2 in the ear following challenge. Additionally, in vitro stimulation with immune complexes resulted in significantly less CXCL-1 and CXCL-2 production by eosinophils from chronically infected mice. Expression of Fc gamma RI was also significantly reduced on eosinophils from infected animals. These data indicate that chronic filarial infection suppresses eosinophilic responses to Ab-mediated activation and has the potential to be used as a therapeutic for pre-existing hypersensitivity diseases. C1 [Evans, Holly; Morris, C. Paul; Kim, So-Young; Mitre, Edward] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Killoran, Kristin E.] Iowa State Univ, Coll Vet Med, Ames, IA 50011 USA. [Mitre, Blima K.] Univ Pittsburgh, Med Ctr, Passavant Hosp, Dept Pathol, Pittsburgh, PA 15213 USA. [Morris, C. Paul] NIAID, NIH, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM Edward.mitre@usuhs.edu FU National Institute of Allergy and Infectious Diseases [1R01AI076522]; Uniformed Services University [R073UE247414] FX This work was supported by National Institute of Allergy and Infectious Diseases Grant 1R01AI076522 and Uniformed Services University Grant R073UE247414. NR 36 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2015 VL 195 IS 7 BP 2973 EP 2984 DI 10.4049/jimmunol.1500081 PG 12 WC Immunology SC Immunology GA CS0ID UT WOS:000361741200005 PM 26324775 ER PT J AU Arai, Y Yamashita, K Kuriyama, K Shiokawa, M Kodama, Y Sakurai, T Mizugishi, K Uchida, K Kadowaki, N Takaori-Kondo, A Kudo, M Okazaki, K Strober, W Chiba, T Watanabe, T AF Arai, Yasuyuki Yamashita, Kouhei Kuriyama, Katsutoshi Shiokawa, Masahiro Kodama, Yuzo Sakurai, Toshiharu Mizugishi, Kiyomi Uchida, Kazushige Kadowaki, Norimitsu Takaori-Kondo, Akifumi Kudo, Masatoshi Okazaki, Kazuichi Strober, Warren Chiba, Tsutomu Watanabe, Tomohiro TI Plasmacytoid Dendritic Cell Activation and IFN-alpha Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; REGULATORY T-CELLS; CLINICAL-SIGNIFICANCE; SCLEROSING DISEASE; IMMUNE-RESPONSE; INNATE IMMUNITY; IGG4; MICE; INVOLVEMENT AB The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-alpha production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-alpha, and with pDC depletion and IFN-alpha-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-alpha. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-alpha-expressing pDCs and had significantly higher serum IFN-alpha levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-alpha and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-alpha is a major cause of murine AIP; in addition, the increased pDC production of IFN-alpha and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease. C1 [Arai, Yasuyuki; Yamashita, Kouhei; Mizugishi, Kiyomi; Kadowaki, Norimitsu; Takaori-Kondo, Akifumi] Kyoto Univ, Dept Hematol & Oncol, Grad Sch Med, Kyoto 6068507, Japan. [Kuriyama, Katsutoshi; Shiokawa, Masahiro; Kodama, Yuzo; Chiba, Tsutomu; Watanabe, Tomohiro] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Kyoto 6068507, Japan. [Sakurai, Toshiharu; Kudo, Masatoshi] Kinki Univ, Dept Gastroenterol & Hepatol, Sch Med, Osaka 5898511, Japan. [Uchida, Kazushige; Okazaki, Kazuichi] Kansai Med Univ, Dept Gastroenterol & Hepatol, Osaka 5731191, Japan. [Strober, Warren; Watanabe, Tomohiro] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Watanabe, Tomohiro] Kyoto Univ, Ctr Innovat Immunoregulat Technol & Therapeut, Grad Sch Med, Kyoto 6068507, Japan. RP Watanabe, T (reprint author), Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Sakyo Ku, 54 Shogoin Kawahara Cho, Kyoto 6068507, Japan. EM kouhei@k-uhp.kyoto-u.ac.jp; tnahrwtnb@k-uhp.kyoto-u.ac.jp OI Kudo, Masatoshi/0000-0002-4102-3474 FU Japan Society for the Promotion of Science [25293172, 15K15370, 15K09499]; Japanese Society of Gastroenterology; Kato Memorial Trust for Nambyo Research; Special Coordination Funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Astellas Pharma Inc.; Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan FX This work was supported by Grants-in-Aid for Scientific Research 25293172 and 15K15370 from the Japan Society for the Promotion of Science, the Japanese Society of Gastroenterology, the Kato Memorial Trust for Nambyo Research, Special Coordination Funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Astellas Pharma Inc. in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program. This work was also supported by Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan (to T.W.) and by Grant-in-Aid for Scientific Research 15K09499 from the Japan Society for the Promotion of Science (to K.Y.). NR 57 TC 8 Z9 8 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2015 VL 195 IS 7 BP 3033 EP 3044 DI 10.4049/jimmunol.1500971 PG 12 WC Immunology SC Immunology GA CS0ID UT WOS:000361741200011 PM 26297761 ER PT J AU Blackburn, MJ Zhong-Min, M Caccuri, F McKinnon, K Schifanella, L Guan, YJ Gorini, G Venzon, D Fenizia, C Binello, N Gordon, SN Miller, CJ Franchini, G Vaccari, M AF Blackburn, Matthew J. Zhong-Min, Ma Caccuri, Francesca McKinnon, Katherine Schifanella, Luca Guan, Yongjun Gorini, Giacomo Venzon, David Fenizia, Claudio Binello, Nicolo Gordon, Shari N. Miller, Christopher J. Franchini, Genoveffa Vaccari, Monica TI Regulatory and Helper Follicular T Cells and Antibody Avidity to Simian Immunodeficiency Virus Glycoprotein 120 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GERMINAL CENTER REACTIONS; CXC CHEMOKINE RECEPTOR-5; B-CELLS; HIV-INFECTION; IMMUNE-RESPONSES; RHESUS MACAQUES; MUCOSAL SITES; LYMPH-NODE; TFH CELLS; ACTIVATION AB T follicular regulatory cells (T-FR) are a suppressive CD4(+) T cell subset that migrates to germinal centers (GC) during Ag presentation by upregulating the chemokine receptor CXCR5. In the GC, T-FR control T follicular helper cell (T-FH) expansion andmodulate the development of high-affinity Ag-specific responses. In this study, we identified and characterized T-FR as CXCR5(+) CCR7(-) "follicular" T regulatory cells in lymphoid tissues of healthy rhesus macaques, and we studied their dynamics throughout infection in a welldefined animal model of HIV pathogenesis. T-FR were infected by SIVmac251 and had comparable levels of SIV DNA to CXCR5(-) CCR7(+) "T zone" T regulatory cells and T-FH. Contrary to the SIV-associated T-FH expansion in the chronic phase of infection, we observed an apparent reduction of T-FR frequency in cell suspension, as well as a decrease of CD3(+)Foxp3(+) cells in the GC of intact lymph nodes. T-FR frequency was inversely associated with the percentage of T-FH and, interestingly, with the avidity of the Abs that recognize the SIV gp120 envelope protein. Our findings show changes in the T-FH/T-FR ratio during chronic infection and suggest possible mechanisms for the unchecked expansion of T-FH cells in HIV/SIV infection. C1 [Blackburn, Matthew J.; Caccuri, Francesca; McKinnon, Katherine; Schifanella, Luca; Gorini, Giacomo; Fenizia, Claudio; Binello, Nicolo; Gordon, Shari N.; Franchini, Genoveffa; Vaccari, Monica] NCI, Anim Models & Retroviral Vaccine Sect, NIH, Bethesda, MD 20892 USA. [Zhong-Min, Ma; Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Guan, Yongjun] Univ Maryland, Dept Microbial Pathogenesis, Sch Dent, Baltimore, MD 21201 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20852 USA. RP Vaccari, M (reprint author), NCI, Anim Models & Retroviral Vaccine Sect, NIH, 9000 Rockville Pike,Bldg 41,Room C303, Bethesda, MD 20892 USA. EM vaccarim@mail.nih.gov FU Intramural Research Program at the National Cancer Institute, National Institutes of Health FX This work was supported entirely by the Intramural Research Program at the National Cancer Institute, National Institutes of Health. NR 65 TC 10 Z9 10 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2015 VL 195 IS 7 BP 3227 EP 3236 DI 10.4049/jimmunol.1402699 PG 10 WC Immunology SC Immunology GA CS0ID UT WOS:000361741200029 PM 26297759 ER PT J AU DeMicco, A Naradikian, MS Sindhava, VJ Yoon, JH Gorospe, M Wertheim, GB Cancro, MP Bassine, CH AF DeMicco, Amy Naradikian, Martin S. Sindhava, Vishal J. Yoon, Je-Hyun Gorospe, Myriam Wertheim, Gerald B. Cancro, Michael P. Bassine, Craig H. TI B Cell-Intrinsic Expression of the HuR RNA-Binding Protein Is Required for the T Cell-Dependent Immune Response In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS SWITCH RECOMBINATION; GERMINAL CENTER FORMATION; IMPAIRED UP-REGULATION; MESSENGER-RNA; LYMPHOCYTE DEVELOPMENT; ANTIBODY-RESPONSE; CRE RECOMBINASE; POLYMERASE-II; MARGINAL ZONE; PLASMA-CELLS AB The HuR RNA-binding protein posttranscriptionally controls expression of genes involved in cellular survival, proliferation, and differentiation. To determine roles of HuR in B cell development and function, we analyzed mice with B lineage-specific deletion of the HuR gene. These HuR Delta/Delta mice have reduced numbers of immature bone marrow and mature splenic B cells, with only the former rescued by p53 inactivation, indicating that HuR supports B lineage cells through developmental stage-specific mechanisms. Upon in vitro activation, HuR Delta/Delta B cells have a mild proliferation defect and impaired ability to produce mRNAs that encode IgH chains of secreted Abs, but no deficiencies in survival, isotype switching, or expression of germinal center (GC) markers. In contrast, HuR Delta/Delta mice have minimal serum titers of all Ab isotypes, decreased numbers of GC and plasma B cells, and few peritoneal B-1 B cells. Moreover, HuR Delta/Delta mice have severely decreased GCs, T follicular helper cells, and high-affinity Abs after immunization with a T cell-dependent Ag. This failure of HuR Delta/Delta mice to mount a T cell-dependent Ab response contrasts with the ability of HuR Delta/Delta B cells to become GC-like in vitro, indicating that HuR is essential for aspects of B cell activation unique to the in vivo environment. Consistent with this notion, we find in vitro stimulated HuR Delta/Delta B cells exhibit modestly reduced surface expression of costimulatory molecules whose expression is similarly decreased in humans with common variable immunodeficiency. HuR Delta/Delta mice provide a model to identify B cell-intrinsic factors that promote T cell-dependent immune responses in vivo. C1 [DeMicco, Amy; Bassine, Craig H.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Ctr Childhood Canc Res, Div Canc Pathobiol, Philadelphia, PA 19104 USA. [DeMicco, Amy; Bassine, Craig H.] Univ Penn, Abramson Family Canc Res Inst, Dept Pathol & Lab Med, Cell & Mol Biol Grad Grp,Perelman Sch Med, Philadelphia, PA 19104 USA. [Naradikian, Martin S.; Cancro, Michael P.] Univ Penn, Perelman Sch Med, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Naradikian, Martin S.; Sindhava, Vishal J.; Cancro, Michael P.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Yoon, Je-Hyun; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wertheim, Gerald B.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Bassine, CH (reprint author), Childrens Hosp Philadelphia, 4054 Colket Translat Res Bldg,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bassing@email.chop.edu OI Naradikian, Martin/0000-0003-1926-0382 FU Training Program in Cell and Molecular Biology of the University of Pennsylvania [5T32GM007229]; National Cancer Institute [CA177092]; Patel Family Scholar Award of Abramson Cancer Center of Perelman School of Medicine; National Research Service Award [2T32AI055428]; National Institute on Aging-Intramural Research Program, National Institutes of Health; Department of Pathology and Laboratory Medicine of Children's Hospital of Philadelphia, Leukemia and Lymphoma Society Scholar Award; National Institutes of Health [CA125195, CA136470] FX This work was supported by Training Program in Cell and Molecular Biology 5T32GM007229 of the University of Pennsylvania, National Cancer Institute F31 Predoctoral Fellowship CA177092, and the Patel Family Scholar Award of Abramson Cancer Center of Perelman School of Medicine (to A.D.); National Research Service Award 2T32AI055428 (to M.S.N.); the National Institute on Aging-Intramural Research Program, National Institutes of Health (to J.-H.Y. and M.G.); the Department of Pathology and Laboratory Medicine of Children's Hospital of Philadelphia, Leukemia and Lymphoma Society Scholar Award; and National Institutes of Health R01 Grants CA125195 and CA136470 (to C.H.B.). NR 75 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2015 VL 195 IS 7 BP 3449 EP 3462 DI 10.4049/jimmunol.1500512 PG 14 WC Immunology SC Immunology GA CS0ID UT WOS:000361741200050 PM 26320247 ER PT J AU Zhu, ZQ Cuss, SM Singh, V Gurusamy, D Shoe, JL Leighty, R Bronte, V Hurwitz, AA AF Zhu, Ziqiang Cuss, Steven M. Singh, Vinod Gurusamy, Devikala Shoe, Jennifer L. Leighty, Robert Bronte, Vincenzo Hurwitz, Arthur A. TI CD4(+) T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; SELF-ANTIGENS; MELANOMA; TOLERANCE; MEMORY; IMMUNOTHERAPY; INFILTRATION; LYMPHOCYTES; ENVIRONMENT; PROGRESSION AB Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy. We and others have previously reported that high-avidity CD8(+) T cells are more susceptible to tolerance induction in the tumor microenvironment. In the present study, we used a novel model where T cells derived from two independent TCR transgenic mouse lines recognize the same melanoma antigenic epitope but differ in their avidity. We tested whether providing CD4(+) T cell help would improve T cell responsiveness as a function of effector T cell avidity. Interestingly, delivery of CD4(+) T cell help during in vitro priming of CD8(+) T cells improved cytokine secretion and lytic capacity of high-avidity T cells, but not low-avidity T cells. Consistent with this observation, copriming with CD4(+) T cells improved antitumor immunity mediated by higher avidity, melanoma-specific CD8(+) T cells, but not T cells with similar specificity but lower avidity. Enhanced tumor immunity was associated with improved CD8(+) T cell expansion and reduced tolerization, and it was dependent on presentation of both CD4(+) and CD8(+) T cell epitopes by the same dendritic cell population. Our findings demonstrate that CD4(+) T cell help preferentially augments high-avidity CD8(+) T cells and provide important insight for understanding the requirements to elicit and maintain durable tumor immunity. C1 [Zhu, Ziqiang; Cuss, Steven M.; Singh, Vinod; Gurusamy, Devikala; Hurwitz, Arthur A.] NCI, Tumor Immun & Tolerance Sect, Lab Mol Immunoregulat, Canc & Inflammat Program,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Shoe, Jennifer L.] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick, MD 21072 USA. [Leighty, Robert] NCI, Data Management Serv, Frederick, MD 21702 USA. [Bronte, Vincenzo] Univ Verona, Dept Pathol & Diagnost, Immunol Sect, I-37134 Verona, Italy. RP Hurwitz, AA (reprint author), Agenus Inc, 3 Forbes Rd, Lexington, MA 02421 USA. EM Andy.Hurwitz@Agenusbio.com RI Bronte, Vincenzo/K-7902-2016 OI Bronte, Vincenzo/0000-0002-3741-5141 FU Intramural Research Program of the National Cancer Institute/National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute/National Institutes of Health. NR 32 TC 3 Z9 3 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2015 VL 195 IS 7 BP 3482 EP 3489 DI 10.4049/jimmunol.1401571 PG 8 WC Immunology SC Immunology GA CS0ID UT WOS:000361741200053 PM 26320256 ER PT J AU van der Marel, J Rodriguez, A del Pino, M van Baars, R Jenkins, D van de Sandt, MM Torne, A Ordi, J ter Harmsel, B Verheijen, RHM Schiffman, M Gage, JC Quint, WGV Wentzensen, N AF van der Marel, Jacolien Rodriguez, Agata del Pino, Marta van Baars, Romy Jenkins, David van de Sandt, Miekel M. Torne, Aureli Ordi, Jaume ter Harmsel, Bram Verheijen, Rene H. M. Schiffman, Mark Gage, Julia C. Quint, Wim G. V. Wentzensen, Nicolas TI The Value of Endocervical Curettage in Addition to Biopsies in Women Referred to Colposcopy SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE colposcopy; endocervical curettage; cervical intraepithelial neoplasia; biopsy ID CERVICAL INTRAEPITHELIAL NEOPLASIA; CANCER SCREENING-TESTS; CONSENSUS GUIDELINES; DIRECTED BIOPSY; UTERINE CERVIX; GRADE 2; MANAGEMENT; CYTOLOGY; PRECURSORS; DIAGNOSIS AB Objective Performing endocervical curettage (ECC) at colposcopy may increase the yield of cervical intraepithelial neoplasia grade 2 (CIN2) or worse (CIN2+) compared to biopsies alone. The additional benefit of ECC in detecting CIN2+ was studied in women with lesion-targeted biopsies (low-grade or worse impression) and women with biopsies of normal-appearing cervix (less than low-grade impression). Methods In this subanalysis of a multicenter study, 126 women referred to colposcopy who had an ECC were included. Multiple directed biopsies were taken from lesions, and a nontargeted biopsy was added if fewer than 4 biopsies were collected. Risk strata of CIN2+ were evaluated based on cytology and colposcopic appearance to identify women for whom ECC would be most valuable. Results The CIN2+ yield of ECC in addition to biopsies was 15 (11.9%) of 126. In women with lesion-targeted biopsies and ECC, the CIN2+ yield of targeted biopsies was 34 (51.5%) of 66, the yield of additional nontargeted biopsies was 1 (1.5%) of 66, and the additional CIN2+ yield of ECC was 5 (7.6%) of 66. The yield in women with nontargeted biopsies only and ECC was 5 (8.3%) 60, and the additional yield for ECC was 10 (16.7%) of 60. Endocervical curettage did not find disease in women with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion. Conclusions In women with less than low-grade impression and especially those with unsatisfactory colposcopy, the yield of CIN2+ was higher for ECC compared to nontargeted biopsies. The highest yield of CIN2+ from ECC was observed in women with high-grade squamous intraepithelial lesion and less than low-grade impression, suggesting that disease is higher up in the endocervix in this group. C1 [van der Marel, Jacolien; van Baars, Romy; Jenkins, David; van de Sandt, Miekel M.; Quint, Wim G. V.] DDL Diagnost Lab, Dept Res & Dev, NL-2288 ER Rijswijk, Netherlands. [Rodriguez, Agata; del Pino, Marta; Torne, Aureli] Hosp Clin Barcelona, IDIBAPS, Inst Clin Gynecol Obstet & Neonatol, Barcelona, Spain. [Ordi, Jaume] Hosp Clin Barcelona, CRESIB, Dept Pathol, Barcelona, Spain. [ter Harmsel, Bram] Roosevelt Klin, Dept Gynaecol, Leiden, Netherlands. [Verheijen, Rene H. M.] Univ Med Ctr Utrecht, Dept Gynaecol Oncol, Div Oncol, Utrecht, Netherlands. [Schiffman, Mark; Gage, Julia C.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP van der Marel, J (reprint author), DDL Diagnost Lab, Visseringlaan 25, NL-2288 ER Rijswijk, Netherlands. EM jacolien.van.der.marel@DDL.nl FU Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands FX This research was funded by the Stichting Pathologie Ontwikkeling en Onderzoek (SPOO) Foundation, The Netherlands. The sponsor had no involvement in study design, data interpretation, writing of the manuscript, and decision to submit the manuscript for publication. NR 27 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD OCT PY 2015 VL 19 IS 4 BP 282 EP 287 DI 10.1097/LGT.0000000000000124 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CS1AK UT WOS:000361793700005 PM 26083332 ER PT J AU Samal, BB Waites, CK Almeida-Suhett, C Li, Z Marini, AM Samal, NR Elkahloun, A Braga, MFM Eiden, LE AF Samal, Babru B. Waites, Cameron K. Almeida-Suhett, Camila Li, Zheng Marini, Ann M. Samal, Nihar R. Elkahloun, Abdel Braga, Maria F. M. Eiden, Lee E. TI Acute Response of the Hippocampal Transcriptome Following Mild Traumatic Brain Injury After Controlled Cortical Impact in the Rat SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Hippocampus; Controlled cortical impact; Inflammation; Mild traumatic brain injury ID CYCLASE-ACTIVATING POLYPEPTIDE; LENTIVIRAL INFECTION; REGULATED GENES; IN-VIVO; EXPRESSION; MODEL; SEQUELAE; STRESS; VIRUS; CELLS AB We have previously demonstrated that mild controlled cortical impact (mCCI) injury to rat cortex causes indirect, concussive injury to underlying hippocampus and other brain regions, providing a reproducible model for mild traumatic brain injury (mTBI) and its neurochemical, synaptic, and behavioral sequelae. Here, we extend a preliminary gene expression study of the hippocampus-specific events occurring after mCCI and identify 193 transcripts significantly upregulated, and 21 transcripts significantly downregulated, 24 h after mCCI. Fifty-three percent of genes altered by mCCI within 24 h of injury are predicted to be expressed only in the non-neuronal/glial cellular compartment, with only 13 % predicted to be expressed only in neurons. The set of upregulated genes following mCCI was interrogated using Ingenuity Pathway Analysis (IPA) augmented with manual curation of the literature (190 transcripts accepted for analysis), revealing a core group of 15 first messengers, mostly inflammatory cytokines, predicted to account for > 99 % of the transcript upregulation occurring 24 h after mCCI. Convergent analysis of predicted transcription factors (TFs) regulating the mCCI target genes, carried out in IPA relative to the entire Affymetrix-curated transcriptome, revealed a high concordance with TFs regulated by the cohort of 15 cytokines/cytokine-like messengers independently accounting for upregulation of the mCCI transcript cohort. TFs predicted to regulate transcription of the 193-gene mCCI cohort also displayed a high degree of overlap with TFs predicted to regulate glia-, rather than neuron-specific genes in cortical tissue. We conclude that mCCI predominantly affects transcription of non-neuronal genes within the first 24 h after insult. This finding suggests that early non-neuronal events trigger later permanent neuronal changes after mTBI, and that early intervention after mTBI could potentially affect the neurochemical cascade leading to later reported synaptic and behavioral dysfunction. C1 [Samal, Babru B.; Waites, Cameron K.; Eiden, Lee E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Almeida-Suhett, Camila; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Li, Zheng] NIMH, Unit Synapse Dev & Plast, Bethesda, MD 20892 USA. [Marini, Ann M.] Uniformed Serv Univ Hlth Sci, Dept Neurol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Elkahloun, Abdel] NHGRI, Microarray Core, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Waites, Cameron/0000-0001-6926-4643 FU NIMH [Z01 MH002386-22] FX We thank Chang-Mei Hsu for expert technical assistance in preparation of RNA for microarray and qRT-PCR analysis. This work was supported by the NIMH Intramural Research Program Project Z01 MH002386-22. NR 30 TC 5 Z9 5 U1 1 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD OCT PY 2015 VL 57 IS 2 BP 282 EP 303 DI 10.1007/s12031-015-0626-2 PG 22 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CR7VN UT WOS:000361560000016 PM 26319264 ER PT J AU Marx, A Chan, JKC Coindre, JM Detterbeck, F Girard, N Harris, NL Jaffe, ES Kurrer, MO Marom, EM Moreira, AL Mukai, K Orazi, A Strobel, P AF Marx, Alexander Chan, John K. C. Coindre, Jean-Michel Detterbeck, Frank Girard, Nicolas Harris, Nancy L. Jaffe, Elaine S. Kurrer, Michael O. Marom, Edith M. Moreira, Andre L. Mukai, Kiyoshi Orazi, Attilio Stroebel, Philipp TI The 2015 World Health Organization Classification of Tumors of the Thymus Continuity and Changes SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Classification; Thymus; Thymoma; Atypical type A thymoma; Thymic carcinoma; Adenocarcinoma; NUT carcinoma; Carcinoid; Neuroendocrine; Combined large-cell neuroendocrine carcinoma; Combined thymic carcinoma; Mediastinal; Mediastinum; Germ cell tumor; Lymphoma; Primary mediastinal large B-cell lymphoma; Grey zone lymphoma; Hodgkin lymphoma; Dendritic cell tumor; Sarcoma; Neuroblastoma; Metastasis; Ectopic tumor; Positron emission tomography; Computed tomography; Cytology; Histology; Pathology; Immunohistochemistry; Immunohistology; Staging; Genetic; GTF2I; International Thymic Malignancy Interest Group; World Health Organization ID B-CELL LYMPHOMA; FORTHCOMING 8TH EDITION; NUT MIDLINE CARCINOMA; CLASSICAL HODGKINS LYMPHOMA; STAGING PROJECT PROPOSALS; MALIGNANCY INTEREST GROUP; GRAY ZONE LYMPHOMA; EPITHELIAL TUMORS; MUCOEPIDERMOID CARCINOMA; TNM CLASSIFICATION AB This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed. C1 [Marx, Alexander] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, D-68167 Mannheim, Germany. [Chan, John K. C.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Coindre, Jean-Michel] Inst Bergonie, Dept Pathol, Bordeaux, France. [Detterbeck, Frank] Yale Univ, Sch Med, Dept Thorac Surg, New Haven, CT USA. [Girard, Nicolas] Hosp Civils Lyon, Louis Pradel Hosp, Dept Resp Med, Lyon, France. [Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Kurrer, Michael O.] Gemeinschaftspraxis Pathol, Zurich, Switzerland. [Marom, Edith M.] Chaim Sheba Med Ctr, Dept Diagnost Imaging, IL-52621 Tel Hashomer, Israel. [Moreira, Andre L.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Mukai, Kiyoshi] Saiseikai Cent Hosp, Dept Diagnost Pathol, Tokyo, Japan. [Orazi, Attilio] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Pathol & Lab Med, New York, NY USA. [Stroebel, Philipp] Univ Gottingen, Dept Pathol, Univ Med Ctr Gottingen, Inst Pathol, Gottingen, Germany. RP Marx, A (reprint author), Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. EM alexander.marx@umm.de FU Intramural NIH HHS [Z01 BC011070-01] NR 91 TC 21 Z9 21 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2015 VL 10 IS 10 BP 1383 EP 1395 DI 10.1097/JTO.0000000000000654 PG 13 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CS0AP UT WOS:000361719200001 PM 26295375 ER PT J AU Wijndaele, K Westgate, K Stephens, SK Blair, SN Bull, FC Chastin, SFM Dunstan, DW Ekelund, U Esliger, DW Freedson, PS Granat, MH Matthews, CE Owen, N Rowlands, AV Sherar, LB Tremblay, MS Troiano, RP Brage, S Healy, GN AF Wijndaele, Katrien Westgate, Kate Stephens, Samantha K. Blair, Steven N. Bull, Fiona C. Chastin, Sebastien F. M. Dunstan, David W. Ekelund, Ulf Esliger, Dale W. Freedson, Patty S. Granat, Malcolm H. Matthews, Charles E. Owen, Neville Rowlands, Alex V. Sherar, Lauren B. Tremblay, Mark S. Troiano, Richard P. Brage, Soren Healy, Genevieve N. TI Utilization and Harmonization of Adult Accelerometry Data: Review and Expert Consensus SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETRY; ADULT; GLOBAL; PHYSICAL ACTIVITY; SEDENTARY; POOLING; SENSOR ID MEASURED PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE RISK; RANDOMIZED CONTROLLED-TRIAL; SEDENTARY BEHAVIOR; OLDER-ADULTS; PROSPECTIVE COHORT; ACTIVITY PATTERNS; BLOOD-PRESSURE; BODY-WEIGHT; US ADULTS AB Purpose This study aimed to describe the scope of accelerometry data collected internationally in adults and to obtain a consensus from measurement experts regarding the optimal strategies to harmonize international accelerometry data. Methods In March 2014, a comprehensive review was undertaken to identify studies that collected accelerometry data in adults (sample size, n 400). In addition, 20 physical activity experts were invited to participate in a two-phase Delphi process to obtain consensus on the following: unique research opportunities available with such data, additional data required to address these opportunities, strategies for enabling comparisons between studies/countries, requirements for implementing/progressing such strategies, and value of a global repository of accelerometry data. Results The review identified accelerometry data from more than 275,000 adults from 76 studies across 36 countries. Consensus was achieved after two rounds of the Delphi process; 18 experts participated in one or both rounds. The key opportunities highlighted were the ability for cross-country/cross-population comparisons and the analytic options available with the larger heterogeneity and greater statistical power. Basic sociodemographic and anthropometric data were considered a prerequisite for this. Disclosure of monitor specifications and protocols for data collection and processing were deemed essential to enable comparison and data harmonization. There was strong consensus that standardization of data collection, processing, and analytical procedures was needed. To implement these strategies, communication and consensus among researchers, development of an online infrastructure, and methodological comparison work were required. There was consensus that a global accelerometry data repository would be beneficial and worthwhile. Conclusions This foundational resource can lead to implementation of key priority areas and identification of future directions in physical activity epidemiology, population monitoring, and burden of disease estimates. C1 [Wijndaele, Katrien; Westgate, Kate; Ekelund, Ulf; Brage, Soren] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England. [Stephens, Samantha K.; Healy, Genevieve N.] Univ Queensland, Sch Publ Hlth, Brisbane, Qld 4072, Australia. [Blair, Steven N.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. [Bull, Fiona C.] Univ Western Australia, Sch Earth & Environm, Nedlands, WA 6009, Australia. [Bull, Fiona C.] Univ Western Australia, Sch Sports Sci Exercise & Hlth, Nedlands, WA 6009, Australia. [Chastin, Sebastien F. M.] Glasgow Caledonian Univ, Sch Hlth & Life Sci, Glasgow G4 0BA, Lanark, Scotland. [Dunstan, David W.; Owen, Neville] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Ekelund, Ulf] Norwegian Sch Sport Sci, Dept Sport Med, Oslo, Norway. [Esliger, Dale W.; Sherar, Lauren B.] Univ Loughborough, Sch Sport Exercise & Hlth Sci, Natl Ctr Sport & Exercise Med, Loughborough, Leics, England. [Esliger, Dale W.; Rowlands, Alex V.] Univ S Australia, Sch Hlth Sci, Adelaide, SA 5001, Australia. [Freedson, Patty S.] Univ Massachusetts, Dept Kinesiol, Amherst, MA 01003 USA. [Granat, Malcolm H.] Univ Salford, Sch Hlth Sci, Manchester, Lancs, England. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherar, Lauren B.] NIHR Leicester Loughborough, Diet Lifestyle & Phys Act Biomed Res Unit, Loughborough, Leics, England. [Tremblay, Mark S.] Univ Ottawa, Dept Pediat, Childrens Hosp Eastern Ontario Res Inst, Hlth Act Living & Obes Res Grp, Ottawa, ON K1N 6N5, Canada. [Troiano, Richard P.] NCI, Risk Factor Assessment Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Healy, GN (reprint author), Univ Queensland, Sch Populat Hlth, Herston Rd, Brisbane, Qld 4006, Australia. EM g.healy@uq.edu.au RI Healy, Genevieve/A-7408-2008; Rowlands, Alex/B-4543-2013; Dunstan, David/E-8473-2010; OI Healy, Genevieve/0000-0001-7093-7892; Rowlands, Alex/0000-0002-1463-697X; Dunstan, David/0000-0003-2629-9568; Sherar, Lauren/0000-0002-9942-5433; Troiano, Richard/0000-0002-6807-989X; Owen, Neville/0000-0003-2784-4820; Westgate, Kate/0000-0002-0283-3562 FU United Kingdom Medical Research Council [MC_UU_12015/3]; British Heart Foundation [FS/12/58/29709]; Australian Heart Foundation [PH 12B 7054]; Australian National Health and Medical Research Council; National Health and Medical Research Council Centre for Research Excellence Grant in the Translational Science of Sedentary Behaviour [APP1041056]; Australian postgraduate award; Coca-Cola Company; Body Media; US National Institutes of Health; Technogym; MRC; Chartered Society of Physiotherapy; Engineering, and Physical Sciences Research Council; Greater Manchester Academic Health Science Network; Australian Research Council [FT100100918]; University of South Carolina from the Coca-Cola Company FX This work and authors involved in this work were supported by the United Kingdom Medical Research Council (grants MC_UU_12015/3 and MRC Centenary Award to K. Wi., S. B.), the British Heart Foundation (grant FS/12/58/29709 to K. Wi.), the Australian Heart Foundation (grant PH 12B 7054 to G. N. H.), the Australian National Health and Medical Research Council (fellowship to N. O., program grant to N. O., and National Health and Medical Research Council Centre for Research Excellence Grant in the Translational Science of Sedentary Behaviour APP1041056 to G. N. H., N. O., and D. D.), an Australian postgraduate award (to S. S.), the Coca-Cola Company, Body Media, US National Institutes of Health and Technogym (to S. B.), MRC, Chartered Society of Physiotherapy, Engineering, and Physical Sciences Research Council, Greater Manchester Academic Health Science Network (to M. G.), and Australian Research Council (Future Fellowship, FT100100918, to D. D.).; D. E. is the founder and CEO of KineSoft, an accelerometry analytics software; S. N. B. is supported by unrestricted research grants from the University of South Carolina from the Coca-Cola Company, Body Media, and Technogym; M. H. G. is the director of PAL Technologies Ltd., Glasgow, United Kingdom; and Soren Brage is an advisor for the UK Biobank. NR 75 TC 23 Z9 23 U1 6 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD OCT PY 2015 VL 47 IS 10 BP 2129 EP 2139 DI 10.1249/MSS.0000000000000661 PG 11 WC Sport Sciences SC Sport Sciences GA CR5DP UT WOS:000361360500015 PM 25785929 ER PT J AU Gottlieb, DJ Hek, K Chen, TH Watson, NF Eiriksdottir, G Byrne, EM Cornelis, M Warby, SC Bandinelli, S Cherkas, L Evans, DS Grabe, HJ Lahti, J Li, M Lehtimaki, T Lumley, T Marciante, KD Perusse, L Psaty, BM Robbins, J Tranah, GJ Vink, JM Wilk, JB Stafford, JM Bellis, C Biffar, R Bouchard, C Cade, B Curhan, GC Eriksson, JG Ewert, R Ferrucci, L Fulop, T Gehrman, PR Goodloe, R Harris, TB Heath, AC Hernandez, D Hofman, A Hottenga, JJ Hunter, DJ Jensen, MK Johnson, AD Kahonen, M Kao, L Kraft, P Larkin, EK Lauderdale, DS Luik, AI Medici, M Montgomery, GW Palotie, A Patel, SR Pistis, G Porcu, E Quaye, L Raitakari, O Redline, S Rimm, EB Rotter, JI Smith, AV Spector, TD Teumer, A Uitterlinden, AG Vohl, MC Widen, E Willemsen, G Young, T Zhang, X Liu, Y Blangero, J Boomsma, DI Gudnason, V Hu, F Mangino, M Martin, NG O'Connor, GT Stone, KL Tanaka, T Viikari, J Gharib, SA Punjabi, NM Raikkonen, K Volzke, H Mignot, E Tiemeier, H AF Gottlieb, D. J. Hek, K. Chen, T-h Watson, N. F. Eiriksdottir, G. Byrne, E. M. Cornelis, M. Warby, S. C. Bandinelli, S. Cherkas, L. Evans, D. S. Grabe, H. J. Lahti, J. Li, M. Lehtimaki, T. Lumley, T. Marciante, K. D. Perusse, L. Psaty, B. M. Robbins, J. Tranah, G. J. Vink, J. M. Wilk, J. B. Stafford, J. M. Bellis, C. Biffar, R. Bouchard, C. Cade, B. Curhan, G. C. Eriksson, J. G. Ewert, R. Ferrucci, L. Fulop, T. Gehrman, P. R. Goodloe, R. Harris, T. B. Heath, A. C. Hernandez, D. Hofman, A. Hottenga, J-J Hunter, D. J. Jensen, M. K. Johnson, A. D. Kahonen, M. Kao, L. Kraft, P. Larkin, E. K. Lauderdale, D. S. Luik, A. I. Medici, M. Montgomery, G. W. Palotie, A. Patel, S. R. Pistis, G. Porcu, E. Quaye, L. Raitakari, O. Redline, S. Rimm, E. B. Rotter, J. I. Smith, A. V. Spector, T. D. Teumer, A. Uitterlinden, A. G. Vohl, M-C Widen, E. Willemsen, G. Young, T. Zhang, X. Liu, Y. Blangero, J. Boomsma, D. I. Gudnason, V. Hu, F. Mangino, M. Martin, N. G. O'Connor, G. T. Stone, K. L. Tanaka, T. Viikari, J. Gharib, S. A. Punjabi, N. M. Raikkonen, K. Volzke, H. Mignot, E. Tiemeier, H. TI Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study SO MOLECULAR PSYCHIATRY LA English DT Article ID BODY-MASS INDEX; OSTEOPOROTIC FRACTURES; HYPOTHYROID PATIENTS; COHORT PROFILE; PHASE SYNDROME; DESIGN; RISK; VARIANTS; WOMEN; GENE AB Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P = 1.1 x 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P = 9.3 x 10(-4)). The strongest combined association was at rs1823125 (P = 1.5 x 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease. C1 [Gottlieb, D. J.; Chen, T-h] VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. [Gottlieb, D. J.; Cade, B.; Patel, S. R.; Redline, S.] Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Gottlieb, D. J.; Chen, T-h; O'Connor, G. T.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Gottlieb, D. J.; O'Connor, G. T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hek, K.; Tiemeier, H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hek, K.; Hofman, A.; Luik, A. I.; Uitterlinden, A. G.; Tiemeier, H.] Erasmus MC, Dept Psychiat, Epidemiol & Social Psychiat Res Inst, Rotterdam, Netherlands. [Watson, N. F.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Watson, N. F.; Gharib, S. A.] Univ Washington, UW Med Sleep Ctr, Seattle, WA 98195 USA. [Eiriksdottir, G.; Smith, A. V.; Gudnason, V.] Icelandic Heart Assoc, Kopavogur, Iceland. [Byrne, E. M.] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia. [Byrne, E. M.; Montgomery, G. W.; Martin, N. G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Cornelis, M.; Jensen, M. K.; Rimm, E. B.; Hu, F.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cornelis, M.; Curhan, G. C.; Rimm, E. B.; Hu, F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Warby, S. C.; Mignot, E.] Stanford Univ, Ctr Sleep Sci & Med, Palo Alto, CA 94304 USA. [Bandinelli, S.] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Cherkas, L.; Quaye, L.; Spector, T. D.; Mangino, M.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Evans, D. S.; Tranah, G. J.; Stone, K. L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Grabe, H. J.] Univ Med Greifswald, HELIOS Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Lahti, J.; Raikkonen, K.] Univ Helsinki, Dept Behav Sci, Helsinki, Finland. [Lahti, J.; Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Li, M.; Kao, L.; Punjabi, N. M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lehtimaki, T.] Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland. [Lehtimaki, T.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Lumley, T.] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Marciante, K. D.; Psaty, B. M.; Gharib, S. A.] Univ Washington, Dept Med, Seattle, WA USA. [Marciante, K. D.; Psaty, B. M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Perusse, L.] Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada. [Perusse, L.; Vohl, M-C] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada. [Psaty, B. M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Robbins, J.] Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. [Vink, J. M.; Hottenga, J-J; Willemsen, G.; Boomsma, D. I.] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands. [Wilk, J. B.] Precis Med, Cambridge, MA USA. [Stafford, J. M.; Liu, Y.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Bellis, C.; Blangero, J.] Texas Biomed Res Inst, San Antonio, TX USA. [Biffar, R.] Univ Med Greifswald, Ctr Oral Hlth, Dept Prosthodont Gerodontol & Dent Mat, Greifswald, Germany. [Bouchard, C.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Curhan, G. C.; Hunter, D. J.; Kraft, P.; Rimm, E. B.; Hu, F.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. Vasa Cent Hosp, Vaasa, Finland. [Ewert, R.] Univ Med Greifswald, Dept Internal Med B, Cardiol Pulm Med Infect Dis & Intens Care Med, Greifswald, Germany. [Ferrucci, L.; Tanaka, T.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Fulop, T.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Gehrman, P. R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Goodloe, R.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Heath, A. C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Hernandez, D.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hunter, D. J.; Kraft, P.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Johnson, A. D.; Zhang, X.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA USA. [Kahonen, M.] Univ Tampere, Tampere Univ Hosp, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, M.] Univ Tampere, Tampere Univ Hosp, Sch Med, FIN-33101 Tampere, Finland. [Larkin, E. K.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Lauderdale, D. S.] Univ Chicago, Dept Hlth Studies, Chicago, IL USA. [Medici, M.; Uitterlinden, A. G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Palotie, A.; Widen, E.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Palotie, A.] Broad Inst MIT & Harvard, Genet Anal Platform, Cambridge, MA USA. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Pistis, G.] San Raffaele Res Inst, Div Genet & Cell Biol, Milan, Italy. [Pistis, G.] Univ Trieste, Trieste, Italy. [Pistis, G.; Porcu, E.] CNR, IRGB, Cagliari, Italy. [Pistis, G.; Porcu, E.] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Raitakari, O.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, O.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Rotter, J. I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, J. I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Smith, A. V.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Teumer, A.] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Teumer, A.; Volzke, H.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Uitterlinden, A. G.] Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Vohl, M-C] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ, Canada. [Young, T.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. [Viikari, J.] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Viikari, J.] Univ Turku, Turku, Finland. [Punjabi, N. M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Tiemeier, H.] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. RP Gottlieb, DJ (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy 111PI, West Roxbury, MA 02132 USA. EM djgottlieb@partners.org RI Montgomery, Grant/B-7148-2008; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011; Johnson, Andrew/G-6520-2013; OI Montgomery, Grant/0000-0002-4140-8139; Lahti, Jari/0000-0002-4310-5297; Martin, Nicholas/0000-0003-4069-8020; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470; Tiemeier, Henning/0000-0002-4395-1397; Patel, Sanjay/0000-0002-9142-5172 FU National Heart, Lung and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C, , ]; NIH Roadmap for Medical Research [, U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, UL1 RR024140]; NHLBI [, HHSN268201200036C, N01-HC-85239, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, HL080295, HL087652, HL105756]; National Institute on Aging (NIA) [, AG023629, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, R01 AG026720]; National Center for Advancing Translational Sciences CTSI grant [, UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [, DK063491]; National Heart, Lung and Blood Institute's Framingham Heart Study [, N01-HC-25195]; Affymetrix, Inc [, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NIA [N01-AG-62101, N01-AG-62103, N01-AG-62106, 1R01AG032098-01A1, 1R01AG030474-01A1]; NIH, NIA; Academy of Finland [134309, 126925, 121584, 124282, 129378, 117787, 41071]; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062]; National Institutes of Health [NCI] [CA40356, CA087969, CA055075, CA98233]; National Institutes of Health [NIDDK] [DK058845, DK070756]; National Institutes of Health [NHGRI] [HG004399]; National Institutes of Health [NHLBI] [HL35464]; Merck/Rosetta Research Laboratories, North Wales, PA; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]; National Center for Research Resources (NCRR); National Heart, Lung, and Blood Institute (NHLBI) [R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, R01 HL070839]; NIAMS [RC2ARO58973]; Medical Research Council of Canada; Canadian Institutes for Health Research [FRN-CCT-83028]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498]; Australian Research Council [A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health (NIH) [AA07535, AA10249, AA11998, AA13320, AA13321, AA13326, AA14041, MH66206]; Netherlands Scientific Organization [NWO 480-05-003]; NHMRC grant [613608]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus MC; Erasmus MC, Rotterdam; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; VIDI grant of ZonMw [2009-017.106.370]; BavoEuropoort; Netherlands Organization for Scientific Research (NWO: MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; Center for Medical Systems Biology (CSMB, NWO Genomics) [NBIC/BioAssist/RK(2008.024)]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007]; VU University's Institute for Health and Care Research (EMGO+ ); Neuroscience Campus Amsterdam (NCA); European Science Foundation (ESF) [EU/QLRT-2001-01254]; European Community [HEALTH-F4-2007-201413]; ENGAGE [HEALTH-F4-2007-201413]; European Science Council [ERC 230374]; Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06]; Avera Institute, Sioux Falls, South Dakota (USA); National Institutes of Health (NIH) [R01D0042157-01A, 1RC2MH089951-01, 1RC2 MH089995-01]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; King's College London; National Eye Institute via an NIH/CIDR genotyping project; National Heart, Lung, and Blood Institute [R01HL62252]; National Center for Research Resources [1UL1RR025011]; Social Insurance Institution of Finland, Kuopio, Tampere; Turku University Hospital Medical Funds [9M048 for 9N035]; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Tampere Tuberculosis Foundation; Finnish Cultural Foundation; [NS23724] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, 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. The Cardiovascular Health Study was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). DNA handling and genotyping was supported in part by the National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Sciences CTSI grant UL1TR000124; the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health, Aging and Body Composition Study supported by NIA contracts N01-AG-62101, N01-AG-62103 and N01-AG-62106 and NIA grants 1R01AG032098-01A1 and 1R01AG030474-01A1. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). The Nurses Health Study and Health Professional Follow-Up Study GWAS were supported by grants from the National Institutes of Health [NCI (CA40356, CA087969, CA055075, CA98233), NIDDK (DK058845, DK070756), NHGRI (HG004399), NHLBI (HL35464)] with additional support from Merck/Rosetta Research Laboratories, North Wales, PA. The Invecchiare in CHIANTI study baseline (1998 2000) was supported as a 'targeted project' (ICS110.1/RF97.; 71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, and UL1 RR024140. The National Heart, Lung, and Blood Institute (NHLBI) provides funding for the MrOS Sleep ancillary study 'Outcomes of Sleep Disorders in Older Men' under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839'. The NIAMS provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. The Quebec Family Study was funded by multiple grants from the Medical Research Council of Canada and the Canadian Institutes for Health Research. This work was supported by a team grant from the Canadian Institutes for Health Research (FRN-CCT-83028). Funding for the Queensland Institute of Medical Research Twin Study was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH grants AA07535, AA10249, AA11998, AA13320, AA13321, AA13326, AA14041, MH66206). A portion of the genotyping on which this study was based (Illumina 370K scans) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). EMB is supported by NHMRC grant 613608. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Henning Tiemeier was supported by the VIDI grant of ZonMw (2009-017.106.370). Karin Hek was supported by a grant from BavoEuropoort. Netherlands Twin Registry funding was obtained from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.; 024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL, 184.021.007), VU University's Institute for Health and Care Research (EMGO+ ) and Neuroscience Campus Amsterdam (NCA), European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); European Science Council (ERC 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA), and the National Institutes of Health (NIH, R01D0042157-01A, Grand Opportunity grants 1RC2MH089951-01 and 1RC2 MH089995-01). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. The Study of Osteoporotic Fractures is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. Genotyping was performed by the Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project. This research was supported for the Wisconsin Sleep Cohort Study by the National Heart, Lung, and Blood Institute (R01HL62252) and National Center for Research Resources (1UL1RR025011) and by NS23724. The Young Finns Study has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 for 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation. NR 61 TC 14 Z9 14 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2015 VL 20 IS 10 BP 1232 EP 1239 DI 10.1038/mp.2014.133 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CS2OE UT WOS:000361909800011 PM 25469926 ER PT J AU Zhang, Y Su, HC Lenardo, MJ AF Zhang, Yu Su, Helen C. Lenardo, Michael J. TI Genomics is rapidly advancing precision medicine for immunological disorders SO NATURE IMMUNOLOGY LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; FAS GENE-MUTATIONS; IMMUNE DYSREGULATION; INBORN-ERRORS; GERMLINE MUTATIONS; HUMAN-DISEASE; IMMUNODEFICIENCY; DEFICIENCY; APOPTOSIS; HUMANS AB Advances in human genomics, when validated functionally, can lead to new insights into how the immune system works. Notably, previously unknown mechanisms revealed by genomics can lead to the development of precision medicine unanticipated on the basis of phenotype alone. C1 [Zhang, Yu; Su, Helen C.] NIAID, Human Immunol Dis Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Zhang, Yu; Su, Helen C.; Lenardo, Michael J.] NIAID, Clin Genom Program, NIH, Bethesda, MD 20892 USA. [Zhang, Yu; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIAID, Human Immunol Dis Unit, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 FU Intramural NIH HHS NR 39 TC 9 Z9 9 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2015 VL 16 IS 10 BP 1001 EP 1004 DI 10.1038/ni.3275 PG 4 WC Immunology SC Immunology GA CR9OO UT WOS:000361686500001 PM 26382860 ER PT J AU Yang, Q Li, FY Harly, C Xing, SJ Ye, LY Xia, XF Wang, HK Wang, XX Yu, SY Zhou, XY Cam, M Xue, HH Bhandoola, A AF Yang, Qi Li, Fengyin Harly, Christelle Xing, Shaojun Ye, Longyun Xia, Xuefeng Wang, Haikun Wang, Xinxin Yu, Shuyang Zhou, Xinyuan Cam, Maggie Xue, Hai-Hui Bhandoola, Avinash TI TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow SO NATURE IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELL; TRANSCRIPTION FACTOR; RECEPTOR ACQUISITION; THYMOCYTE SURVIVAL; HMG-BOX; DIFFERENTIATION; NOTCH; INFLAMMATION; GENERATION; LINEAGES AB The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate. C1 [Yang, Qi; Harly, Christelle; Ye, Longyun; Bhandoola, Avinash] NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Qi; Xia, Xuefeng; Wang, Haikun; Wang, Xinxin] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Li, Fengyin; Xing, Shaojun; Yu, Shuyang; Zhou, Xinyuan; Xue, Hai-Hui] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. [Cam, Maggie] NCI, CCR Collaborat Bioinformat Resource, Bethesda, MD 20892 USA. RP Bhandoola, A (reprint author), NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. EM hai-hui-xue@uiowa.edu; avinash.bhandoola@nih.gov FU American Cancer Society [RSG-11-161-01-MPC]; National Institutes of Health [AI105351, AI112579, AI115149, AI119160, AI059621, AI098428, HL11074103]; National Institutes of Health, the National Cancer Institute; Center for Cancer Research FX We thank M. Greene and G. Massey for essential support. We thank the laboratories of A. Haczku, Y. Belkaid, R. Bosselut and D. Artis for technical and scientific advice. OP9-DL1 stromal cell lines were obtained from J.C. Zuniga-Pflucker (University of Toronto, Toronto, Ontario, Canada). Reagents for recombineering were kindly provided by D.L. Court (National Cancer Institute, Frederick, Maryland, USA) and N.G. Copeland (Houston Methodist Research Institute, Houston, Texas, USA). We thank T.L. Saunders at the University of Michigan for blastocyst injection of Tcf7-GFP+ embryonic stem cells. We also thank Y. Yokota (University of Fukui, Fukui, Japan) for Id2-/- mice. This work was supported by the American Cancer Society (RSG-11-161-01-MPC to H.-H.X.) and the National Institutes of Health (AI105351, AI112579, AI115149 and AI119160 to H.-H.X.; AI059621, AI098428 and HL11074103 to A.B.). A.B. is supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 49 TC 26 Z9 27 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2015 VL 16 IS 10 BP 1044 EP + DI 10.1038/ni.3248 PG 8 WC Immunology SC Immunology GA CR9OO UT WOS:000361686500009 PM 26280998 ER PT J AU Guo, LY Huang, YF Chen, X Hu-Li, J Urban, JF Paul, WE AF Guo, Liying Huang, Yuefeng Chen, Xi Hu-Li, Jane Urban, Joseph F., Jr. Paul, William E. TI Innate immunological function of T(H)2 cells in vivo SO NATURE IMMUNOLOGY LA English DT Article ID CHRONIC HELMINTH INFECTIONS; LYMPHOID-CELLS; AIRWAY INFLAMMATION; CYTOKINE PRODUCTION; HYGIENE HYPOTHESIS; IMMUNE-RESPONSES; IL-1 FAMILY; DISEASE; ASTHMA; INTERLEUKIN-13 AB Type 2 helper T cells (T(H)2 cells) produce interleukin 13 (IL-13) when stimulated by papain or house dust mite extract (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2 cells) are the dominant innate producers of IL-13 in naive mice, we found here that helminth-infected mice had more T(H)2 cells compared to uninfected mice, and these cells became major mediators of innate type 2 responses. T(H)2 cells made important contributions to HDM-induced antigen-nonspecific eosinophilic inflammation and protected mice recovering from infection with Ascaris suum against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role for effector T(H)2 cells during TCR-independent innate-like immune responses. C1 [Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Urban, Joseph F., Jr.] ARS, USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD USA. RP Guo, LY (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lguo@niaid.nih.gov; wpaul@niaid.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institute of Health) FX We thank A.N. McKenzie (Medical Research Council Laboratory of Molecular Biology, Cambridge, UK) for Il1rl1-/- mice; J.-P. Girard (Centre National de la Recherche Scientifique, Institute de Pharmacology et de Biologie Structurale) for Il33-LacZ gene-trap reporter mice; J. Ward for help with pathology analysis; and J. Edwards and K. Weng for help with cell sorting. Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institute of Health). NR 38 TC 27 Z9 27 U1 3 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2015 VL 16 IS 10 BP 1051 EP + DI 10.1038/ni.3244 PG 11 WC Immunology SC Immunology GA CR9OO UT WOS:000361686500010 PM 26322482 ER PT J AU Takada, K Van Laethem, F Xing, Y Akane, K Suzuki, H Murata, S Tanaka, K Jameson, SC Singer, A Takahama, Y AF Takada, Kensuke Van Laethem, Francois Xing, Yan Akane, Kazuyuki Suzuki, Haruhiko Murata, Shigeo Tanaka, Keiji Jameson, Stephen C. Singer, Alfred Takahama, Yousuke TI TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells SO NATURE IMMUNOLOGY LA English DT Article ID CORTICAL EPITHELIAL-CELLS; CLASS-I MOLECULES; MHC CLASS-I; NEGATIVE SELECTION; DEVELOPING THYMOCYTES; MEMORY PHENOTYPE; SELF-PEPTIDES; MICE; REPERTOIRE; RECOGNITION AB In the thymus, low-affinity T cell antigen receptor (TCR) engagement facilitates positive selection of a useful T cell repertoire. Here we report that TCR responsiveness of mature CD8(+) T cells is fine tuned by their affinity for positively selecting peptides in the thymus and that optimal TCR responsiveness requires positive selection on major histocompatibility complex class I-associated peptides produced by the thymoproteasome, which is specifically expressed in the thymic cortical epithelium. Thymoproteasome-independent positive selection of monoclonal CD8(+) T cells results in aberrant TCR responsiveness, homeostatic maintenance and immune responses to infection. These results demonstrate a novel aspect of positive selection, in which TCR affinity for positively selecting peptides produced by thymic epithelium determines the subsequent antigen responsiveness of mature CD8(+) T cells in the periphery. C1 [Takada, Kensuke; Takahama, Yousuke] Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima, Tokushima, Japan. [Van Laethem, Francois; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Xing, Yan; Jameson, Stephen C.] Univ Minnesota, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55455 USA. [Akane, Kazuyuki; Suzuki, Haruhiko] Nagoya Univ, Dept Immunol, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Murata, Shigeo] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. [Tanaka, Keiji] Tokyo Metropolitan Inst Med Sci, Tokyo 113, Japan. RP Takahama, Y (reprint author), Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima, Tokushima, Japan. EM takahama@genome.tokushima-u.ac.jp RI Takahama, Yousuke/A-5863-2010 FU MEXT-JSPS [24111004, 23249025, 24790475, 26460576]; Naito Foundation; Takeda Science Foundation; Uehara Memorial Foundation FX We thank H. Kosako, I. Ohigashi, M. Kozai and B. Kim for helpful discussion and reading the manuscript. This work was supported by grants from MEXT-JSPS (24111004 and 23249025 to Y.T. and 24790475 and 26460576 to K. Takada), Naito Foundation (to Y.T. and K. Takada), Takeda Science Foundation (to K. Takada), and Uehara Memorial Foundation (to K. Takada). NR 46 TC 8 Z9 8 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2015 VL 16 IS 10 BP 1069 EP + DI 10.1038/ni.3237 PG 9 WC Immunology SC Immunology GA CR9OO UT WOS:000361686500012 PM 26301566 ER PT J AU Nakatsukasa, H Zhang, DF Maruyama, T Chen, H Cui, KR Ishikawa, M Deng, LS Zanvit, P Tu, E Jin, WW Abbatiello, B Goldberg, N Chen, QM Sun, LY Zhao, KJ Chen, WJ AF Nakatsukasa, Hiroko Zhang, Dunfang Maruyama, Takashi Chen, Hua Cui, Kairong Ishikawa, Masaki Deng, Lisa Zanvit, Peter Tu, Eric Jin, Wenwen Abbatiello, Brittany Goldberg, Nathan Chen, Qianming Sun, Lingyun Zhao, Keji Chen, WanJun TI The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells SO NATURE IMMUNOLOGY LA English DT Article ID LOOP-HELIX PROTEINS; TGF-BETA; AIRWAY INFLAMMATION; GENE-EXPRESSION; IFN-GAMMA; DIFFERENTIATION; INDUCTION; GENERATION; IMMUNITY; PATHWAYS AB The molecular mechanisms by which signaling via transforming growth factor-beta (TGF-beta) and interleukin 4 (IL-4) control the differentiation of CD4(+) IL-9-producing helper T cells (T(H)9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated T(H)9 differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-beta 1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of T(H)9 differentiation regulated anti-tumor immunity in an experimental melanomabearing model in vivo and also in human CD4(+) T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates T(H)9 differentiation. C1 [Nakatsukasa, Hiroko; Zhang, Dunfang; Maruyama, Takashi; Chen, Hua; Deng, Lisa; Zanvit, Peter; Tu, Eric; Jin, Wenwen; Abbatiello, Brittany; Goldberg, Nathan; Chen, WanJun] NIDCR, Mucosal Immunol Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Zhang, Dunfang; Chen, Qianming] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Ishikawa, Masaki] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Sun, Lingyun] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Rheumatol & Immunol, Nanjing 210008, Jiangsu, Peoples R China. RP Chen, WJ (reprint author), NIDCR, Mucosal Immunol Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM wchen@dir.nidcr.nih.gov FU National Institute of Dental and Craniofacial Research (US National Institutes of Health); JSPS Research Fellowship Program for Japanese Biomedical and Behavioral Researchers at the US National Institutes of Health FX We thank J.E. Konkel and C. Chia for critical reading of the manuscript; Y. Zhuang (Duke University) for Id3f/fCd4-Cre+ mice; X.C. Li (Harvard Medical School) for antigen-presenting cells with transgenic expression of the ligand for OX40; Y. Wan (University of North Carolina) for Tak1f/fER-Cre mice; and A. Yoshimura (Keio University of Medicine) for Smad2f/fLck-Cre+ mice. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (US National Institutes of Health) and the JSPS Research Fellowship Program for Japanese Biomedical and Behavioral Researchers at the US National Institutes of Health (H.N). NR 35 TC 12 Z9 13 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2015 VL 16 IS 10 BP 1077 EP + DI 10.1038/ni.3252 PG 9 WC Immunology SC Immunology GA CR9OO UT WOS:000361686500013 PM 26322481 ER PT J AU Liu, TY Cheng, Y Qin, XY Yu, LC AF Liu, Tao-Yan Cheng, Yong Qin, Xiao-Yan Yu, Long-Chuan TI Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain SO NEUROSCIENCE BULLETIN LA English DT Article DE periaqueductal grey; AMPA receptor; GluA(2-3y); internalization; morphine; hindpaw withdrawal latency ID AMPA RECEPTOR TRAFFICKING; PERIAQUEDUCTAL GRAY; GENERAL-POPULATION; RATS; MONONEUROPATHY; SENSITIZATION; PREVALENCE; ACTIVATION; NEURONS AB Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments, so it is critical to find new drugs for this condition. Recently, the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain. Here, we used the short peptide GluA(2-3y), which specifically inhibits the GluA2-dependent endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and tested its anti-nociceptive effect in the periaqueductal grey (PAG) of intact rats and rats with neuropathic pain. Intra-PAG injection of 0.15, 1.5, 7.5, and 15 pmol of GluA(2-3y) induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats, suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation. Furthermore, GluA(2-3y) had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation. Interestingly, the intra-PAG injection of 15 pmol GluA(2-3y) had an analgesic effect similar to 10 mu g (35 nmol) morphine in rats with neuropathic pain. Taken together, our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation, and inhibiting GluA2 endocytosis with GluA(2-3y) has potent analgesic effects in rats with neuropathic pain. These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain. C1 [Liu, Tao-Yan; Qin, Xiao-Yan] Minzu Univ China, Beijing Engn Res Ctr Food Environm & Hlth, Beijing 100081, Peoples R China. [Liu, Tao-Yan; Qin, Xiao-Yan] Minzu Univ China, Coll Life & Environm Sci, Beijing 100081, Peoples R China. [Cheng, Yong; Yu, Long-Chuan] Peking Univ, Coll Life Sci, Neurobiol Lab, Beijing 100871, Peoples R China. [Cheng, Yong; Yu, Long-Chuan] Peking Univ, Coll Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. RP Cheng, Y (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM chengy4@mail.nih.gov; zhongsijia01@163.com FU National Natural Science Foundation of China [30670658]; Minzu University 985 Academic Team-building Fund [YLDX01013, 2015MDTD13C, 25C]; 111 Project of China [B08044] FX This work was supported by the National Natural Science Foundation of China (30670658). Also, the author is grateful for support from the Minzu University 985 Academic Team-building Fund (YLDX01013, 2015MDTD13C and 25C) and the 111 Project of China (B08044). NR 19 TC 2 Z9 2 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1673-7067 EI 1995-8218 J9 NEUROSCI BULL JI Neurosci. Bull. PD OCT PY 2015 VL 31 IS 5 BP 611 EP 616 DI 10.1007/s12264-015-1556-2 PG 6 WC Neurosciences SC Neurosciences & Neurology GA CR8SY UT WOS:000361625500010 PM 26248656 ER PT J AU Donny, EC Denlinger, RL Tidey, JW Koopmeiners, JS Benowitz, NL Vandrey, RG Al'Absi, M Carmella, SG Cinciripini, PM Dermody, SS Drobes, DJ Hecht, SS Jensen, J Lane, T Le, CT McClernon, FJ Montoya, ID Murphy, SE Robinson, JD Stitzer, ML Strasser, AA Tindle, H Hatsukami, DK AF Donny, Eric C. Denlinger, Rachel L. Tidey, Jennifer W. Koopmeiners, Joseph S. Benowitz, Neal L. Vandrey, Ryan G. al'Absi, Mustafa Carmella, Steven G. Cinciripini, Paul M. Dermody, Sarah S. Drobes, David J. Hecht, Stephen S. Jensen, Joni Lane, Tonya Le, Chap T. McClernon, F. Joseph Montoya, Ivan D. Murphy, Sharon E. Robinson, Jason D. Stitzer, Maxine L. Strasser, Andrew A. Tindle, Hilary Hatsukami, Dorothy K. TI Randomized Trial of Reduced-Nicotine Standards for Cigarettes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPENSATORY SMOKING; EXPOSURE; DEPENDENCE; BIOMARKERS; WITHDRAWAL; METABOLISM; REDUCTION; COTININE AB BACKGROUND The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. C1 [Donny, Eric C.; Denlinger, Rachel L.; Dermody, Sarah S.; Lane, Tonya] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Tindle, Hilary] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Tidey, Jennifer W.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Koopmeiners, Joseph S.; Le, Chap T.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Murphy, Sharon E.] Univ Minnesota, Dept Biochem, Minneapolis, MN 55455 USA. [Murphy, Sharon E.] Univ Minnesota, Dept Mol Biol, Minneapolis, MN 55455 USA. [Murphy, Sharon E.] Univ Minnesota, Dept Biophys, Minneapolis, MN 55455 USA. [Hatsukami, Dorothy K.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Koopmeiners, Joseph S.; Carmella, Steven G.; Hecht, Stephen S.; Jensen, Joni; Le, Chap T.; Murphy, Sharon E.; Hatsukami, Dorothy K.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA. [al'Absi, Mustafa] Univ Minnesota, Sch Med, Duluth, MN 55812 USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA USA. [Vandrey, Ryan G.; Stitzer, Maxine L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Montoya, Ivan D.] NIDA, Bethesda, MD 20892 USA. [Cinciripini, Paul M.; Robinson, Jason D.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Drobes, David J.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33682 USA. [McClernon, F. Joseph] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Strasser, Andrew A.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Strasser, Andrew A.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Donny, EC (reprint author), Univ Pittsburgh, Dept Psychol, 210 S Bouquet St, Pittsburgh, PA 15260 USA. EM edonny@pitt.edu OI Hecht, Stephen/0000-0001-7228-1356; Donny, Eric/0000-0003-3288-9652 FU National Institute on Drug Abuse; Food and Drug Administration Center for Tobacco Products FX Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875. NR 32 TC 36 Z9 37 U1 3 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 1 PY 2015 VL 373 IS 14 BP 1340 EP 1349 DI 10.1056/NEJMsa1502403 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CS3CI UT WOS:000361948600008 PM 26422724 ER PT J AU Ashinsky, BG Coletta, CE Bouhrara, M Lukas, VA Boyle, JM Reiter, DA Neu, CP Goldberg, IG Spencer, RG AF Ashinsky, B. G. Coletta, C. E. Bouhrara, M. Lukas, V. A. Boyle, J. M. Reiter, D. A. Neu, C. P. Goldberg, I. G. Spencer, R. G. TI Machine learning classification of OARSI-scored human articular cartilage using magnetic resonance imaging SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Human articular cartilage; MRI; Pattern recognition; Classification ID IN-VIVO; MULTIVARIATE-ANALYSIS; OSTEOARTHRITIS; KNEE; MRI; HISTOPATHOLOGY; ARTHROSCOPY; RELIABILITY; DIAGNOSIS; ARTHRITIS C1 [Ashinsky, B. G.; Bouhrara, M.; Lukas, V. A.; Boyle, J. M.; Spencer, R. G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Reiter, D. A.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Coletta, C. E.; Goldberg, I. G.] NIA, Image Informat & Computat Biol Unit, NIH, Baltimore, MD 21224 USA. [Neu, C. P.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, NIH, Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA. EM beth.ashinsky@gmail.com; christopher.coletta@nih.gov; mustapha.bouhrara2@nih.gov; vannylukas@gmail.com; jmboyle@oakland.edu; reiterda@nia.nih.gov; cpneu@purdue.edu; goldbergil@helix.nih.gov; spencer@helix.nih.gov RI Goldberg, Ilya/H-5307-2011; OI Goldberg, Ilya/0000-0001-8514-6110; Boyle, Julianne/0000-0002-5687-9857 FU NIH, National Institute on Aging; NIH [R01 AR063712]; [R21 AR066230] FX This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, by NIH R01 AR063712 and by R21 AR066230. The study sponsors had no involvement in study design, collection and interpretation of data, writing of the manuscript, or manuscript submission. NR 48 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD OCT PY 2015 VL 23 IS 10 BP 1704 EP 1712 DI 10.1016/j.joca.2015.05.028 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA CR8TS UT WOS:000361627500008 PM 26067517 ER PT J AU Blanch-Hartigan, D Chawla, N Beckjord, EI Forsythe, LP de Moor, JS Hesse, BW Arora, NK AF Blanch-Hartigan, Danielle Chawla, Neetu Beckjord, Ellen I. Forsythe, Laura P. de Moor, Janet S. Hesse, Bradford W. Arora, Neeraj K. TI Cancer survivors' receipt of treatment summaries and implications for patient-centered communication and quality of care SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT Conference of the European-Association-for-Communication-in-Healthcare (EACH) CY SEP 28-OCT 01, 2014 CL Amsterdam, NETHERLANDS ID UNITED-STATES; ONCOLOGISTS; DIAGNOSIS; KNOWLEDGE; PHYSICIANS; BREAST; PLANS AB Objective: The Institute of Medicine recommends cancer survivors completing treatment be provided with a treatment summary to facilitate delivery of patient-centered survivorship care. However, the relationship between treatment summary receipt and patient-centered communication (PCC) and overall quality of care (QOC) are not well understood. Methods: Cancer survivors responding to the Health Information National Trends Survey reported treatment summary receipt, QOC, and experiences of six core functions of PCC. Multivariable logistic regression assessed the relationship between treatment summary receipt and PCC. The prevalence of survivors' treatment summary receipt and demographic/clinical characteristics. predictive of treatment summary receipt were also assessed. Results: Of 359 respondents with a cancer history, 34.5% reported receiving a treatment summary. Greater treatment burden was associated with increased treatment summary receipt. Treatment summary receipt was associated with higher QOC and more PCC, both overall and for five of the six PCC functions. Conclusion: The receipt of cancer treatment summaries may improve PCC and QOC for survivors. Practice implications: The positive relationship between treatment summary receipt and survivors' PCC experience substantiates continued efforts to provide treatment summaries to survivors transitioning from active treatment to survivorship care. Future research should characterize mechanisms by which treatment summary provision may enhance PCC. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Blanch-Hartigan, Danielle] Bentley Univ, Dept Nat & Appl Sci, Waltham, MA 02452 USA. [Chawla, Neetu] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Beckjord, Ellen I.] Univ Pittsburgh, Dept Psychiat & Clin & Translat Sci, Pittsburgh, PA USA. [Forsythe, Laura P.] Patient Ctr Outcomes Res Inst, Res Integrat & Evaluat, Washington, DC USA. [de Moor, Janet S.; Hesse, Bradford W.; Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Blanch-Hartigan, D (reprint author), Bentley Univ, Dept Nat & Appl Sci, 175 Forest St,Jennison 103, Waltham, MA 02452 USA. EM danielleblanch@gmail.com OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute [HHSN26120100064C] FX The Health Information National Trends Survey is supported by contract number HHSN26120100064C from the National Cancer Institute. The views expressed in the manuscript do not necessarily represent the views of the US federal government. NR 31 TC 4 Z9 4 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD OCT PY 2015 VL 98 IS 10 SI SI BP 1274 EP 1279 DI 10.1016/j.pec.2015.06.005 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA CS1XR UT WOS:000361862700016 PM 26146237 ER PT J AU Han, PKJ Duarte, CW Daggett, S Siewers, A Killam, B Smith, KA Freedman, AN AF Han, Paul K. J. Duarte, Christine W. Daggett, Susannah Siewers, Andrea Killam, Bill Smith, Kahsi A. Freedman, Andrew N. TI Effects of personalized colorectal cancer risk information on laypersons' interest in colorectal cancer screening: The importance of individual differences SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT Conference of the European-Association-for-Communication-in-Healthcare (EACH) CY SEP 28-OCT 01, 2014 CL Amsterdam, NETHERLANDS DE Personalized risk information; Colorectal cancer; Screening ID RANDOMIZED-CONTROLLED-TRIAL; BREAST-CANCER; UNITED-STATES; ADHERENCE; COMMUNICATION; POPULATION; INTENTIONS; NEOPLASIA; TOOL AB Objective: To evaluate how personalized quantitative colorectal cancer (CRC) risk information affects laypersons' interest in CRC screening, and to explore factors influencing these effects. Methods: An online pre-post experiment was conducted in which a convenience sample (N=578) of laypersons, aged >50, were provided quantitative personalized estimates of lifetime CRC risk, calculated by the National Cancer Institute Colorectal Cancer Risk Assessment Tool (CCRAT). Self-reported interest in CRC screening was measured immediately before and after CCRAT use; sociodemographic characteristics and prior CRC screening history were also assessed. Multivariable analyses assessed participants' change in interest in screening, and subgroup differences in this change. Results: Personalized CRC risk information had no overall effect on CRC screening interest, but significant subgroup differences were observed. Change in screening interest was greater among individuals with recent screening (p=.015), higher model-estimated cancer risk (p=.0002), and lower baseline interest (p <.0001), with individuals at highest baseline interest demonstrating negative (not neutral) change in interest. Conclusion: Effects of quantitative personalized CRC risk information on laypersons' interest in CRC screening differ among individuals depending on prior screening history, estimated cancer risk, and baseline screening interest. Practice implications: Personalized cancer risk information has personalized effects increasing and decreasing screening interest in different individuals. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Han, Paul K. J.; Duarte, Christine W.; Siewers, Andrea; Smith, Kahsi A.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04101 USA. [Daggett, Susannah] Tufts Univ, Medford, MA 02155 USA. [Killam, Bill] User Ctr Design, Ashburn, VA USA. [Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 509 Forest Ave, Portland, ME 04101 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute [HSN261201000608P] FX The study was supported by Contract HSN261201000608P from the National Cancer Institute. The funder provided the statistical algorithm for the Colorectal Cancer Risk Assessment Tool, and input in interpretation of data and preparation and review of the manuscript. Portions of the study were presented at the International Conference on Communication in Healthcare (ICCH) 2014 Annual Meeting, Amsterdam, Netherlands, September 30, 2014. We thank Barbara Barry, Jessica Begley, and Janell Lewis for invaluable assistance in website programming and data collection. Drs. Han and Duarte had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 42 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD OCT PY 2015 VL 98 IS 10 SI SI BP 1280 EP 1286 DI 10.1016/j.pec.2015.07.010 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA CS1XR UT WOS:000361862700017 PM 26227576 ER PT J AU Etz, KE Arroyo, JA AF Etz, Kathleen E. Arroyo, Judith A. TI Small Sample Research: Considerations Beyond Statistical Power SO PREVENTION SCIENCE LA English DT Article ID COMMUNITY; PREVENTION; ABUSE AB Small sample research presents a challenge to current standards of design and analytic approaches and the underlying notions of what constitutes good prevention science. Yet, small sample research is critically important as the research questions posed in small samples often represent serious health concerns in vulnerable and underrepresented populations. This commentary considers the Special Section on small sample research and also highlights additional challenges that arise in small sample research not considered in the Special Section, including generalizability, determining what constitutes knowledge, and ensuring that research designs match community desires. It also points to opportunities afforded by small sample research, such as a focus on and increased understanding of context and the emphasis it may place on alternatives to the randomized clinical trial. The commentary urges the development and adoption of innovative strategies to conduct research with small samples. C1 [Etz, Kathleen E.] NIDA, NIH, Bethesda, MD 20852 USA. [Arroyo, Judith A.] NIAAA, NIH, Bethesda, MD 20852 USA. RP Etz, KE (reprint author), NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20852 USA. EM ketz@nih.gov NR 13 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD OCT PY 2015 VL 16 IS 7 BP 1033 EP 1036 DI 10.1007/s11121-015-0585-4 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CS0NP UT WOS:000361758100016 PM 26281902 ER PT J AU Fourie, NH Turner, TR Brown, JL Pampush, JD Lorenz, JG Bernstein, RM AF Fourie, Nicolaas H. Turner, Trudy R. Brown, Janine L. Pampush, James D. Lorenz, Joseph G. Bernstein, Robin M. TI Variation in vervet (Chlorocebus aethiops) hair cortisol concentrations reflects ecological disturbance by humans SO PRIMATES LA English DT Article DE Hair; Cortisol; Stress; Vervets; Human impact; Human food ID CERCOPITHECUS-AETHIOPS; NONHUMAN-PRIMATES; PAPIO-ANUBIS; STRESS; MONKEYS; WILD; BABOONS; MACAQUES; POPULATION; CONFLICT AB Vervet monkeys (Chlorocebus aethiops) often live in close proximity to humans. Vervets are known to raid crops, homes and gardens in suburban areas leading to human-vervet conflict. In general, primate groups with access to human foods experience increased population densities and intra-group aggression. This suggests high stress loads for vervets living in environments with high levels of human habitat disturbance and close proximity to humans. We tested the hypothesis that populations characterized by high levels of human impact are more physiologically stressed than low human impact populations, and that this increased stress would be reflected in higher concentrations of hair cortisol. We predicted that because females would be less likely to engage in high risk foraging activities, and hence keep more distance from humans than males, their hair cortisol levels should be lower than those in males. We quantified cortisol in the hair of wild caught individuals from populations that experienced different degrees of human habitat disturbance and differences in access to human food. We found that males in high human impact groups had significantly higher hair cortisol concentrations than those in low human impact groups, although this difference was not observed in female vervets. Human impacts on vervet behavioral ecology appear to be a significant source of stress for male animals in particular. C1 [Fourie, Nicolaas H.] NINR, Biobehav Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Turner, Trudy R.] Univ Wisconsin, Dept Anthropol, Milwaukee, WI 53201 USA. [Turner, Trudy R.] Univ Orange Free State, Dept Genet, ZA-9300 Bloemfontein, South Africa. [Brown, Janine L.] Smithsonian Conservat Biol Inst, Ctr Species Survival, Front Royal, VA 22630 USA. [Pampush, James D.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC 27708 USA. [Lorenz, Joseph G.] Cent Washington Univ, Dept Anthropol & Museum Studies, Ellensburg, WA 98926 USA. [Bernstein, Robin M.] Univ Colorado, Dept Anthropol, Boulder, CO 80309 USA. RP Fourie, NH (reprint author), NINR, Biobehav Branch, Div Intramural Res, NIH, Room 2N104,10 Ctr Dr, Bethesda, MD 20892 USA. EM fourienh@mail.nih.gov OI Fourie, Nicolaas/0000-0002-5167-8570 FU Lewis Cotlow Fund; National Science Foundation Integrative Graduate Education and Research Traineeship award (NSF IGERT-Award) [0801634]; NSF [BCS0938969] FX We thank all those who have taken part in sample and data collection over the course of 2002-2009. We are also indebted to the Environmental Affairs offices in Limpopo, Mpumalanga, Kwa-Zulu Natal, Gauteng, Free State and the Eastern Cape Provinces of South Africa for their assistance. We acknowledge the Smithsonian's Conservation Biology Institute's Endocrinology Laboratory, in particular Nicole Presley and Sarah Putman for their friendly assistance and advice. Analyses were carried out with support from the Lewis Cotlow Fund (2008 and 2010) and the National Science Foundation Integrative Graduate Education and Research Traineeship award (NSF IGERT-Award ID: 0801634). Sampling was supported by NSF grant BCS0938969. NR 56 TC 5 Z9 5 U1 7 U2 41 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0032-8332 EI 1610-7365 J9 PRIMATES JI Primates PD OCT PY 2015 VL 56 IS 4 BP 365 EP 373 DI 10.1007/s10329-015-0486-y PG 9 WC Zoology SC Zoology GA CS1DT UT WOS:000361803500011 PM 26318176 ER PT J AU Adachi, K Klausner, JD Bristow, CC Xu, JH Ank, B Morgado, MG Watts, DH Weir, F Persing, D Mofenson, LM Veloso, VG Pilotto, JH Joao, E Nielsen-Saines, K AF Adachi, Kristina Klausner, Jeffrey D. Bristow, Claire C. Xu, Jiahong Ank, Bonnie Morgado, Mariza G. Watts, D. Heather Weir, Fred Persing, David Mofenson, Lynne M. Veloso, Valdilea G. Pilotto, Jose Henrique Joao, Esau Nielsen-Saines, Karin CA NICHD HPTN Study Team TI Chlamydia and Gonorrhea in HIV-Infected Pregnant Women and Infant HIV Transmission SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; HUMAN-IMMUNODEFICIENCY-VIRUS; TO-CHILD TRANSMISSION; GENITAL-TRACT INFECTIONS; SUB-SAHARAN AFRICA; PERINATAL TRANSMISSION; TRACHOMATIS INFECTION; PRETERM BIRTH; RISK-FACTORS; PREVALENCE AB Background Sexually transmitted infections (STIs) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) can lead to adverse pregnancy and neonatal outcomes. The prevalence of STIs and its association with HIV mother-to-child transmission (MTCT) were evaluated in a substudy analysis from a randomized, multicenter clinical trial. Methodology Urine samples from HIV-infected pregnant women collected at the time of labor and delivery were tested using polymerase chain reaction testing for the detection of CT and NG (Xpert CT/NG; Cepheid, Sunnyvale, CA). Infant HIV infection was determined by HIV DNA polymerase chain reaction at 3 months. Results Of the 1373 urine specimens, 249 (18.1%) were positive for CT and 63 (4.6%) for NG; 35 (2.5%) had both CT and NG detected. Among 117 cases of HIV MTCT (8.5% transmission), the lowest transmission rate occurred among infants born to CT- and NG-uninfected mothers (8.1%) as compared with those infected with only CT (10.7%) and both CT and NG (14.3%; P = 0.04). Infants born to CT-infected mothers had almost a 1.5-fold increased risk for HIV acquisition (odds ratio, 1.47; 95% confidence interval, 0.9-2.3; P = 0.09). Conclusions This cohort of HIV-infected pregnant women is at high risk for infection with CT and NG. Analysis suggests that STIs may predispose to an increased HIV MTCT risk in this high-risk cohort of HIV-infected women. C1 [Adachi, Kristina; Klausner, Jeffrey D.; Ank, Bonnie; Nielsen-Saines, Karin] David Geffen UCLA Sch Med, Los Angeles, CA USA. [Bristow, Claire C.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Xu, Jiahong] Westat Corp, Rockville, MD USA. [Morgado, Mariza G.; Veloso, Valdilea G.] Fundacao Oswaldo Cruz FIOCRUZ, Rio De Janeiro, RJ, Brazil. [Watts, D. Heather] US DOE, Off Global AIDS Coordinator, Washington, DC 20585 USA. [Weir, Fred; Persing, David] Cepheid, Sunnyvale, CA USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Pilotto, Jose Henrique] Hosp Geral Nova Iguacu, Nova Iguacu, RJ, Brazil. [Joao, Esau] Hosp Fed Servidores Estado, Rio De Janeiro, RJ, Brazil. RP Adachi, K (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Div Infect Dis, 10833 Le Conte Ave,MDCC 22-442, Los Angeles, CA 90095 USA. EM kadachi@mednet.ucla.edu FU NICHD, NIAID/NIH [HHSN267200800001C, N01-HD-8-0001, U01 AI047986]; NIAIDU01 [AI068632]; Eunice Kennedy Shriver NICHD; National Institute of Mental Health [AI068632]; Boehringer Ingelheim Pharmaceuticals Inc; GlaxoSmithKline on behalf of ViiV Healthcare; Cepheid, Sunnyvale, CA FX The NICHD HPTN 040 study was supported by NICHD Contract Nos. HHSN267200800001C (NICHD Control No. N01-HD-8-0001) and U01 AI047986 (Brazilian AIDS Prevention Trials International Network), NIAID/NIH. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by NIAIDU01 AI068632, the Eunice Kennedy Shriver NICHD, and the National Institute of Mental Health (AI068632). In addition, the parent study was supported, in part, by Boehringer Ingelheim Pharmaceuticals Inc and GlaxoSmithKline on behalf of ViiV Healthcare. This particular substudy was supported by Cepheid, Sunnyvale, CA, where Chlamydia trachomatis and Neisseria gonorrhoeae testing of specimens was performed. The authors would also like to acknowledge 2 laboratory personnel who conducted all of the urine specimen preparation and shipment, Mary Ann Hausner and Jessica Liu. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, affiliated universities, programs, or companies of the authors. NR 48 TC 8 Z9 8 U1 5 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2015 VL 42 IS 10 BP 554 EP 565 DI 10.1097/OLQ.0000000000000340 PG 12 WC Infectious Diseases SC Infectious Diseases GA CR8LZ UT WOS:000361605700005 PM 26372927 ER PT J AU Dunn, LL Boyer, PL McWilliams, MJ Smith, SJ Hughes, SH AF Dunn, Linda L. Boyer, Paul L. McWilliams, Mary Jane Smith, Steven J. Hughes, Stephen H. TI Mutations in human immunodeficiency virus type 1 reverse transcriptase that make it sensitive to degradation by the viral protease in virions are selected against in patients SO VIROLOGY LA English DT Article DE HIV; RT; Protease; Temperature sensitive; RNase H; Gag-Pol ID IN-VIVO; HIV-1; SPECIFICITY; REPLICATION; INFECTION; PROTEINS; MUTANT; DNA AB Mutations in the thumb subdomain of reverse transcriptase (RT) of HIV-1 can cause this enzyme to be degraded in virions by the viral protease (PR). Many of these mutations confer a temperature-sensitive phenotype on RT and viral replication. The degradation of RT by PR appears to take place after Gag-Pol has been processed. We show here that mutations in other parts of RI, including the RNase H domain, can make RI PR-sensitive and temperature-sensitive. These data explain why some mutations in the RNase H domain, which had little or no effect on the polymerase activity of purified recombinant RT, had a profound effect on viral titer. Because the PR-sensitive phenotype significantly reduced viral titer, we previously suggested that these mutations would be selected against in patients. We also show that RI mutations that are known to confer a temperature sensitive phenotype are rarely found in the Stanford database. Published by Elsevier Inc. C1 [Dunn, Linda L.; Boyer, Paul L.; McWilliams, Mary Jane; Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. EM hughesst@mail.nih.gov FU Intramural Research Program of the NIH, NCI FX This research was supported by the Intramural Research Program of the NIH, NCI. The authors are grateful to T. Burdette for help in preparing the manuscript, and to A. Kane and J. Meyer for help preparing the figures. NR 23 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT PY 2015 VL 484 BP 127 EP 135 DI 10.1016/j.virol.2015.05.020 PG 9 WC Virology SC Virology GA CR8CG UT WOS:000361578100014 PM 26093496 ER PT J AU Kim, SH Chen, S Jiang, X Green, KY Samal, SK AF Kim, Shin-Hee Chen, Shun Jiang, Xi Green, Kim Y. Samal, Siba K. TI Immunogenicity of Newcastle disease virus vectors expressing Norwalk virus capsid protein in the presence or absence of VP2 protein SO VIROLOGY LA English DT Article DE Norwalk virus; Newcastle disease virus; Vaccine; Virus-like particles; VP1 protein ID IMMUNE-RESPONSES; VACCINE; PARTICLES; MUCOSAL; MICE; CELLS; EPIDEMIOLOGY; VOLUNTEERS; ANTIBODIES; ILLNESS AB Noroviruses are the most common cause of acute gastroenteritis in humans. Development of an effective vaccine is required for reducing their outbreaks. In order to develop a GI norovirus vaccine, Newcastle disease virus vectors, rLaSota and modified rBC, were used to express VP1 protein of Norwalk virus. Co-expression of VP1 and VP2 proteins by Newcastle disease virus vectors resulted in enhanced expression of Norwalk virus VP1 protein and self-assembly of VP1 protein into virus-like particles. Furthermore, the Norwalk virus-specific IgG response induced in mice by Newcastle disease virus vectors was similar to that induced by baculovirus-expressed virus-like particles in mice. However, the modified rBC vector in the presence of VP2 protein induced significantly higher levels of cellular and mucosal immune responses than those induced by baculovirus-expressed VLPs. These results indicate that Newcastle disease virus has great potential for developing a live Norwalk virus vaccine by inducing humoral, cellular and mucosal immune responses in humans. (C) 2015 Elsevier Inc. All rights reserved. C1 [Kim, Shin-Hee; Chen, Shun; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Jiang, Xi] Univ Cincinnati, Div Infect Dis, Cincinnati Childrens Hosp Med Ctr, Coll Med, Cincinnati, OH USA. [Green, Kim Y.] NIAID, Infect Dis Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [1R21AI100195] FX We thank Daniel Rockemann, Girmay Gebreluul, Yonas Araya, and our laboratory members for excellent technical assistance; and Dr. Bernard Moss (NIAID, NIH) for providing the vaccinia T7 recombinant virus and the pTM1 plasmid. This research was supported by NIAID (1R21AI100195). The views expressed herein do not necessarily reflect the official policies of the Depai talent of Health and Human Services, nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. NR 32 TC 2 Z9 2 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT PY 2015 VL 484 BP 163 EP 169 DI 10.1016/j.virol.2015.06.003 PG 7 WC Virology SC Virology GA CR8CG UT WOS:000361578100018 PM 26099695 ER PT J AU Demberg, T Mohanram, V Musich, T Brocca-Cofano, E McKinnon, KM Venzon, D Robert-Guroff, M AF Demberg, Thorsten Mohanram, Venkatramanan Musich, Thomas Brocca-Cofano, Egidio McKinnon, Katherine M. Venzon, David Robert-Guroff, Marjorie TI Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection SO VIROLOGY LA English DT Article DE Rhesus macaque; Simian-human immunodeficiency virus infection; Marginal zone B cells; B cell dysregulation ID IMMUNODEFICIENCY VIRUS-INFECTION; ANTIRETROVIRAL THERAPY; HIV-INFECTION; CELLULAR-DYNAMICS; BCL-2 FAMILY; T-CELLS; RECEPTOR; ACTIVATION; DISEASE; BLOOD AB Marginal zone (MZ) B cells generate T-independent antibody responses to pathogens before T-dependent antibodies arise in germinal centers. They have been identified in cynomolgus monkeys and monitored during acute SIV infection, yet have not been well-studied in rhesus macaques. Here we characterized rhesus macaque MZ B cells, present in secondary lymphoid tissue but not peripheral blood, as CD19(+), CD20(+), CD21(hi), IgM(+), CD22(+), CD38(+), BTLA(+), CD40(+), CCR6(+) and BCL-2(+). Compared to healthy macaques, SHIVSF162P4-infected animals showed decreased total B cells and MZ B cells and increased MZ B cell Ki-67 expression early in chronic infection. These changes persisted in late chronic infection, despite viremia reductions to low or undetectable levels. Expression levels of additional phenotypic markers and RNA PCR array analyses were in concert with continued low-level activation and diminished function of MZ B cells. We conclude that MZ B-cell dysregulation and dysfunction associated with SIV/HIV infection are not readily reversible. Published by Elsevier Inc. C1 [Demberg, Thorsten; Mohanram, Venkatramanan; Musich, Thomas; Brocca-Cofano, Egidio; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, Bethesda, MD 20892 USA. [McKinnon, Katherine M.] NCI, FACS Core, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Mohanram, Venkatramanan/I-3652-2016 FU National Institutes of Health, National Cancer Institute FX We thank DJ. Liewehr for helping with the statistical analysis, critical reading of the manuscript and helpful suggestions. We further thank S. Waggoner and S. Cranert, Cincinnati Children's Hospital Medical Center, for sharing some of their unpublished LCMV work with us. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 60 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT PY 2015 VL 484 BP 323 EP 333 DI 10.1016/j.virol.2015.06.022 PG 11 WC Virology SC Virology GA CR8CG UT WOS:000361578100034 PM 26151223 ER PT J AU Nikolaitchik, O Keele, B Gorelick, R Alvord, WG Mazurov, D Pathak, VK Hu, WS AF Nikolaitchik, Olga Keele, Brandon Gorelick, Robert Alvord, W. Gregory Mazurov, Dmitriy Pathak, Vinay K. Hu, Wei-Shau TI High recombination potential of subtype A HIV-1 SO VIROLOGY LA English DT Article DE HIV-1; Recombination; Subtype A ID IMMUNODEFICIENCY-VIRUS TYPE-1; GENETIC-RECOMBINATION; RETROVIRAL RECOMBINATION; REVERSE-TRANSCRIPTASE; VIRAL REPLICATION; TARGET-CELLS; GENOMIC RNA; HOT-SPOT; IDENTIFICATION; RESISTANCE AB Recombination can assort polymorphic alleles to increase diversity in the HIV-1 population. To better understand the recombination potential of subtype A HIV-I, we generated viruses containing sequences from two variants circulating in Russia and analyzed the polymerase gene (pol) of the recombinants after one round of HIV-1 replication using single-genome sequencing. We observed that recombination occurred throughout pol and could easily assort alleles containing mutations that conferred resistance to currently approved antivirals. We measured the recombination rate in various regions of pal including a G-rich region that has been previously proposed to be a recombination hot spot. Our study does not support a recombination hot spot in this G-rich region. Importantly, of the 58 proviral sequences containing crossover event(s) in pol, we found that each sequence was a unique genotype indicating that recombination is a powerful genetic mechanism in assorting the genomes of subtype A HIV-I variants. Published by Elsevier Inc. C1 [Nikolaitchik, Olga; Pathak, Vinay K.; Hu, Wei-Shau] NCI, HIV Dynam & Replicat Program, Ft Detrick, MD 21702 USA. [Keele, Brandon; Gorelick, Robert] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Ft Detrick, MD 21702 USA. [Alvord, W. Gregory] NCI, Data Management Serv, Ft Detrick, MD 21702 USA. [Mazurov, Dmitriy] Inst Immunol, Moscow 115478, Russia. RP Hu, WS (reprint author), NCI, HIV Dynam & Replicat Program, Ft Detrick, MD 21702 USA. EM Wei-Shau.Hu@nih.gov FU Intramural Research, National Cancer Institute; National Cancer Institute (NCI); National Institutes of Health (NIH) [HHSN261200800001E]; Russian Foundation for Basic Research [NIH-RFBR 12-04-91451] FX We thank Krista Delviks-Frankenberry for discussions and critical reading of the manuscript; this research is supported in part with funds from the Intramural Research, National Cancer Institute, funds from Intramural to Russia Initiative, with federal funds from the National Cancer Institute (NCI); National Institutes of Health (NIH) under Contract HHSN261200800001E, and from Russian Foundation for Basic Research (Grant NIH-RFBR 12-04-91451). NR 31 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT PY 2015 VL 484 BP 334 EP 340 DI 10.1016/j.virol.2015.06.025 PG 7 WC Virology SC Virology GA CR8CG UT WOS:000361578100035 PM 26164392 ER PT J AU Muller, BG van den Bos, W Brausi, M Futterer, JJ Ghai, S Pinto, PA Popeneciu, IV de Reijke, TM Robertson, C de la Rosette, JJMCH Scionti, S Turkbey, B Wijkstra, H Ukimura, O Polascik, TJ AF Muller, B. G. van den Bos, W. Brausi, M. Futterer, J. J. Ghai, S. Pinto, P. A. Popeneciu, I. V. de Reijke, T. M. Robertson, C. de la Rosette, J. J. M. C. H. Scionti, S. Turkbey, B. Wijkstra, H. Ukimura, O. Polascik, T. J. TI Follow-up modalities in focal therapy for prostate cancer: results from a Delphi consensus project SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Focal therapy; Follow-up; Consensus; Prostate cancer ID FOCUSED ULTRASOUND HIFU; QUALITY-OF-LIFE; RECTAL EXAMINATION; ANTIGEN; BIOPSY; CYSTOSCOPY; TRIAL; MEN AB Focal therapy can offer the middle ground for treatment between active surveillance and radical therapy in patients with low- and intermediate-risk prostate cancer. Factors that prohibit focal therapy from being standard of care are numerous. Several consensus projects have been conducted to position the utilization of imaging and trial design in focal therapy. However, the literature is still scarce on patient follow-up after focal therapy. For these reasons, an international multidisciplinary consensus project was established in order to reach consensus about a uniform follow-up protocol after focal therapy. To standardize patient follow-up after focal therapy. A literature study was performed, and a questionnaire was constructed. The questionnaire was sent out to 76 participants (70 % urologists, 28 % radiologists and 2 % biomedical engineers) in three consecutive rounds according to the Delphi method. In each round, the panelists were presented with the results of the previous round. Participants each had the opportunity to adapt, delete or add questions. The topics discussed pertaining to follow-up after focal therapy were as follows: (1) general,(2) biopsies, (3) PSA, (4) digital rectal examination (DRE), (5) imaging, (6) quality of life (QoL) and (7) registration and pooling of data. The project was concluded with a face-to-face meeting in which final conclusions were formulated. The follow-up after focal therapy should be a minimum of 5 years. The following modalities should be included in assessing post-treatment outcomes: multiparametric MRI (mpMRI), biopsies, assessment of erectile function, QoL, urinary symptoms and incontinence. A systematic 12-core TRUS biopsy combined with 4-6 targeted biopsy cores of the treated area and any suspicious lesion(s) should be performed after 1 year, and thereafter only when there is suspicion on imaging. The ideal way to perform targeted biopsies is to use TRUS-MRI fusion technology. PSA should be performed for research purposes, in the first year, every 3 months, and after the first year, every 6 months. mpMRI is the optimal imaging modality for follow-up after focal therapy. On a 1.5T scanner, an endorectal coil is strongly advised by the panel, whereas on a 3T machine, it is optional, however, it will improve image quality. The following sequences should be included: T2WI, DWI including high b values of > 1,000 and ADC maps of DWI, DCE and T1WI. Imaging should be performed at 6 months and at 1 year following treatment; after the first year post-treatment, it should be performed every year until 5 years following treatment. All data should ideally be pooled in a common global database. Focal therapy is a relatively new form of treatment for prostate cancer. In order to include focal therapy as a standard of care treatment, consistent follow-up is necessary. By implementing the results of this consensus study, focal therapy users will be able to provide important and standardized outcome data. C1 [Muller, B. G.; van den Bos, W.; de Reijke, T. M.; de la Rosette, J. J. M. C. H.; Wijkstra, H.] AMC Univ Hosp, Dept Urol, Amsterdam, Netherlands. [Brausi, M.] Estense S Agostino Hosp, Dept Urol, Modena, Italy. [Futterer, J. J.] Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6525 ED Nijmegen, Netherlands. [Futterer, J. J.] Univ Twente, MIRA Inst Biomed Technol & Tech Med, NL-7500 AE Enschede, Netherlands. [Ghai, S.] Univ Toronto, Mt Sinai Hosp, Womens Coll Hosp, Univ Hlth Network,Joint Dept Med Imaging, Toronto, ON M5G 1X5, Canada. [Pinto, P. A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Popeneciu, I. V.] Univ Clin Heidelberg, Dept Urol, Heidelberg, Germany. [Robertson, C.; Polascik, T. J.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Robertson, C.; Polascik, T. J.] Duke Univ, Med Ctr, Dept Urol, Durham, NC USA. [Scionti, S.] Scionti Prostate Ctr, Urol, Sarasota, FL USA. [Turkbey, B.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Wijkstra, H.] Eindhoven Univ Technol, Dept Elect Engn, NL-5600 MB Eindhoven, Netherlands. [Ukimura, O.] Univ So Calif, Dept Urol, Norris Cotton Canc Ctr, Los Angeles, CA USA. RP Muller, BG (reprint author), AMC Univ Hosp, Dept Urol, Amsterdam, Netherlands. EM berrend@gmail.com FU Endocare FX The following authors declare no conflict of interest: B.G. Muller, W. van den Bos, M. Brausi, J.J. Futterer, S. Ghai, P.A. Pinto, I.V. Popeneciu, T.M. de Reijke, B. Turkbey and H. Wijkstra. C. Robertson is consultant/PI at EDAP TMS Inc., S. Scionti is consultant at SonaCare Medical, T.J. Polascik receives a research grant from Endocare, O. Ukimura is advisory board member at SonaCare Medical, J.J. M. C. H. and de la Rosette is consultant to AngioDynamics. NR 25 TC 8 Z9 8 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD OCT PY 2015 VL 33 IS 10 BP 1503 EP 1509 DI 10.1007/s00345-014-1475-2 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CS1QH UT WOS:000361841900017 PM 25559111 ER PT J AU Matthews, L Kleiner, DE Chairez, C McManus, M Nettles, MJ Zemanick, K Morse, CG Benator, D Kovacs, JA Hadigan, C AF Matthews, Lindsay Kleiner, David E. Chairez, Cheryl McManus, Maryellen Nettles, Mary Jane Zemanick, Kira Morse, Caryn Gee Benator, Debra Kovacs, Joseph A. Hadigan, Colleen TI Pioglitazone for Hepatic Steatosis in HIV/Hepatitis C Virus Coinfection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; PPAR-GAMMA; HIV; HCV; THERAPY; PEGINTERFERON; INFECTION; RIBAVIRIN AB Chronic hepatitis C infection frequently coexists with human immunodeficiency virus (HIV) and together are associated with increased hepatic steatosis. Steatosis is a risk factor for progression of liver disease and may persist despite a sustained virologic response to hepatitis C treatment. Therefore, therapies to target hepatic steatosis are important for individuals with HIV and hepatitis C virus (HCV) coinfection. We completed a 48-week, randomized, double-blind, placebo-controlled trial of pioglitazone (45 mg/day) in 13 subjects with HIV/HCV coinfection. The primary outcome variable was hepatic fat content, measured by magnetic resonance spectroscopy (MRS) imaging. Individuals randomized to pioglitazone had a significant decrease in hepatic fat content measured by MRS from baseline (15.1 +/- 7.0%) to week 48 (7.6 +/- 3.9%), with a mean difference of -7.4% (p = 0.02, n = 5). There was no significant change in hepatic fat content with placebo. Glycemic control as measured by oral glucose challenge improved significantly with pioglitazone (p = 0.047). Though not statistically significant, there were trends toward improved alanine aminotransferase (ALT) and histopathologic grade of steatosis in subjects who received pioglitazone. Pioglitazone was well tolerated and no one discontinued due to side effects. This study demonstrates that 48 weeks of pioglitazone therapy, and not placebo, results in significant reductions in hepatic fat content as measured by MRS in subjects with HIV and HCV coinfection and hepatic steatosis. This small study shows that pioglitazone helps ameliorate steatosis in the context of HIV/HCV coinfection. C1 [Matthews, Lindsay; Morse, Caryn Gee; Kovacs, Joseph A.] NIH, Dept Crit Care Med, NIH Clin Ctr, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chairez, Cheryl; Hadigan, Colleen] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [McManus, Maryellen] Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD USA. [Nettles, Mary Jane; Benator, Debra] Vet Affairs Med Ctr, Infect Dis Sect, Med Serv, Washington, DC 20422 USA. [Zemanick, Kira] NIH, NIH Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. [Benator, Debra] George Washington Univ, Med Ctr, Div Infect Dis, Washington, DC 20037 USA. RP Hadigan, C (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 11C103, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by resources from the National Institute of Allergy and Infectious Diseases Intramural Program through the National Institutes of Health, and the Washington DC VA Medical Center. This project was also funded in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. Takeda Pharmaceuticals U.S.A., Inc. provided study medication for the trial. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 27 TC 1 Z9 1 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT 1 PY 2015 VL 31 IS 10 BP 961 EP 966 DI 10.1089/aid.2015.0093 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CR5PL UT WOS:000361395500004 PM 26214341 ER PT J AU Arteaga, SS Loria, CM Crawford, PB Fawcett, SB Fishbein, HA Gregoriou, M John, LV Kelley, M Pate, RR Ritchie, LD Strauss, WJ AF Arteaga, S. Sonia Loria, Catherine M. Crawford, Patricia B. Fawcett, Stephen B. Fishbein, Howard A. Gregoriou, Maria John, Lisa V. Kelley, Melinda Pate, Russell R. Ritchie, Lorrene D. Strauss, Warren J. TI The Healthy Communities Study Its Rationale, Aims, and Approach SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COMPETITIVE FOOD; UNITED-STATES; OBESITY; CHILDHOOD; CHILDREN; ADOLESCENTS; POLICIES; PREVALENCE; NUTRITION; BMI AB Communities across the U.S. are implementing programs and policies designed to address the epidemic of childhood obesity. These programs vary widely in their approaches, including the intensity level, duration, funding, target population, and implementation techniques. However, no previous studies have examined these variations and determined how such aspects of community programs and policies are related to childhood obesity outcomes. The Healthy Communities Study is an observational study that is assessing the associations between characteristics of community programs and policies and BMI, nutrition, and physical activity in children. The Healthy Communities Study was funded in 2010, field data collection and medical record abstraction will be completed in 2015, and data cleaning and analyses will be completed by mid-year 2016. One-hundred and thirty communities (defined as a high school catchment area) and approximately 5,000 children in kindergarten through eighth grade and their parents have been recruited from public elementary and middle schools across the country. The study is examining quantitative and qualitative information obtained from community-based initiatives; measures of community characteristics (e.g., school environment); and child and parent measures, including children's physical activity levels and dietary practices and children's and parents' BMI. The Healthy Communities Study employs a complex study design that includes a diverse sample of communities across the country and combines current/cross-sectional and retrospective data (abstracted from children's medical records). This paper describes the rationale for the Healthy Communities Study, the study aims and logic model, and a brief overview of the study design. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Arteaga, S. Sonia; Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Crawford, Patricia B.; Ritchie, Lorrene D.] Univ Calif Oakland, Div Agr & Nat Resources, Nutr Policy Inst, Oakland, CA USA. [Fawcett, Stephen B.] Univ Kansas, Work Grp Community Dev, Lawrence, KS 66045 USA. [Fawcett, Stephen B.] Westat Corp, Rockville, MD USA. [Gregoriou, Maria] Battelle Hlth & Analyt, Arlington, VA USA. [John, Lisa V.] Battelle Hlth & Analyt, St Louis, MO USA. [Kelley, Melinda] NIA, Bethesda, MD 20892 USA. [Pate, Russell R.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. [Strauss, Warren J.] Battelle Hlth & Analyt, Columbus, OH USA. RP Arteaga, SS (reprint author), NHLBI, 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20892 USA. EM arteagass@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute; NIH Office of Behavioral and Social Sciences Research; National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Disorders; Eunice Kennedy Shriver National Institute of Child Health and Development; DHHS [HHSN268201000041C] FX The Healthy Communities Study is funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 41 TC 5 Z9 5 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 615 EP 623 DI 10.1016/j.amepre.2015.06.029 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200016 PM 26384931 ER PT J AU Strauss, WJ Sroka, CJ Frongillo, EA Arteaga, SS Loria, CM Leifer, ES Wu, CO Patrick, H Fishbein, HA John, LV AF Strauss, Warren J. Sroka, Christopher J. Frongillo, Edward A. Arteaga, S. Sonia Loria, Catherine M. Leifer, Eric S. Wu, Colin O. Patrick, Heather Fishbein, Howard A. John, Lisa V. TI Statistical Design Features of the Healthy Communities Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; LIKELIHOOD METHOD; MISSINGNESS; ASSOCIATION AB The Healthy Communities Study is designed to assess relationships between characteristics of community programs and policies targeting childhood obesity and children's BMI, diet, and physical activity. The study involved a complex data collection protocol implemented over a 2-year period (2013-2015) across a diverse sample of 130 communities, defined as public high school catchment areas. The protocol involved baseline assessment within each community that included in-person or telephone interviews regarding community programs and policies and in-home collection of BMI, nutritional, and physical activity outcomes from a sample of up to 81 children enrolled in kindergarten through eighth grade in public schools. The protocol also involved medical record reviews to establish a longitudinal trajectory of BMI for an estimated 70% of participating children. Staged sampling was used to collect less detailed measures of physical activity and nutrition across the entire sample of children, with a subset assessed using more costly, burdensome, and detailed measures. Data from the Healthy Community Study will be analyzed using both cross-sectional and longitudinal models that account for the complex design and correct for measurement error and bias using a likelihood-based Markov-chain Monte Carlo methodology. This methods paper provides insights into the complex design features of the Healthy Communities Study and may serve as an example for future large-scale studies that assess the relationship between community-based programs and policies and health outcomes of community residents. (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [Strauss, Warren J.; Sroka, Christopher J.] Battelle Hlth & Analyt, Columbus, OH 43201 USA. [Frongillo, Edward A.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. [Arteaga, S. Sonia; Loria, Catherine M.; Leifer, Eric S.; Wu, Colin O.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Patrick, Heather] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fishbein, Howard A.] Battelle Hlth & Analyt, Arlington, VA USA. [John, Lisa V.] Battelle Hlth & Analyt, St Louis, MO USA. RP Strauss, WJ (reprint author), Battelle Hlth & Analyt, 505 King Ave, Columbus, OH 43201 USA. EM strauss@battelle.org FU federal funds from the National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Diabetes and Digestive and Kidney Disorders; National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C] FX The Healthy Communities Study is funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 29 TC 5 Z9 5 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 624 EP 630 DI 10.1016/j.amepre.2015.06.021 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200017 PM 26384932 ER PT J AU John, LV Gregoriou, M Pate, RR Fawcett, SB Crawford, PB Strauss, WJ Frongillo, EA Ritchie, LD Loria, CM Kelley, M Fishbein, HA Arteaga, SS AF John, Lisa V. Gregoriou, Maria Pate, Russell R. Fawcett, Stephen B. Crawford, Patricia B. Strauss, Warren J. Frongillo, Edward A. Ritchie, Lorrene D. Loria, Catherine M. Kelley, Melinda Fishbein, Howard A. Arteaga, S. Sonia TI Operational Implementation of the Healthy Communities Study How Communities Shape Children's Health SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article AB The Healthy Communities Study (HCS) is examining how characteristics of community programs and policies targeting childhood obesity are related to childhood diet, physical activity, and obesity outcomes. The study involves selected districts and public schools in 130 communities; families recruited through schools; and data collected at the community, school, household, and child levels. Data collection took place in two waves-Wave 1 in Spring 2012 and Wave 2 from 2013 to 2015-with analysis to be completed by August 2016. This paper describes operational elements of the HCS, including recruitment activities, field operations, training of data collectors, human subjects protection, and quality assurance and quality control procedures. Experienced trainers oversaw and conducted all training, including training of (1) district and school recruitment staff; (2) telephone interviewers for household screening and recruitment; (3) field data collectors for conducting household data collection; and (4) community liaisons for conducting key informant interviews, document abstraction, and community observations. The study team developed quality assurance and quality control procedures that were implemented for all aspects of the study. Planning and operationalizing a study of this complexity and magnitude, with multiple functional teams, required frequent communication and strong collaboration among all study partners to ensure timely and effective decision making. (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [John, Lisa V.] Battelle Hlth & Analyt, St Louis, MO 63110 USA. [Gregoriou, Maria; Fishbein, Howard A.] Battelle Hlth & Analyt, Arlington, VA USA. [Pate, Russell R.; Frongillo, Edward A.] Univ S Carolina, Dept Exercise Sci, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Fawcett, Stephen B.] Univ Kansas, Work Grp Community Hlth & Dev, Lawrence, KS 66045 USA. [Crawford, Patricia B.; Ritchie, Lorrene D.] Univ Calif Berkeley, Atkins Ctr Weight & Hlth, Berkeley, CA 94720 USA. [Strauss, Warren J.] Battelle Hlth & Analyt, Columbus, OH USA. [Ritchie, Lorrene D.] Univ Calif Oakland, Nutr Policy Inst, Oakland, CA USA. [Loria, Catherine M.; Arteaga, S. Sonia] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Kelley, Melinda] NIA, Bethesda, MD 20892 USA. RP John, LV (reprint author), Battelle Hlth & Analyt, 5712 Oakland Ave, St Louis, MO 63110 USA. EM johnl@battelle.org FU federal funds from the National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Diabetes and Digestive and Kidney Disorders; National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C] FX The Healthy Communities Study was funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and the NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 6 TC 6 Z9 6 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 631 EP 635 DI 10.1016/j.amepre.2015.06.019 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200018 PM 26384933 ER PT J AU Fawcett, SB Collie-Akers, VL Schultz, JA Kelley, M AF Fawcett, Stephen B. Collie-Akers, Vicki L. Schultz, Jerry A. Kelley, Melinda TI Measuring Community Programs and Policies in the Healthy Communities Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RE-AIM FRAMEWORK; IMPACT AB Childhood obesity is a challenging public health issue facing communities throughout the U.S. Local efforts are believed to be essential to assuring environments that support physical activity and healthy food/beverage consumption among children and their families. However, little is known about how broadly and intensively communities are implementing combinations of programs and policies that address childhood nutrition, physical activity, and weight control. The Healthy Communities Study is a nationwide scientific study in diverse communities to identify characteristics of communities and programs that may be associated with childhood obesity. Data collection occurred in 2013-2015; data analysis will be completed in 2016. As part of the Healthy Communities Study, researchers designed a measurement system to assess the number and scope of community programs and policies and to examine possible associations between calculated "intensity" scores for these programs and policies and behavioral and outcome measures related to healthy weight among children. This report describes the protocol used to capture and code instances of community programs and policies, to characterize attributes of community programs and policies related to study hypotheses, and to calculate the intensity of combinations of community programs and policies (i.e., using the attributes of change strategy, duration, and reach). (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [Fawcett, Stephen B.; Collie-Akers, Vicki L.; Schultz, Jerry A.] Univ Kansas, Work Grp Community Hlth & Dev, Lawrence, KS 66045 USA. [Kelley, Melinda] NIA, Bethesda, MD 20892 USA. RP Fawcett, SB (reprint author), Univ Kansas, Work Grp Community Hlth & Dev, 1000 Sunnyside Dr, Lawrence, KS 66045 USA. EM sfawcett@ku.edu FU federal funds from the National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Diabetes and Digestive and Kidney Disorders; National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C]; DHHS NIH National Heart, Lung, and Blood Institute [HHSN268201000041C]; University of South Carolina; University of California-Berkeley; University of Kansas FX The Healthy Communities Study was funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and the NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C.; The DHHS NIH National Heart, Lung, and Blood Institute contract (HHSN268201000041C) to Battelle Memorial Institute funded this research; with subcontracts to scientific partners at the University of South Carolina, University of California-Berkeley, and the University of Kansas. The Community Measurement Subcommittee of the Healthy Communities Study-including representatives from the National Cancer Institute, National Institute of Child. Health and Human Development, CDC, and Robert Wood Johnson Foundation-contributed to the development of the community measurement approach. More detail on the context, methods, and emerging findings from the HCS can be found elsewhere in this issue and at the HCS website hosted by the National Heart, Lung, and Blood Institute. Copies of the codebooks and scoring instructions used in the community measurement protocol are available from the Healthy Communities Study/National Heart, Lung, and Blood Institute website and from the University of Kansas team that leads that aspect of the study: http://communityhealth.ku.edu/. NR 13 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 636 EP 641 DI 10.1016/j.amepre.2015.06.027 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200019 PM 26384934 ER PT J AU Sroka, CJ McIver, KL Sagatov, RDF Arteaga, SS Frongillo, EA AF Sroka, Christopher J. McIver, Kerry L. Sagatov, Robyn D. F. Arteaga, S. Sonia Frongillo, Edward A. TI Weight Status Measures Collected in the Healthy Communities Study Protocols and Analyses SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID ADIPOSITY; CHILDHOOD; OBESITY; ADULTHOOD; CHILDREN; BMI AB The Healthy Communities Study is one of the largest studies to assess the relationship between characteristics of community programs and policies to prevent childhood obesity and obesity-related outcomes. The purpose of this paper is to describe the protocol that was developed for collecting the anthropometric data for the study and the procedures for analyzing the data. Data were collected from 2013 to 2015 and analyses will be completed by mid-2016. During in-home visits, Healthy Communities Study staff collected height, weight, and waist circumference measurements from child participants and height and weight measurements from adult participants. The protocol for obtaining these measurements was adapted from the protocol used by the National Health and Nutrition Examination Survey, with modifications to accommodate assessments conducted in homes rather than in a Mobile Examination Center. In addition to anthropometric data from in-home visits, the Healthy Communities Study collected retrospective height and weight measurements from the medical records of child participants. These data were used to calculate trajectories of BMI and BMI z-scores. The study implemented procedures for ensuring the accuracy of the in-home measurements and abstracted medical data. These procedures included automatically checking the ranges on entered data, reviewing data for end-digit patterns, and abstracting selected medical records using two independent abstractors to assess agreement. The collection of longitudinal height and weight measures will allow researchers to address several pressing questions related to how characteristics of community programs and policies are associated with obesity-related outcomes among children. (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [Sroka, Christopher J.] Battelle Mem Inst, Columbus, OH USA. [McIver, Kerry L.] Univ S Carolina, Dept Exercise Sci, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Sagatov, Robyn D. F.] Battelle Mem Inst, Baltimore, MD USA. [Arteaga, S. Sonia] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Frongillo, Edward A.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. RP Sroka, CJ (reprint author), 3216 Milton Rd, Raleigh, NC 27609 USA. EM csroka@outlook.com FU federal funds from the National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Diabetes and Digestive and Kidney Disorders; National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C] FX The Healthy Communities Study is funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 21 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 642 EP 646 DI 10.1016/j.amepre.2015.07.001 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200020 PM 26384935 ER PT J AU Ritchie, LD Wakimoto, P Woodward-Lopez, G Thompson, FE Loria, CM Wilson, DK Kao, J Crawford, PB Webb, KL AF Ritchie, Lorrene D. Wakimoto, Patricia Woodward-Lopez, Gail Thompson, Frances E. Loria, Catherine M. Wilson, Dawn K. Kao, Janice Crawford, Patricia B. Webb, Karen L. TI The Healthy Communities Study Nutrition Assessments Child Diet and the School Nutrition Environment SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; OBESITY PREVENTION; PHYSICAL-ACTIVITY; FOOD ENVIRONMENT; RECALL; ADOLESCENTS; PREVALENCE; OVERWEIGHT; INTERVENTIONS; ASSOCIATION AB Multifaceted community interventions directed at improving food environments are emerging, but their impact on dietary change and obesity prevalence has not been adequately documented. The Healthy Communities Study (HCS) is seeking to identify characteristics and combinations of programs and policies that are associated with children's diets and obesity-related outcomes in various types of communities across the U.S. The purpose of this paper is to describe the methods used in 2013-2015 in the HCS to assess dietary intake, school nutrition environments, and other nutrition-related behaviors. The conceptual framework of the HCS is based on the socioecological model and behaviors shown in previous studies to be related to obesity in children guided selection of domains. Nine domains were identified as essential measures of nutrition in the HCS: (1) intake of selected foods and beverages; (2) food patterns and behaviors; (3) social support; (4) home environment; (5) school environment; (6) community environment; (7) breastfeeding history; (8) household food insecurity; and (9) dieting behaviors and body image. Children's dietary intake was assessed using a dietary screener and up to two automated 24-hour recalls. Dietary-related behaviors were assessed by a survey administered to the parent, child, or both, depending on child age. School nutrition measures were obtained from a combination of school staff surveys and researcher observations. Information from these measures is expected to contribute to a better understanding of "what is working" to improve the dietary behaviors that are likely to prevent obesity and improve health in children. (C) 2015 American Journal of Preventive Medicine. All rights reserved. C1 [Ritchie, Lorrene D.] Univ Calif, Nutr Policy Inst, Div Agr & Nat Resources, Oakland, CA 94607 USA. [Ritchie, Lorrene D.; Wakimoto, Patricia; Woodward-Lopez, Gail; Kao, Janice; Crawford, Patricia B.; Webb, Karen L.] Univ Calif Berkeley, Atkins Ctr Weight & Hlth, Berkeley, CA 94720 USA. [Thompson, Frances E.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Wilson, Dawn K.] Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. RP Ritchie, LD (reprint author), Univ Calif, Nutr Policy Inst, Div Agr & Nat Resources, 1111 Franklin St,Tenth Floor, Oakland, CA 94607 USA. EM lritchie@ucanr.edu FU National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institute of Diabetes and Digestive and Kidney Disorders; National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C] FX The Healthy Communities Study is funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 36 TC 5 Z9 5 U1 4 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 647 EP 652 DI 10.1016/j.amepre.2015.06.016 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200021 PM 26384936 ER PT J AU Pate, RR McIver, KL Colabianchi, N Troiano, RP Reis, JP Carroll, DD Fulton, JE AF Pate, Russell R. McIver, Kerry L. Colabianchi, Natalie Troiano, Richard P. Reis, Jared P. Carroll, Dianna D. Fulton, Janet E. TI Physical Activity Measures in the Healthy Communities Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID MIDDLE SCHOOL GIRLS; ADOLESCENT GIRLS; ENVIRONMENTS; CHILDREN; YOUTH; PARENT; BOYS AB The risk of obesity is reduced when youth engage in recommended levels of physical. activity (PA). For that reason, public health organizations in the U.S. have encouraged communities to implement programs and policies designed to increase PA in youth, and many communities have taken on that challenge. However, the long-term effects of those programs and policies on obesity are largely unknown. The Healthy Communities Study is a large-scale observational study of U.S. communities that is examining the characteristics of programs and policies designed to promote healthy behaviors (e.g., increase PA and improve diet) and determining their association with obesity-related outcomes. The purpose of this paper is to describe the methods used to measure PA in children and the personal and community factors that may influence it. The study used both self-reported and objective measures of PA, and measured personal, family, and home influences on PA via three constructs: (1) PA self-schema; (2) parental support; and (3) parental rules regarding PA. Neighborhood and community factors related to PA were assessed using three measures: (1) child perceptions of the neighborhood environment; (2) availability of PA equipment; and (3) attributes of the child's street segment via direct observation. School influences on children's PA were assessed via three constructs: (1) school PA policies; (2) child perceptions of the school PA environment; and (3) school outdoor PA environment. These measures will enable examination of the associations between characteristics of community PA programs and policies and obesity-related outcomes in children and youth. C1 [Pate, Russell R.; McIver, Kerry L.] Univ S Carolina, Dept Exercise Sci, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Colabianchi, Natalie] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Carroll, Dianna D.; Fulton, Janet E.] Ctr Dis Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. RP Pate, RR (reprint author), Publ Hlth Res Ctr, 921 Assembly St,Suite 212, Columbia, SC 29208 USA. EM rpate@mailbox.sc.edu OI Troiano, Richard/0000-0002-6807-989X FU National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute; NIH Office of Behavioral and Social Sciences Research; DHHS [HHSN268201000041C] FX The Healthy Communities Study was funded with federal funds from the National Heart, Lung, and Blood Institute, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Diabetes and Digestive and Kidney Disorders, National Cancer Institute, and NIH Office of Behavioral and Social Sciences Research; DHHS, under Contract No. HHSN268201000041C. NR 42 TC 6 Z9 6 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 653 EP 659 DI 10.1016/j.amepre.2015.06.020 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200022 PM 26384937 ER PT J AU George, SM Ballard, R Shikany, JM Crane, TE Neuhouser, ML AF George, Stephanie M. Ballard, Rachel Shikany, James M. Crane, Tracy E. Neuhouser, Marian L. TI A prospective analysis of diet quality and endometrial cancer among 84,415 postmenopausal women in the Women's Health Initiative SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Diet quality; Endometrial cancer; Prospective cohort study ID MENOPAUSAL HORMONE-THERAPY; CHRONIC DISEASE; MULTIETHNIC COHORT; EATING INDEX-2005; CLINICAL-TRIAL; BLOOD-PRESSURE; RISK; PATTERNS; MORTALITY; INDEXES AB Purpose: Endometrial cancer is the most commonly diagnosed gynecologic cancer, but no convincing dietary risk factors for this cancer have been identified. Among postmenopausal women, we examined how four key a priori diet quality indices-the Healthy Eating Index-2010, Alternative Healthy Eating Index-2010, alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension are related to the risk of endometrial cancer in the Women's Health Initiative Clinical Trials and Observational Study. Methods: Our prospective cohort study included 84,415 postmenopausal women with a uterus who completed a food frequency questionnaire at enrollment. Cox proportional hazards models were used to estimate multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer associated with increasing quintiles of diet quality index scores. Results: During 13.3 years of follow-up, 1392 endometrial cancer cases occurred. After adjustment for known risk factors, having better diet quality (Q5 vs. Q1) was not associated with the risk of endometrial cancer, as evidenced using Healthy Eating Index-2010 (HR: 1.11, 95% CI: 0.93-1.33), Alternative Healthy Eating Index-2010 (HR: 0.98, 95% CI: 0.82-1.17), alternate Mediterranean Diet (HR: 0.98, 95% CI: 0.82-1.17), or Dietary Approaches to Stop Hypertension (HR: 1.00, 95% CI: 0.84-119). Conclusions: Diet quality was not associated with endometrial cancer risk in this large cohort of postmenopausal women. Published by Elsevier Inc. C1 [George, Stephanie M.; Ballard, Rachel] NIH, Off Dis Prevent, Bethesda, MD 20982 USA. [Shikany, James M.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL USA. [Crane, Tracy E.] Univ Arizona, Dept Nutr Sci, Tucson, AZ USA. [Crane, Tracy E.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Crane, Tracy E.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP George, SM (reprint author), NIH, Off Dis Prevent, 6100 Executive Blvd,Suite 2B03, Bethesda, MD 20982 USA. EM stephanie.george@nih.gov FU Division of Cancer Control and Population Sciences of the National Cancer Institute; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 321115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX This work was supported by the Division of Cancer Control and Population Sciences of the National Cancer Institute. The Women's Health Initiative study is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 321115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. NR 42 TC 4 Z9 4 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2015 VL 25 IS 10 BP 788 EP 793 DI 10.1016/j.annepidem.2015.05.009 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR5XZ UT WOS:000361419000012 PM 26260777 ER PT J AU Karzai, FH Apolo, AB Cao, L Madan, RA Adelberg, DE Parnes, H McLeod, DG Harold, N Peer, C Yu, YK Tomita, Y Lee, MJ Lee, S Trepel, JB Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima H. Apolo, Andrea B. Cao, Liang Madan, Ravi A. Adelberg, David E. Parnes, Howard McLeod, David G. Harold, Nancy Peer, Cody Yu, Yunkai Tomita, Yusuke Lee, Min-Jung Lee, Sunmin Trepel, Jane B. Gulley, James L. Figg, William D. Dahut, William L. TI A phase I study of TRC105 anti-endoglin (CD105) antibody in metastatic castration-resistant prostate cancer SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; metastatic; angiogenesis inhibitors; anti CD105; endogolin; TRC105 ID REGULATORY T-CELLS; TUMOR ANGIOGENESIS; PLUS PREDNISONE; DOUBLE-BLIND; III TRIAL; THERAPY; DOCETAXEL; BEVACIZUMAB; PLACEBO; TARGET AB Objective TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design. Results A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction. Conclusion TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity. C1 [Karzai, Fatima H.; Apolo, Andrea B.; Cao, Liang; Madan, Ravi A.; Adelberg, David E.; Parnes, Howard; McLeod, David G.; Harold, Nancy; Peer, Cody; Yu, Yunkai; Tomita, Yusuke; Lee, Min-Jung; Lee, Sunmin; Trepel, Jane B.; Gulley, James L.; Figg, William D.; Dahut, William L.] NCI, Med Oncol Serv, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 37 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD OCT PY 2015 VL 116 IS 4 BP 546 EP 555 DI 10.1111/bju.12986 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CR3GA UT WOS:000361217900014 PM 25407442 ER PT J AU Toyoda, H Miyagawa, T Koike, A Kanbayashi, T Imanishi, A Sagawa, Y Kotorii, N Kotorii, T Hashizume, Y Ogi, K Hiejima, H Kamei, Y Hida, A Miyamoto, M Imai, M Fujimura, Y Tamura, Y Ikegami, A Wada, Y Moriya, S Furuya, H Takeuchi, M Kirino, Y Meguro, A Remmers, EF Kawamura, Y Otowa, T Miyashita, A Kashiwase, K Khor, SS Yamasaki, M Kuwano, R Sasaki, T Ishigooka, J Kuroda, K Kume, K Chiba, S Yamada, N Okawa, M Hirata, K Mizuki, N Uchimura, N Shimizu, T Inoue, Y Honda, Y Mishima, K Honda, M Tokunaga, K AF Toyoda, Hiromi Miyagawa, Taku Koike, Asako Kanbayashi, Takashi Imanishi, Aya Sagawa, Yohei Kotorii, Nozomu Kotorii, Tatayu Hashizume, Yuji Ogi, Kimihiro Hiejima, Hiroshi Kamei, Yuichi Hida, Akiko Miyamoto, Masayuki Imai, Makoto Fujimura, Yota Tamura, Yoshiyuki Ikegami, Azusa Wada, Yamato Moriya, Shunpei Furuya, Hirokazu Takeuchi, Masaki Kirino, Yohei Meguro, Akira Remmers, Elaine F. Kawamura, Yoshiya Otowa, Takeshi Miyashita, Akinori Kashiwase, Koichi Khor, Seik-Soon Yamasaki, Maria Kuwano, Ryozo Sasaki, Tsukasa Ishigooka, Jun Kuroda, Kenji Kume, Kazuhiko Chiba, Shigeru Yamada, Naoto Okawa, Masako Hirata, Koichi Mizuki, Nobuhisa Uchimura, Naohisa Shimizu, Tetsuo Inoue, Yuichi Honda, Yutaka Mishima, Kazuo Honda, Makoto Tokunaga, Katsushi TI A polymorphism in CCR1/CCR3 is associated with narcolepsy SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Narcolepsy; Chemokine receptor; Neuroinflammation; Genome-wide association study; Complex traits; Microglia ID GENOME-WIDE ASSOCIATION; CC-CHEMOKINE RECEPTORS; CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; SLEEP REGULATION; ETHNIC-GROUPS; NEURONS; EXPRESSION; CATAPLEXY; BRAIN AB Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P = 1.6 x 10(-5), odds ratio [OR] = 1.86). This rs3181077 association was replicated with the independent sample set (P = 0.032, OR = 1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. (C) 2015 Elsevier Inc. All rights reserved. C1 [Toyoda, Hiromi; Miyagawa, Taku; Khor, Seik-Soon; Yamasaki, Maria; Tokunaga, Katsushi] Univ Tokyo, Grad Sch Med, Dept Human Genet, Tokyo 1130033, Japan. [Koike, Asako] Hitachi Ltd, Res & Dev Grp, Tokyo, Japan. [Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Shimizu, Tetsuo] Akita Univ, Sch Med, Dept Neuropsychiat, Akita 010, Japan. [Kotorii, Nozomu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Uchimura, Naohisa] Kurume Univ, Sch Med, Dept Neuropsychiat, Fukuoka, Japan. [Kotorii, Nozomu; Kotorii, Tatayu] Kotorii Isahaya Hosp, Nagasaki, Japan. [Kamei, Yuichi] Natl Ctr Hosp, Natl Ctr Neurol & Psychiat, Sleep Disorder Ctr, Tokyo, Japan. [Hida, Akiko; Mishima, Kazuo] Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Dept Psychophysiol, Tokyo, Japan. [Miyamoto, Masayuki; Hirata, Koichi] Dokkyo Med Univ, Dept Neurol, Mibu, Tochigi, Japan. [Imai, Makoto; Yamada, Naoto] Shiga Univ Med Sci, Dept Psychiat, Otsu, Shiga, Japan. [Fujimura, Yota; Tamura, Yoshiyuki; Chiba, Shigeru] Asahikawa Med Univ, Dept Psychiat & Neurol, Asahikawa, Hokkaido, Japan. [Ikegami, Azusa; Kume, Kazuhiko] Kuwamizu Hosp, Sleep Ctr, Kumamoto, Japan. [Wada, Yamato; Kuroda, Kenji] Hannan Hosp, Dept Psychiat, Osaka, Japan. [Moriya, Shunpei; Ishigooka, Jun] Tokyo Womens Med Univ, Sch Med, Dept Psychiat, Tokyo, Japan. [Furuya, Hirokazu] Natl Omuta Hosp, Neuromuscular Ctr, Dept Neurol, Fukuoka, Japan. [Takeuchi, Masaki; Meguro, Akira; Mizuki, Nobuhisa] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa, Japan. [Takeuchi, Masaki; Kirino, Yohei; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Kirino, Yohei] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Yokohama, Kanagawa, Japan. [Kawamura, Yoshiya] Sakae Seijinkai Hosp, Dept Psychiat, Kagawa, Kanagawa, Japan. [Otowa, Takeshi] Univ Tokyo, Grad Sch Med, Dept Neuropsychiat, Tokyo, Japan. [Miyashita, Akinori; Kuwano, Ryozo] Niigata Univ, Brain Res Inst, Ctr Bioresources, Dept Mol Genet, Niigata, Japan. [Kashiwase, Koichi] Japanese Red Cross Kanto Koshinetsu Block Blood C, Dept HLA Lab, Tokyo, Japan. [Sasaki, Tsukasa] Univ Tokyo, Grad Sch Educ, Lab Hlth Educ, Tokyo, Japan. [Kume, Kazuhiko] Kumamoto Univ, Inst Mol Genet & Embryol, Dept Stem Cell Biol, Kumamoto, Japan. [Kume, Kazuhiko] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Neuropharmacol, Nagoya, Aichi, Japan. [Okawa, Masako] Shiga Univ Med Sci, Dept Sleep Med, Otsu, Shiga, Japan. [Okawa, Masako] Japan Fdn Neurosci & Mental Hlth, Tokyo, Japan. [Inoue, Yuichi; Honda, Yutaka; Honda, Makoto] Neuropsychiat Res Inst, Japan Somnol Ctr, Tokyo, Japan. [Okawa, Masako; Inoue, Yuichi] Tokyo Med Univ, Dept Somnol, Tokyo 1608402, Japan. [Honda, Makoto] Tokyo Metropolitan Inst Med Sci, Dept Psychiat & Behav Sci, Sleep Disorders Project, Tokyo 113, Japan. RP Miyagawa, T (reprint author), Univ Tokyo, Grad Sch Med, Dept Human Genet, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM miyagawa-taku@umin.ac.jp RI 桐野, 洋平/B-3701-2009 OI 桐野, 洋平/0000-0002-9488-661X FU Ministry of Education, Culture, Sports, Science and Technology of Japan [24890047, 26870117, 23689022, 15H04709, 22133008]; Takeda Science Foundation, Japan; SENSHIN Medical Research Foundation; Alfresa Pharma Corporation; Intramural Research Grant for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry [23-3] FX We thank all of the participants in this study. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan with Grants to H.T. (Grant-in-Aid for Research Activity Start-up, 24890047, and Grant-in-Aid for Young Scientists (B), 26870117), to T.M. (Grants-in-Aid for Young Scientists (A), 23689022, and Grant-in-Aid for Scientific Research (B), 15H04709) and to K.T. (Scientific Research on Innovative Areas, 22133008). T. M. receives research support from Grants-in-Aid from the Takeda Science Foundation, Japan and the SENSHIN Medical Research Foundation. Y.I. receives a commercial research Grant from Alfresa Pharma Corporation. This study was partly supported by an Intramural Research Grant for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry (23-3). NR 55 TC 4 Z9 4 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD OCT PY 2015 VL 49 BP 148 EP 155 DI 10.1016/j.bbi.2015.05.003 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CR3UF UT WOS:000361257900018 PM 25986216 ER PT J AU Scheinert, RB Asokan, A Rani, A Kumar, A Foster, TC Ormerod, BK AF Scheinert, Rachel B. Asokan, Aditya Rani, Asha Kumar, Ashok Foster, Thomas C. Ormerod, Brandi K. TI Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Aging; Inflammation; Neuroinflammation; Memory; Hippocampus; Water maze; xMAP technology; Cytokines; Chemokines ID CENTRAL-NERVOUS-SYSTEM; AGE-RELATED IMPAIRMENTS; BLOOD-BRAIN-BARRIER; SPATIAL MEMORY; HIPPOCAMPAL NEUROGENESIS; SYNAPTIC PLASTICITY; WATER MAZE; RECEPTOR ANTAGONIST; ADULT NEUROGENESIS; DECLINE AB We trained and tested young (6-8 months; n = 13), middle-aged (12-14 months; n = 41), and aged (22-24 months; n = 24) male Fischer 344 rats in a rapid acquisition water maze task and then quantified 27 stress hormones, cytokines and chemokines in their serum, hippocampi and frontal cortices using bead assay kits and xMAP technology. Middle-aged and aged rats learned the location of the hidden platform over training trials more slowly than their young counterparts. After training, young rats outperformed middle-aged and aged rats on both immediate and 24 h retention probe trials and about half of the middle-aged and aged (aging) rats exhibited impaired performances when tested on the retention probe trial 24 h later. The concentrations of many serum, hippocampal and cortical analytes changed with age often in networks that may represent age-sensitive signaling pathways and the concentrations of some of these analytes correlated with water maze learning and/or memory scores. Serum GRO/KC and RANTES levels, hippocampal GM-CSF levels and cortical IL-9 and RANTES levels were significantly higher in rats categorized as memory-impaired versus elite agers based upon their 24 h probe trial performances. Our data add to the emerging picture of how age-related changes in immune and neuroimmune system signaling impacts cognition. (C) 2015 Elsevier Inc. All rights reserved. C1 [Scheinert, Rachel B.] NIMH, NIH, Bethesda, MD USA. [Scheinert, Rachel B.; Asokan, Aditya; Ormerod, Brandi K.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL USA. [Rani, Asha; Kumar, Ashok; Foster, Thomas C.; Ormerod, Brandi K.] Univ Florida, Dept Neurosci, Gainesville, FL 32611 USA. [Rani, Asha; Kumar, Ashok; Foster, Thomas C.; Ormerod, Brandi K.] Univ Florida, McKnight Brain Inst, Gainesville, FL 32611 USA. RP Foster, TC (reprint author), Univ Florida, Dept Neurosci, Evelyn F & William L McKnight Brain Inst, Gainesville, FL 32611 USA. EM fosterl@ufl.edu; bormerod@bme.ufl.edu FU National Institutes of Health [AG014979-11, AG037984, AG036800, MH059891-10]; Evelyn F. McKnight Brain Research Foundation; Ruth K. Broad Biomedical Research Foundation Funding; National Science Foundation Graduate Research Fellowship [DGE-0802270] FX The study was supported by grants from the National Institutes of Health (AG014979-11, AG037984, AG036800 and MH059891-10) to T.C.F., the Evelyn F. McKnight Brain Research Foundation to T.C.F. and B.K.O., Ruth K. Broad Biomedical Research Foundation Funding to B.K.O. and a National Science Foundation Graduate Research Fellowship (DGE-0802270) to R.B.S. NR 114 TC 2 Z9 2 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD OCT PY 2015 VL 49 BP 216 EP 232 DI 10.1016/j.bbi.2015.06.005 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CR3UF UT WOS:000361257900025 PM 26093306 ER PT J AU Holleran, JL Beumer, JH McCormick, DL Johnson, WD Newman, EM Doroshow, JH Kummar, S Covey, JM Davis, M Eiseman, JL AF Holleran, Julianne L. Beumer, Jan H. McCormick, David L. Johnson, William D. Newman, Edward M. Doroshow, James H. Kummar, Shivaani Covey, Joseph M. Davis, Myrtle Eiseman, Julie L. TI Oral and intravenous pharmacokinetics of 5-fluoro-2 '-deoxycytidine and THU in cynomolgus monkeys and humans SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Fluorodeoxycytidine; Tetrahydrouridine; Toxicokinetics; Toxicity; Monkeys; DNA methylation inhibitor ID METHYLTRANSFERASE INHIBITOR 5-FLUORO-2'-DEOXYCYTIDINE; CYTIDINE DEAMINASE INHIBITOR; DNA METHYLTRANSFERASE; MYELODYSPLASTIC SYNDROMES; TETRAHYDROURIDINE THU; MICE; 5-FLUORO-2-DEOXYCYTIDINE; METABOLISM; PLASMA; 5-FLUORODEOXYCYTIDINE AB 5-Fluoro-2'-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability. After IV FdCyd and THU administration, FdCyd C (max) and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %). Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from < 1 to 24 %. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times three at the beginning of the first and second weeks of a 28-day cycle. C1 [Holleran, Julianne L.; Beumer, Jan H.; Eiseman, Julie L.] Univ Pittsburgh, Inst Canc, Canc Therapeut Program, Pittsburgh, PA 15213 USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [McCormick, David L.; Johnson, William D.] IIT, Res Inst, Chicago, IL 60616 USA. [Newman, Edward M.] City Hope Beckman Res Inst, Dept Canc Biol, Duarte, CA 91010 USA. [Doroshow, James H.; Kummar, Shivaani; Covey, Joseph M.; Davis, Myrtle] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Eiseman, Julie L.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Beumer, Jan H.; Eiseman, Julie L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Inst Canc, Canc Therapeut Program, Pittsburgh, PA 15213 USA. EM beumerj@gmail.com; eisemanj@upmc.edu OI Beumer, Jan/0000-0002-8978-9401 FU NCI [N01-CM-42202, N01-CM-52202, N01CM-2011-0015, UM1CA186690, UM1CA186717]; [P30CA047904] FX Funding for these studies was provided by NCI contracts N01-CM-42202 (IIT Research Institute), N01-CM-52202, N01CM-2011-0015, UM1CA186690 (University of Pittsburgh), and UM1CA186717 (City of Hope). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904. The authors would like to thank the Merrill Egorin Writing Group at UPCI for careful review of this manuscript. NR 17 TC 3 Z9 3 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2015 VL 76 IS 4 BP 803 EP 811 DI 10.1007/s00280-015-2857-x PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CR6YN UT WOS:000361494600015 PM 26321472 ER PT J AU Papadakis, GZ Millo, C Bagci, U Patronas, NJ Stratakis, CA AF Papadakis, Georgios Z. Millo, Corina Bagci, Ulas Patronas, Nicholas J. Stratakis, Constantine A. TI Talc Pleurodesis With Intense 18F-FDG Activity But No 68Ga-DOTA-TATE Activity on PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material ID POSITRON-EMISSION-TOMOGRAPHY; FDG-PET/CT; PLEURAL METASTASES; SOMATOSTATIN; PNEUMOTHORAX; MACROPHAGES; EXPRESSION; GRANULOMA; PATIENT; CT AB Talc pleurodesis (TP) is a technique, widely employed in the management of patients with persistent pleural effusions or pneumothoraces not amenable to other treatment options. It is well documented that talc deposits produce areas of highly increased F-18-FDG uptake, because of talc-induced inflammation. We present a case of a patient with history of TP who was evaluated with both F-18-FDG and Ga-68-DOTA-TATE. The hypermetabolic area seen on F-18-FDG-PET-CT in the region of talc placement showed no uptake by Ga-68-DOTA-TATE, suggesting the potential role of Ga-68-DOTA-TATE-PET-CT in elucidating F-18-FDG-postitive lesions in patients with history of both neuroendocrine malignancy and TP. C1 [Papadakis, Georgios Z.; Bagci, Ulas; Patronas, Nicholas J.] Warren Grant Magnuson Clin Ctr, Radiol & Imaging Sci, Orlando, FL 32835 USA. [Millo, Corina] NIH, Div Nucl Med, RAD&IS, Ctr Clin, Orlando, FL USA. [Bagci, Ulas] Univ Cent Florida, Ctr Comp Vis Res, Orlando, FL 32816 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 24 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD OCT PY 2015 VL 40 IS 10 BP 819 EP 820 DI 10.1097/RLU.0000000000000807 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CR6JB UT WOS:000361451300015 PM 26018715 ER PT J AU Suffredini, AF AF Suffredini, Anthony F. TI Caring for Critically Ill Ebola Virus Disease Patients With One Hand Tied Behind Your Back SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE Ebola treatment units; Ebola virus disease; multiple organ failure; personal protective equipment; West Africa ID UNITED-STATES; CRITICAL-CARE; MANAGEMENT C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Suffredini, AF (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 15 TC 1 Z9 1 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD OCT PY 2015 VL 43 IS 10 BP 2249 EP 2250 DI 10.1097/CCM.0000000000001221 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA CR5DC UT WOS:000361358900026 PM 26376249 ER PT J AU Sun, L He, C Nair, L Yeung, J Egwuagu, CE AF Sun, Lin He, Chang Nair, Lekha Yeung, Justine Egwuagu, Charles E. TI Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease SO CYTOKINE LA English DT Review DE Autoimmune disease; Cytokine therapy; IL-12 family cytokines; Regulatory B cells (Bregs and i35-Bregs); Adoptive B cell therapy ID T-CELL RESPONSES; ROR-GAMMA-T; MULTIPLE-SCLEROSIS; P35 SUBUNIT; HETERODIMERIC CYTOKINE; B-CELLS; INFLAMMATION; UVEITIS; IL-27; P40 AB Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naive T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naive T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL-12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis. Published by Elsevier Ltd. C1 [Sun, Lin; He, Chang; Nair, Lekha; Yeung, Justine; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bldg 10,Room 10N109A,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov RI Sun, Lin/I-3146-2016 FU Intramural NIH HHS [Z01 EY000262-13] NR 71 TC 11 Z9 12 U1 2 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD OCT PY 2015 VL 75 IS 2 BP 249 EP 255 DI 10.1016/j.cyto.2015.01.030 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CR3TQ UT WOS:000361256400007 PM 25796985 ER PT J AU Reichard, A Gulley, SP Rasch, EK Chan, L AF Reichard, Amanda Gulley, Stephen P. Rasch, Elizabeth K. Chan, Leighton TI Diagnosis isn't enough: Understanding the connections between high health care utilization, chronic conditions and disabilities among US working age adults SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE People with disabilities; Chronic conditions; Health service utilization; Health care needs ID COMMUNITY-DWELLING ADULTS; UNITED-STATES; MOBILITY LIMITATIONS; HOSPITALIZATION; POPULATION; SERVICES; COSTS AB Background: Under the ACA, new programs are being developed to enhance care coordination and reduce health care costs among people with chronic conditions, disabilities, and high utilization of health care. However, the relationships between these groups are not well understood. Objectives: Our aims were to (1) identify high utilizers of health care in the U.S. working age (18-64) population, (2) examine the overlap between this group and people with chronic conditions and/or disabilities, (3) identify predictors of high service use or cost among these subpopulations, and (4) recommend approaches for stratification of individuals with high health care utilization. Methods: Using pooled national data from the Medical Expenditure Panel Survey (2006-2008), we created indices to identify elevated or high utilization and cost groups. We performed descriptive analyses, bivariate comparisons and multivariate analyses to examine the relations between these populations and individuals with chronic conditions and/or disabilities. Results: While the large majority of persons with high use/cost had chronic conditions, the minority of persons with chronic conditions had high health care utilization. However, among persons with chronic conditions, disability was a significant predictor of high utilization. Annual expenditures were significantly elevated among people with disabilities, particularly when activities of daily living were limited. Conclusions: We conclude that medical diagnosis alone is insufficient for the development of eligibility criteria for, or the evaluation of, programs intended to better the delivery or coordination of services for high utilizers of health care services. New approaches are needed to assess functional limitations and identify ongoing needs for services and supports. Published by Elsevier Inc. C1 [Reichard, Amanda] Univ New Hampshire, Inst Disabil, Durham, NH 03824 USA. [Gulley, Stephen P.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Gulley, Stephen P.; Rasch, Elizabeth K.; Chan, Leighton] NIH, Clin Res Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Gulley, SP (reprint author), NIH, Mark O Hatfield Clin Res Ctr, Dept Rehabil Med, 6100 Execut Blvd,Suite 3C01,MSC 7515, Bethesda, MD 20892 USA. EM gulley@brandeis.edu FU NIH Intramural Research Program FX NIH Intramural Research Program. NR 34 TC 3 Z9 3 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD OCT PY 2015 VL 8 IS 4 BP 535 EP 546 DI 10.1016/j.dhjo.2015.04.006 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CR3RD UT WOS:000361249900012 PM 26082321 ER PT J AU Marino, ME Meterko, M Marfeo, EE McDonough, CM Jette, AM Ni, PS Bogusz, K Rasch, EK Brandt, DE Chan, L AF Marino, Molly Elizabeth Meterko, Mark Marfeo, Elizabeth E. McDonough, Christine M. Jette, Alan M. Ni, Pengsheng Bogusz, Kara Rasch, Elizabeth K. Brandt, Diane E. Chan, Leighton TI Work-related measures of physical and behavioral health function: Test-retest reliability SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability evaluation; Psychometrics; United States Social Security Administration; Computer-adaptive test; Reliability ID INTRACLASS CORRELATION-COEFFICIENTS; ITEM POOL CONSTRUCTION; QUALITY-OF-LIFE; DISABILITY EVALUATION; FUNCTION INSTRUMENT; OUTCOMES; VALIDITY; SYSTEM AB Background: The Work Disability Functional Assessment Battery (WD-FAB), developed for potential use by the US Social Security Administration to assess work-related function, currently consists of five multi-item scales assessing physical function and four multi-item scales assessing behavioral health function; the WD-FAB scales are administered as Computerized Adaptive Tests (CATs). Objective: The goal of this study was to evaluate the test-retest reliability of the WD-FAB Physical Function and Behavioral Health CATs. Methods: We administered the WD-FAB scales twice, 7-10 days apart, to a sample of 376 working age adults and 316 adults with work-disability. Intraclass correlation coefficients were calculated to measure the consistency of the scores between the two administrations. Standard error of measurement (SEM) and minimal detectable change (MDC90) were also calculated to measure the scales precision and sensitivity. Results: For the Physical Function CAT scales, the ICCs ranged from 0.76 to 0.89 in the working age adult sample, and 0.77-0.86 in the sample of adults with work-disability. ICCs for the Behavioral Health CAT scales ranged from 0.66 to 0.70 in the working age adult sample, and 0.77-0.80 in the adults with work-disability. The SEM ranged from 3.25 to 4.55 for the Physical Function scales and 5.27-6.97 for the Behavioral Health function scales. For all scales in both samples, the MDC90 ranged from 7.58 to 16.27. Conclusion: Both the Physical Function and Behavioral Health CATs of the WD-FAB demonstrated good test-retest reliability in adults with work-disability and general adult samples, a critical requirement for assessing work related functioning in disability applicants and in other contexts. (C) 2015 Elsevier Inc. All rights reserved. C1 [Marino, Molly Elizabeth; Meterko, Mark; Marfeo, Elizabeth E.; McDonough, Christine M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Meterko, Mark] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Marino, ME (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM memarino@bu.edu FU Social Security Administration-National Institutes of Health under the National Institutes of Health [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I]; National Institutes of Health Intramural Research Program FX This study was supported by Social Security Administration-National Institutes of Health Interagency Agreements under the National Institutes of Health (contract nos. HHSN269200900004C, HHSN269201000011C, HHSN269201100009I), and by the National Institutes of Health Intramural Research Program. NR 25 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD OCT PY 2015 VL 8 IS 4 BP 652 EP 657 DI 10.1016/j.dhjo.2015.04.001 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CR3RD UT WOS:000361249900027 PM 25991419 ER PT J AU Ramirez, AS Graff, K Nelson, D Galica, K Leyva, B Banegas, M Huerta, E AF Ramirez, A. Susana Graff, Kaitlin Nelson, David Galica, Kasia Leyva, Bryan Banegas, Mateo Huerta, Elmer TI Who Seeks Cita Con El Doctor? Twelve Years of Spanish-Language Radio Program Targeting US Latinos SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE cancer prevention; community health promotion; health communications; Hispanic; information seeking; Latino; mass media; media; radio ID CANCER-RELATED INFORMATION; HEALTH INFORMATION; MEDICAL ENCOUNTER; BEHAVIORS; MESSAGES; EDUCATION; DISPARITIES; ETHNICITY; IMPACT; REACH AB Purpose. Spanish-dominant Latinos make up 13% of the U.S. population, and this group is poorer and faces multiple threats to health compared with the general population. Additionally, Spanish speakers face challenges accessing health information that is often not available in Spanish. This study provides a descriptive epidemiology of a unique, low-cost health information source: the longest-running U.S.-based Spanish-language call-in radio health education program. Method. From the universe of all calls 1999 to 2011, stratified random sampling yielded 1,237 analyzed calls, which were manually coded for caller sex, age, proxy status, and health concern. Descriptive statistics were used to examine basic demographics of callers and call topics overall and by sex and proxy caller status. Results. Among all calls, the top three call-generating health topics were specific symptoms/conditions, sexual/reproductive health, and gastrointestinal concerns. The top nine topics were consistent among women, men, and proxy callers; however, relative frequency of topics varied across groups. Nearly one quarter of calls were initiated on behalf of someone, generally a child, spouse or sibling, or parent. Sixty percent of callers were women; women made 70% of proxy calls. Conclusion. Understanding the differences in information seeking behaviors, information needs, and source preferences is important for determining where and how to disseminate health information and may help explain disparities in knowledge and health outcomes. The radio talk show format provides a uniquely personal, culturally sensitive channel for meeting health information needs of a vulnerable population while leveraging the cost-effectiveness and wide reach of a mass medium. C1 [Ramirez, A. Susana] Univ Calif Merced, Merced, CA 95343 USA. [Graff, Kaitlin] Washington Univ, St Louis, MO USA. [Nelson, David; Galica, Kasia; Leyva, Bryan; Banegas, Mateo] NCI, Bethesda, MD 20892 USA. [Huerta, Elmer] Washington Hosp Ctr, Washington, DC 20010 USA. RP Ramirez, AS (reprint author), Univ Calif Merced, Sch Social Sci Humanities & Arts, 5200 North Lake Rd, Merced, CA 95343 USA. EM a.susana.ramirez@gmail.com NR 56 TC 1 Z9 1 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2015 VL 42 IS 5 BP 611 EP 620 DI 10.1177/1090198114543009 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR8KB UT WOS:000361599100006 PM 25121981 ER PT J AU Piccinino, L Griffey, S Gallivan, J Lotenberg, LD Tuncer, D AF Piccinino, Linda Griffey, Susan Gallivan, Joanne Lotenberg, Lynne Doner Tuncer, Diane TI Recent Trends in Diabetes Knowledge, Perceptions, and Behaviors: Implications for National Diabetes Education SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE cardiovascular disease; chronic disease management; diabetes; evaluation; health behavior; health protective behavior ID UNITED-STATES; RISK-FACTORS; PREVALENCE; AWARENESS; MELLITUS; PEOPLE; ADULTS; US AB Objectives. Examine trends in diabetes-related knowledge, perceptions, and behavior among U.S. adults with and without a diagnosis of diabetes and among subpopulations at risk. Discuss implications for national diabetes education and for the National Diabetes Education Program (NDEP) in particular. Methods. Three population-based NDEP National Diabetes Surveys (2006, 2008, and 2011) collected information on diabetes knowledge, education, and self-management; perceived and actual risk of diabetes; and lifestyle changes. Results. Since 2006, U.S. adults significantly advanced their knowledge and awareness of diabetes and prediabetes. Perceived personal risk did not increase among people with prediabetes (PWP) or people at risk. Family history as a risk factor dropped in reported importance, especially among PWP and Hispanics. Diabetes self-management rose modestly, although checking blood sugar significantly declined. Trends in understanding the diabetes and cardiovascular disease link, A1C testing, and adjusted logistic regression results for perceived risk are discussed. Discussion and Implications. Although diabetes-related knowledge has reached high levels, stagnant perceived risk suggests people at risk are not applying this knowledge to themselves. Future surveys are planned to include additional, specific questions to capture people's movement toward behavior change and to identify where strategic efforts and educational interventions can help promote improved behaviors. C1 [Piccinino, Linda; Griffey, Susan] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Gallivan, Joanne; Tuncer, Diane] NIH, Bethesda, MD 20892 USA. [Lotenberg, Lynne Doner] Hager Sharp Inc, Washington, DC USA. RP Piccinino, L (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM lpiccinino@s-3.com FU National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [GS23F0024M, HHSN276201200001U]; NIH Evaluation Set-Aside Office [04-207-NIDDK, 07-2006-NIDDK] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under Contract No. GS23F0024M/Task Order Number HHSN276201200001U and by the NIH Evaluation Set-Aside Office under Contract No. 04-207-NIDDK and No. 07-2006-NIDDK. This support was received by the employers of authors Piccinino, Griffey, and Lotenberg. Authors Gallivan and Tuncer are NIH employees. NR 26 TC 2 Z9 2 U1 2 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2015 VL 42 IS 5 BP 687 EP 696 DI 10.1177/1090198115577373 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR8KB UT WOS:000361599100015 PM 25800032 ER PT J AU Taber, JM Klein, WMP Ferrer, RA Han, PKJ Lewis, KL Biesecker, LG Biesecker, BB AF Taber, Jennifer M. Klein, William M. P. Ferrer, Rebecca A. Han, Paul K. J. Lewis, Katie L. Biesecker, Leslie G. Biesecker, Barbara B. TI Perceived ambiguity as a barrier to intentions to learn genome sequencing results SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Genetic/genome testing; Ambiguity aversion; Perceived ambiguity; Optimism; Tolerance for uncertainty; Response efficacy ID THREAT-MANAGEMENT RESOURCES; INFORMATION AVOIDANCE; MEDICAL TESTS; UNCERTAINTY; CANCER; COMMUNICATION; RISK; ASSOCIATION; PREFERENCES; RECOMMENDATIONS AB Many variants that could be returned from genome sequencing may be perceived as ambiguous-lacking reliability, credibility, or adequacy. Little is known about how perceived ambiguity influences thoughts about sequencing results. Participants (n = 494) in an NIH genome sequencing study completed a baseline survey before sequencing results were available. We examined how perceived ambiguity regarding sequencing results and individual differences in medical ambiguity aversion and tolerance for uncertainty were associated with cognitions and intentions concerning sequencing results. Perceiving sequencing results as more ambiguous was associated with less favorable cognitions about results and lower intentions to learn and share results. Among participants low in tolerance for uncertainty or optimism, greater perceived ambiguity was associated with lower intentions to learn results for non-medically actionable diseases; medical ambiguity aversion did not moderate any associations. Results are consistent with the phenomenon of "ambiguity aversion" and may influence whether people learn and communicate genomic information. C1 [Taber, Jennifer M.; Klein, William M. P.; Ferrer, Rebecca A.] NCI, Bethesda, MD 20892 USA. [Han, Paul K. J.] Maine Med Ctr, Portland, ME 04102 USA. [Lewis, Katie L.; Biesecker, Leslie G.; Biesecker, Barbara B.] NHGRI, Bethesda, MD 20892 USA. RP Taber, JM (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM Jennifer.taber@nih.gov OI Han, Paul/0000-0003-0165-1940 FU National Human Genome Research Institute FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 44 TC 4 Z9 4 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD OCT PY 2015 VL 38 IS 5 SI SI BP 715 EP 726 DI 10.1007/s10865-015-9642-5 PG 12 WC Psychology, Clinical SC Psychology GA CR6VF UT WOS:000361485300003 PM 26003053 ER PT J AU Cote, LR Kwak, K Putnick, DL Chung, HJ Bornstein, MH AF Cote, Linda R. Kwak, Keumjoo Putnick, Diane L. Chung, Hyun Jin Bornstein, Marc H. TI The Acculturation of Parenting Cognitions: A Comparison of South Korean, Korean Immigrant, and European American Mothers SO JOURNAL OF CROSS-CULTURAL PSYCHOLOGY LA English DT Article DE acculturation; cultural psychology; family/child rearing; values; attitudes; beliefs; social cognition ID SCALE; ATTRIBUTIONS AB A three-culture comparisonnative South Korean, Korean immigrants to the United States, and native European American mothersof two types of parenting cognitionsattributions and self-perceptionswas undertaken to explore cultural contributions to parenting cognitions and their adaptability among immigrant mothers. Attributions and self-perceptions of parenting were chosen because they influence parenting behavior and children's development and vary cross-culturally. One hundred seventy-nine mothers of 20-month-old children participated: 73 South Korean, 50 Korean immigrant, and 56 European American. Korean mothers differed from European American mothers on four of the five types of attributions studied and on all four self-perceptions of parenting, and these differences were largely consistent with the distinct cultural values of South Korea and the United States. Generally, Korean immigrant mothers' attributions for parenting more closely resembled those of mothers in the United States, whereas their self-perceptions of parenting more closely resembled those of mothers in South Korea. This study provides insights into similarities and differences in cultural models of parenting, and information about the acculturation of parenting cognitions among immigrants from South Korea. C1 [Cote, Linda R.] Marymount Univ, Arlington, VA 22207 USA. [Cote, Linda R.; Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Kwak, Keumjoo] Seoul Natl Univ, Seoul 151, South Korea. [Chung, Hyun Jin] Bourne Publ Sch, Bourne, MA USA. RP Cote, LR (reprint author), Marymount Univ, Dept Psychol, 2807 N Glebe Rd, Arlington, VA 22207 USA. EM lcote@marymount.edu OI Putnick, Diane/0000-0002-6323-749X FU U.S. Government-Intramural Research Program of National Institutes of Health; Marymount University Faculty Development grant FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the U.S. Government-Intramural Research Program of the National Institutes of Health and by a Marymount University Faculty Development grant to the first author. NR 56 TC 1 Z9 1 U1 4 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0221 EI 1552-5422 J9 J CROSS CULT PSYCHOL JI J. Cross-Cult. Psychol. PD OCT PY 2015 VL 46 IS 9 BP 1115 EP 1130 DI 10.1177/0022022115600259 PG 16 WC Psychology, Social SC Psychology GA CR6XT UT WOS:000361492500001 PM 26912926 ER PT J AU Kumar, M Mazur, S Ork, BL Postnikova, E Hensley, LE Jahrling, PB Johnson, R Holbrook, MR AF Kumar, Mia Mazur, Steven Ork, Britini L. Postnikova, Elena Hensley, Lisa E. Jahrling, Peter B. Johnson, Reed Holbrook, Michael R. TI Inactivation and safety testing of Middle East Respiratory Syndrome Coronavirus SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE MERS-CoV; Coronavims; Inactivation; Irradiation; Fixation ID SARS-CORONAVIRUS; COV; INFECTION; REAGENTS AB Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a recently emerged virus that has caused a number of human infections and deaths, primarily in the Middle East. The transmission of MERS-CoV to humans has been proposed to be as a result of contact with camels, but evidence of human-to-human transmission also exists. In order to work with MERS-CoV in a laboratory setting, the US Centers for Disease Control and Prevention (CDC) has determined that MERS-CoV should be handled at a biosafety level (BSL) 3 (BSL-3) biocontainment level. Many processes and procedures used to characterize MERS-CoV and to evaluate samples from MERS-CoV infected animals are more easily and efficiently completed at BSL-2 or lower containment. In order to complete experimental work at BSL-2, demonstration or proof of inactivation is required before removal of specimens from biocontainment laboratories. In the studies presented here, we evaluated typical means of inactivating viruses prior to handling specimens at a lower biocontainment level. We found that Trizol, AVL buffer and gamma irradiation were effective at inactivating MERS-CoV, that formaldehyde-based solutions required at least 30 min of contact time in a cell culture system while a mixture of methanol and acetone required 60 min to inactivate MERS-CoV. Together, these data provide a foundation for safely inactivating MERS-CoV, and potentially other coronaviruses, prior to removal from biocontainment facilities. (C) 2015 Elsevier B.V. All rights reserved. C1 [Kumar, Mia; Jahrling, Peter B.; Johnson, Reed] NIAID, Emerging Viral Pathogens Sect, Div Intramural Res, NIH, Frederick, MD 21702 USA. [Mazur, Steven; Ork, Britini L.; Postnikova, Elena; Hensley, Lisa E.; Jahrling, Peter B.; Holbrook, Michael R.] NIAID, Integrated Res Facil, Frederick, MD 21702 USA. RP Holbrook, MR (reprint author), NIAID, Integrated Res Facil, 8200 Res Plaza, Frederick, MD 21702 USA. EM michael.holbrook@nih.gov OI Ork, Britini/0000-0001-9803-824X; Postnikova, Elena/0000-0002-0275-2148 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); Integrated Research Facility (NIAID, Division of Clinical Research); Battelle Memorial Institute; NIAID [HHSN2722007000161] FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), the Integrated Research Facility (NIAID, Division of Clinical Research) and Battelle Memorial Institute's prime contract with NIAID (Contract # HHSN2722007000161). NR 19 TC 1 Z9 1 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD OCT PY 2015 VL 223 BP 13 EP 18 DI 10.1016/j.jviromet.2015.07.002 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA CR3UN UT WOS:000361258700003 PM 26190637 ER PT J AU Vanzolini, KL Vieira, LCC Correa, AG Moaddel, R Cass, QB AF Vanzolini, Kenia L. Vieira, Lucas C. C. Correa, Arlene. G. Moaddel, Ruin Cass, Quezia B. TI Acetylcholinesterase immobilized on modified magnetic beads as a tool for screening a compound library SO MICROCHIMICA ACTA LA English DT Article DE Binding affinity assay; Acetylcholinesterase inhibitor; Label-free assay; Fishing assay; Ligand fishing; Coumarin library ID TANDEM MASS-SPECTROMETRY; ENZYME REACTOR; LC-MS; LIGAND; IDENTIFICATION; INHIBITORS; NANOPARTICLES; MS/MS; TEA AB Acetylcholinesterase (AChE) from Electrophorus electricus was immobilized on the surface of amino-modified magnetic beads (AChE-MB), and its activity evaluated by the quantification of acetylcholine hydrolysis. A reference mixture composed of AChE binders (galanthamine and a probe coumarin, K (i) = 0.031 +/- 0.010 mu M) and non-binders (ketamine and propranolol) was used to probe the fishing assay. The performance of the bioconjugation assay was demonstrated with a library of 12 reference coumarins from which two ligands were directly identified by LC-MS/MS in a single assay, demonstrating the usefulness of this approach. C1 [Vanzolini, Kenia L.; Vieira, Lucas C. C.; Correa, Arlene. G.; Cass, Quezia B.] Univ Fed Sao Carlos, Dept Quim, SEPARARE Nucleo Pesquisa Cromatog, BR-13565905 Sao Carlos, SP, Brazil. [Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Cass, QB (reprint author), Univ Fed Sao Carlos, Dept Quim, SEPARARE Nucleo Pesquisa Cromatog, Caixa Postal 676, BR-13565905 Sao Carlos, SP, Brazil. EM quezia@pq.cnpq.br RI Cass, Quezia/B-8188-2012; Correa, Arlene/C-1926-2012 OI Cass, Quezia/0000-0002-6550-1194; Correa, Arlene/0000-0003-4247-2228 FU Sao Paulo Research Foundation (FAPESP) [2013/01710-1, 2013/02054-0]; National Council for Scientific and Technological Development (CNPq); National Institute of Science and Technology (INCT) - Controle Biorracional de Insetos Praga (CBIP); Intramural Research Program of the National Institute on Aging/NIH FX This work was supported by a research 2013/01710-1 and a studentship grant 2013/02054-0 from the Sao Paulo Research Foundation (FAPESP). The authors also thank the National Council for Scientific and Technological Development (CNPq) and National Institute of Science and Technology (INCT) - Controle Biorracional de Insetos Praga (CBIP) for financial support. This work was also supported in part by the Intramural Research Program of the National Institute on Aging/NIH (RM) NR 23 TC 3 Z9 3 U1 10 U2 34 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0026-3672 EI 1436-5073 J9 MICROCHIM ACTA JI Microchim. Acta PD OCT PY 2015 VL 182 IS 13-14 BP 2209 EP 2213 DI 10.1007/s00604-015-1562-0 PG 5 WC Chemistry, Analytical SC Chemistry GA CR5PH UT WOS:000361394900014 ER PT J AU Borghero, G Pugliatti, M Marrosu, F Marrosu, MG Murru, MR Floris, G Cannas, A Parish, LD Cau, TB Loi, D Ticca, A Traccis, S Manera, U Canosa, A Moglia, C Calvo, A Barberis, M Brunetti, M Renton, AE Nalls, MA Traynor, BJ Restagno, G Chio, A AF Borghero, Giuseppe Pugliatti, Maura Marrosu, Francesco Marrosu, Maria Giovanna Murru, Maria Rita Floris, Gianluca Cannas, Antonino Parish, Leslie D. Cau, Tea B. Loi, Daniela Ticca, Anna Traccis, Sebastiano Manera, Umberto Canosa, Antonio Moglia, Cristina Calvo, Andrea Barberis, Marco Brunetti, Maura Renton, Alan E. Nalls, Mike A. Traynor, Bryan J. Restagno, Gabriella Chio, Adriano CA ITALSGEN SARDINALS Consortia TI ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; Ataxin 2 gene; Genetic modifier ID AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT EXPANSION; C9ORF72; MUTATION; GENE; FTD AB Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that >= 31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of >= 31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with >= 31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that >= 31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival. (C) 2015 Elsevier Inc. All rights reserved. C1 [Borghero, Giuseppe; Marrosu, Francesco; Floris, Gianluca; Cannas, Antonino] Azienda Univ Osped Cagliari, Dept Neurol, Cagliari, Italy. [Borghero, Giuseppe; Marrosu, Francesco; Floris, Gianluca; Cannas, Antonino] Univ Cagliari, Cagliari, Italy. [Pugliatti, Maura; Parish, Leslie D.] Univ Sassari, Dept Clin & Expt Med, I-07100 Sassari, Italy. [Marrosu, Maria Giovanna; Murru, Maria Rita] Univ Cagliari, Multiple Sclerosis Ctr Lab, Cagliari, Italy. [Cau, Tea B.; Loi, Daniela] Azienda Sanit Locale 2, Olbia Tempio, Italy. [Ticca, Anna] Azienda Osped San Francesco, Dept Neurol, Nuoro, Italy. [Traccis, Sebastiano] Osped Antonio Segni, Dept Neurol, Ozieri, Italy. [Manera, Umberto; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; Barberis, Marco; Brunetti, Maura; Chio, Adriano] Univ Turin, Rita Levi Montalcini Dept Neurosci, ALS Ctr, I-10126 Turin, Italy. Univ Genoa, Dept Neurosci Ophthalmol Genet Rehabil & Child Hl, Genoa, Italy. [Calvo, Andrea; Chio, Adriano] Azienda Osped Univ Citta Salute & Sci, Neurol 2, Turin, Italy. [Barberis, Marco; Brunetti, Maura; Traynor, Bryan J.; Restagno, Gabriella] Azienda Osped Univ Citta Salute & Sci, Mol Genet Lab, Turin, Italy. [Renton, Alan E.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Nalls, Mike A.] NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Chio, Adriano] NIT, Turin, Italy. RP Chio, A (reprint author), Univ Turin, Rita Levi Montalcini Dept Neurosci, ALS Ctr, Via Cherasco 15, I-10126 Turin, Italy. EM achio@usa.net RI Spataro, Rossella/B-3656-2016; Mosca, Lorena/K-4015-2016; Calvo, Andrea/K-4141-2016; LOGROSCINO, GIANCARLO/K-5148-2016; Lunetta, Christian/K-9214-2016; MANDRIOLI, JESSICA/K-7235-2016; Moglia, Cristina/K-4142-2016 OI Simone, Isabella Laura/0000-0002-7429-3091; Ilardi, Antonio/0000-0002-8305-0518; Penco, Silvana/0000-0003-1050-095X; Riva, Nilo/0000-0002-0513-9517; Marrosu, Maria Giovanna/0000-0003-2334-2081; Battistini, Stefania/0000-0003-2887-7624; Spataro, Rossella/0000-0002-8910-3131; Mosca, Lorena/0000-0002-6767-2368; Chio, Adriano/0000-0001-9579-5341; Cammarosano, Stefania/0000-0002-0981-5252; Calvo, Andrea/0000-0002-5122-7243; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Lunetta, Christian/0000-0002-4788-1875; MANDRIOLI, JESSICA/0000-0002-9244-9782; Sabatelli, Mario/0000-0001-6635-4985; Moglia, Cristina/0000-0001-7377-7222 FU Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata) [RF-2010-2309489]; European Community's Health Seventh Framework Programme (FP7) [259867]; Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Sophia and Strength Projects); Agenzia Italiana per la Ricerca sulla SLA (ARISLA) (SARDINIALS project); Associazione Piemontese per l'Assistenza alla SLA (APASLA), Torino, Italy; Fondazione Mario e Anna Magnetto, Alpignano, Torino, Italy; Intramural Research Program of the National Institute on Aging [Z01 AG000949-02]; National Institute of Neurological Disorders and Stroke; National Institute of Mental Health FX This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, 2010, grant RF-2010-2309489), the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Sophia and Strength Projects), the Agenzia Italiana per la Ricerca sulla SLA (ARISLA) (SARDINIALS project), the Associazione Piemontese per l'Assistenza alla SLA (APASLA), Torino, Italy, and the Fondazione Mario e Anna Magnetto, Alpignano, Torino, Italy. This work was supported by the Intramural Research Program of the National Institute on Aging (project Z01 AG000949-02), the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health. Study concept and design was contributed by Borghero, Pugliatti, Traynor, Restagno, Chio. Acquisition of data was done by Murru, Floris, Cannas, Parish, Occhineri, Cau, Loi, Ticca, Manera, Canosa, Miglia, Calvo, Barberis, Brunetti, Renton, Nalls. Analysis and interpretation of data was done by Borghero, Pugliatti, F. Marrosu, M.G: Marrosu, Murru, Renton, Nalls, Traynor, Restagno, Chio. Drafting of the manuscript was done by Borghero, Pugliatti, Traynor, Chio. Critical revision of the manuscript for important intellectual content was done by Borghero, Pugliatti, F. Marrosu, M.G Marrosu, Murru, Floris, Cannas, Parish, Occhineri, Cau, Loi, Ticca, Manera, Canosa, Moglia, Calvo, Barberis, Brunetti, Renton, Nalls, Traynor, Restagno, Chio. Funding was obtained from Borghero, Pugliatti, Restagno, Chio. Administrative, technical, and material support was from Murru, Floris, Cannas, Parish, Occhineri, Cau, Loi, Ticca, Manera, Canosa, Moglia, Calvo, Barberis, Brunetti, Renton, Nalls. Study supervision was done by Borghero, Pugliatti, Traynor, Restagno, Chio. Adriano Chio has full access to data. The corresponding author confirm that all authors have read and approved the final draft of the manuscript and given written permission to include their names in the manuscript. NR 17 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2015 VL 36 IS 10 AR 2906.e1 DI 10.1016/j.neurobiolaging.2015.06.013 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CQ9JA UT WOS:000360929100034 PM 26208502 ER PT J AU Chio, A Mora, G Sabatelli, M Caponnetto, C Lunetta, C Traynor, BJ Johnson, JO Nalls, MA Calvo, A Moglia, C Borghero, G Monsurro, MR La Bella, V Volanti, P Simone, I Salvi, F Logullo, FO Nilo, R Giannini, F Mandrioli, J Tanel, R Murru, MR Mandich, P Zollino, M Conforti, FL Penco, S Brunetti, M Barberis, M Restagno, G AF Chio, Adriano Mora, Gabriele Sabatelli, Mario Caponnetto, Claudia Lunetta, Christian Traynor, Bryan J. Johnson, Janel O. Nalls, Mike A. Calvo, Andrea Moglia, Cristina Borghero, Giuseppe Monsurro, Maria Rosaria La Bella, Vincenzo Volanti, Paolo Simone, Isabella Salvi, Fabrizio Logullo, Francesco O. Nilo, Riva Giannini, Fabio Mandrioli, Jessica Tanel, Raffaella Murru, Maria Rita Mandich, Paola Zollino, Marcella Conforti, Francesca L. Penco, Silvana Brunetti, Maura Barberis, Marco Restagno, Gabriella CA ITALSGEN Consortium SARDINIALS Consortium TI HFE p.H63D polymorphism does not influence ALS phenotype and survival SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; HFE polymorphisms; phenotype; survival; SOD1 ID AMYOTROPHIC-LATERAL-SCLEROSIS; GENE; DISEASE; HEMOCHROMATOSIS; ASSOCIATION; MUTATIONS AB It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chio, Adriano; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Barberis, Marco] Univ Turin, Rita Levi Montalcini Dept Neurosci, ALS Ctr, Neurol 2, Turin, Italy. [Chio, Adriano; Calvo, Andrea] Azienda Osped Univ Citta Salute & Sci, Turin, Italy. [Mora, Gabriele] Ist Sci Milano, IRCCS, Fdn Salvatore Maugeri, Dept Neurol Rehabil, Milan, Italy. [Sabatelli, Mario] Catholic Univ, Neurol Inst, Rome, Italy. [Sabatelli, Mario] ICOMM Assoc ALS Res, Rome, Italy. [Caponnetto, Claudia; Mandich, Paola] Univ Genoa, Dept Neurosci Ophthalmol Genet Rehabil & Child Hl, IRCCS Azienda Osped Univ San Martino IST, Genoa, Italy. [Lunetta, Christian] Serena Onlus Fdn, NEuroMuscular Omnictr, Milan, Italy. [Traynor, Bryan J.; Johnson, Janel O.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Janel O.] Cleveland Clin, Dept Neurol, Neurol Inst, Neuromuscular Ctr, Cleveland, OH 44106 USA. [Nalls, Mike A.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Borghero, Giuseppe] Azienda Univ Osped Cagliari, Dept Neurol, Cagliari, Italy. [Borghero, Giuseppe] Univ Cagliari, Cagliari, Italy. [Monsurro, Maria Rosaria] Univ Naples 2, Dept Neurol Sci, Naples, Italy. [La Bella, Vincenzo] Univ Palermo, ALS Clin Res Ctr, Dept Expt Biomed & Clin Neurosci, Palermo, Italy. [Volanti, Paolo] Sci Inst Mistretta, IRCCS, Salvatore Maugeri Fdn, Neurorehabil Unit ALS Ctr, Mistretta, Italy. [Simone, Isabella] Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs, Bari, Italy. [Salvi, Fabrizio] IRCCS Inst Neurol Sci, Dept Neurol, Ctr Diag & Cure Rare Dis, Bologna, Italy. [Logullo, Francesco O.] Marche Polytech Univ, Neurol Clin, Ancona, Italy. [Nilo, Riva] IRCCS San Raffaele Sci Inst, Dept Neurol, Milan, Italy. [Nilo, Riva] IRCCS San Raffaele Sci Inst, Inst Expt Neurol INSPE, Milan, Italy. [Giannini, Fabio] Univ Siena, Dept Med Surg & Neurol Sci, I-53100 Siena, Italy. [Mandrioli, Jessica] Univ Modena & Reggio Emilia, S Agostino Estense Hosp, Dept Neurosci, Modena, Italy. [Tanel, Raffaella] Santa Chiara Hosp, Dept Neurol, Trento, Italy. [Murru, Maria Rita] Univ Cagliari, Multiple Sclerosis Ctr, Cagliari Dept Publ Hlth Clin & Mol Med, ASL 8, Cagliari, Italy. [Zollino, Marcella] Univ Cattolica Sacro Cuore, Inst Med Genet, I-00168 Rome, Italy. [Conforti, Francesca L.] CNR, Inst Neurol Sci, Cosenza, Italy. [Penco, Silvana] Osped Niguarda Ca Granda, Med Genet, Dept Lab Med, Milan, Italy. [Brunetti, Maura; Barberis, Marco; Restagno, Gabriella] Azienda Osped Univ Citta Salute & Sci, Mol Genet Lab, Turin, Italy. RP Chio, A (reprint author), ALS Ctr, Rita Levi Montalcini Dept Neurosci, Via Cherasco 15, I-10126 Turin, Italy. EM achio@usa.net RI Conforti, Francesca Luisa/K-8877-2016; mancardi, giovanni luigi/K-8656-2016; Lunetta, Christian/K-9214-2016; La Bella, Vincenzo/H-4532-2012; MANDRIOLI, JESSICA/K-7235-2016; Moglia, Cristina/K-4142-2016; Spataro, Rossella/B-3656-2016; benigni, michele/J-7830-2016; Mosca, Lorena/K-4015-2016; Calvo, Andrea/K-4141-2016; LOGROSCINO, GIANCARLO/K-5148-2016 OI Conforti, Francesca Luisa/0000-0001-8364-1783; mancardi, giovanni luigi/0000-0001-8427-118X; Chio, Adriano/0000-0001-9579-5341; Cammarosano, Stefania/0000-0002-0981-5252; Simone, Isabella Laura/0000-0002-7429-3091; Ilardi, Antonio/0000-0002-8305-0518; Penco, Silvana/0000-0003-1050-095X; Riva, Nilo/0000-0002-0513-9517; Marrosu, Maria Giovanna/0000-0003-2334-2081; Battistini, Stefania/0000-0003-2887-7624; Lunetta, Christian/0000-0002-4788-1875; BENIGNI, MICHELE/0000-0002-3270-4761; MANDRIOLI, JESSICA/0000-0002-9244-9782; Sabatelli, Mario/0000-0001-6635-4985; Moglia, Cristina/0000-0001-7377-7222; Spataro, Rossella/0000-0002-8910-3131; Mosca, Lorena/0000-0002-6767-2368; Calvo, Andrea/0000-0002-5122-7243; LOGROSCINO, GIANCARLO/0000-0003-0423-3242 FU Intramural Research Programs of the US National Institutes of Health (NIH); National Institute on Aging [Z01-AG000949-02]; Packard Centre for ALS Research at Johns Hopkins; Fondazione Vialli e Mauro Onlus; Compagnia di San Paolo; European Community's Health Seventh Framework Programme (FP7) [259867]; Joint Programme-Neurodegenerative Disease Research (Sophia Project - Italian Health Ministry, Strength Project - Italian Ministry of University and Research); Agenzia Italian per la Ricerca sulla SLA (ARISLA, SARDINIALS grant); Fondazione Mario e Anna Magnetto; Associazione Piemontese per l'Assistenza alla Sclerosi Laterale Amiotrofica (APASLA) FX Funding/Support. This work was supported in part by the Intramural Research Programs of the US National Institutes of Health (NIH) and National Institute on Aging (Z01-AG000949-02). The work was also supported by the Packard Centre for ALS Research at Johns Hopkins, Fondazione Vialli e Mauro Onlus, Compagnia di San Paolo, European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement #259867, the Joint Programme-Neurodegenerative Disease Research (Sophia Project, granted by the Italian Health Ministry, and Strength Project, granted by the Italian Ministry of University and Research), the Agenzia Italian per la Ricerca sulla SLA (ARISLA, SARDINIALS grant), the Fondazione Mario e Anna Magnetto, and the Associazione Piemontese per l'Assistenza alla Sclerosi Laterale Amiotrofica (APASLA). NR 18 TC 0 Z9 0 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2015 VL 36 IS 10 AR 2906.e7 DI 10.1016/j.neurobiolaging.2015.06.016 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CQ9JA UT WOS:000360929100033 PM 26174855 ER PT J AU Ferrari, R Grassi, M Salvi, E Borroni, B Palluzzi, F Pepe, D D'Avila, F Padovani, A Archetti, S Rainero, I Rubino, E Pinessi, L Benussi, L Binetti, G Ghidoni, R Galimberti, D Scarpini, E Serpente, M Rossi, G Giaccone, G Tagliavini, F Nacmias, B Piaceri, I Bagnoli, S Bruni, AC Maletta, RG Bernardi, L Postiglione, A Milan, G Franceschi, M Puca, AA Novelli, V Barlassina, C Glorioso, N Manunta, P Singleton, A Cusi, D Hardy, J Momeni, P AF Ferrari, Raffaele Grassi, Mario Salvi, Erika Borroni, Barbara Palluzzi, Fernando Pepe, Daniele D'Avila, Francesca Padovani, Alessandro Archetti, Silvana Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Benussi, Luisa Binetti, Giuliano Ghidoni, Roberta Galimberti, Daniela Scarpini, Elio Serpente, Maria Rossi, Giacomina Giaccone, Giorgio Tagliavini, Fabrizio Nacmias, Benedetta Piaceri, Irene Bagnoli, Silvia Bruni, Amalia C. Maletta, Raffaele G. Bernardi, Livia Postiglione, Alfredo Milan, Graziella Franceschi, Massimo Puca, Annibale A. Novelli, Valeria Barlassina, Cristina Glorioso, Nicola Manunta, Paolo Singleton, Andrew Cusi, Daniele Hardy, John Momeni, Parastoo TI A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia SO NEUROBIOLOGY OF AGING LA English DT Article DE Frontotemporal dementia; Association study; Case-control; Genetic risk factors; Functional annotation; Population ID AMYOTROPHIC-LATERAL-SCLEROSIS; PRIMARY PROGRESSIVE APHASIA; LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT; ALZHEIMERS-DISEASE; COMMON VARIANTS; DIAGNOSTIC-CRITERIA; MUTATIONS; PREVALENCE; C9ORF72 AB Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values similar to 10(-7) and odds ratio >2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of ecis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Ferrari, Raffaele; Hardy, John] UCL, Dept Mol Neurosci, Inst Neurol, London WC1N 3BG, England. [Ferrari, Raffaele; Momeni, Parastoo] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Neurogenet Lab, Lubbock, TX 79430 USA. [Grassi, Mario; Palluzzi, Fernando; Pepe, Daniele] Univ Pavia, Dept Brain & Behav Sci, Med & Genom Stat Unit, I-27100 Pavia, Italy. [Salvi, Erika; D'Avila, Francesca; Barlassina, Cristina; Cusi, Daniele] Univ Milan, Dept Hlth Sci, San Paolo Hosp, Milan, Italy. [Borroni, Barbara; Padovani, Alessandro; Archetti, Silvana] Univ Brescia, Neurol Clin, Brescia, Italy. [Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo] Univ Turin, Dept Neurosci, Neurol 1, Turin, Italy. [Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo] Citta Salute & Sci Torino, Turin, Italy. [Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta] IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Mol Markers Lab, Brescia, Italy. [Galimberti, Daniela; Scarpini, Elio; Serpente, Maria] Univ Milan, Dept Pathophysiol & Transplantat, Neurol Unit, Fdn Ca Granda,IRCCS Osped Policlin, Milan, Italy. [Rossi, Giacomina; Giaccone, Giorgio; Tagliavini, Fabrizio] Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, Italy. [Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy. [Bruni, Amalia C.; Maletta, Raffaele G.; Bernardi, Livia] Neurogenet Reg Ctr ASPCZ Lamezia Terme, Lamezia TErme, Italy. [Postiglione, Alfredo] Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy. [Milan, Graziella] Geriatr Ctr Frullone ASL Napoli 1 Ctr, Naples, Italy. [Franceschi, Massimo] IRCCS Multimed, Dept Neurol, Milan, Italy. [Puca, Annibale A.] Univ Salerno, Dept Med & Surg, I-84100 Salerno, Italy. [Puca, Annibale A.] IRCCS Multimed, Cardiovasc Res Unit, Milan, Italy. [Novelli, Valeria] IRCCS Fdn S Maugeri, Dept Mol Cardiol, Pavia, Italy. [Glorioso, Nicola] AOU Univ Sassari, Hypertens & Related Dis Ctr, Sassari, Italy. [Manunta, Paolo] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Nephrol & Dialysis & Hypertens Unit, Chair Nephrol, Milan, Italy. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Cusi, Daniele] Italian Natl Res Council, Inst Biomed Technol, Milan, Italy. RP Ferrari, R (reprint author), UCL, Dept Mol Neurosci, Inst Neurol, Room 610,Queen Sq House,Queen Sq, London WC1N 3BG, England. EM r.ferrari@ucl.ac.uk RI , raffaele/K-4421-2016; Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Rossi, Giacomina/I-2783-2012; Piaceri, Irene /J-4310-2016; Rubino, Elisa/K-3282-2016; BENUSSI, LUISA/K-4409-2016; Ghidoni, Roberta/K-4507-2016; Binetti, Giuliano/K-4519-2016; OI , raffaele/0000-0002-0758-1835; scarpini, elio/0000-0002-6395-2119; Salvi, Erika/0000-0002-2724-2291; Rossi, Giacomina/0000-0001-6680-2725; Piaceri, Irene /0000-0001-6787-2223; NACMIAS, Benedetta/0000-0001-9338-9040; Rubino, Elisa/0000-0002-7553-7553; BENUSSI, LUISA/0000-0003-2836-8141; Ghidoni, Roberta/0000-0002-7691-1957; Binetti, Giuliano/0000-0003-2759-5844; galimberti, daniela/0000-0002-9284-5953 FU European Union [FP7-HEALTH-F4-2007-201550]; InterOmics [MIUR-CNR Italian Flagship Project] [PB05]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA); Wellcome Trust/MRC Centre on Parkinson's disease; office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center FX The authors would like to thank the patients and their families for allowing and supporting this research. The authors also thank Mike Hubank and Kerra Pearce at the Genomic core facility at the Institute of Child Health (ICH), University College of London (UCL), for assisting Raffaele Ferrari in performing Illumina genotyping experiments (FTD genotyping). This work was supported by the European Union [grant FP7-HEALTH-F4-2007-201550, HYPERGENES]; InterOmics [PB05 MIUR-CNR Italian Flagship Project]; Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA); the Wellcome Trust/MRC Centre on Parkinson's disease; and the office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center provided financial support for genotyping and data analysis. The funding agencies had no role in study design, data collection, data analysis, data interpretation, or writing of the report. NR 64 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2015 VL 36 IS 10 AR 2904.e13 DI 10.1016/j.neurobiolaging.2015.06.005 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CQ9JA UT WOS:000360929100028 PM 26154020 ER PT J AU Bilgel, M Carass, A Resnick, SM Wong, DF Prince, JL AF Bilgel, Murat Carass, Aaron Resnick, Susan M. Wong, Dean F. Prince, Jerry L. TI Deformation field correction for spatial normalization of PET images SO NEUROIMAGE LA English DT Article DE PET registration; Deformation field; Ridge regression; Pittsburgh compound B (PiB) ID RIDGE-REGRESSION; NONORTHOGONAL PROBLEMS; PARAMETRIC IMAGES; ALZHEIMER-DISEASE; OLDER-ADULTS; FDG-PET; BRAIN; REGISTRATION; TEMPLATE; QUANTIFICATION AB Spatial normalization of positron emission tomography (PET) images is essential for population studies, yet the current state of the art in PET-to-PET registration is limited to the application of conventional deformable registration methods that were developed for structural images. A method is presented for the spatial normalization of PET images that improves their anatomical alignment over the state of the art. The approach works by correcting the deformable registration result using a model that is learned from training data having both PET and structural images. In particular, viewing the structural registration of training data as ground truth, correction factors are learned by using a generalized ridge regression at each voxel given the PET intensities and voxel locations in a population-based PET template. The trained model can then be used to obtain more accurate registration of PET images to the PET template without the use of a structural image. A cross validation evaluation on 79 subjects shows that the proposed method yields more accurate alignment of the PET images compared to deformable PET-to-PET registration as revealed by 1) a visual examination of the deformed images, 2) a smaller error in the deformation fields, and 3) a greater overlap of the deformed anatomical labels with ground truth segmentations. Published by Elsevier Inc. C1 [Bilgel, Murat; Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Sch Engn, Image Anal & Commun Lab, Baltimore, MD USA. [Bilgel, Murat; Prince, Jerry L.] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Bilgel, Murat; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Sch Engn, Baltimore, MD 21218 USA. [Carass, Aaron] Johns Hopkins Univ, Dept Comp Sci, Sch Engn, Baltimore, MD 21218 USA. [Wong, Dean F.; Prince, Jerry L.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Bilgel, M (reprint author), NIA, Lab Behav Neurosci, 251 Bayview Blvd,Suite 100,Rm 04B316, Baltimore, MD 21224 USA. EM murat.bilgel@nih.gov OI Carass, Aaron/0000-0003-4939-5085; Bilgel, Murat/0000-0001-5042-7422 FU Intramural Research Program of the National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Institutes of Health. NR 35 TC 4 Z9 4 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2015 VL 119 BP 152 EP 163 DI 10.1016/j.neuroimage.2015.06.063 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CR2TB UT WOS:000361182400015 PM 26142272 ER PT J AU Venkatraman, VK Gonzalez, CE Landman, B Goh, J Reiter, DA An, Y Resnick, SM AF Venkatraman, Vijay K. Gonzalez, Christopher E. Landman, Bennett Goh, Joshua Reiter, David A. An, Yang Resnick, Susan M. TI Region of interest correction factors improve reliability of diffusion imaging measures within and across scanners and field strengths SO NEUROIMAGE LA English DT Article DE White matter; Gray matter; DTI; Reliability; Correction factor; Longitudinal ID FRACTIONAL ANISOTROPY; MULTIPLE-SCLEROSIS; GRAY-MATTER; HUMAN BRAIN; TENSOR; MRI; REPRODUCIBILITY; IMAGES; AGE; REGISTRATION AB Diffusion tensor imaging (DTI) measures are commonly used as imaging markers to investigate individual differences in relation to behavioral and health-related characteristics. However, the ability to detect reliable associations in cross-sectional or longitudinal studies is limited by the reliability of the diffusion measures. Several studies have examined the reliability of diffusion measures within (i.e. intra-site) and across (i.e. inter-site) scanners with mixed results. Our study compares the test-retest reliability of diffusion measures within and across scanners and field strengths in cognitively normal older adults with a follow-up interval less than 2.25 years. Intra-class correlation (ICC) and coefficient of variation (CoV) of fractional anisotropy (FA) and mean diffusivity (MD) were evaluated in sixteen white matter and twenty-six gray matter bilateral regions. The ICC for intra-site reliability (0.32 to 0.96 for FA and 0.18 to 0.95 for MD in white matter regions; 0.27 to 0.89 for MD and 0.03 to 0.79 for FA in gray matter regions) and inter-site reliability (0.28 to 0.95 for FA in white matter regions, 0.02 to 0.86 for MD in gray matter regions) with longer follow-up intervals were similar to earlier studies using shorter follow-up intervals. The reliability of across field strengths comparisons was lower than intra- and inter-site reliabilities. Within and across scanner comparisons showed that diffusion measures were more stable in larger white matter regions (>1500 mm(3)). For gray matter regions, the MD measure showed stability in specific regions and was not dependent on region size. Linear correction factor estimated from cross-sectional or longitudinal data improved the reliability across field strengths. Our findings indicate that investigations relating diffusion measures to external variables must consider variable reliability across the distinct regions of interest and that correction factors can be used to improve consistency of measurement across field strengths. An important result of this work is that inter-scanner and field strength effects can be partially mitigated with linear correction factors specific to regions of interest. These data-driven linear correction techniques can be applied in cross-sectional or longitudinal studies. Published by Elsevier Inc. C1 [Venkatraman, Vijay K.; Gonzalez, Christopher E.; Goh, Joshua; Reiter, David A.; An, Yang; Resnick, Susan M.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Landman, Bennett] Vanderbilt Univ, Inst Imaging Sci, Nashville, TN 37235 USA. [Landman, Bennett] Vanderbilt Univ, Dept Elect Engn, Nashville, TN 37235 USA. [Goh, Joshua] Natl Taiwan Univ, Coll Med, Grad Inst Brain & Mind Sci, Taipei 10764, Taiwan. RP Resnick, SM (reprint author), NIA, Intramural Res Program, 251 Bayview Blvd Suite 100,Room 04B335, Baltimore, MD 21224 USA. EM vijay.venkatraman@nih.gov; resnicks@grc.nia.nih.gov OI GOH, JOSHUA/0000-0001-7808-5452 FU Intramural Research Program of the National Institute on Aging, National Institute of Health; [N01-AG-3-2124] FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institute of Health and part by Research and Development Contract N01-AG-3-2124. NR 45 TC 3 Z9 3 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2015 VL 119 BP 406 EP 416 DI 10.1016/j.neuroimage.2015.06.078 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CR2TB UT WOS:000361182400040 PM 26146196 ER PT J AU Daniels, RD Bertke, S Dahm, MM Yiin, JH Kubale, TL Hales, TR Baris, D Zahm, SH Beaumont, JJ Waters, KM Pinkerton, LE AF Daniels, Robert D. Bertke, Stephen Dahm, Matthew M. Yiin, James H. Kubale, Travis L. Hales, Thomas R. Baris, Dalsu Zahm, Shelia H. Beaumont, James J. Waters, Kathleen M. Pinkerton, Lynne E. TI Exposure-response relationships for select cancer and non-cancer health outcomes in a cohort of US firefighters from San Francisco, Chicago and Philadelphia (1950-2009) SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID FLORIDA PROFESSIONAL FIREFIGHTERS; FIRE-FIGHTERS; LEUKEMIA MORTALITY; UNITED-STATES; OCCUPATIONAL COHORT; IONIZING-RADIATION; FOLLOW-UP; RISK; TIME; SEATTLE AB Objectives To examine exposure-response relationships between surrogates of firefighting exposure and select outcomes among previously studied US career firefighters. Methods Eight cancer and four non-cancer outcomes were examined using conditional logistic regression. Incidence density sampling was used to match each case to 200 controls on attained age. Days accrued in firefighting assignments (exposed-days), run totals (fire-runs) and run times (fire-hours) were used as exposure surrogates. HRs comparing 75th and 25th centiles of lagged cumulative exposures were calculated using loglinear, linear, log-quadratic, power and restricted cubic spline general relative risk models. Piecewise constant models were used to examine risk differences by time since exposure, age at exposure and calendar period. Results Among 19 309 male firefighters eligible for the study, there were 1333 cancer deaths and 2609 cancer incidence cases. Significant positive associations between fire-hours and lung cancer mortality and incidence were evident. A similar relation between leukaemia mortality and fire-runs was also found. The lung cancer associations were nearly linear in cumulative exposure, while the association with leukaemia mortality was attenuated at higher exposure levels and greater for recent exposures. Significant negative associations were evident for the exposure surrogates and colorectal and prostate cancers, suggesting a healthy worker survivor effect possibly enhanced by medical screening. Conclusions Lung cancer and leukaemia mortality risks were modestly increasing with firefighter exposures. These findings add to evidence of a causal association between firefighting and cancer. Nevertheless, small effects merit cautious interpretation. We plan to continue to follow the occurrence of disease and injury in this cohort. C1 [Daniels, Robert D.; Bertke, Stephen; Dahm, Matthew M.; Yiin, James H.; Kubale, Travis L.; Hales, Thomas R.; Waters, Kathleen M.; Pinkerton, Lynne E.] Natl Inst Occupat Safety & Hlth, Div Surveillance Hazard Evaluat & Field Studies, Cincinnati, OH 45226 USA. [Baris, Dalsu; Zahm, Shelia H.] NCI, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. [Beaumont, James J.] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. RP Daniels, RD (reprint author), Natl Inst Occupat Safety & Hlth, IWSB, Div Surveillance Hazard Evaluat & Field Studies, 1090 Tusculum Ave,Mailstop R-13, Cincinnati, OH 45226 USA. EM rtd2@cdc.gov FU National Institute for Occupational Safety and Health (NIOSH), National Occupational Research Agenda (NORA); US Fire Administration (USFA); National Institutes of Health (NIH), National Cancer Institute (NCI) FX Research funding was provided by the National Institute for Occupational Safety and Health (NIOSH) by intramural award under the National Occupational Research Agenda (NORA), and by the US Fire Administration (USFA). This research was also supported in part by the intramural research programme of the National Institutes of Health (NIH), National Cancer Institute (NCI). NR 45 TC 2 Z9 2 U1 5 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2015 VL 72 IS 10 BP 699 EP 706 DI 10.1136/oemed-2014-102671 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR7AC UT WOS:000361498700004 PM 25673342 ER PT J AU Lerro, CC Koutros, S Andreotti, G Friesen, MC Alavanja, MC Blair, A Hoppin, JA Sandler, DP Lubin, JH Ma, XM Zhang, YW Freeman, LEB AF Lerro, Catherine C. Koutros, Stella Andreotti, Gabriella Friesen, Melissa C. Alavanja, Michael C. Blair, Aaron Hoppin, Jane A. Sandler, Dale P. Lubin, Jay H. Ma, Xiaomei Zhang, Yawei Freeman, Laura E. Beane TI Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROSTATE-CANCER; THYROID-CANCER; ENDOCRINE DISRUPTORS; OXIDATIVE STRESS; 3A4 METABOLISM; BREAST CELLS; RISK-FACTORS; LUNG-CANCER; IN-VITRO AB Objectives Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. We evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. Methods At enrolment (1993-1997), spouses provided information about ever use of specific pesticides, including 10 OPs, demographic information, reproductive health history and other potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% CIs for all cancers diagnosed through 2010 for North Carolina and through 2011 for Iowa. Results Among 30 003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43). Conclusions We observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation. C1 [Lerro, Catherine C.; Koutros, Stella; Andreotti, Gabriella; Friesen, Melissa C.; Alavanja, Michael C.; Blair, Aaron; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lerro, Catherine C.; Ma, Xiaomei; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Lubin, Jay H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lerro, CC (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E624,MSC 7991, Bethesda, MD 20892 USA. EM lerrocc@mail.nih.gov RI Friesen, Melissa/A-5362-2009; Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, the National Cancer Institute [Z01-CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030] FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (Z01-CP010119) and the National Institute of Environmental Health Sciences (Z01-ES049030). NR 63 TC 11 Z9 11 U1 2 U2 10 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD OCT PY 2015 VL 72 IS 10 BP 736 EP 744 DI 10.1136/oemed-2014-102798 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR7AC UT WOS:000361498700009 PM 26150671 ER PT J AU Malayeri, AA Spevak, PJ Zimmerman, SL AF Malayeri, Ashkan A. Spevak, Philip J. Zimmerman, Stefan L. TI Utility of a High-Resolution 3D MRI Sequence (3D-SPACE) for Evaluation of Congenital Heart Disease SO PEDIATRIC CARDIOLOGY LA English DT Article DE Congenital; Cardiac; MRI; SPACE; High-resolution imaging ID MAGNETIC-RESONANCE; TSE AB The purpose of this study was to evaluate the role of a high-resolution 3D dark-blood turbo spin echo sequence with variable flip angles (3D-SPACE) in evaluation of congenital heart disease. SPACE sequence was performed in 20 patients (mean age, 17.6 +/- A 12.6 years, range 9 months-57 years, M: 13) with either unrepaired (N = 3) or post-repair (n = 17) congenital heart disease. All scans were performed on 1.5 T Aera scanners (Siemens). Two separate observers with expertise in cardiovascular imaging scored the quality of the images for blood suppression and definition of key anatomical structures in a blinded fashion using a 5 grade scoring system. Mean of average overall quality scores for two observers was 4 +/- A 0.62. All overall quality scores were greater than 3. None of the studies were deemed nondiagnostic. Mean length of the SPACE acquisition time was 12.7 min (4-21 min). There was no significant correlation between image quality and duration of scans. Lack of blood suppression was the limiting factor in image quality with the most common place being ascending aorta in nine patients. However, overall blood suppression score was very good with score of 3.9 +/- A 0.43. There was very good overall agreement between observers in rating the image quality (85.6 % agreement, kappa 0.5, standard error 0.04, p < 0.0001). The 3D-SPACE dark-blood sequence with near-isotropic spatial resolution coupled with respiratory and cardiac gating can be feasibly performed in all age groups with diagnostic image quality in all cases in this study. C1 [Malayeri, Ashkan A.; Spevak, Philip J.; Zimmerman, Stefan L.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. RP Malayeri, AA (reprint author), NIH, BLDG 10 RM 1C371,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ashkan.malayeri@nih.gov NR 7 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0172-0643 EI 1432-1971 J9 PEDIATR CARDIOL JI Pediatr. Cardiol. PD OCT PY 2015 VL 36 IS 7 BP 1510 EP 1514 DI 10.1007/s00246-015-1194-5 PG 5 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA CR6AY UT WOS:000361426700028 PM 26015086 ER PT J AU Paksarian, D Eaton, WW Mortensen, PB Merikangas, KR Pedersen, CB AF Paksarian, D. Eaton, W. W. Mortensen, P. B. Merikangas, K. R. Pedersen, C. B. TI A population-based study of the risk of schizophrenia and bipolar disorder associated with parent-child separation during development SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Bipolar disorder; parental separation; psychosis; schizophrenia ID PITUITARY-ADRENAL AXIS; CENTRAL RESEARCH REGISTER; MAJOR DEPRESSION; MENTAL-HEALTH; ADULT PSYCHOPATHOLOGY; MATERNAL SEPARATION; SOCIAL COGNITION; FAMILY DISCORD; FOLLOW-UP; COHORT AB Background. There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics. Method. We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1-15 years among a cohort of 985 058 individuals born in Denmark 1971-1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed. Results. Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective. Conclusions. Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity. C1 [Paksarian, D.; Eaton, W. W.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Paksarian, D.; Merikangas, K. R.] NIMH, Bethesda, MD 20892 USA. [Mortensen, P. B.; Pedersen, C. B.] Natl Ctr Register Based Res, Aarhus, Denmark. [Mortensen, P. B.; Pedersen, C. B.] Aarhus Univ, Ctr Integrated Register Based Res, CIRRAU, Aarhus, Denmark. [Mortensen, P. B.; Pedersen, C. B.] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark. [Mortensen, P. B.; Pedersen, C. B.] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Copenhagen, Denmark. RP Paksarian, D (reprint author), NIMH, Genet Epidemiol Res Branch, 35A Convent Dr,MSC3720, Bethesda, MD 20892 USA. EM diana.paksarian@nih.gov RI Pedersen, Carsten Bocker/B-8441-2013; OI Pedersen, Carsten Bocker/0000-0003-2077-8533; Mortensen, Preben Bo/0000-0002-5230-9865 FU National Institute of Mental Health (NIMH) [5T32MH014592]; NIMH; National Institute on Drug Abuse [R01 026652]; Stanley Medical Research Institute; Lundbeck Foundation FX This work was supported by the National Institute of Mental Health (NIMH; grant 5T32MH014592), the Intramural Research Program of the NIMH, the National Institute on Drug Abuse (W.W.E., grant R01 026652), the Stanley Medical Research Institute (P.B.M. and C.B.P.) and The Lundbeck Foundation (P.B.M. and C.B.P). NR 76 TC 6 Z9 7 U1 3 U2 19 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 13 BP 2825 EP 2837 DI 10.1017/S0033291715000781 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CR2JQ UT WOS:000361156000014 PM 25952483 ER PT J AU Stager, SV Freeman, FJ Braun, A AF Stager, Sheila V. Freeman, Frances J. Braun, Allen TI Characteristics of Fluency and Speech in Two Families With High Incidences of Stuttering SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article ID RECOVERY; GENETICS; LINKAGE; NONFLUENCY; TWINS AB Purpose: This study presents data from 2 families with high incidence of stuttering, comparing methods of phenotype assignment and exploring the presence of other fluency disorders and corresponding speech characteristics. Method: Three methods for assigning phenotype of stuttering were used: self-identification, family identification, and expert identification. Agreement on which individuals were assigned by each of these methods was studied. Multiple measures of fluency and speech production were obtained. Results: Self-reports and descriptions of blocking rather than self-identification as a person who stutters demonstrated the best agreement with expert identification of stuttering. Family identification showed poor agreement with both expert and self-identification of stuttering. Using binary categories of fluent or stuttering, 90% of individuals in 1 family were classified by expert consensus. Only 70% of the other family could be similarly categorized. Experts required 2 other categories, cluttering and other fluency disorders, to fully characterize dysfluency within this family. These 2 families also demonstrated differences in speech production. Conclusion: Some families with high incidence of stuttering may also have high incidence of other fluency disorders and other speech-production difficulties. This finding may have ramifications for genetic studies, including criteria for defining phenotype and collapsing data across multiple families. C1 [Stager, Sheila V.; Braun, Allen] NIDCD, NIH, Bethesda, MD 20892 USA. [Freeman, Frances J.] Stephen F Austin State Univ, Nacogdoches, TX 75962 USA. RP Stager, SV (reprint author), NIDCD, NIH, Bethesda, MD 20892 USA. EM sstager@mfa.gwu.ed OI Stager, Sheila/0000-0002-4294-2114 FU Intramural Division of the National Institute on Deafness and Other Communications [97-DC-0002] FX This research was funded by the Intramural Division of the National Institute on Deafness and Other Communications, Protocol #97-DC-0002, titled "Genetic Linkage Analysis in Developmental Stuttering: Gene Mapping in Extended Kindreds and Candidate Gene Analyses" (Principal Investigator: Sheila Stager). NR 37 TC 0 Z9 0 U1 5 U2 6 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1092-4388 EI 1558-9102 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT PY 2015 VL 58 IS 5 BP 1440 EP 1451 DI 10.1044/2015_JSLHR-S-14-0080 PG 12 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA DX6XL UT WOS:000384529200004 PM 26126023 ER PT J AU Kriley, IR Feldman, SA Tran, E Black, M Xu, H Rosenberg, SA Goff, S AF Kriley, Isaac R. Feldman, Steve A. Tran, Eric Black, Mary Xu, Hui Rosenberg, Steven A. Goff, Stephanie TI Transient retroviral transfection for single patient cancer immunotherapy SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Kriley, Isaac R.; Feldman, Steve A.; Tran, Eric; Black, Mary; Xu, Hui; Rosenberg, Steven A.; Goff, Stephanie] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E135 EP E135 PG 1 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000332 ER PT J AU Schrump, DS Zhang, M Hong, JL Shukla, V Ripley, RT Atay, SM Hong, Y Peer, CJ Sissung, TM Figg, WD AF Schrump, David S. Zhang, Mary Hong, Julie Shukla, Vivek Ripley, R. Taylor Atay, Scott M. Hong, Young Peer, Cody J. Sissung, Tristan M. Figg, William D. TI Gene expression analysis enables repositioning of mithramycin for precision medicine inhibition of cancer stem cell signaling in thoracic malignancies SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Schrump, David S.; Zhang, Mary; Hong, Julie; Shukla, Vivek; Ripley, R. Taylor; Atay, Scott M.; Hong, Young; Peer, Cody J.; Sissung, Tristan M.; Figg, William D.] NCI, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E128 EP E129 PG 2 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000315 ER PT J AU Chang, LW Nakigozi, G Billioux, VG Gray, RH Serwadda, D Quinn, TC Wawer, MJ Bollinger, RC Reynolds, SJ AF Chang, Larry W. Nakigozi, Gertrude Billioux, Veena G. Gray, Ronald H. Serwadda, David Quinn, Thomas C. Wawer, Maria J. Bollinger, Robert C. Reynolds, Steven J. TI Effectiveness of Peer Support on Care Engagement and Preventive Care Intervention Utilization Among Pre-antiretroviral Therapy, HIV-Infected Adults in Rakai, Uganda: A Randomized Trial SO AIDS AND BEHAVIOR LA English DT Article DE Peer support; Randomized controlled trial; Uganda; Implementation science; Linkage ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUB-SAHARAN AFRICA; COTRIMOXAZOLE PROPHYLAXIS; DEVELOPING-COUNTRIES; ART INITIATION; CLINICAL-TRIAL; RETENTION; ADHERENCE; IMPLEMENTATION; METAANALYSIS AB 442 pre-ART, HIV-infected adults were randomized to peer support consisting of structured home visits to promote clinic attendance and preventive care intervention use or standard of care. At baseline, 62 % reported previously visiting an HIV clinic, 45 % reported taking cotrimoxazole prophylaxis, and 31 % were "care-na < ve" (no previous clinic visit and not on cotrimoxazole). After 1 year, intervention participants were more likely to report being in care (92 vs 84 %; PRR 1.09, p = 0.039), on cotrimoxazole (89 vs 81 %; PRR 1.10, p = 0.047), and safe water vessel adherence (23 vs 14 %; PRR 1.64, p = 0.024). The effect was observed only among care-na < ve participants (n = 139) with 83 % intervention versus 56 % controls reporting being in HIV care (PRR 1.47, p = 0.006), 78 versus 58 % on cotrimoxazole (PRR 1.35, p = 0.04), and 20 versus 4 % safe water vessel adherence (PRR 5.78, p = 0.017). Peer support may be an effective intervention to facilitate pre-ART care compliance in this important population. C1 [Chang, Larry W.; Quinn, Thomas C.; Bollinger, Robert C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Chang, Larry W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Social & Behav Intervent Program, Baltimore, MD USA. [Chang, Larry W.; Billioux, Veena G.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nakigozi, Gertrude; Serwadda, David] Rakai Hlth Sci Program, Rakai, Uganda. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Chang, LW (reprint author), Johns Hopkins Sch Med, Div Infect Dis, 725 N Wolfe St,Suite 216, Baltimore, MD 21205 USA. EM larrywillchang@gmail.com FU National Institute of Mental Health, National Institutes of Health [K23MH086338]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health; Johns Hopkins University Center for AIDS Research [P30AI094189] FX The authors thank Caitlin Kennedy (Johns Hopkins University, USA) for editorial contributions and Megan Hosein (Johns Hopkins University, USA) and Julia Peterson (USA) for data collection contributions. This study was supported by The National Institute of Mental Health, National Institutes of Health (K23MH086338), the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, and the Johns Hopkins University Center for AIDS Research (P30AI094189). NR 47 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD OCT PY 2015 VL 19 IS 10 BP 1742 EP 1751 DI 10.1007/s10461-015-1159-y PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CR0HK UT WOS:000360999000002 PM 26271815 ER PT J AU Feld, JJ Kato, GJ Koh, C Shields, T Hildesheim, M Kleiner, DE Taylor, JG Sandler, NG Douek, D Haynes-Williams, V Nichols, JS Hoofnagle, JH Liang, TJ Gladwin, MT Heller, T AF Feld, J. J. Kato, G. J. Koh, C. Shields, T. Hildesheim, M. Kleiner, D. E. Taylor, J. G. Sandler, N. G. Douek, D. Haynes-Williams, V. Nichols, J. S. Hoofnagle, J. H. Liang, T. Jake Gladwin, M. T. Heller, T. TI Liver injury is associated with mortality in sickle cell disease SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID NODULAR REGENERATIVE HYPERPLASIA; CHRONIC GRANULOMATOUS-DISEASE; PORTAL-HYPERTENSION; PULMONARY-HYPERTENSION; BACTERIAL-INFECTIONS; IRON OVERLOAD; RISK-FACTORS; DEATH; THALASSEMIA; CIRRHOSIS AB BackgroundIncreased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems. AimTo report the long-term consequences of liver dysfunction in SCD. MethodsA cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. ResultsExactly, 247 SCD patients were followed up for 30months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. ConclusionsFerritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults. C1 [Feld, J. J.; Koh, C.; Haynes-Williams, V.; Hoofnagle, J. H.; Liang, T. Jake; Heller, T.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Feld, J. J.] Univ Toronto, Sandra Rotman Ctr Global Hlth, Toronto Ctr Liver Dis, Toronto, ON, Canada. [Kato, G. J.; Shields, T.; Hildesheim, M.; Taylor, J. G.; Nichols, J. S.; Gladwin, M. T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Kato, G. J.; Gladwin, M. T.] Univ Pittsburgh, Med Ctr, Vasc Med Inst, Pittsburgh, PA USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Sandler, N. G.; Douek, D.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr MSC 1800, Bethesda, MD 20892 USA. EM theller@nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Utay, Netanya/0000-0002-6407-8670; Taylor, James/0000-0002-4421-1809 FU NIDDK [DK075008]; NHLBI; NIAID; NCI; CC NIH FX This study along with preparation of the manuscript and data analysis was funded by the Intramural Research Programs of the NIDDK (DK075008), NHLBI, NIAID, NCI, CC NIH. No writing support was provided. NR 29 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD OCT PY 2015 VL 42 IS 7 BP 912 EP 921 DI 10.1111/apt.13347 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA CQ8ZO UT WOS:000360900300012 PM 26235444 ER PT J AU Dineen, SP Royal, RE Hughes, MS Sagebiel, T Bhosale, P Overman, M Matamoros, A Mansfield, PF Fournier, KF AF Dineen, Sean P. Royal, Richard E. Hughes, Marybeth S. Sagebiel, Tara Bhosale, Priya Overman, Michael Matamoros, Aurelio Mansfield, Paul F. Fournier, Keith F. TI A Simplified Preoperative Assessment Predicts Complete Cytoreduction and Outcomes in Patients with Low-Grade Mucinous Adenocarcinoma of the Appendix SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY; PSEUDOMYXOMA PERITONEI; NEOPLASMS; SURGERY; IMPACT; RISK AB Complete cytoreduction with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve survival in patients with low-grade mucinous adenocarcinoma (LGMA). However, incomplete cytoreduction exposes patients to significant morbidity without a similar survival benefit. Preoperative assessment of the ability to achieve CRS is therefore a critical step in selecting patients for CRS/HIPEC. The aim of this study was to develop and validate a preoperative scoring system to accurately predict the ability to achieve complete cytoreduction in patients with LGMA of the appendix. A simplified preoperative assessment for appendix tumor (SPAAT) score was developed based on computed tomography scan findings thought to predict incomplete cytoreduction. We applied the SPAAT score to patients with LGMA to determine the ability of the score to predict complete cytoreduction. This scoring system was then applied to a separate cohort of patients from a different institution. Sensitivity and specificity were determined for the SPAAT score. Survival was calculated and correlated with the SPAAT score and the completeness of cytoreduction score. A SPAAT score of < 3 is a significant predictor of complete cytoreduction in the derivation cohort. In the validation cohort, 40 of 42 patients with a SPAAT score < 3 achieved a complete cytoreduction, for a positive predictive value of 95.2 % and a negative predictive value of 100 %. Additionally, the SPAAT score was a significant predictor of disease-free survival. The SPAAT score is a useful tool in the preoperative assessment of patients with LGMA who are under consideration for cytoreductive surgery. Prospective analysis of this scoring system is warranted to appropriately select patients who will benefit from CRS/HIPEC. C1 [Dineen, Sean P.; Royal, Richard E.; Mansfield, Paul F.; Fournier, Keith F.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Hughes, Marybeth S.] NIH, Div Gastrointestinal Oncol, Bethesda, MD USA. [Sagebiel, Tara; Bhosale, Priya; Matamoros, Aurelio] Univ Texas Houston, MD Anderson Canc Ctr, Div Diagnost Imaging, Houston, TX 77030 USA. [Overman, Michael] Univ Texas Houston, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. RP Dineen, SP (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Surg Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM spdineen@mdanderson.org NR 16 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2015 VL 22 IS 11 BP 3640 EP 3646 DI 10.1245/s10434-015-4446-y PG 7 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900031 PM 25698402 ER PT J AU Johnson, KA Lovinger, DM AF Johnson, Kari A. Lovinger, David M. TI Metabotropic Glutamate Receptor 2 Positive Allosteric Modulators: Closing the Gate on Drug Abuse? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID DEPENDENCE; ADDICTION; MGLUR2 C1 [Johnson, Kari A.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Johnson, KA (reprint author), NIAAA, Lab Integrat Neurosci, Div Intramural Clin & Biol Res, NIH, 5625 Fishers Lane,Room TS-24, Bethesda, MD 20892 USA. EM kari.johnson@nih.gov FU Intramural NIH HHS [Z01 AA000407-07] NR 10 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2015 VL 78 IS 7 BP 436 EP 438 DI 10.1016/j.biopsych.2015.07.008 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9YX UT WOS:000360974400002 PM 26360546 ER PT J AU Justinova, Z Panlilio, LV Secci, ME Redhi, GH Schindler, CW Cross, AJ Mrzljak, L Medd, A Shaham, Y Goldberg, SR AF Justinova, Zuzana Panlilio, Leigh V. Secci, Maria E. Redhi, Godfrey H. Schindler, Charles W. Cross, Alan J. Mrzljak, Ladislav Medd, Amy Shaham, Yavin Goldberg, Steven R. TI The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Allosteric modulation; Glutamate; Nicotine; Relapse; Self-administration; Smoking cessation ID VENTRAL TEGMENTAL AREA; AGONIST LY379268; PHARMACOLOGICAL CHARACTERIZATION; INDUCED REINSTATEMENT; NUCLEUS-ACCUMBENS; COCAINE-SEEKING; HEROIN SEEKING; SMOKING; RATS; DEPENDENCE AB BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment. C1 [Justinova, Zuzana; Panlilio, Leigh V.; Secci, Maria E.; Redhi, Godfrey H.; Schindler, Charles W.; Shaham, Yavin; Goldberg, Steven R.] NIDA, Behav Neurosci Res Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Cross, Alan J.] AstraZeneca Neurosci Innovat Med, Cambridge, MA USA. [Mrzljak, Ladislav; Medd, Amy] AstraZeneca, Wilmington, DE USA. RP Justinova, Z (reprint author), NIDA, Preclin Pharmacol Sect, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zjustino@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011; Cross, Alan/L-5456-2016 OI Justinova, Zuzana/0000-0001-5793-7484; Cross, Alan/0000-0002-2992-2258 FU National Institute on Drug Abuse Intramural Research Program; Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This work was supported by the National Institute on Drug Abuse Intramural Research Program and Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institutes of Health, Department of Health and Human Services. AZD8529 was kindly provided by AstraZeneca. NR 52 TC 10 Z9 10 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2015 VL 78 IS 7 BP 452 EP 462 DI 10.1016/j.biopsych.2015.01.014 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9YX UT WOS:000360974400005 PM 25802079 ER PT J AU Caprioli, D Venniro, M Zeric, T Li, X Adhikary, S Madangopal, R Marchant, NJ Lucantonio, F Schoenbaum, G Bossert, JM Shaham, Y AF Caprioli, Daniele Venniro, Marco Zeric, Tamara Li, Xuan Adhikary, Sweta Madangopal, Rajtarun Marchant, Nathan J. Lucantonio, Federica Schoenbaum, Geoffrey Bossert, Jennifer M. Shaham, Yavin TI Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Abstinence; Addiction models; Discrete choice; Extended access; Glutamate; Incubation of drug craving; mGluR2/3; Palatable food; Positive allosteric modulator; Psychostimulants; Relapse; Self-administration ID VENTRAL TEGMENTAL AREA; TIME-DEPENDENT CHANGES; CUE-INDUCED RELAPSE; COCAINE-SEEKING; DRUG RELAPSE; AGONIST LY379268; ALCOHOL-SEEKING; INDUCED REINSTATEMENT; PHARMACOLOGICAL CHARACTERIZATION; CONTINGENCY MANAGEMENT AB BACKGROUND: Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence. METHODS: We trained rats to self-administer palatable food (6 sessions) and then to self-administer methamphetamine under two conditions: 12 sessions (9 hours/day) or 50 sessions (3 hours/day). We then assessed cue-induced methamphetamine seeking in extinction tests after 1 or 21 abstinence days. Between tests, the rats underwent either forced abstinence (no access to the food- or drug-paired levers) or voluntary abstinence (achieved via a discrete choice procedure between methamphetamine and palatable food; 20 trials per day) for 19 days. We also determined the effect of subcutaneous injections of AZD8529 (20 and 40 mg/kg) on cue-induced methamphetamine seeking 1 day or 21 days after forced or voluntary abstinence. RESULTS: Under both training and abstinence conditions, cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day (incubation of methamphetamine craving). AZD8529 decreased cue-induced methamphetamine seeking on day 21 but not day 1 of forced or voluntary abstinence. CONCLUSIONS: We introduce a novel animal model to study incubation of drug craving and cue-induced drug seeking after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Our data suggest that positive allosteric modulators of metabotropic glutamate receptor 2 should be considered for relapse prevention. C1 [Caprioli, Daniele; Venniro, Marco; Zeric, Tamara; Li, Xuan; Adhikary, Sweta; Madangopal, Rajtarun; Marchant, Nathan J.; Schoenbaum, Geoffrey; Bossert, Jennifer M.; Shaham, Yavin] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,US Dept HHS, Baltimore, MD 21224 USA. [Venniro, Marco] Univ Verona, Dept Publ Hlth & Community Med, Pharmacol Sect, Neuropsychopharmacol Lab, I-37100 Verona, Italy. [Marchant, Nathan J.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. [Lucantonio, Federica] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Brain Sci Inst, Sch Med, Baltimore, MD USA. RP Caprioli, D (reprint author), NIDA, IRP, NIH, Behav Neurosci Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM daniele.caprioli@nih.gov OI Madangopal, Rajtarun/0000-0001-6202-302X FU National Institute on Drug Abuse, Intramural Research Program funds; National Health and Medical Research Council [1053308] FX This research was supported by the National Institute on Drug Abuse, Intramural Research Program funds (YS and GS). NJM received support from Early Career Fellowship 1053308 by the National Health and Medical Research Council. NR 89 TC 16 Z9 16 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2015 VL 78 IS 7 BP 463 EP 473 DI 10.1016/j.biopsych.2015.02.018 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9YX UT WOS:000360974400006 PM 25861699 ER PT J AU Adinoff, B Gu, H Merrick, C McHugh, M Jeon-Slaughter, H Lu, HZ Yang, YH Stein, EA AF Adinoff, Bryon Gu, Hong Merrick, Carmen McHugh, Meredith Jeon-Slaughter, Haekyung Lu, Hanzhang Yang, Yihong Stein, Elliot A. TI Basal Hippocampal Activity and Its Functional Connectivity Predicts Cocaine Relapse SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cocaine dependence; Functional connectivity; Functional MRI; Hippocampus; Limbic system; Regional cerebral blood flow ID DORSOMEDIAL PREFRONTAL CORTEX; VENTRAL TEGMENTAL AREA; SELF-RATED INSTRUMENT; DORSAL HIPPOCAMPUS; BASOLATERAL AMYGDALA; DEPENDENT PATIENTS; BRAIN-FUNCTION; DRUG-SEEKING; MEMORY RECONSOLIDATION; INTRINSIC CONNECTIVITY AB BACKGROUND: Cocaine-induced neuroplastic changes may result in a heightened propensity for relapse. Using regional cerebral blood flow (rCBF) as a marker of basal neuronal activity, this study assessed alterations in rCBF and related resting state functional connectivity (rsFC) to prospectively predict relapse in patients following treatment for cocaine use disorder (CUD). METHODS: Pseudocontinuous arterial spin labeling functional magnetic resonance imaging and resting blood oxygen level-dependent functional magnetic resonance imaging data were acquired in the same scan session in abstinent participants with CUD before residential treatment discharge and in 20 healthy matched control subjects. Substance use was assessed twice weekly following discharge. Relapsed participants were defined as those who used stimulants within 30 days following treatment discharge (n = 22); early remission participants (n = 18) did not. RESULTS: Voxel-wise, whole-brain analysis revealed enhanced rCBF only in the left posterior hippocampus (pHp) in the relapsed group compared with the early remission and control groups. Using this pHp as a seed, increased rsFC strength with the posterior cingulate cortex (PCC)/precuneus was seen in the relapsed versus early remission subgroups. Together, both increased pHp rCBF and strengthened pHp-PCC rsFC predicted relapse with 75% accuracy at 30, 60, and 90 days following treatment. CONCLUSIONS: In CUD participants at risk of early relapse, increased pHp basal activity and pHp-PCC circuit strength may reflect the propensity for heightened reactivity to cocaine cues and persistent cocaine-related ruminations. Mechanisms to mute hyperactivated brain regions and delink dysregulated neural circuits may prove useful to prevent relapse in patients with CUD. C1 [Adinoff, Bryon] Univ Texas SW Med Ctr Dallas, Vet Affairs North Texas Hlth Care Syst, Dallas, TX 75390 USA. [Adinoff, Bryon; Jeon-Slaughter, Haekyung; Lu, Hanzhang] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Gu, Hong; McHugh, Meredith; Yang, Yihong; Stein, Elliot A.] Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD USA. [Merrick, Carmen] Univ Texas Dallas, Sch Behav & Brain Sci, Dallas, TX 75230 USA. [Lu, Hanzhang] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA. RP Adinoff, B (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Bryon.adinoff@utsouthwestern.edu FU National Institute on Drug Abuse [DA023203]; National Institute on Drug Abuse Intramural Research Program; University of Texas Southwestern Center for Translational Medicine [UL1TR000451]; National Institute on Arthritis and Musculoskeletal and Skin Disorders; National Institute of Mental Health FX This study was supported by the National Institute on Drug Abuse Grant DA023203, the National Institute on Drug Abuse Intramural Research Program, and the University of Texas Southwestern Center for Translational Medicine UL1TR000451.; BA is funded by the National Institute on Drug Abuse and the National Institute on Arthritis and Musculoskeletal and Skin Disorders, and has received honoraria from the American Academy of Addiction Psychiatry. HL is funded by the National Institute of Mental Health. All authors report no biomedical financial interests or potential conflicts of interest. NR 80 TC 6 Z9 7 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 1 PY 2015 VL 78 IS 7 BP 496 EP 504 DI 10.1016/j.biopsych.2014.12.027 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ9YX UT WOS:000360974400009 PM 25749098 ER PT J AU Jones, MF Li, XL Subramanian, M Shabalina, SA Hara, T Zhu, Y Huang, J Yang, Y Wakefield, LM Prasanth, KV Lal, A AF Jones, M. F. Li, X. Ling Subramanian, M. Shabalina, Svetlana A. Hara, T. Zhu, Y. Huang, J. Yang, Y. Wakefield, L. M. Prasanth, K. V. Lal, A. TI Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID MACROPHAGE INHIBITORY CYTOKINE-1; TGF-BETA SUPERFAMILY; WILD-TYPE; HISTONE DEACETYLASES; MIR-34A CONTRIBUTES; POSITIVE FEEDBACK; TUMOR SUPPRESSION; GENE-EXPRESSION; NONCODING RNA; P53 NETWORK AB According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53-regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR-3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53(-/-) cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors. C1 [Jones, M. F.; Li, X. Ling; Subramanian, M.; Hara, T.; Lal, A.] NCI, Regulatory RNAs & Canc Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Zhu, Y.] NCI, Mol Genet Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Huang, J.] NCI, Canc & Stem Cell Epigenet Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Yang, Y.; Wakefield, L. M.] NCI, Canc Biol TGF Beta Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Prasanth, K. V.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL USA. RP Lal, A (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 6134, Bethesda, MD 20892 USA. EM ashish.lal@nih.gov RI Huang, Jing/A-2566-2009 OI Huang, Jing/0000-0002-7163-5156 FU Marshall Scholarship; NIH Fellowship; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; American Cancer Society [RSG-11-174-01-RMC]; NIH/NIGMS [GM088252] FX MFJ was supported by a Marshall Scholarship and an NIH Fellowship. AL, JH and LMW were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. KVP was supported by grants from American Cancer Society (RSG-11-174-01-RMC) and NIH/NIGMS (GM088252). We thank Dr. Bert Vogelstein for the HCT116 isogenic cell lines and Dr Zissimos Mourelatos for the Ago2 (2A8) antibody. NR 60 TC 3 Z9 3 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD OCT PY 2015 VL 22 IS 10 BP 1641 EP 1653 DI 10.1038/cdd.2015.9 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR0DV UT WOS:000360989400007 PM 25698447 ER PT J AU Francescangeli, F Contavalli, P De Angelis, ML Baiocchi, M Gambara, G Pagliuca, A Fiorenzano, A Prezioso, C Boe, A Todaro, M Stassi, G Castro, NP Watanabe, K Salomon, DS De Maria, R Minchiotti, G Zeuner, A AF Francescangeli, F. Contavalli, P. De Angelis, M. L. Baiocchi, M. Gambara, G. Pagliuca, A. Fiorenzano, A. Prezioso, C. Boe, A. Todaro, M. Stassi, G. Castro, N. P. Watanabe, K. Salomon, D. S. De Maria, R. Minchiotti, G. Zeuner, A. TI Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID COLLECTIVE DYNAMICS; GROWTH FACTOR; PLURIPOTENCY; POPULATIONS; MARKER; STATE; GLYCOSYLPHOSPHATIDYLINOSITOL; HETEROGENEITY; EQUILIBRIUM; METASTASIS AB Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer. C1 [Francescangeli, F.; Contavalli, P.; De Angelis, M. L.; Baiocchi, M.; Pagliuca, A.; Boe, A.; Zeuner, A.] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. [Francescangeli, F.; De Maria, R.] Regina Elena Inst Canc Res, Rome, Italy. [Gambara, G.] Univ Roma La Sapienza, Sect Histol & Med Embryol, Dept Anat Histol Forens Med & Orthoped, I-00185 Rome, Italy. [Fiorenzano, A.; Prezioso, C.; Minchiotti, G.] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, I-80125 Naples, Italy. [Todaro, M.; Stassi, G.] Univ Palermo, Dept Surg & Oncol Sci, Palermo, Italy. [Castro, N. P.; Salomon, D. S.] NCI, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Watanabe, K.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. RP Zeuner, A (reprint author), Ist Super Sanita, Dept Hematol Oncol & Mol Med, Viale Regina Elena 299, I-00161 Rome, Italy. EM a.zeuner@iss.it RI Todaro, Matilde/K-9523-2016; OI Zeuner, Ann/0000-0002-8295-3715 FU Ricerca Finalizzata grant (Italian Ministry of Health); AIRC IG grant [15749, 11599]; AIRC 5 per Mille grant [9979]; Epigenomics Flagship Project (EPIGEN) MIUR-CNR; Italian Ministry of Education-University-Research (MIUR-PRIN) FX We thank Stefano Guida and Gennaro Andolfi for excellent technical assistance, Alessandro Giuliani for helpful discussion, Boris Fehse and Kristoffer Riecken for providing the LeGO vectors, Anna Rizzo for help with statistical analysis, Valeria Coppola for help with the Oncomine database and Mario Falchi for image quantification. This work was supported by a Ricerca Finalizzata grant (Italian Ministry of Health) and AIRC IG grant 15749 to AZ, AIRC 5 per Mille 9979 grant to RDM and GS, AIRC IG grant 11599, Epigenomics Flagship Project (EPIGEN) MIUR-CNR and Italian Ministry of Education-University-Research (MIUR-PRIN) grants to GM. NR 40 TC 7 Z9 8 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD OCT PY 2015 VL 22 IS 10 BP 1700 EP 1713 DI 10.1038/cdd.2015.19 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR0DV UT WOS:000360989400012 PM 26343543 ER PT J AU Somanna, NK Yariswamy, M Garagliano, JM Siebenlist, U Mummidi, S Valente, AJ Chandrasekar, B AF Somanna, Naveen K. Yariswamy, Manjunath Garagliano, Joseph M. Siebenlist, Ulrich Mummidi, Srinivas Valente, Anthony J. Chandrasekar, Bysani TI Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2 SO CELLULAR SIGNALLING LA English DT Article DE RAAS; Aldosterone; TRAF3IP2; Hypertrophy; Mitogenesis; Migration ID KAPPA-B KINASE; HEART-FAILURE; ANGIOTENSIN-II; MYOCARDIAL FIBROSIS; CARDIAC-HYPERTROPHY; MATRIX METALLOPROTEINASES; HYPERTENSIVE PATIENTS; SYSTOLIC DYSFUNCTION; PRESSURE-OVERLOAD; OXIDATIVE STRESS AB Sustained activation of the Renin-Angiotensin-Aldosterone System (RAAS) contributes to the pathogenesis of heart failure. Aldosterone (Aldo) is known to induce both myocardial hypertrophy and fibrosis through oxidative stress and proinflammatory pathways. Here we have investigated whether Aldo-mediated cardiomycocyte hypertrophy is dependent on TRAF3IP2, an upstream regulator of IKK and JNIC We also investigated whether the pro-mitogenic and pro-migratory effects of Aldo on cardiac fibroblasts are also mediated by TRAF3IP2. Aldo induced both superoxide and hydrogen peroxide in isolated adult mouse cardiomyocytes (CM), and upregulated TRAF3IP2 expression in part via the mineralocorticoid receptor and oxidative stress. Silencing TRAF3IP2 blunted Aldo-induced IKK beta, p65, JNK, and c-Jun activation, IL-18, IL-6 and CT-1 upregulation, and cardiomyocyte hypertrophy. In isolated adult mouse cardiac fibroblasts (CF), Aldo stimulated TRAF3IP2-dependent IL-18 and IL-6 production, CTGF, collagen land III expression, MMP2 activation, and proliferation and migration. These in vitro results suggest that TRAF3IP2 may play a causal role in Aldo-induced adverse cardiac remodeling in vivo, and identify TRAF3IP2 as a potential therapeutic target in hypertensive heart disease. (C) 2015 Elsevier Inc. All rights reserved. C1 [Somanna, Naveen K.] Tulane Univ, Sch Med, Dept Microbiol, New Orleans, LA 70112 USA. [Yariswamy, Manjunath; Garagliano, Joseph M.; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Yariswamy, Manjunath; Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, New Orleans, LA 70161 USA. [Siebenlist, Ulrich; Chandrasekar, Bysani] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Siebenlist, Ulrich; Chandrasekar, Bysani] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Mummidi, Srinivas; Valente, Anthony J.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave,SL-48, New Orleans, LA 70112 USA. FU Department of Veterans Affairs Research Career Scientist award; U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award [VA-I01 BX002255]; Usha Ramadhyani Bourgeois Medical Student Research Endowed Fund; NIH/NIAID FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by the U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award VA-I01 BX002255. JMG is a recipient of The Warren R Bourgeois III and Usha Ramadhyani Bourgeois Medical Student Research Endowed Fund. US is supported by the Intramural Research Program of the NIH/NIAID. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government NR 44 TC 7 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2015 VL 27 IS 10 BP 1928 EP 1938 DI 10.1016/j.cellsig.2015.07.001 PG 11 WC Cell Biology SC Cell Biology GA CQ7ID UT WOS:000360775300002 PM 26148936 ER PT J AU Kurtoglu, M Davarpanah, NN Qin, R Powles, T Rosenberg, JE Apolo, AB AF Kurtoglu, Metin Davarpanah, Nicole N. Qin, Rui Powles, Thomas Rosenberg, Jonathan E. Apolo, Andrea B. TI Elevating the Horizon: Emerging Molecular and Genomic Targets in the Treatment of Advanced Urothelial Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Review DE Bladder cancer; Clinical trials; Immune checkpoints; Novel agents; Targeted therapy ID TRANSITIONAL-CELL CARCINOMA; INVASIVE BLADDER-CANCER; PHASE-II TRIAL; CISPLATIN-BASED CHEMOTHERAPY; EPIDERMAL-GROWTH-FACTOR; COOPERATIVE-ONCOLOGY-GROUP; RADICAL CYSTECTOMY; CLINICAL ACTIVITY; TRACT CARCINOMA; OPEN-LABEL AB Despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in vitro, patients with advanced urothelial carcinomas continue to have poor clinical outcomes. In the present review, we focus on targeted therapies that have yielded the most promising results alone or combined with traditional chemotherapy, including the antiangiogenesis agent bevacizumab, the human epidermal growth factor receptor 2 antibody trastuzumab, and the tyrosine kinase inhibitor cabozantinib. We also describe ongoing and developing clinical trials that use innovative approaches, including dose-dense scheduling of singular chemotherapy combinations, prospective screening of tumor tissues for mutational targets and biomarkers to predict chemosensitivity before the determination of the therapeutic regimen, and novel agents that target proteins in the immune checkpoint regulation pathway (programmed cell death protein 1 [PD-1] and anti-PD-ligand 1) that have shown significant potential in preclinical models and early clinical trials. New agents and targeted therapies, alone or combined with traditional chemotherapy, will only be validated through accrual to developing clinical trials that aim to translate these therapies into individualized treatments and improved survival rates in urothelial carcinoma. C1 [Kurtoglu, Metin; Davarpanah, Nicole N.; Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Qin, Rui] Mayo Clin, Hlth Sci Res, Rochester, MN USA. [Powles, Thomas] Queen Mary Univ London, St Bartholomews Hosp, Barts Canc Inst, Ctr Expt Canc Med, London, England. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, New York, NY 10021 USA. RP Apolo, AB (reprint author), NCI, NIH, 10 Ctr Dr 12N226,MSC 1906, Bethesda, MD 20892 USA. EM andrea.apolo@nih.gov OI Rosenberg, Jonathan/0000-0003-2637-4249 FU Intramural NIH HHS [ZIA BC011351-03, ZIA BC011351-01, ZIA BC011351-02] NR 80 TC 5 Z9 5 U1 0 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2015 VL 13 IS 5 BP 410 EP 420 DI 10.1016/j.clgc.2015.02.009 PG 11 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CQ9EK UT WOS:000360914600011 PM 25862322 ER PT J AU Wang, QS Oyarzabal, E Wilson, B Qian, L Hong, JS AF Wang, Qingshan Oyarzabal, Esteban Wilson, Belinda Qian, Li Hong, Jau-Shyong TI Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice SO CLINICAL SCIENCE LA English DT Article DE chemotaxis; microglia distribution; Parkinson's disease ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; NADPH OXIDASE; NEURODEGENERATIVE DISEASES; NEUTROPHIL MIGRATION; ACTIVATED MICROGLIA; RAT-BRAIN; EXPRESSION; SYSTEM; PHOSPHORYLATION; NEUROPEPTIDES AB The distribution of microglia varies greatly throughout the brain. The substantia nigra (SN) contains the highest density of microglia among different brain regions. However, the mechanism underlying this uneven distribution remains unclear. Substance P (SP) is a potent proinflammatory neuropeptide with high concentrations in the SN. We recently demonstrated that SP can regulate nigral microglial activity. In the present study, we further investigated the involvement of SP in modulating nigral microglial density in postnatal developing mice. Nigral microglial density was quantified in wild-type (WT) and SP-deficient mice from postnatal day 1 (P1) to P30. SP was detected at high levels in the SN as early as P1 and microglial density did not peak until around P30 in WT mice. SP-deficient mice (TAC1(-/-)) had a significant reduction in nigral microglial density. No differences in the ability of microglia to proliferate were observed between TAC1(-/-) and WT mice, suggesting that SP may alter microglial density through chemotaxic recruitment. SP was confirmed to dose-dependently attract microglia using a trans-well culture system. Mechanistic studies revealed that both the SP receptor neurokinin-1 receptor (NK1R) and the superoxide-producing enzyme NADPH oxidase (NOX2) were necessary for SP-mediated chemotaxis in microglia. Furthermore, genetic ablation and pharmacological inhibition of NK1R or NOX2 attenuated SP-induced microglial migration. Finally, protein kinase C delta (PKC delta) was recognized to couple SP/NK1R-mediated NOX2 activation. Altogether, we found that SP partly accounts for the increased density of microglia in the SN through chemotaxic recruitment via a novel NK1R-NOX2 axis-mediated pathway. C1 [Wang, Qingshan; Oyarzabal, Esteban; Wilson, Belinda; Qian, Li; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Wang, Qingshan] Dalian Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Dalian 116044, Liaoning, Peoples R China. RP Wang, QS (reprint author), NIEHS, Neuropharmacol Sect, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM wangq4@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 37 TC 0 Z9 0 U1 2 U2 5 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD OCT 1 PY 2015 VL 129 IS 8 BP 757 EP 767 DI 10.1042/CS20150008 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CR0XM UT WOS:000361047000007 PM 26223840 ER PT J AU Thayer, KA Doerge, DR Hunt, D Schurman, SH Twaddle, NC Churchwell, MI Garantziotis, S Kissling, GE Easterling, MR Bucher, JR Birnbaum, LS AF Thayer, Kristina A. Doerge, Daniel R. Hunt, Dawn Schurman, Shepherd H. Twaddle, Nathan C. Churchwell, Mona I. Garantziotis, Stavros Kissling, Grace E. Easterling, Michael R. Bucher, John R. Birnbaum, Linda S. TI Pharmacokinetics of bisphenol A in humans following a single oral administration SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Deuterated bisphenol A; Endocrine disruptor; ADME; Bioavailability; Metabolism; Excretion ID SPRAGUE-DAWLEY RATS; HUMAN EXPOSURE; RHESUS-MONKEYS; HUMAN SERUM; BPA; URINE; POPULATION; ADULT; CONTAMINATION; CHEMICALS AB Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. Objective: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. Methods: We exposed six men and eight women to 100 mu g/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. Results: Mean serum total (unconjugated and conjugated) d6-BPA C-max of 1711 nM (390 ng/ml) was observed at T-max of 1.1 +/- 0.50 h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean C-max of 6.5 nM (1.5 ng/ml) observed at T-max of 1.3 +/- 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 +/- 2.0 hand 6.2 +/- 2.6 h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24 h. Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24 h. Published by Elsevier Ltd C1 [Thayer, Kristina A.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Doerge, Daniel R.; Twaddle, Nathan C.; Churchwell, Mona I.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Hunt, Dawn; Schurman, Shepherd H.; Garantziotis, Stavros] NIEHS, Clin Res Unit, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Easterling, Michael R.] Social & Sci Syst Inc, Durham, NC 27703 USA. [Birnbaum, Linda S.] NCI, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NCI, NIH, US Dept HHS, POB 12233,Mail Drop B2-01, Res Triangle Pk, NC 27709 USA. EM thayer@niehs.nih.gov; daniel.doerge@fda.hhs.gov; dawnhunt2233@outlook.com; schurmansh@niehs.nih.gov; Nathan.Twaddle@fda.hhs.gov; Mona.Churchwell@fda.hhs.gov; garantziotis@niehs.nih.gov; kissling@niehs.nih.gov; MEasterling@s-3.com; bucher@niehs.nih.gov; birnbaumls@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Schurman, Shepherd/0000-0002-9133-7906 FU intramural research program of the National Institute of Environmental Health Sciences; intramural research program of the National Cancer Institute, National Institutes of Health FX We gratefully acknowledge the contributions of Gail McCarver and Karthika Divakaran (Medical College of Wisconsin, Milwaukee, Wisconsin, USA) for conducting genotype analyses and Mike DeVito, Jeffrey Fisher, Jerry Heindel, and Matthew Longnecker for reviewing a draft version of the manuscript. Funding: This research was supported by the intramural research programs of the National Institute of Environmental Health Sciences and the National Cancer Institute, National Institutes of Health. NR 48 TC 23 Z9 23 U1 9 U2 41 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD OCT PY 2015 VL 83 BP 107 EP 115 DI 10.1016/j.envint.2015.06.008 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA CR2LN UT WOS:000361161300010 PM 26115537 ER PT J AU Shitara, A Weigert, R AF Shitara, Akiko Weigert, Roberto TI Imaging membrane remodeling during regulated exocytosis in live mice SO EXPERIMENTAL CELL RESEARCH LA English DT Review ID INTRAVITAL 2-PHOTON MICROSCOPY; FUSED SECRETORY VESICLES; MYOSIN-II; PANCREATIC ACINI; PLASMA-MEMBRANE; ACTIN; FUSION; GRANULE; CELLS; ANIMALS AB In this mini-review we focus on the use of time-lapse light microscopy to study membrane remodeling during protein secretion in live animals. In particular, we highlight how subcellular intravital microscopy has enabled imaging the dynamics of both individual secretory vesicles and the plasma membrane, during different steps in the exocytic process. This powerful approach has provided us with the unique opportunity to unravel the role of the actin cytoskeleton in regulating this process under physiological conditions, and to overcome the shortcomings of more reductionist model systems. Published by Elsevier Inc. C1 [Shitara, Akiko; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Sect, Oral & Phalyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Sect, Oral & Phalyngeal Canc Branch, NIH, 30 Convent Dr 303A, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov FU Intramural Research Program of the NIH, NIDCR FX Work in the author'(s) laboratory is supported by the Intramural Research Program of the NIH, NIDCR. We would like to thank Drs. Amornphimoltham and Ms. Olivia Harding for critical reading of the manuscript. NR 55 TC 2 Z9 2 U1 1 U2 14 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD OCT 1 PY 2015 VL 337 IS 2 SI SI BP 219 EP 225 DI 10.1016/j.yexcr.2015.06.018 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CR2LF UT WOS:000361160400011 PM 26160452 ER PT J AU Chumak, V Drozdovitch, V Kryuchkov, V Bakhanova, E Babkina, N Bazyka, D Gudzenko, N Hatch, M Trotsuk, N Zablotska, L Golovanov, I Luckyanov, N Voilleque, P Bouville, A AF Chumak, Vadim Drozdovitch, Vladimir Kryuchkov, Victor Bakhanova, Elena Babkina, Natalya Bazyka, Dimitry Gudzenko, Natalya Hatch, Maureen Trotsuk, Natalya Zablotska, Lydia Golovanov, Ivan Luckyanov, Nickolas Voilleque, Paul Bouville, Andre TI Dosimetry Support of the Ukrainian-American Case-control Study of Leukemia and Related Disorders Among Chornobyl Cleanup Workers SO HEALTH PHYSICS LA English DT Article ID EMERGENCY WORKERS; RADIATION; RISK; RECONSTRUCTION; LIQUIDATORS AB This paper describes dose reconstruction for a joint Ukrainian-American case-control study of leukemia that was conducted in a cohort of 110,645 male Ukrainian cleanup workers of the Chornobyl (Chernobyl) accident who were exposed to various radiation doses over the 1986-1990 time period. Individual bone-marrow doses due to external irradiation along with respective uncertainty distributions were calculated for 1,000 study subjects using the RADRUE method, which employed personal cleanup history data collected in the course of an interview with the subject himself if he was alive or with two proxies if he was deceased. The central estimates of the bone-marrow dose distributions range from 3.7 x 10(-5) to 3,260 mGy, with an arithmetic mean of 92 mGy. The uncertainties in the individual stochastic dose estimates can be approximated by lognormal distributions; the average geometric standard deviation is 2.0. C1 [Chumak, Vadim; Bakhanova, Elena; Babkina, Natalya; Bazyka, Dimitry; Gudzenko, Natalya; Trotsuk, Natalya] Natl Res Ctr Radiat Med, Kiev, Ukraine. [Drozdovitch, Vladimir; Hatch, Maureen; Luckyanov, Nickolas; Bouville, Andre] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kryuchkov, Victor; Golovanov, Ivan] Burnasyan Fed Med Biophys Ctr, Moscow, Russia. [Zablotska, Lydia] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Voilleque, Paul] MJP Risk Assessment Inc, Denver, CO USA. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS 9609 Med Ctr Dr,Room 7E548,MSC 9778, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov RI Chumak, Vadim/N-6960-2015 OI Chumak, Vadim/0000-0001-6045-9356 FU Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institute of Allergy and Infectious Diseases (U.S.); National Cancer Institute (NIAID) [Y2-Al-5077]; National Cancer Institute (NCI) [Y3-CO-5117] FX The authors are especially grateful to Anatoly E. Romanenko, Geoffrey R. Howe, Gilbert W. Beebe, and Stuart C. Finch for setting up and spearheading the Ukrainian-American case-control study of leukemia during its early years of development and implementation. Funding for radiation dose reconstruction was provided by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, and was partially supported by an intra-agency agreement between the National Institute of Allergy and Infectious Diseases (U.S.) and the National Cancer Institute (NIAID agreement #Y2-Al-5077 and NCI agreement #Y3-CO-5117). NR 19 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD OCT PY 2015 VL 109 IS 4 BP 296 EP 301 DI 10.1097/HP.0000000000000341 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA CQ8DT UT WOS:000360837200004 PM 26313587 ER PT J AU Musci, RJ Uhl, G Maher, B Ialongo, NS AF Musci, Rashelle J. Uhl, George Maher, Brion Ialongo, Nicholas S. TI Testing Gene x Environment Moderation of Tobacco and Marijuana Use Trajectories in Adolescence and Young Adulthood SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE substance use; polygenic score; social environment; Gene x Environment interaction; trajectories ID ALCOHOL-USE; SUBSTANCE USE; MOLECULAR-GENETICS; DRUG-USE; POLYSUBSTANCE ABUSERS; USE DISORDERS; ASSOCIATION; PEERS; TWINS; AGE AB Objective: This study examines the main and interaction effects of known social risk factors for substance use (inadequate parental monitoring and substance using friends) in adolescence and a polygenic score in predicting marijuana and tobacco use in adolescence and young adulthood. Method: Phenotypic and genetic data were derived from a longitudinal study of a cohort of urban, predominately African American youth. Last year substance-use measures were collected annually from 8th grade through age 22. Participant self-reports of substance-using friends and parent monitoring were obtained yearly from Grades 8 to 12. Using longitudinal latent class analysis, the authors identified parallel developmental trajectories of tobacco and marijuana use and parent monitoring and the proportion of substance-using friends. Results: Two trajectories were identified for tobacco and marijuana use, characterized by moderate versus little-to-no use. Additionally, 2 latent profiles were found for the social environment profiles: those characterized by higher parent monitoring and a lower proportion of substance-using friends versus lower parent monitoring and a higher proportion of substance-using friends. Conclusions: We found main and interaction effects for the polygenic score and social environment profile in predicting the longitudinal classes of marijuana and tobacco use. With respect to the interaction effect, membership in the moderate-use classes of marijuana and tobacco use was highest among those in the social environment profile characterized by lower parent monitoring and a higher proportion of substance-using friends. C1 [Musci, Rashelle J.; Maher, Brion; Ialongo, Nicholas S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Uhl, George] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP Musci, RJ (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, 624 N Broadway, Baltimore, MD 21205 USA. EM rmusci@jhsph.edu FU National Institute of Mental Health [MH57005, T32 MH18834]; National Institute on Drug Abuse [NIDA R37 DA11796]; Maternal and Child Health Bureau [T71MC08054] FX This research was supported by Grants MH57005 and T32 MH18834 from the National Institute of Mental Health, Grant NIDA R37 DA11796 from the National Institute on Drug Abuse, and Grant T71MC08054 from the Maternal and Child Health Bureau. NR 62 TC 0 Z9 0 U1 2 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2015 VL 83 IS 5 BP 866 EP 874 DI 10.1037/a0039537 PG 9 WC Psychology, Clinical SC Psychology GA CR3IS UT WOS:000361226400003 PM 26214541 ER PT J AU Sasso, KE Strunk, DR Braun, JD DeRubeis, RJ Brotman, MA AF Sasso, Katherine E. Strunk, Daniel R. Braun, Justin D. DeRubeis, Robert J. Brotman, Melissa A. TI Identifying Moderators of the Adherence-Outcome Relation in Cognitive Therapy for Depression SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE therapist adherence; cognitive therapy; moderation ID BEHAVIORAL THERAPY; PERSONALITY-DISORDER; RECURRENT DEPRESSION; CRITICAL SESSIONS; MAJOR DEPRESSION; SYMPTOM CHANGE; SUDDEN GAINS; FOLLOW-UP; MEDICATIONS; PREDICTORS AB Objective: Little is known about the influence of patients' pretreatment characteristics on the adherence-outcome relation in cognitive therapy (CT) for depression. In a sample of 57 depressed adults participating in CT, the authors examined interactions between pretreatment patient characteristics and therapist adherence in predicting session-to-session symptom change. Method: Using items from the Collaborative Study Psychotherapy Rating Scale, the authors assessed 3 facets of therapist adherence: cognitive methods, negotiating/structuring, and behavioral methods/homework. Two graduate students rated Sessions 1-4 for adherence. Symptoms were assessed prior to each session with the Beck Depression Inventory-II. Moderators were assessed as part of patients' intake evaluations. Results: After correcting for multiple comparisons, patient gender remained a significant moderator of the relationship between cognitive methods and next-session symptom change; cognitive methods more strongly predicted greater symptom improvement for women as compared to men. Pretreatment anxiety and number of prior depressive episodes were significant moderators of the relationship between behavioral methods/homework and next-session symptom change, with greater behavioral methods/homework predicting symptom improvement more strongly among patients high in pretreatment anxiety and among patients with relatively few prior depressive episodes. Conclusions: This is the first study to provide evidence of how therapist adherence is differentially related to outcome among depressed patients with different characteristics. If replicated, these findings may inform clinical decisions regarding the use of specific facets of adherence in CT for depression with specific patients. C1 [Sasso, Katherine E.; Strunk, Daniel R.; Braun, Justin D.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [DeRubeis, Robert J.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. [Brotman, Melissa A.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Strunk, DR (reprint author), Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA. EM strunk.20@osu.edu RI Strunk, Daniel/F-4153-2011; Brotman, Melissa/H-7409-2013 OI Strunk, Daniel/0000-0002-7444-0741; FU NIMH NIH HHS [R10 MH055877] NR 50 TC 2 Z9 2 U1 3 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD OCT PY 2015 VL 83 IS 5 BP 976 EP 984 DI 10.1037/ccp0000045 PG 9 WC Psychology, Clinical SC Psychology GA CR3IS UT WOS:000361226400012 PM 26214542 ER PT J AU Hamilton, JG Hutson, SP Frohnmayer, AE Han, PKJ Peters, JA Carr, AG Alter, BP AF Hamilton, Jada G. Hutson, Sadie P. Frohnmayer, Amy E. Han, Paul K. J. Peters, June A. Carr, Ann G. Alter, Blanche P. TI Genetic Information-Seeking Behaviors and Knowledge among Family Members and Patients with Inherited Bone Marrow Failure Syndromes SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Genetic counseling; Information seeking; Genetic literacy; Inherited bone marrow failure syndromes; Fanconi anemia; Dyskeratosis congenita; Diamond-Blackfan anemia; Shwachman-Diamond syndrome ID CYSTIC-FIBROSIS; FANCONI-ANEMIA; INTERNET; ATTITUDES; UNDERSTANDINGS; EXPERIENCE; DISORDER; RESOURCE; CHILDREN; PARENTS AB Inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are rare genetic disorders characterized by hematologic complications and increased risk of cancer. Patients and their families likely experience obstacles in obtaining sufficient health information given their disorders' rarity. To investigate this possibility, we examined information-seeking behaviors and levels of general and disorder-specific genetic knowledge among 315 members of 174 families with an IBMFS, and how information-seeking behaviors and socio-demographic factors may be associated with their genetic knowledge. Cross-sectional survey data indicated that participants were most likely to have ever used the Internet or healthcare providers for genetic information. On average, participants correctly answered 57 % of items assessing general genetic knowledge and 49-59 % of disorder-specific knowledge items. Greater knowledge was associated with greater education and ever experiencing genetic counseling, attending a scientific meeting, and seeking information from the Internet and scientific literature. Among families with Fanconi anemia (whose family support organization has the longest history of providing information), greater disorder-specific genetic knowledge was also associated with seeking information from support groups and other affected families. Results suggest that families with IBMFS have uncertainty regarding genetic aspects of their disorder, and highlight potential channels for delivering educational resources. C1 [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10022 USA. [Hutson, Sadie P.] Univ Tennessee, Coll Nursing, Knoxville, TN USA. [Frohnmayer, Amy E.] Oregon State Univ Cascades, Clin Mental Hlth Counseling Program, Bend, OR USA. [Han, Paul K. J.] Maine Med Ctr, Res Inst, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [Peters, June A.; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Carr, Ann G.] Westat Corp, Rockville, MD USA. RP Hamilton, JG (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM hamiltoj@mskcc.org OI Han, Paul/0000-0003-0165-1940 FU Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute; Westat [HHSN261200655001C]; National Cancer Institute Cancer Prevention Fellowship Program; National Human Genome Research Institute through the Intergovernmental Personnel Act FX This research was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute (JAP, BPA), and by contract HHSN261200655001C with Westat (AGC). JGH was supported in part by the National Cancer Institute Cancer Prevention Fellowship Program. PKJH was supported by the National Human Genome Research Institute through the Intergovernmental Personnel Act. We are extremely grateful to all participating patients and families affected with an IBMFS. NR 34 TC 1 Z9 1 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD OCT PY 2015 VL 24 IS 5 BP 760 EP 770 DI 10.1007/s10897-014-9807-3 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CR0KC UT WOS:000361006400007 PM 25540896 ER PT J AU Draughon, JE Lucea, MB Campbell, JC Paterno, MT Bertrand, DR Sharps, PW Campbell, DW Stockman, JK AF Draughon, Jessica E. Lucea, Marguerite B. Campbell, Jacquelyn C. Paterno, Mary T. Bertrand, Desiree R. Sharps, Phyllis W. Campbell, Doris W. Stockman, Jamila K. TI Impact of Intimate Partner Forced Sex on HIV Risk Factors in Physically Abused African American and African Caribbean Women SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE HIV/AIDS; Intimate partner violence; Forced sex; Sexual violence; Women ID SEXUALLY-TRANSMITTED INFECTIONS; DOMESTIC VIOLENCE; INTERPERSONAL VIOLENCE; SOUTH-AFRICA; ASSOCIATION; PREVALENCE; BEHAVIORS; HIV/AIDS; HEALTH; COMMUNITY AB We examined associations between intimate partner forced sex (IPFS) and HIV sexual risk behaviors among physically abused Black women. Women aged 18-55 in intimate relationships were interviewed in health clinics in Baltimore, MD and St. Thomas and St. Croix, US Virgin Islands (USVI). Of 426 physically abused women, 38 % experienced IPFS; (Baltimore = 44 and USVI = 116). USVI women experiencing IPFS were more likely to have 3+ past-year sex partners (AOR 2.06, 95 % CI 1.03-4.14), casual sex partners (AOR 2.71, 95 % CI 1.42-5.17), and concurrent sex partners (AOR 1.94, 95 % CI 1.01-3.73) compared to their counterparts. Baltimore women reporting IPFS were more likely to have exchanged sex (AOR 3.57, 95 % CI 1.19-10.75). Women experiencing IPFS were more likely to report their abuser having other sexual partners in Baltimore (AOR 3.30, 95 % CI 1.22-8.88) and USVI (AOR 2.03, 95 % CI 1.20-3.44). Clinicians should consider the influence of IPFS on individual and partnership HIV sexual risk behaviors. C1 [Draughon, Jessica E.; Lucea, Marguerite B.; Campbell, Jacquelyn C.; Sharps, Phyllis W.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Draughon, Jessica E.] Univ Calif San Francisco, Sch Nursing, Dept Community Hlth Syst, San Francisco, CA 94143 USA. [Paterno, Mary T.] Pioneer Womens Hlth, Greenfield, MA USA. [Bertrand, Desiree R.; Campbell, Doris W.] Univ Virgin Isl, Caribbean Exploratory NIMHD Res Ctr, St Thomas, VI USA. [Stockman, Jamila K.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. RP Draughon, JE (reprint author), Univ Calif San Francisco, Sch Nursing, Dept Community Hlth Syst, 2 Koret Way Box 0608, San Francisco, CA 94143 USA. EM jessica.draughon@nursing.ucsf.edu; marguerite.lucea@gmail.com; jcampbe1@jhu.edu; mpaterno@juno.com; dbertra@uvi.edu; psharps1@jhu.edu; dcampbe@uvi.edu; jstockman@ucsd.edu OI Draughon Moret, Jessica/0000-0002-2597-021X FU National Institutes of Health (Caribbean Exploratory Research Center, University of the Virgin Islands) [NIMHD P20MD002286]; NIMH [F31MH088850, R25MH080664, R25MH080665]; NINR [T32NR007081]; NICHD [T32HD064428, R01HD077891]; NIMHD [L60MD006272, L60MD003701]; NIDA [K01DA031593, R25DA025571] FX This study was supported by the National Institutes of Health (NIMHD P20MD002286, Caribbean Exploratory Research Center, University of the Virgin Islands). J.E.D. was supported by NIMH (F31MH088850) and NINR (T32NR007081). M.B.L. is supported by NICHD (T32HD064428 and R01HD077891) and NIMHD (L60MD006272). J.K.S. is supported by NICHD (R01HD077891) NIDA (K01DA031593 and R25DA025571), NIMHD (L60MD003701) and NIMH (R25MH080664 and R25MH080665). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 45 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD OCT PY 2015 VL 17 IS 5 BP 1313 EP 1321 DI 10.1007/s10903-014-0112-x PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CQ9DL UT WOS:000360911300004 PM 25248623 ER PT J AU Griffiths, C Reich, K Leonard, C Blauvelt, A Mehta, N Tsai, TF Gong, YK Huang, JQ Fox, T AF Griffiths, Christopher Reich, Kristian Leonard, Craig Blauvelt, Andrew Mehta, Nehal Tsai, Tsen-Fang Gong, Yankun Huang, Jiaqing Fox, Todd TI Secukinumab demonstrates an acceptable safety profile in moderate to severe plaque psoriasis: Pooled analysis of 10 phase 2/3 studies SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 4th World Psoriasis and Psoriatic Arthritis Conference on Psoriasis - New Insights and Innovations CY OCT, 2015 CL Stockholm, SWEDEN C1 [Griffiths, Christopher] Univ Manchester, Salford Royal Hosp, Dermatol Ctr, Manchester, Lancs, England. [Reich, Kristian] Dermatologikum Hamburg, Gottingen, Germany. [Reich, Kristian] Univ Gottingen, D-37073 Gottingen, Germany. [Leonard, Craig] St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. [Blauvelt, Andrew] Oregon Med Res Ctr, Portland, OR USA. [Mehta, Nehal] NHLBI, Bethesda, MD 20892 USA. [Tsai, Tsen-Fang] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Taipei 10764, Taiwan. [Gong, Yankun] Beijing Novartis Pharma Co Ltd, Shanghai, Peoples R China. [Huang, Jiaqing] Novartis Pharmaceut, E Hanover, NJ USA. [Fox, Todd] Novartis Pharma AG, Basel, Switzerland. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 SU 3 MA P051 BP S14 EP S14 PG 1 WC Dermatology SC Dermatology GA CR2LG UT WOS:000361160500050 ER PT J AU Ugaonkar, SR Clark, JT English, LB Johnson, TJ Buckheit, KW Bahde, RJ Appella, DH Buckheit, RW Kiser, PF AF Ugaonkar, Shweta R. Clark, Justin T. English, Lexie B. Johnson, Todd J. Buckheit, Karen W. Bahde, Robert J. Appella, Daniel H. Buckheit, Robert W., Jr. Kiser, Patrick F. TI An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE polymeric drug delivery system; stability; epithelial delivery; permeability; HIV; AIDS; mucosal drug delivery; extrusion; biocompatibility; physicochemical properties; preformulation; controlled release ID IMMUNODEFICIENCY-VIRUS TYPE-1; CONTRACEPTIVE VAGINAL RING; ZINC-FINGER INHIBITORS; NUCLEOCAPSID PROTEIN; PREEXPOSURE PROPHYLAXIS; IN-VITRO; TENOFOVIR GEL; PREVENTION; INFECTION; MICROBICIDES AB Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable because of their hydrolytically labile thioester bond, thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]--alaninamide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse-transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40 degrees C/75% relative humidity. In vitro, 25 +/- 3 mg/IVR of SAMT-10 and 86 +/- 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell-based assays. Toxicological evaluations performed on an organotypic EpiVaginal tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation. (c) 2015 Wiley Periodicals, Inc. C1 [Ugaonkar, Shweta R.; English, Lexie B.; Johnson, Todd J.; Kiser, Patrick F.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [Clark, Justin T.; Kiser, Patrick F.] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA. [Buckheit, Karen W.; Buckheit, Robert W., Jr.] ImQuest BioSci, Frederick, MD 21704 USA. [Bahde, Robert J.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kiser, PF (reprint author), Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. EM patrick.kiser@northwestern.edu RI Kiser, Patrick/C-2843-2014 OI Kiser, Patrick/0000-0002-3868-7122 FU NIH [5U19AI077289] FX This work was supported by NIH grant #5U19AI077289. NR 55 TC 4 Z9 4 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD OCT PY 2015 VL 104 IS 10 BP 3426 EP 3439 DI 10.1002/jps.24551 PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA CR0EP UT WOS:000360991400016 PM 26149293 ER PT J AU Azoury, SC Oyetunji, S Xi, SC Straughan, D Reardon, ES Zhang, M Hong, J Xiong, Y Ripley, RT Schrump, DS AF Azoury, Said C. Oyetunji, Shakirat Xi, Sichuan Straughan, David Reardon, Emily S. Zhang, Mary Hong, Julie Xiong, Yin Ripley, R. Taylor Schrump, David S. TI Cigarette Smoke Represses MicroRNA-143 During Esophageal Adenocarcinogenesis SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 NCI, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S149 EP S149 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700312 ER PT J AU Patel, D Thompson, M Manna, S Krausz, K Zhang, L Nilubol, N Gonzalez, FJ Kebebew, E AF Patel, Dhaval Thompson, Matthew Manna, Soumen Krausz, Kristopher Zhang, Lisa Nilubol, Naris Gonzalez, Frank J. Kebebew, Electron TI Urinary Metabolomics Analyses Identify Novel Markers of Malignant Adrenocortical Neoplasms SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Patel, Dhaval; Thompson, Matthew; Manna, Soumen; Krausz, Kristopher; Zhang, Lisa; Nilubol, Naris; Gonzalez, Frank J.; Kebebew, Electron] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S61 EP S62 PG 2 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700115 ER PT J AU Satoh, K Dieckmann, W Nilubol, N Kebebew, E Patel, D AF Satoh, Kei Dieckmann, William Nilubol, Naris Kebebew, Electron Patel, Dhaval TI Detection of Grade 2/3 Von Hippel-Lindau Associated Pancreatic Lesions by 18-FDG PET/CT Volumetric Parameters SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Satoh, Kei; Dieckmann, William; Nilubol, Naris; Kebebew, Electron; Patel, Dhaval] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S59 EP S59 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700109 ER PT J AU Nalls, MA McLean, CY Rick, J Eberly, S Hutten, SJ Gwinn, K Sutherland, M Martinez, M Heutink, P Williams, NM Hardy, J Gasser, T Brice, A Price, TR Nicolas, A Keller, MF Molony, C Gibbs, JR Chen-Plotkin, A Suh, E Letson, C Fiandaca, MS Mapstone, M Federoff, HJ Noyce, AJ Morris, H Van Deerlin, VM Weintraub, D Zabetian, C Hernandez, DG Lesage, S Mullins, M Conley, ED Northover, CAM Frasier, M Marek, K Day-Williams, AG Stone, DJ Ioannidis, JPA Singleton, AB AF Nalls, Mike A. McLean, Cory Y. Rick, Jacqueline Eberly, Shirley Hutten, Samantha J. Gwinn, Katrina Sutherland, Margaret Martinez, Maria Heutink, Peter Williams, Nigel M. Hardy, John Gasser, Thomas Brice, Alexis Price, T. Ryan Nicolas, Aude Keller, Margaux F. Molony, Cliona Gibbs, J. Raphael Chen-Plotkin, Alice Suh, Eunran Letson, Christopher Fiandaca, Massimo S. Mapstone, Mark Federoff, Howard J. Noyce, Alastair J. Morris, Huw Van Deerlin, Vivianna M. Weintraub, Daniel Zabetian, Cyrus Hernandez, Dena G. Lesage, Suzanne Mullins, Meghan Conley, Emily Drabant Northover, Carrie A. M. Frasier, Mark Marek, Ken Day-Williams, Aaron G. Stone, David J. Ioannidis, John P. A. Singleton, Andrew B. CA Parkinson's Dis Biomarkers Program TI Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study SO LANCET NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; MUTATIONS; IDENTIFICATION; METAANALYSIS AB Background Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts. Methods We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD). Findings In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0.923 (95% CI 0.900-0.946) with high sensitivity (0.834, 95% CI 0.711-0.883) and specificity (0.903, 95% CI 0.824-0.946) at its optimum AUC threshold (0.655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0.894 (95% CI 0.867-0.921) in the PDBP cohort, 0.998 (0.992-1.000) in PARS, 0.955 (no 95% CI available) in 23andMe, 0.929 (0.896-0.962) in LABS-PD, and 0.939 (0.891-0.986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0.003). Interpretation Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions. C1 [Nalls, Mike A.; Price, T. Ryan; Nicolas, Aude; Gibbs, J. Raphael; Letson, Christopher; Hernandez, Dena G.; Singleton, Andrew B.] NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [McLean, Cory Y.; Mullins, Meghan; Conley, Emily Drabant; Northover, Carrie A. M.] 23andMe, Mountain View, CA USA. [Rick, Jacqueline; Chen-Plotkin, Alice; Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Eberly, Shirley] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. [Hutten, Samantha J.; Frasier, Mark] Michael J Fox Fdn, Parkinsons Res, New York, NY USA. [Gwinn, Katrina; Sutherland, Margaret] NINDS, NIH, Bethesda, MD 20892 USA. [Martinez, Maria] INSERM, UMR 1043, Ctr Physiopathol Toulouse Purpan, Toulouse, France. [Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Heutink, Peter] German Ctr Neurodegenerat Dis, Genome Biol Neurodegenerat Dis, Tubingen, Germany. [Williams, Nigel M.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Hardy, John; Noyce, Alastair J.; Morris, Huw] UCL, Inst Neurol, Reta Lila Weston Inst, London, England. [Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Brice, Alexis; Lesage, Suzanne] Sorbonne Univ, UPMC Univ Paris 06, 1127, Paris, France. [Brice, Alexis; Lesage, Suzanne] CNRS, INSERM, UMR 7225,U 1127, Inst Cerveau & Moelle Epiniere, Paris, France. [Brice, Alexis; Lesage, Suzanne] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Keller, Margaux F.; Molony, Cliona; Stone, David J.] Merck Res Labs, Genet & Pharmacogen, West Point, PA USA. [Keller, Margaux F.; Molony, Cliona; Stone, David J.] Merck Res Labs, Boston, MA USA. [Suh, Eunran; Van Deerlin, Vivianna M.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Fiandaca, Massimo S.; Federoff, Howard J.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Mapstone, Mark] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Zabetian, Cyrus] VA Puget Sound Hlth Care Syst, Div Neurogenet, Dept Neurol, Seattle, WA USA. [Marek, Ken] Inst Neurodegenerat Disorders, New Haven, CT USA. [Day-Williams, Aaron G.] Biogen, Precis Med, Cambridge, MA USA. [Ioannidis, John P. A.] Stanford Univ, Meta Res Innovat Ctr Stanford METRICS, Stanford, CA 94305 USA. RP Nalls, MA (reprint author), NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Martinez, Maria/B-3111-2013; Morris, Huw/B-8527-2008; corvol, jean-christophe/I-6387-2012; OI Martinez, Maria/0000-0003-2180-4537; Morris, Huw/0000-0002-5473-3774; corvol, jean-christophe/0000-0001-7325-0199; Gwinn, Katrina/0000-0002-8277-651X FU National Institute on Aging, National Institute of Neurological Disorders and Stroke; Michael J Fox Foundation FX National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation. NR 20 TC 26 Z9 26 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD OCT PY 2015 VL 14 IS 10 BP 1002 EP 1009 DI 10.1016/S1474-4422(15)00178-7 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CR2VI UT WOS:000361188400011 PM 26271532 ER PT J AU Kodama, S Yamazaki, Y Negishi, M AF Kodama, Susumu Yamazaki, Yuichi Negishi, Masahiko TI Pregnane X Receptor Represses HNF4 alpha Gene to Induce Insulin-Like Growth Factor-Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; ENHANCER-PROMOTER COMMUNICATION; COLON-CANCER CELLS; HEPATOCELLULAR-CARCINOMA; CROSS-TALK; ALPHA-5-BETA-1 INTEGRIN; PROSTATE-CANCER; RISK-FACTORS; EXPRESSION; LIVER AB Upon treatment with the pregnane X receptor (PXR) activator rifampicin (RIF), human hepatocellular carcinoma HepG2-derived ShP51 cells that stably express PXR showed epithelialmesenchymal transition (EMT)-like morphological changes and migration. Our recent DNA microarrays have identified hepatocyte nuclear factor (HNF) 4 alpha and insulin-like growth factorbinding protein (IGFBP) 1 mRNAs to be downregulated and upregulated, respectively, in RIF-treated ShP51 cells, and these regulations were confirmed by the subsequent real-time polymerase chain reaction and Western blot analyses. Using this cell system, we demonstrated here that the PXR-HNF4 alpha-IGFBP1 pathway is an essential signal for PXR-induced morphological changes and migration. First, we characterized the molecular mechanism underlying the PXR-mediated repression of the HNF4 alpha gene. Chromatin conformation capture and chromatin immunoprecipitation (ChIP) assays revealed that PXR activation by RIF disrupted enhancer-promoter communication and prompted deacetylation of histone H3 in the HNF4 alpha P1 promoter. Cell-based reporter and ChIP assays showed that PXR targeted the distal enhancer of the HNF4 alpha P1 promoter and stimulated dissociation of HNF3 beta from the distal enhancer. Subsequently, small interfering RNA knockdown of HNF4 alpha connected PXR-mediated gene regulation with the PXRinduced cellular responses, showing that the knockdown resulted in the upregulation of IGFBP1 and EMT-like morphological changes without RIF treatment. Moreover, recombinant IGFBP1 augmented migration, whereas an anti-IGFBP1 antibody attenuated both PXR-induced morphological changes and migration in ShP51 cells. PXR indirectly activated the IGFBP1 gene by repressing the HNF4 alpha gene, thus enabling upregulation of IGFBP1 to change the morphology of ShP51 cells and cause migration. These results provide new insights into PXR-mediated cellular responses toward xenobiotics including therapeutics. C1 [Kodama, Susumu; Yamazaki, Yuichi; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health and National Institute of Environmental Health Sciences [Z01-ES1005-01] FX This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences [Grant Z01-ES1005-01]. NR 58 TC 1 Z9 1 U1 0 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2015 VL 88 IS 4 BP 746 EP 757 DI 10.1124/mol.115.099341 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR0SY UT WOS:000361034700012 PM 26232425 ER PT J AU Lovallo, WR Enoch, MA Acheson, A Cohoon, AJ Sorocco, KH Hodgkinson, CA Vincent, AS Glahn, DC Goldman, D AF Lovallo, William R. Enoch, Mary-Anne Acheson, Ashley Cohoon, Andrew J. Sorocco, Kristen H. Hodgkinson, Colin A. Vincent, Andrea S. Glahn, David C. Goldman, David TI Cortisol Stress Response in Men and Women Modulated Differentially by the Mu-Opioid Receptor Gene Polymorphism OPRM1 A118G SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID PITUITARY-ADRENAL AXIS; SINGLE-NUCLEOTIDE POLYMORPHISM; HEALTH PATTERNS PROJECT; MENSTRUAL-CYCLE PHASE; SALIVARY CORTISOL; PSYCHOSOCIAL STRESS; SEX-DIFFERENCES; BETA-ENDORPHIN; FAMILY-HISTORY; NALTREXONE AB Differences in stress reactivity may affect long-term health outcomes, but there is little information on how these differences arise. The stress axis is regulated by, in part, the endogenous opioid, beta-endorphin, acting on mu-opioid receptors. Persons carrying one or two copies of the G allele of the mu-opioid receptor gene (OPRM1 A118G) may have higher receptor binding for beta-endorphin compared with AA homozygotes that may contribute to individual differences in cortisol reactivity to stress, leading to a relative blunting of cortisol stress reactivity in G allele genotypes. We measured cortisol in 251 young adults (69 GA/GG vs 182 AA genotypes) exposed to mental arithmetic plus public speaking stress relative to a resting control day. Women had smaller cortisol responses than men (F = 10.2, p = 0.002), and women with GA or GG genotypes (N = 39) had an absence of cortisol response relative to AA carriers (N = 110) (F = 18.4, p < 0.0001). Male genotypes had no such difference in response (F = 0.29). Cortisol response following mu-opioid receptor blockade using naltrexone in 119 of these subjects unmasked a greater tonic opioid inhibition of cortisol secretion in women (N = 64), consistent with their blunted stress reactivity. Compared with men, women may have cortisol stress responses that are more heavily regulated by endogenous opioid mechanisms, and the OPRM1 GA/GG genotypes may affect females differentially relative to males. Diminished cortisol responses to stress may have consequences for health behaviors in women with GA/GG genotypes. C1 [Lovallo, William R.; Cohoon, Andrew J.; Sorocco, Kristen H.] VA Med Ctr, Oklahoma City, OK USA. [Lovallo, William R.] Univ Oklahoma, Hlth Sci Ctr, Dept Psychiat & Behav Sci, Oklahoma City, OK 73190 USA. [Enoch, Mary-Anne; Hodgkinson, Colin A.; Goldman, David] NIAAA, Lab Neurogenet, NIH, Bethesda, MD USA. [Acheson, Ashley] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Acheson, Ashley] UTHSCSA, Res Imaging Inst, San Antonio, TX USA. [Sorocco, Kristen H.] OUHSC, Dept Geriatr Med, Donald W Reynolds, Oklahoma City, OK USA. [Vincent, Andrea S.] Univ Oklahoma, Cognit Sci Res Ctr, Norman, OK 73019 USA. [Glahn, David C.] Hartford Hosp, Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT 06115 USA. [Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Lovallo, WR (reprint author), 755 Res Pkwy,Suite 586, Oklahoma City, OK 73104 USA. EM bill@mindbody1.org RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Department of Veterans Affairs Medical Research Service; NIH [NIRR M01 RR014467, NIAAA R01AA019691, R01 AA012207]; NIAAA Intramural Research Program; University of Oklahoma Department of Psychology; University of Oklahoma Health Sciences Center Department of Psychiatry and Behavioral Sciences; Cognitive Science Research Center at the University of Oklahoma FX This work was supported by Department of Veterans Affairs Medical Research Service; NIH Grants NIRR M01 RR014467, NIAAA R01AA019691 and R01 AA012207; and the NIAAA Intramural Research Program. The content is solely the view of the authors and does not necessarily represent the official view of the National Institutes of Health or the Department of Veterans Affairs. Dr Vincent receives income from the University of Oklahoma Department of Psychology, the University of Oklahoma Health Sciences Center Department of Psychiatry and Behavioral Sciences, and the Cognitive Science Research Center at the University of Oklahoma. None of these sources involves producing a product that is used or featured as a result of this research. The authors declare no conflict of interest. NR 47 TC 4 Z9 4 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2015 VL 40 IS 11 BP 2546 EP 2554 DI 10.1038/npp.2015.101 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CR2EM UT WOS:000361138300007 PM 25881118 ER PT J AU Robinson, JE Vardy, E DiBerto, JF Chefer, VI White, KL Fish, EW Chen, M Gigante, E Krouse, MC Sun, H Thorsell, A Roth, BL Heilig, M Malanga, CJ AF Robinson, J. Elliott Vardy, Eyal DiBerto, Jeffrey F. Chefer, Vladimir I. White, Kate L. Fish, Eric W. Chen, Meng Gigante, Eduardo Krouse, Michael C. Sun, Hui Thorsell, Annika Roth, Bryan L. Heilig, Markus Malanga, C. J. TI Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; SURFACE EXPRESSION; N-GLYCOSYLATION; MORPHINE; RESENSITIZATION; NEURONS; DESENSITIZATION; BINDING; ALTERS; REWARD AB The OPRM1 A118G polymorphism is the most widely studied mu-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function. C1 [Robinson, J. Elliott; DiBerto, Jeffrey F.; Chen, Meng; Krouse, Michael C.; Malanga, C. J.] Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. [Robinson, J. Elliott; DiBerto, Jeffrey F.; Fish, Eric W.; Chen, Meng; Malanga, C. J.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Vardy, Eyal; White, Kate L.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Chefer, Vladimir I.; Gigante, Eduardo] NIDA, Intramural Res Program, Baltimore, MD USA. [Sun, Hui; Heilig, Markus] NIAAA, Intramural Res Program, Bethesda, MD USA. [Thorsell, Annika; Heilig, Markus] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program PDSP, Chapel Hill, NC 27599 USA. RP Malanga, CJ (reprint author), Univ N Carolina, Sch Med, Dept Neurol, Phys Off Bldg,170 Manning Dr,CB 7025, Chapel Hill, NC 27599 USA. EM malangacj@neurology.unc.edu RI Roth, Bryan/F-3928-2010; OI Robinson, J. Elliott/0000-0001-9417-3938 FU National Institute on Alcohol Abuse and Alcoholism [F30 AA021312, R01 AA018335]; National Institute on Drug Abuse [R01 DA017204]; Swedish Research Council [2010-3219]; intramural programs of the National Institute on Drug Abuse; NIH; Dai Nippon Sumitomo; Merck; Asubio Pharmaceuticals FX This work was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (F30 AA021312 to JER; R01 AA018335 to CJM), the National Institute on Drug Abuse (R01 DA017204 to BLR), and the Swedish Research Council (Grant no. 2010-3219 to MH); and by the intramural programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. All the work reported here was supported by NIH. Dr Roth has received unrestricted grant support from Dai Nippon Sumitomo, Merck, and Asubio Pharmaceuticals. Dr Roth has consulted for Merck, Novartis, and Pfizer over the past 12 months. The authors declare no conflict of interest. NR 49 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2015 VL 40 IS 11 BP 2614 EP 2622 DI 10.1038/npp.2015.109 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CR2EM UT WOS:000361138300014 PM 25881115 ER PT J AU Goeckeler-Fried, J Chung, W Chiang, A Denny, RA Weissman, AM Sorscher, EJ Brodsky, JL AF Goeckeler-Fried, J. Chung, W. Chiang, A. Denny, R. A. Weissman, A. M. Sorscher, E. J. Brodsky, J. L. TI INHIBITORS OF CFTR UBIQUITINATION ACT SYNERGISTICALLY WITH SMALL MOLECULE CORRECTORS TO ENHANCE F508DEL-CFTR MATURATION AND ACTIVITY SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Goeckeler-Fried, J.; Chiang, A.; Brodsky, J. L.] Univ Pittsburgh, Biol Sci, Pittsburgh, PA USA. [Chung, W.; Sorscher, E. J.] Univ Alabama Birmingham, Birmingham, AL USA. [Denny, R. A.] Pfizer Worldwide Med Chem, Cambridge, MA USA. [Weissman, A. M.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21701 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 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 10 BP 196 EP 196 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500080 ER PT J AU Kumar, P Bhattacharyya, S Tsuchiya, M Gorospe, M Frizzell, RA Pollard, H Biswas, R AF Kumar, P. Bhattacharyya, S. Tsuchiya, M. Gorospe, M. Frizzell, R. A. Pollard, H. Biswas, R. TI MICRO-REGULATION OF INFLAMMATION IN CYSTIC FIBROSIS SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Kumar, P.; Bhattacharyya, S.; Tsuchiya, M.; Pollard, H.; Biswas, R.] USUHS, Anat, Physiol & Genet, Bethesda, MD USA. [Frizzell, R. A.] Univ Pittsburgh, Pittsburgh, PA USA. [Gorospe, M.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 84 BP 221 EP 222 PG 2 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500154 ER PT J AU Domes, K Patrucco, E Loga, F Dietrich, A Birnbaumer, L Wegener, JW Hofmann, F AF Domes, Katrin Patrucco, Enrico Loga, Florian Dietrich, Alexander Birnbaumer, Lutz Wegener, Joerg W. Hofmann, Franz TI Murine cardiac growth, TRPC channels, and cGMP kinase I SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Cardiac myocytes; Endothelium/fibrocytes; Nitric oxide/PKG-I; Signal transduction; TRPC channels ID DEPENDENT PROTEIN-KINASE; NATRIURETIC PEPTIDES; HYPERTROPHY; CARDIOMYOCYTE; INHIBITION; MICE; CONTRIBUTES; HEART; PHOSPHORYLATION; MITOCHONDRIA AB Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), trpc6(-/-), trpc3(-/-), trpc3(-/-)/6(-/-), beta RM mice, and trpc3(-/-)/6(-/-) x beta RM mice. beta RM mice express cGKI beta only in the smooth muscle on a cGKI(-/-) background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, trpc6(-/-), trpc3(-/-), trpc3(-/-)/6(-/-), beta RM, and trpc3(-/-)/6(-/-) x beta RM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3 (-/-) mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and trpc6(-/-), minimal or absent in trpc3(-/-), moderate in beta RM, and dramatic in trpc3(-/-)/6(-/-) beta RM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in beta RM mice on a TRPC3/6 x cGKI(-/-)KO background, indicating an "additive" coupling between both signaling pathways. C1 [Domes, Katrin; Patrucco, Enrico; Loga, Florian; Wegener, Joerg W.; Hofmann, Franz] Tech Univ Munich, Inst Pharmakol & Toxikol, FOR923, D-80802 Munich, Germany. [Dietrich, Alexander] Univ Munich, Walther Straub Inst Pharmakol & Toxikol, D-80539 Munich, Germany. [Birnbaumer, Lutz] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Hofmann, F (reprint author), Tech Univ Munich, Inst Pharmakol & Toxikol, FOR923, Biedersteiner Str 29, D-80802 Munich, Germany. EM Franz.Hofmann@mytum.de FU Deutsche Forschungsgemeinschaft; Fond der Chemischen Industrie; Intramural Research Program of the NIH [Z01-ES-101684] FX The experimental work was supported by grants from Deutsche Forschungsgemeinschaft, Fond der Chemischen Industrie, and by the Intramural Research Program of the NIH (Project Z01-ES-101684 to LB). NR 36 TC 2 Z9 2 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2015 VL 467 IS 10 BP 2229 EP 2234 DI 10.1007/s00424-014-1682-0 PG 6 WC Physiology SC Physiology GA CR0IB UT WOS:000361000800014 PM 25547873 ER PT J AU Franco, EL Shinder, GA Tota, JE Lsidean, SD AF Franco, Eduardo L. Shinder, Gayle A. Tota, Joseph E. Lsidean, Sandra D. TI An elusive low-hanging fruit for public health: Gun violence prevention SO PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Franco, Eduardo L.; Shinder, Gayle A.; Lsidean, Sandra D.] McGill Univ, Dept Oncol, Montreal, PQ H2W1S6, Canada. [Franco, Eduardo L.; Lsidean, Sandra D.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H2W1S6, Canada. [Tota, Joseph E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Franco, EL (reprint author), McGill Univ, Dept Oncol, 546 Pine Ave West, Montreal, PQ H2W1S6, Canada. OI Franco, Eduardo/0000-0002-4409-8084 NR 1 TC 2 Z9 2 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD OCT PY 2015 VL 79 SI SI BP 1 EP 2 DI 10.1016/j.ypmed.2015.06.008 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR1IK UT WOS:000361078200001 PM 26116132 ER PT J AU Furnari, M Epstein, DH Phillips, KA Jobes, ML Kowalczyk, WJ Vahabzadeh, M Lin, JL Preston, KL AF Furnari, Melody Epstein, David H. Phillips, Karran A. Jobes, Michelle L. Kowalczyk, William J. Vahabzadeh, Massoud Lin, Jia-Ling Preston, Kenzie L. TI Some of the people, some of the time: field evidence for associations and dissociations between stress and drug use SO PSYCHOPHARMACOLOGY LA English DT Article DE Cocaine; Heroin; Ecological momentary assessment; Stress; Craving ID CHILDHOOD SEXUAL-ABUSE; SUBSTANCE USE; COCAINE; RELAPSE; SMOKING; SEEKING; MAINTENANCE; ABSTINENCE; ADDICTION; SEVERITY AB Rationale Stress's role in drug use is supported by retrospective interview and laboratory studies, but prospective data confirming the association in daily life are sparse. Objectives This study aims to assess the relationship between drug use and stress in real time with ambulatory monitoring. Methods For up to 16 weeks, 133 outpatients on opiate agonist treatment used smartphones to report each time they used drugs or felt more stressed than usual. They rated stress-event severity on a 10-point scale and as a hassle, day spoiler, or more than a day spoiler. For analysis, stress reports made within 72 h before a reported use of cocaine or opioid were binned into 24-h periods. Results Of 52 participants who reported stress events in the 72-h timeframe, 41 reported stress before cocaine use and 26 before opioid use. For cocaine use, the severity of stressors, rated numerically (r(effect)=0.42, CL95 0.17-0.62, p=0.00061) and percent rated as "more than a day spoiler" (r(effect)=0.34, CL95 0.07-0.56, p=0.0292)], increased linearly across the three days preceding use. The number of stressors did not predict cocaine use, and no measure of stress predicted opioid use. In ecological momentary assessment (EMA) from the whole sample of 133, stress and drug use occurred independently and there was no overall relationship. Conclusions EMA did not support the idea that stress is a necessary or sufficient trigger for cocaine or heroin use after accounting for the base rates of stress and use. But EMA did show that stressful events can increase in severity in the days preceding cocaine use. C1 [Furnari, Melody; Epstein, David H.; Phillips, Karran A.; Jobes, Michelle L.; Kowalczyk, William J.; Preston, Kenzie L.] NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Vahabzadeh, Massoud; Lin, Jia-Ling] NIDA, Biomed Informat Sect, Adm Management Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM KPRESTON@intra.nida.nih.gov OI Kowalczyk, William/0000-0001-8026-285X FU National Institute on Drug Abuse Intramural Research Program FX This research was supported by the National Institute on Drug Abuse Intramural Research Program. NR 37 TC 1 Z9 1 U1 2 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2015 VL 232 IS 19 BP 3529 EP 3537 DI 10.1007/s00213-015-3998-7 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CQ8ND UT WOS:000360863600005 PM 26153066 ER PT J AU Ben Dor, R Marx, CE Shampine, LJ Rubinow, DR Schmidt, PJ AF Ben Dor, Rivka Marx, Christine E. Shampine, Lawrence J. Rubinow, David R. Schmidt, Peter J. TI DHEA metabolism to the neurosteroid androsterone: a possible mechanism of DHEA's antidepressant action (vol 232, pg 3375, 2015) SO PSYCHOPHARMACOLOGY LA English DT Correction C1 [Ben Dor, Rivka; Schmidt, Peter J.] NIMH, Behav Endocrinol Branch, NIH, Publ Hlth Serv,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Marx, Christine E.; Shampine, Lawrence J.] Duke Univ, Med Ctr, Psychiat & Behav Sci, VA Med Ctr, Durham, NC USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, NIH, Publ Hlth Serv,Dept Hlth & Human Serv, Bldg 10,Room 25330,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2015 VL 232 IS 19 BP 3682 EP 3682 DI 10.1007/s00213-015-4046-3 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CQ8ND UT WOS:000360863600020 PM 26271211 ER PT J AU Radke, AK Nakazawa, K Holmes, A AF Radke, Anna K. Nakazawa, Kazu Holmes, Andrew TI Cortical GluN2B deletion attenuates punished suppression of food reward-seeking SO PSYCHOPHARMACOLOGY LA English DT Article DE Addiction; NMDA; Prefrontal cortex; Motivation; Striatum; Interneuron; Alcohol; Drug ID LONG-TERM DEPRESSION; OBSESSIVE-COMPULSIVE DISORDER; ADDICTION-LIKE BEHAVIOR; NMDA RECEPTOR SUBUNITS; PREFRONTAL CORTEX; DORSAL STRIATUM; ALCOHOL-DRINKING; COCAINE SEEKING; HIPPOCAMPAL; EXTINCTION AB Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-d-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear. The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking. Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment. Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays. Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions. C1 [Radke, Anna K.; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Nakazawa, Kazu] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. RP Radke, AK (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. EM anna.radke@nih.gov OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU NIAAA; NIMH [K22MH099164] FX We are grateful to Munisa Bachu, Shaun Flynn, and Adrina Kocharian for technical assistance and to Dr. Jonathan Brigman for the cartoons of the behavioral procedures. This research was supported by the NIAAA Intramural Research Program and NIMH grant K22MH099164. NR 57 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2015 VL 232 IS 20 BP 3753 EP 3761 DI 10.1007/s00213-015-4033-8 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CQ8NC UT WOS:000360863500007 PM 26223494 ER PT J AU Jensen, RE Potosky, AL Reeve, BB Hahn, E Cella, D Fries, J Smith, AW Keegan, THM Wu, XC Paddock, L Moinpour, CM AF Jensen, Roxanne E. Potosky, Arnold L. Reeve, Bryce B. Hahn, Elizabeth Cella, David Fries, James Smith, Ashley Wilder Keegan, Theresa H. M. Wu, Xiao-Cheng Paddock, Lisa Moinpour, Carol M. TI Validation of the PROMIS physical function measures in a diverse US population-based cohort of cancer patients SO QUALITY OF LIFE RESEARCH LA English DT Article DE Patient-reported outcomes; Oncology; Validation studies; Physical function ID QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; KARNOFSKY PERFORMANCE STATUS; IMPACT; SURVIVORS; FLOOR; SCALE; CARE; RESPONSIVENESS AB Purpose To evaluate the validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) physical function measures in a diverse, population-based cancer sample. Methods Cancer patients 6-13 months post-diagnosis (n = 4840) were recruited for the Measuring Your Health study. Participants were diagnosed between 2010 and 2013 with non-Hodgkin lymphoma or cancers of the colorectum, lung, breast, uterus, cervix, or prostate. Four PROMIS physical function short forms (4a, 6b, 10a, and 16) were evaluated for validity and reliability across age and race-ethnicity groups. Covariates included gender, marital status, education level, cancer site and stage, comorbidities, and functional status. Results PROMIS physical function short forms showed high internal consistency (Cronbach's alpha = 0.92-0.96), convergent validity (fatigue, pain interference, FACT physical well-being all r a parts per thousand yen 0.68), and discriminant validity (unrelated domains all r a parts per thousand currency sign 0.3) across survey short forms, age, and race-ethnicity. Known-group differences by demographic, clinical, and functional characteristics performed as hypothesized. Ceiling effects for higher-functioning individuals were identified on most forms. Conclusions This study provides strong evidence that PROMIS physical function measures are valid and reliable in multiple race-ethnicity and age groups. Researchers selecting specific PROMIS short forms should consider the degree of functional disability in their patient population to ensure that length and content are tailored to limit response burden. C1 [Jensen, Roxanne E.; Potosky, Arnold L.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC 20007 USA. [Reeve, Bryce B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Hahn, Elizabeth; Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Fries, James] Stanford Univ, Palo Alto, CA 94304 USA. [Smith, Ashley Wilder] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Wu, Xiao-Cheng] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Paddock, Lisa] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Jensen, RE (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM rj222@georgetown.edu FU Northwestern University [1U54AR057951, 1U54AR057943]; American Institutes for Research [1U54AR057926]; State University of New York, Stony Brook [1U01AR057948]; University of Washington, Seattle [1U01AR057954, 1U01AR052171]; University of North Carolina, Chapel Hill [2U01AR052181]; Children's Hospital of Philadelphia [1U01AR057956]; Stanford University [2U01AR052158]; Boston University [1U01AR057929]; University of California, Los Angeles [1U01AR057936]; University of Pittsburgh [2U01AR052155]; Georgetown University [U01AR057971]; Children's Hospital Medical Center, Cincinnati [17 1U01AR057940]; University of Maryland, Baltimore [1U01AR057967]; Duke University [2U01AR052186] FX PROMIS II was funded by cooperative agreements with a Statistical Center (Northwestern University, PI: David Cella, PhD, 1U54AR057951), a Technology Center (Northwestern University, PI: Richard C. Gershon, PhD, 1U54AR057943), a Network Center (American Institutes for Research, PI: Susan (San) D. Keller, PhD, 1U54AR057926), and thirteen Primary Research Sites which may include more than one institution (State University of New York, Stony Brook, PIs: Joan E. Broderick, PhD, and Arthur A. Stone, PhD, 1U01AR057948; University of Washington, Seattle, PIs: Heidi M. Crane, MD, MPH; Paul K. Crane, MD, MPH; and Donald L. Patrick, PhD, 1U01AR057954; University of Washington, Seattle, PIs: Dagmar Amtmann, PhD, and Karon Cook, PhD, 1U01AR052171; University of North Carolina, Chapel Hill, PI: Darren A. DeWalt, MD, MPH, 2U01AR052181; Children's Hospital of Philadelphia, PI: Christopher B. Forrest, MD, PhD, 1U01AR057956; Stanford University, PI: James F. Fries, MD, 2U01AR052158 ; Boston University, PIs: Stephen M. Haley, PhD and David Scott Tulsky, PhD (University of Michigan, Ann Arbor), 1U01AR057929; University of California, Los Angeles, PIs: Dinesh Khanna, MD and Brennan Spiegel, MD, MSHS, 1U01AR057936; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, 2U01AR052155; Georgetown University, PIs: Arnold L. Potosky, PhD and Carol. M. Moinpour, PhD (Fred Hutchinson Cancer Research Center, Seattle), U01AR057971; Children's Hospital Medical Center, Cincinnati, PI: Esi M. Morgan DeWitt, MD, MSCE, 17 1U01AR057940; University of Maryland, Baltimore, PI: Lisa M. Shulman, MD, 1U01AR057967; and Duke University, PI: Kevin P. Weinfurt, PhD, 2U01AR052186). NIH Science Officers on this project have included Deborah Ader, PhD; Vanessa Ameen, MD; Susan Czajkowski, PhD; Basil Eldadah, MD, PhD; Lawrence Fine, MD, DrPH; Lawrence Fox, MD, PhD; Lynne Haverkos, MD, MPH; Thomas Hilton, PhD; Laura Lee Johnson, PhD; Michael Kozak, PhD; Peter Lyster, PhD; Donald Mattison, MD; Claudia Moy, PhD; Louis Quatrano, PhD; Bryce B. Reeve, PhD; William Riley, PhD; Ashley Wilder Smith, PhD, MPH; Susana Serrate- Sztein, MD; Ellen Werner, PhD; and James Witter, MD, PhD. This project was supported by the following: U01AR057971 (PIs: Potosky, Moinpour), National Cancer Institute supplement P30CA051008, NCI P30CA051008, UL1TR000101 (previously UL1RR031975) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA). NR 46 TC 13 Z9 13 U1 3 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 IS 10 BP 2333 EP 2344 DI 10.1007/s11136-015-0992-9 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CR0LO UT WOS:000361010400003 PM 25935353 ER PT J AU Persky, S Street, RL AF Persky, Susan Street, Richard L., Jr. TI Evaluating Approaches for Communication About Genomic Influences on Body Weight SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Health care communication; Weight management; Obesity; Genomics ID PRIMARY-CARE PHYSICIANS; PATIENT-CENTERED CARE; CLINICAL-PRACTICE; LOSS MAINTENANCE; MENTAL-ILLNESS; UNITED-STATES; OBESITY; BARRIERS; STIGMA; BEHAVIOR AB Background Developments in genomics may improve patient consultations about weight management; however, optimal approaches for these communications are unstudied. Purpose We assessed the influence of receiving generic, genomic information and of physician communication approach on overweight females in simulated clinical weight counseling interactions. Methods Two hundred participants were randomized to receive information about genomic or behavioral underpinnings of body weight from a virtual reality-based physician who used either a supportive or directive communication approach. Participants completed post-test self-report questionnaires. Results Genomic explanations for body weight led patients to perceive less blame [F (1,196) = 47.68, p < .0001] and weight stigma [F (1,196) = 5.75, p = .017] in the consultation. They did not lead to negative outcomes in physician-patient interaction or affect health behavior-related attitudes and beliefs. Physician's supportive or directive communication approach did not moderate these effects. Conclusion Integrating genomic concepts into health care has potential to positively influence the patient-provider relationship while addressing longstanding challenges in weight management. ClinicalTrials.gov number NCT01443910. C1 [Persky, Susan] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Street, Richard L., Jr.] Texas A&M Univ, Dept Commun, College Stn, TX USA. [Street, Richard L., Jr.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. RP Persky, S (reprint author), NHGRI, Social & Behav Res Branch, NIH, B1B36,31 Ctr Dr, Bethesda, MD 20892 USA. EM perskys@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. This work is based on data collected in the Immersive Virtual Environment Testing Area of the Social and Behavioral Research Branch, NHGRI, NIH. The authors thank ColleenMcBride, Ph.D. and Howard Gordon, MD for advice and feedback during study development and editorial comments on a previous version of this manuscript. We thank Aanand Naik, MD for feedback during study development. We also acknowledge Peter Hanna, Stephanie Browning, and Maie Lee for assistance with data collection. NR 56 TC 6 Z9 6 U1 6 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD OCT PY 2015 VL 49 IS 5 BP 675 EP 684 DI 10.1007/s12160-015-9701-8 PG 10 WC Psychology, Multidisciplinary SC Psychology GA CQ8AS UT WOS:000360829000004 PM 25894275 ER PT J AU Yanovski, JA AF Yanovski, Jack A. TI Pediatric obesity. An introduction SO APPETITE LA English DT Article DE Children; Adolescents; Hyperphagia; Overeating; Etiology ID BODY-MASS INDEX; EARLY-ONSET OBESITY; GENOME-WIDE ASSOCIATION; CARDIOVASCULAR RISK-FACTORS; QUALITY-OF-LIFE; EXPERT COMMITTEE RECOMMENDATIONS; AMERICAN-HEART-ASSOCIATION; FATTY LIVER-DISEASE; ADULT OBESITY; CHILDHOOD OBESITY AB The prevalence of child and adolescent obesity in the United States increased dramatically between 1970 and 2000, and there are few indications that the rates of childhood obesity are decreasing. Obesity is associated with myriad medical, psychological, and neurocognitive abnormalities that impact children's health and quality of life. Genotypic variation is important in determining the susceptibility of individual children to undue gains in adiposity; however, the rapid increase in pediatric obesity prevalence suggests that changes to children's environments and/or to their learned behaviors may dramatically affect body weight regulation. This paper presents an overview of the epidemiology, consequences, and etiopathogenesis of pediatric obesity, serving as a general introduction to the subsequent papers in this Special Issue that address aspects of childhood obesity and cognition in detail. Published by Elsevier Ltd. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jy15i@nih.gov FU NIH Intramural Research Program from National Institute of Child Health and Human Development [1ZIAHD000641]; Office of Behavioral and Social Sciences Research FX NIH Intramural Research Program Grant 1ZIAHD000641 (J. Yanovski) from the National Institute of Child Health and Human Development with supplemental funding from the Office of Behavioral and Social Sciences Research. Disclaimers: The opinions and assertions expressed herein are those of the author and are not to be construed as reflecting the views of the DHHS or the U.S. Public Health Service. NR 208 TC 2 Z9 3 U1 3 U2 62 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD OCT 1 PY 2015 VL 93 SI SI BP 3 EP 12 DI 10.1016/j.appet.2015.03.028 PG 10 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA CQ7IG UT WOS:000360775600002 PM 25836737 ER PT J AU Villalba, JM Lopez-Dominguez, JA Chen, YN Khraiwesh, H Gonzalez-Reyes, JA del Rio, LF Gutierrez-Casado, E del Rio, M Calvo-Rubio, M Ariza, J de Cabo, R Lopez-Lluch, G Navas, P Hagopian, K Buron, MI Ramsey, JJ AF Manuel Villalba, Jose Alberto Lopez-Dominguez, Jose Chen, Yana Khraiwesh, Husam Antonio Gonzalez-Reyes, Jose Fernandez del Rio, Lucia Gutierrez-Casado, Elena del Rio, Mercedes Calvo-Rubio, Miguel Ariza, Julia de Cabo, Rafael Lopez-Lluch, Guillermo Navas, Placido Hagopian, Kevork Isabel Buron, Maria Ramsey, Jon Jay TI The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice SO BIOGERONTOLOGY LA English DT Article DE Apoptotic signaling; Calorie restriction; Dietary fat; Lifespan; Mitochondria; Proton leak ID OXYGEN SPECIES PRODUCTION; CARNITINE PALMITOYLTRANSFERASE-I; HYDROGEN-PEROXIDE PRODUCTION; PROTEIN OXIDATIVE DAMAGE; LONGEVITY-RELATED DEGREE; RAT-HEART MITOCHONDRIA; ALL-CAUSE MORTALITY; FREE-RADICAL THEORY; ACID-COMPOSITION; PROTON LEAK AB The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95 % of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40 % less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H+ leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40 % CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging. C1 [Manuel Villalba, Jose; Alberto Lopez-Dominguez, Jose; Khraiwesh, Husam; Antonio Gonzalez-Reyes, Jose; Fernandez del Rio, Lucia; Calvo-Rubio, Miguel; Ariza, Julia; Isabel Buron, Maria] Univ Cordoba, Dept Cellular Biol Fisiol & Inmunol, Cordoba 14014, Spain. [Chen, Yana; Hagopian, Kevork; Ramsey, Jon Jay] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Lopez-Lluch, Guillermo; Navas, Placido] Univ Pablo Olavide, CSIC, CABD, Seville, Spain. [Lopez-Lluch, Guillermo; Navas, Placido] Inst Salud Carlos III, CIBERER, Seville, Spain. RP Villalba, JM (reprint author), Univ Cordoba, Dept Cellular Biol Fisiol & Inmunol, Campus Rabanales,Edificio Severo Ochoa,3 Planta, Cordoba 14014, Spain. EM jmvillalba@uco.es RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Gonzalez-Reyes, Jose A./0000-0003-1918-5490; , rafael/0000-0003-2830-5693; Lopez-Lluch, Guillermo/0000-0001-9830-8502 FU NIH [1R01AG028125]; Ministerio de Economia y Competitividad [BFU2011-23578]; Junta de Andalucia Proyectos de Excelencia [P09-CVI-4887]; Junta de Andalucia Proyectos Internacionales grant; BIO-276 (Junta de Andalucia); BIO-276 (University of Cordoba); NIA/NIH; Spanish Ministerio de Educacion; BIO-276; Agencia Espanola de Cooperacion Internacional al Desarrollo FX Supported by NIH grant 1R01AG028125 (to JJR, PN and JMV), Ministerio de Economia y Competitividad BFU2011-23578 (to JMV), Junta de Andalucia Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucia Proyectos Internacionales grant (to JMV), and BIO-276 (Junta de Andalucia and the University of Cordoba, to JMV). RdC is funded by the Intramural Research program of the NIA/NIH. JALD, JA, LFdR and EGC were funded by a predoctoral fellowship of the Spanish Ministerio de Educacion and BIO-276. HK was funded by a predoctoral fellowship of the Agencia Espanola de Cooperacion Internacional al Desarrollo and BIO-276. MCR and MdR were supported by BIO-276. NR 141 TC 3 Z9 3 U1 4 U2 49 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-5729 EI 1573-6768 J9 BIOGERONTOLOGY JI Biogerontology PD OCT PY 2015 VL 16 IS 5 SI SI BP 655 EP 670 DI 10.1007/s10522-015-9572-1 PG 16 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CQ4CY UT WOS:000360553100008 PM 25860863 ER PT J AU Correa, R Zilbermint, M Berthon, A Espiard, S Batsis, M Papadakis, GZ Xekouki, P Lodish, MB Bertherat, J Faucz, FR Stratakis, CA AF Correa, Ricardo Zilbermint, Mihail Berthon, Annabel Espiard, Stephanie Batsis, Maria Papadakis, Georgios Z. Xekouki, Paraskevi Lodish, Maya B. Bertherat, Jerome Faucz, Fabio R. Stratakis, Constantine A. TI The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID ADRENAL-HYPERPLASIA; CUSHINGS-SYNDROME; HETEROGENEITY; DISEASE AB Objective: Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing's syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes. Design: All of the nodules were obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocol and the ARMC5 sequence was determined by the Sanger method. Results: Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p. Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: six were frame shift, four were missense, three were nonsense, and one was a splice site variation. Allelic losses were confirmed in two of the nodules. Conclusion: This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, 'private,' and - in most cases - completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery. C1 [Correa, Ricardo; Zilbermint, Mihail; Berthon, Annabel; Espiard, Stephanie; Batsis, Maria; Xekouki, Paraskevi; Lodish, Maya B.; Faucz, Fabio R.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Papadakis, Georgios Z.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Bertherat, Jerome] CNRS, Dept Endocrinol Metab & Diabet, Inst Cochin, INSERM,U1016,UMR 8104, F-75014 Paris, France. [Faucz, Fabio R.] Pontificia Univ Catolica Parana, Sch Med, Grad Program Hlth Sci, Grp Adv Mol Invest, Curitiba, Parana, Brazil. RP Faucz, FR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM fabio.faucz@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [311166/2011-3 - PQ-2] FX This research was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, and in part by a grant from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Process: 311166/2011-3 - PQ-2 (to F R Faucz). NR 19 TC 2 Z9 2 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD OCT PY 2015 VL 173 IS 4 BP 435 EP 440 DI 10.1530/EJE-15-0205 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CQ3HE UT WOS:000360491900016 PM 26162405 ER PT J AU Correa, R Salpea, P Stratakis, CA AF Correa, Ricardo Salpea, Paraskevi Stratakis, Constantine A. TI Carney complex: an update SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Review ID PROTEIN-KINASE-A; NODULAR ADRENOCORTICAL DISEASE; PSAMMOMATOUS MELANOTIC SCHWANNOMA; SPOTTY SKIN PIGMENTATION; INCLUDING CARDIAC MYXOMA; EPITHELIOID BLUE NEVUS; SUBUNIT TYPE 1A; ENDOCRINE OVERACTIVITY; REGULATORY SUBUNIT; PRKAR1A GENE AB Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine tumors. The disease is caused by inactivating mutations or large deletions of the PRKAR1A gene located at 17q22-24 coding for the regulatory subunit type I alpha of protein kinase A (PKA) gene. Most recently, components of the complex have been associated with defects of other PKA subunits, such as the catalytic subunits PRKACA (adrenal hyperplasia) and PRKACB (pigmented spots, myxomas, pituitary adenomas). In this report, we review CNC, its clinical features, diagnosis, treatment and molecular etiology, including PRKAR1A mutations and the newest on PRKACA and PRKACB defects especially as they pertain to adrenal tumors and Cushing's syndrome. C1 [Correa, Ricardo; Salpea, Paraskevi; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NICHD, NIH FX This study was supported by the intramural research program of NICHD, NIH. NR 91 TC 20 Z9 20 U1 3 U2 7 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD OCT PY 2015 VL 173 IS 4 BP M85 EP M97 DI 10.1530/EJE-15-0209 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CQ3HE UT WOS:000360491900009 PM 26130139 ER PT J AU Nieman, LK AF Nieman, Lynnette K. TI Cushing's syndrome: update on signs, symptoms and biochemical screening SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Review ID DEXAMETHASONE-SUPPRESSION TEST; URINARY FREE CORTISOL; NIGHT SALIVARY CORTISOL; DIAGNOSIS; DISEASE; MORTALITY; TESTS; HYPERCORTISOLISM; REMISSION; EXCRETION AB Endogenous pathologic hypercortisolism, or Cushing's syndrome, is associated with poor quality of life, morbidity, and increased mortality. Early diagnosis may mitigate against this natural history of the disorder. The clinical presentation of Cushing's syndrome varies, in part related to the extent and duration of cortisol excess. When hypercortisolism is severe, its signs and symptoms are unmistakable. However, most of the signs and symptoms of Cushing's syndrome are common in the general population (e.g., hypertension and weight gain) and not all are present in every patient. In addition to classical features of glucocorticoid excess, such as proximal muscle weakness and wide purple striae, patients may present with the associated comorbidities that are caused by hypercortisolism. These include cardiovascular disease, thromboembolic disease, psychiatric and cognitive deficits, and infections. As a result, internists and generalists must consider Cushing's syndrome as a cause, and endocrinologists should search for and treat these comorbidities. Recommended tests to screen for Cushing's syndrome include 1 mg dexamethasone suppression, urine free cortisol, and late night salivary cortisol. These may be slightly elevated in patients with physiologic hypercortisolism, which should be excluded, along with exogenous glucocorticoid use. Each screening test has caveats and the choice of tests should be individualized based on each patient's characteristics and lifestyle. The objective of this review is to update the readership on the clinical and biochemical features of Cushing's syndrome that are useful when evaluating patients for this diagnosis. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, CRC, Bldg 10,1 East,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA. NR 38 TC 19 Z9 20 U1 6 U2 17 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD OCT PY 2015 VL 173 IS 4 BP M33 EP M38 DI 10.1530/EJE-15-0464 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CQ3HE UT WOS:000360491900004 PM 26156970 ER PT J AU Grubb, RL Pinsky, P Prorok, PC Andriole, GL AF Grubb, Robert L. Pinsky, Paul Prorok, Philip C. Andriole, Gerald L. TI Screening for Cancer: Lessons Learned from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO EUROPEAN UROLOGY LA English DT Editorial Material ID RANDOMIZED PROSTATE; MORTALITY C1 [Grubb, Robert L.; Andriole, Gerald L.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Pinsky, Paul; Prorok, Philip C.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Grubb, RL (reprint author), Washington Univ, Sch Med, Dept Surg, 4960 Childrens Pl,Box 1242, St Louis, MO 63110 USA. EM grubbr@wustl.edu NR 10 TC 1 Z9 1 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD OCT PY 2015 VL 68 IS 4 BP 545 EP 546 DI 10.1016/j.eururo.2015.04.026 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CQ4KM UT WOS:000360573600007 PM 25959167 ER PT J AU Kim, T Jancel, T Kumar, P Freeman, AF AF Kim, T. Jancel, T. Kumar, P. Freeman, A. F. TI Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Article DE drug-drug interaction; new antifungal agent; therapeutic drug monitoring AB What is known and objectiveDespite the known significant drug-drug interaction between isavuconazole and tacrolimus, there are no recommendations on dose adjustment when these drugs are given concomitantly. We report on a patient with amediastinal Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with tacrolimus therapeutic drug-level monitoring. Case summaryOur patient presented with a mediastial Aspergillus fumigatus infection, 2years after lung transplantation. A.fumigatus was resistant to posaconazole, and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse events. Tacrolimus concentration continued to increase after more than 2weeks of therapy and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8-week period. What is new and conclusionWhen isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25-50% may be required. C1 [Kim, T.; Kumar, P.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Jancel, T.] US FDA, Off Safety & Epidemiol, Silver Spring, MD USA. [Freeman, A. F.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Kim, T (reprint author), NIH, 10 Ctr Dr,Bldg 10 Room 1C240, Bethesda, MD 20892 USA. EM tiffany.kim@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 4 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 EI 1365-2710 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD OCT PY 2015 VL 40 IS 5 BP 609 EP 611 DI 10.1111/jcpt.12308 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ8FW UT WOS:000360842900023 ER PT J AU Yin, LL Coelho, SG Valencia, JC Ebsen, D Mahns, A Smuda, C Miller, SA Beer, JZ Kolbe, L Hearing, VJ AF Yin, Lanlan Coelho, Sergio G. Valencia, Julio C. Ebsen, Dominik Mahns, Andre Smuda, Christoph Miller, Sharon A. Beer, Janusz Z. Kolbe, Ludger Hearing, Vincent J. TI Identification of Genes Expressed in Hyperpigmented Skin Using Meta-Analysis of Microarray Data Sets SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PIGMENTATION; UVB AB More than 375 genes have been identified that are involved in regulating skin pigmentation and these act during development, survival, differentiation, and/or responses of melanocytes to the environment. Many of these genes have been cloned, and disruptions of their functions are associated with various pigmentary diseases; however, many remain to be identified. We have performed a series of microarray analyses of hyperpigmented compared with less pigmented skin to identify genes responsible for these differences. The rationale and goal for this study was to perform a meta-analysis on these microarray databases to identify genes that may be significantly involved in regulating skin phenotype either directly or indirectly that might not have been identified due to subtle differences by any of these individual studies alone. The meta-analysis demonstrates that 1,271 probes representing 921 genes are differentially expressed at significant levels in the 5 microarray data sets compared, providing new insights into the variety of genes involved in determining skin phenotype. Immunohistochemistry was used to validate two of these markers at the protein level (TRIM63 and QPCT), and we discuss the possible functions of these genes in regulating skin physiology. C1 [Yin, Lanlan; Coelho, Sergio G.; Valencia, Julio C.; Ebsen, Dominik; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Mahns, Andre; Smuda, Christoph; Kolbe, Ludger] Beiersdorf AG, R&D Skin Res, D-20245 Hamburg, Germany. [Miller, Sharon A.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Kolbe, L (reprint author), Beiersdorf AG, R&D Skin Res, D-20245 Hamburg, Germany. EM Ludger.Kolbe@Beiersdorf.com FU Intramural NIH HHS [Z01 BC010785-01] NR 21 TC 3 Z9 3 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 IS 10 BP 2455 EP 2463 DI 10.1038/jid.2015.179 PG 9 WC Dermatology SC Dermatology GA CR0GD UT WOS:000360995600018 PM 25950827 ER PT J AU Fontana, J Jurado, KA Cheng, NQ Ly, NL Fuchs, JR Gorelick, RJ Engelman, AN Steven, AC AF Fontana, Juan Jurado, Kellie A. Cheng, Naiqian Ly, Ngoc L. Fuchs, James R. Gorelick, Robert J. Engelman, Alan N. Steven, Alasdair C. TI Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SMALL-MOLECULE INHIBITORS; RADIATION-DAMAGE; CRYOELECTRON TOMOGRAPHY; VIRAL-REPLICATION; ELECTRON CRYOTOMOGRAPHY; 3-DIMENSIONAL STRUCTURE; NUCLEAR-LOCALIZATION; STRUCTURAL-ANALYSIS; IN-VITRO AB During virion maturation, HIV-1 capsid protein assembles into a conical core containing the viral ribonucleoprotein (vRNP) complex, thought to be composed mainly of the viral RNA and nucleocapsid protein (NC). After infection, the viral RNA is reverse transcribed into double-stranded DNA, which is then incorporated into host chromosomes by integrase (IN) catalysis. Certain IN mutations (class II) and antiviral drugs (allosteric IN inhibitors [ALLINIs]) adversely affect maturation, resulting in virions that contain "eccentric condensates," electron-dense aggregates located outside seemingly empty capsids. Here we demonstrate that in addition to this mislocalization of electron density, a class II IN mutation and ALLINIs each increase the fraction of virions with malformed capsids (from similar to 12% to similar to 53%). Eccentric condensates have a high NC content, as demonstrated by "tomo-bubblegram" imaging, a novel labeling technique that exploits the susceptibility of NC to radiation damage. Tomo-bubblegrams also localized NC inside wild-type cores and lining the spherical Gag shell in immature virions. We conclude that eccentric condensates represent nonpackaged vRNPs and that either genetic or pharmacological inhibition of IN can impair vRNP incorporation into mature cores. Supplying IN in trans as part of a Vpr-IN fusion protein partially restored the formation of conical cores with internal electron density and the infectivity of a class II IN deletion mutant virus. Moreover, the ability of ALLINIs to induce eccentric condensate formation required both IN and viral RNA. Based on these observations, we propose a role for IN in initiating core morphogenesis and vRNP incorporation into the mature core during HIV-1 maturation. IMPORTANCE Maturation, a process essential for HIV-1 infectivity, involves core assembly, whereby the viral ribonucleoprotein (vRNP, composed of vRNA and nucleocapsid protein [NC]) is packaged into a conical capsid. Allosteric integrase inhibitors (ALLINIs) affect multiple viral processes. We have characterized ALLINIs and integrase mutants that have the same phenotype. First, by comparing the effects of ALLINIs on several steps of the viral cycle, we show that inhibition of maturation accounts for compound potency. Second, by using cryoelectron tomography, we find that ALLINIs impair conical capsid assembly. Third, by developing tomo-bubblegram imaging, which specifically labels NC protein, we find that ALLINIs block vRNP packaging; instead, vRNPs form "eccentric condensates" outside the core. Fourth, malformed cores, typical of integrase-deleted virus, are partially replaced by conical cores when integrase is supplied in trans. Fifth, vRNA is necessary for ALLINI-induced eccentric condensate formation. These observations suggest that integrase is involved in capsid morphogenesis and vRNP packaging. C1 [Fontana, Juan; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Jurado, Kellie A.; Ly, Ngoc L.; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Gorelick, Robert J.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Engelman, AN (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM alan_engelman@dfci.harvard.edu; stevena@mail.nih.gov RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU Intramural Research Program of NIAMS; Intramural AIDS Targeted Antiviral Program; NIH [AI070042, GM103368]; National Cancer Institute [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX This work was funded in part by the Intramural Research Program of NIAMS (A.C.S.), the Intramural AIDS Targeted Antiviral Program (A.C.S.), NIH grants AI070042 (A.N.E.) and GM103368 (A.N.E. and J.R.F.), and funds of the National Cancer Institute under contract HHSN261200800001E with Leidos Biomedical Research, Inc. (R.J.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 17 Z9 17 U1 1 U2 8 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 19 BP 9765 EP 9780 DI 10.1128/JVI.01522-15 PG 16 WC Virology SC Virology GA CQ6HJ UT WOS:000360704900009 PM 26178982 ER PT J AU Lin, KL Twenhafel, NA Connor, JH Cashman, KA Shamblin, JD Donnelly, GC Esham, HL Wlazlowski, CB Johnson, JC Honko, AN Botto, MA Yen, J Hensley, LE Goff, AJ AF Lin, Kenny L. Twenhafel, Nancy A. Connor, John H. Cashman, Kathleen A. Shamblin, Joshua D. Donnelly, Ginger C. Esham, Heather L. Wlazlowski, Carly B. Johnson, Joshua C. Honko, Anna N. Botto, Miriam A. Yen, Judy Hensley, Lisa E. Goff, Arthur J. TI Temporal Characterization of Marburg Virus Angola Infection following Aerosol Challenge in Rhesus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-FEVER; CYNOMOLGUS MACAQUES; EBOLA; PATHOGENESIS; FILOVIRUSES; PROTECTION; RESPONSES; OUTBREAK; MONKEYS; DISEASE AB Marburg virus (MARV) infection is a lethal hemorrhagic fever for which no licensed vaccines or therapeutics are available. Development of appropriate medical countermeasures requires a thorough understanding of the interaction between the host and the pathogen and the resulting disease course. In this study, 15 rhesus macaques were sequentially sacrificed following aerosol exposure to the MARV variant Angola, with longitudinal changes in physiology, immunology, and histopathology used to assess disease progression. Immunohistochemical evidence of infection and resulting histopathological changes were identified as early as day 3 postexposure (p.e.). The appearance of fever in infected animals coincided with the detection of serum viremia and plasma viral genomes on day 4 p.e. High (> 10(7) PFU/ml) viral loads were detected in all major organs (lung, liver, spleen, kidney, brain, etc.) beginning day 6 p.e. Clinical pathology findings included coagulopathy, leukocytosis, and profound liver destruction as indicated by elevated liver transaminases, azotemia, and hypoalbuminemia. Altered cytokine expression in response to infection included early increases in Th2 cytokines such as interleukin 10 (IL-10) and IL-5 and late-stage increases in Th1 cytokines such as IL-2, IL-15, and granulocyte-macrophage colony-stimulating factor (GM-CSF). This study provides a longitudinal examination of clinical disease of aerosol MARV Angola infection in the rhesus macaque model. IMPORTANCE In this study, we carefully analyzed the timeline of Marburg virus infection in nonhuman primates in order to provide a well-characterized model of disease progression following aerosol exposure. C1 [Lin, Kenny L.; Twenhafel, Nancy A.; Cashman, Kathleen A.; Shamblin, Joshua D.; Donnelly, Ginger C.; Esham, Heather L.; Wlazlowski, Carly B.; Johnson, Joshua C.; Honko, Anna N.; Botto, Miriam A.; Hensley, Lisa E.; Goff, Arthur J.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Connor, John H.; Yen, Judy] Boston Univ, Sch Med, Boston, MA 02118 USA. [Connor, John H.; Yen, Judy] Natl Emerging Infect Dis Lab, Boston, MA USA. [Johnson, Joshua C.; Honko, Anna N.; Hensley, Lisa E.] NIAID, Integrated Res Facil, Ft Detrick, MD USA. RP Goff, AJ (reprint author), US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. EM arthur.j.goff.civ@mail.mil OI Connor, John/0000-0002-8867-7256; Honko, Anna/0000-0001-9165-148X FU TMTI under USAMRIID project [195732] FX This research was funded by TMTI under USAMRIID project number 195732. NR 31 TC 6 Z9 6 U1 1 U2 16 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 19 BP 9875 EP 9885 DI 10.1128/JVI.01147-15 PG 11 WC Virology SC Virology GA CQ6HJ UT WOS:000360704900018 PM 26202230 ER PT J AU Cerrolaza, JJ Reyes, M Summers, RM Gonzalez-Ballester, MA Linguraru, MG AF Cerrolaza, Juan J. Reyes, Mauricio Summers, Ronald M. Gonzalez-Ballester, Miguel Angel Linguraru, Marius George TI Automatic multi-resolution shape modeling of multi-organ structures SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Point distribution model (PDM); Multi-resolution; Hierarchical modeling; Statistical shape model; Active shape model ID OPTIMAL FEATURES; SEGMENTATION; IMAGES; CT AB Point Distribution Models (PDM) are among the most popular shape description techniques and their usefulness has been demonstrated in a wide variety of medical imaging applications. However, to adequately characterize the underlying modeled population it is essential to have a representative number of training samples, which is not always possible. This problem is especially relevant as the complexity of the modeled structure increases, being the modeling of ensembles of multiple 3D organs one of the most challenging cases. In this paper, we introduce a new GEneralized Multi-resolution PDM (GEM-PDM) in the context of multi-organ analysis able to efficiently characterize the different inter-object relations, as well as the particular locality of each object separately. Importantly, unlike previous approaches, the configuration of the algorithm is automated thanks to a new agglomerative landmark clustering method proposed here, which equally allows us to identify smaller anatomically significant regions within organs. The significant advantage of the GEM-PDM method over two previous approaches (PDM and hierarchical PDM) in terms of shape modeling accuracy and robustness to noise, has been successfully verified for two different databases of sets of multiple organs: six subcortical brain structures, and seven abdominal organs. Finally, we propose the integration of the new shape modeling framework into an active shape-model-based segmentation algorithm. The resulting algorithm, named GEMA, provides a better overall performance than the two classical approaches tested, ASM, and hierarchical ASM, when applied to the segmentation of 3D brain MRI. (C) 2015 Elsevier B.V. All rights reserved. C1 [Cerrolaza, Juan J.; Linguraru, Marius George] Sheikh Zayed Inst Pediat Surg Innovat Childrens N, Washington, DC 20009 USA. [Reyes, Mauricio] Univ Bern, Surg Technol & Biomech Dept, Bern, Switzerland. [Summers, Ronald M.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20814 USA. [Gonzalez-Ballester, Miguel Angel] ICREA, Barcelona, Spain. [Gonzalez-Ballester, Miguel Angel] Univ Pompeu Fabra, Barcelona, Spain. [Linguraru, Marius George] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. RP Cerrolaza, JJ (reprint author), Sheikh Zayed Inst Pediat Surg Innovat Childrens N, 1615 Q St NW,Apt 201, Washington, DC 20009 USA. EM jcerrola@cnmc.org; mauricio.reyes@istb.unibe.ch; rms@nih.gov; ma.gonzalez@upf.edu; mlingura@cnmc.org RI Gonzalez Ballester, Miguel Angel/D-1349-2013 OI Gonzalez Ballester, Miguel Angel/0000-0002-9227-6826 FU European Union [304857] FX This project was supported in part by a philanthropic gift from the Government of Abu Dhabi to Children's National Health System, and by the European Union FP7 project HEAR-EU (grant agreement 304857). We also like to thank the Intramural Research Program of the National Institute of Health, Clinical Center. NR 38 TC 4 Z9 4 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD OCT PY 2015 VL 25 IS 1 BP 11 EP 21 DI 10.1016/j.media.2015.04.003 PG 11 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CQ8NJ UT WOS:000360864700003 PM 25977156 ER PT J AU Wong, KCL Summers, RM Kebebew, E Yao, JH AF Wong, Ken C. L. Summers, Ronald M. Kebebew, Electron Yao, Jianhua TI Tumor growth prediction with reaction-diffusion and hyperelastic biomechanical model by physiological data fusion SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Tumor growth prediction; Model personalization; Physiological data fusion; Nonlinear solid mechanics; Derivative-free optimization ID STANDARDIZED UPTAKE VALUE; NEUROENDOCRINE TUMORS; CONTRAST ENHANCEMENT; CANCER INVASION; IMAGES; CT; SEGMENTATION; REGISTRATION; ONCOLOGY; CELL AB The goal of tumor growth prediction is to model the tumor growth process, which can be achieved by physiological modeling and model personalization from clinical measurements. Although image-driven frameworks have been proposed with promising results, several issues such as infinitesimal strain assumptions, complicated personalization procedures, and the lack of functional information, may limit their prediction accuracy. In view of these issues, we propose a framework for pancreatic neuroendocrine tumor growth prediction, which comprises a FEM-based tumor growth model with coupled reaction-diffusion equation and nonlinear biomechanics. Physiological data fusion of structural and functional images is used to improve the subject-specificity of model personalization, and a derivative-free global optimization algorithm is adopted to facilitate the complicated model and accommodate flexible choices of objective functions. With this flexibility, we propose an objective function accounting for both the tumor volume difference and the root-mean-squared error of intracellular volume fractions. Experiments were performed on synthetic and clinical data to verify the parameter estimation capability and the prediction performance. Comparisons of using different biomechanical models and objective functions were also performed. From the experimental results of eight patient data sets, the average recall, precision, Dice coefficient, and relative volume difference between predicted and measured tumor volumes were 84.5 +/- 6.9%, 85.8 +/- 8.2%, 84.6 +/- 1.7%, and 14.2 +/- 8.4%, respectively. Published by Elsevier B.V. C1 [Wong, Ken C. L.; Summers, Ronald M.; Yao, Jianhua] NIH, Clin Image Proc Serv, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Clin Image Proc Serv, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM ken.wong@nih.gov; rsummers@cc.nih.gov; kebebewe@mail.nih.gov; jyao@cc.nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center FX This work was funded by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 50 TC 5 Z9 5 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD OCT PY 2015 VL 25 IS 1 BP 72 EP 85 DI 10.1016/j.media.2015.04.002 PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CQ8NJ UT WOS:000360864700008 PM 25962846 ER PT J AU Mak, TD Tyburski, JB Krausz, KW Kalinich, JF Gonzalez, FJ Fornace, AJ AF Mak, Tytus D. Tyburski, John B. Krausz, Kristopher W. Kalinich, John F. Gonzalez, Frank J. Fornace, Albert J., Jr. TI Exposure to ionizing radiation reveals global dose- and time-dependent changes in the urinary metabolome of rat SO METABOLOMICS LA English DT Article DE Radiation; Biodosimetry; Bioinformatics ID GAMMA-IRRADIATED RATS; ACID TARGET ANALYSIS; MASS-SPECTROMETRY; BIOMARKER DISCOVERY; EARLY TRIAGE; MICE; IDENTIFICATION; INJURY; PLASMA; BIODOSIMETRY AB The potential for exposures to ionizing radiation (IR) has increased in recent years. Although advances have been made, understanding the global metabolic response as a function of both dose and exposure time is challenging considering the complexity of the responses. Herein we report our findings on the dose- and time-dependency of the urinary response to IR in the male rat using radiation metabolomics. Urine samples were collected from adult male rats, exposed to 0.5-10 Gy gamma-radiation, both before from 6 to 72 h following exposures. Samples were analyzed by liquid chromatography coupled with time-of-flight mass spectrometry, and deconvoluted mass chromatographic data were initially analyzed by principal component analysis. However, the breadth and complexity of the data necessitated the development of a novel approach to summarizing biofluid constituents after exposure, called Visual Analysis of Metabolomics Package (VAMP). VAMP revealed clear urine metabolite profile differences to as little as 0.5 Gy after 6 h exposure. Via VAMP, it was discovered that the response to radiation exposure found in rat urine is characterized by an overall net down-regulation of ion excretion with only a modest number of ions excreted in excess over pre-exposure levels. Our results show both similarities and differences with the published mouse urine response and a dose- and time-dependent net decrease in urine ion excretion associated with radiation exposure. These findings mark an important step in the development of minimally invasive radiation biodosimetry. VAMP should have general applicability in metabolomics to visualize overall differences and trends in many sample sets. C1 [Mak, Tytus D.; Fornace, Albert J., Jr.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. [Tyburski, John B.; Fornace, Albert J., Jr.] Georgetown Univ, Biochem & Mol & Cellular Biol, Med Ctr, Washington, DC 20057 USA. [Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Kalinich, John F.] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20814 USA. RP Fornace, AJ (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Med Ctr, 3970 Reservoir Rd NW,Room E504, Washington, DC 20057 USA. EM af294@georgetown.edu FU National Institute of Health (National Institute of Allergy and Infectious Diseases) [U19 A1067773]; National Cancer Instititue Intramural Research Program in Center for Cancer Research; Defense Advanced Research Projects Agency [DARPA-FY08-0004] FX This study was supported by the National Institute of Health (National Institute of Allergy and Infectious Diseases) Grant U19 A1067773. F.J.G. is supported by the National Cancer Instititue Intramural Research Program in the Center for Cancer Research. J.F.K. was supported in part by Grant DARPA-FY08-0004 from the Defense Advanced Research Projects Agency. The views expressed are those of the authors and do not reflect the official policy or position of the Armed Forces Radiobiology Research Institute, the Uniformed Services University, the Department of Defense, or the United States Government. The authors would like to thank Drs. Andrew D. Patterson (Penn. State Univ.) and David J. Brenner for helpful discussions and their support. NR 37 TC 6 Z9 6 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD OCT PY 2015 VL 11 IS 5 BP 1082 EP 1094 DI 10.1007/s11306-014-0765-4 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CQ6LG UT WOS:000360715300007 PM 26557048 ER PT J AU Sharma, HS Kiyatkin, EA Patnaik, R Lafuente, JV Muresanu, DF Sjoquist, PO Sharma, A AF Sharma, Hari Shanker Kiyatkin, Eugene A. Patnaik, Ranjana Lafuente, Jose Vicente Muresanu, Dafin F. Sjoquist, Per-Ove Sharma, Aruna TI Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments: Neuroprotective Effects of an Antioxidant Compound H-290/51 SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Methamphetamine; Ambient temperature; Nanoparticles; Cold environment; Hot environment; Blood-brain barrier; Brain edema; Neuronal injury; Antioxidants; H-290/51; Oxidative stress ID BLOOD-BRAIN-BARRIER; NORMOTENSIVE YOUNG-RATS; NANOWIRED DRUG-DELIVERY; SPINAL-CORD-INJURY; ACIDIC PROTEIN IMMUNOREACTIVITY; CENTRAL-NERVOUS-SYSTEM; UNITED-STATES; HEAT-STRESS; ENGINEERED NANOPARTICLES; CRYSTAL METHAMPHETAMINE AB In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 A degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 A degrees C, 120-180 % larger at 34 A degrees C, and almost absent at 4 A degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 A degrees C, a four- to sixfold increase at 34 A degrees C, and three- to fourfold increase at 4 A degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 A degrees C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects. C1 [Sharma, Hari Shanker; Patnaik, Ranjana; Sharma, Aruna] Uppsala Univ, Univ Hosp, Lab Cerebrovasc Res, Dept Surg Sci Anesthesiol & Intens Care Med, SE-75185 Uppsala, Sweden. [Kiyatkin, Eugene A.] NIDA, Vivo Electrophysiol Unit, Behav Neurosci Branch, IRP,NIH, Baltimore, MD USA. [Patnaik, Ranjana] Banaras Hindu Univ, Dept Biomat, Indian Inst Technol, Sch Biomed Engn, Varanasi 221005, Uttar Pradesh, India. [Lafuente, Jose Vicente] Univ Basque Country, Dept Neurosci, Bilbao, Spain. [Muresanu, Dafin F.] Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania. [Sjoquist, Per-Ove] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Cardiol, Stockholm, Sweden. [Sharma, Hari Shanker] Univ Uppsala Hosp, IECNSIR, SE-75421 Uppsala, Sweden. RP Sharma, HS (reprint author), Uppsala Univ, Univ Hosp, Lab Cerebrovasc Res, Dept Surg Sci Anesthesiol & Intens Care Med, SE-75185 Uppsala, Sweden. EM Sharma@surgsci.uu.se RI Sharma, Hari/G-4508-2016; OI Lafuente, Jose-Vicente/0000-0001-7246-0987; Patnaik, Ranjana/0000-0002-8131-177X FU Air Force Office of Scientific Research (EOARD, London, UK); Air Force Material Command, USAF [FA8655-05-1-3065]; Swedish Medical Research Council [Nr 2710-HSS]; Swedish Strategic Research Foundation, Stockholm, Sweden; Goran Gustafsson Foundation, Stockholm, Sweden; Astra-Zeneca, Molndal, Sweden; University Grants Commission, New Delhi, India; Ministry of Science and Technology, Gov't. of India; Ministry of Science and Technology, Gov't. of Sweden; Indian Medical Research Council, New Delhi, India; India-EU Research Co-operation Program; University of Basque Country, Spain; National Institute on Drug Abuse-Intramural Research Program, NIH; Government of Basque Country; [IT 794/13]; [UFI 11/32] FX This investigation is supported by grants from the Air Force Office of Scientific Research (EOARD, London, UK) and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; Swedish Medical Research Council (Nr 2710-HSS), Swedish Strategic Research Foundation, Stockholm, Sweden; Goran Gustafsson Foundation, Stockholm, Sweden (HSS), Astra-Zeneca, Molndal, Sweden (HSS/AS), The University Grants Commission, New Delhi, India (HSS/AS), Ministry of Science and Technology, Gov't. of India and Gov't. of Sweden (HSS/AS), Indian Medical Research Council, New Delhi, India (HSS/AS); India-EU Research Co-operation Program (RP/AS/HSS) and IT 794/13 (JVL), Government of Basque Country and UFI 11/32 (JVL); University of Basque Country, Spain. This study also is supported in part by the National Institute on Drug Abuse-Intramural Research Program, NIH (EAK). NR 57 TC 2 Z9 2 U1 1 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD OCT PY 2015 VL 52 IS 2 SI SI BP 1023 EP 1033 DI 10.1007/s12035-015-9252-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA CQ6AQ UT WOS:000360687200021 PM 26111626 ER PT J AU Goldscheider, F Scott, ME Lilja, E Bronte-Tinkew, J AF Goldscheider, Frances Scott, Mindy E. Lilja, Emily Bronte-Tinkew, Jacinta TI Becoming a Single Parent: The Role of Father and Mother Characteristics SO JOURNAL OF FAMILY ISSUES LA English DT Article DE single parents; gender and family; household living arrangements; divorce; separation; family processes ID PREGNANCY INTENTIONS; LIVING ARRANGEMENTS; NONRESIDENT FATHERS; CUSTODIAL FATHERS; UNITED-STATES; LOW-INCOME; CHILDREN; MARRIAGE; SUPPORT; FAMILIES AB Using a longitudinal sample of 4,010 mothers and fathers from the Fragile Families and Child Wellbeing Study, we examine factors that predict whether children are living with both parents, only their mother, or only their father when the child is 3 years old. We considered parental characteristics and resources and couple\family-level characteristics and found that although many factors increased the odds of parents living togetherincluding the financial resources of each parent, having a supportive relationship, and having a disability-free childeven more factors disproportionately increased the likelihood of either single fatherhood or single motherhood, including parents' multiple-partner fertility and depression, mother's drug use, and mother's greater alcohol use. Our findings suggest that although most children living with a single parent live with their mothers, they are more likely to do so if their fathers exhibit problem behaviors, and more likely to live with their father if their mothers do so. C1 [Goldscheider, Frances] Univ Maryland, College Pk, MD 20742 USA. [Scott, Mindy E.] Child Trends, Bethesda, MD 20814 USA. [Lilja, Emily] Columbia Univ, New York, NY USA. [Bronte-Tinkew, Jacinta] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. RP Scott, ME (reprint author), Child Trends, 7315 Wisconsin Ave,Suite 1200W, Bethesda, MD 20814 USA. EM mscott@childtrends.org FU National Institute of Child Health and Human Development (NICHD) [1PO1-HD045610-01A1] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research made possible with the generous support of the National Institute of Child Health and Human Development (NICHD) through Grant # 1PO1-HD045610-01A1, Transition to Fatherhood. NR 64 TC 0 Z9 0 U1 16 U2 43 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-513X EI 1552-5481 J9 J FAM ISSUES JI J. Fam. Issues PD OCT PY 2015 VL 36 IS 12 BP 1624 EP 1650 DI 10.1177/0192513X13508405 PG 27 WC Family Studies SC Family Studies GA CQ1ZT UT WOS:000360399800003 ER PT J AU Jousma, E Rizvi, TA Wu, JQ Janhofer, D Dombi, E Dunn, RS Kim, MO Masters, AR Jones, DR Cripe, TP Ratner, N AF Jousma, Edwin Rizvi, Tilat A. Wu, Jianqiang Janhofer, David Dombi, Eva Dunn, Richard S. Kim, Mi-Ok Masters, Andrea R. Jones, David R. Cripe, Timothy P. Ratner, Nancy TI Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE MEK; nerve; neurofibroma; NF1; therapy ID PREVIOUSLY TREATED PATIENTS; PLEXIFORM NEUROFIBROMAS; CLINICAL-TRIALS; PHASE-II; NF1; CANCER; TUMORS; GROWTH; MICROENVIRONMENT; FREQUENCY AB BackgroundNeurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model. ProceduresWe studied effects of MEK inhibition using 1.5mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 (flox/flox); Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. ResultsEarly administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. ConclusionsNeurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design. Pediatr Blood Cancer 2015;62:1709-1716. (c) 2015 Wiley Periodicals, Inc. C1 [Jousma, Edwin; Rizvi, Tilat A.; Wu, Jianqiang; Ratner, Nancy] Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Janhofer, David; Dombi, Eva] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Dunn, Richard S.] Childrens Hosp Med Ctr, Div Imaging Resource Ctr, Cincinnati, OH 45229 USA. [Kim, Mi-Ok] Cincinnati Childrens Hosp Med Ctr, Dept Pediat Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Masters, Andrea R.] Indiana Univ Sch Med, Simon Canc Ctr, Indianapolis, IN 46202 USA. [Jones, David R.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA. [Cripe, Timothy P.] Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, Columbus, OH USA. RP Ratner, N (reprint author), Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. EM Nancy.Ratner@cchmc.org RI Kim, Mi-Ok/O-9626-2015 FU Children's Tumor Foundation; NTAP FX Grant sponsor: Children's Tumor Foundation; Grant sponsor: NTAP NR 39 TC 5 Z9 5 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2015 VL 62 IS 10 BP 1709 EP 1716 DI 10.1002/pbc.25546 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CP9PY UT WOS:000360228000006 PM 25907661 ER PT J AU Ashby, CR Rice, OV Heidbreder, CA Gardner, EL AF Ashby, Charles R. Rice, Onarae V. Heidbreder, Christian A. Gardner, Eliot L. TI The selective dopamine D-3 receptor antagonist SB-277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in male sprague-dawley rats SO SYNAPSE LA English DT Article DE conditioned place preference; dopamine D-3 receptors ID DRUG RELAPSE; TRANSMISSION; ADDICTION; BLOCKADE; SEEKING; MODEL C1 [Ashby, Charles R.] St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [Rice, Onarae V.] Furman Univ, Dept Psychol, Greenville, SC 29613 USA. [Heidbreder, Christian A.] Indivior PLC, Richmond, VA USA. [Gardner, Eliot L.] NIDA, NIH, Neuropsychopharmacol Sect,Intramural Res Program, Mol Targets & Medicat Discovery Branch, Baltimore, MD 21224 USA. RP Ashby, CR (reprint author), St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, 8000 Utopia Pkwy, Jamaica, NY 11439 USA. EM ashbyc@stjohns.edu NR 11 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD OCT PY 2015 VL 69 IS 10 BP 512 EP 514 DI 10.1002/syn.21839 PG 3 WC Neurosciences SC Neurosciences & Neurology GA CP7VT UT WOS:000360097900005 PM 26138517 ER PT J AU Zuehlke, AD Beebe, K Neckers, L Prince, T AF Zuehlke, Abbey D. Beebe, Kristin Neckers, Len Prince, Thomas TI Regulation and function of the human HSP90AA1 gene SO GENE LA English DT Review DE Molecular chaperone; Heat shock protein; Stress response; Heat shock element; Post-translational modification; Drug target; Cancer; Gene ontology; Gene promoter; Interactome ID HEAT-SHOCK-PROTEIN; ACUTE-LEUKEMIA CELLS; MOLECULAR CHAPERONE; TERMINAL DOMAIN; BREAST-CANCER; 90-ALPHA HSP90-ALPHA; BINDING POCKET; NITRIC-OXIDE; ATP-BINDING; PHASE-I AB Heat shock protein 90 alpha (Hsp90 alpha), encoded by the HSP90AA1 gene, is the stress inducible isoform of the molecular chaperone Hsp90 alpha. Hsp90 alpha is regulated differently and has different functions when compared to the constitutively expressed Hsp90 beta isoform, despite high amino acid sequence identity between the two proteins. These differences are likely due to variations in nucleotide sequence within non-coding regions, which allows for specific regulation through interaction with particular transcription factors, and to subtle changes in amino acid sequence that allow for unique post-translational modifications. This article will specifically focus on the expression, function and regulation of Hsp90 alpha. Published by Elsevier B.V. C1 [Zuehlke, Abbey D.; Beebe, Kristin; Neckers, Len; Prince, Thomas] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zuehlke, AD (reprint author), 10-CRC 1W-5848,9000 Rockville Pike, Bethesda, MD 20892 USA. EM abbey.zuehlke@nih.gov OI Zuehlke, Abbey/0000-0003-0432-8823 FU National Institutes of Health [GM089820]; Intramural Research Program of the National Cancer Institute [ZIA BC011032, ZIA SC010074] FX This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series-a series resulting from a collaboration between the journal GENE and the Gene Wild Initiative. The Gene Wiki Initiative is supported by the National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. The authors also would like to acknowledge support from the Intramural Research Program of the National Cancer Institute (grants ZIA BC011032 and ZIA SC010074 to LN). The corresponding Gene Wiki entry for this review can be found here: http://en.wikipedia.org/wiki/Heat_shock_protein_90kDa_alpha_%28cytosolic %29,_member_A1 NR 97 TC 10 Z9 10 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD OCT 1 PY 2015 VL 570 IS 1 BP 8 EP 16 DI 10.1016/j.gene.2015.06.018 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CO9NG UT WOS:000359501900002 PM 26071189 ER PT J AU Brunoni, AR Machado-Vieira, R Sampaio, B Vieira, ELM Valiengo, L Bensenor, IM Lotufo, PA Carvalho, AF Cho, HJ Gattaz, WF Teixeira, AL AF Brunoni, Andre R. Machado-Vieira, Rodrigo Sampaio-Junior, Bernardo Vieira, Erica L. M. Valiengo, Leandro Bensenor, Isabela M. Lotufo, Paulo A. Carvalho, Andre F. Cho, Hyong Jin Gattaz, Wagner F. Teixeira, Antonio L. TI Plasma levels of soluble TNF receptors 1 and 2 after tDCS and sertraline treatment in major depression: Results from the SELECT-TDCS trial SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Major depressive disorder; Transcranial direct current sdmulation; Sertraline; STNFR1; STNFR2 ID ELECTRICAL-CURRENT THERAPY; ANTIDEPRESSANT TREATMENT; CYTOKINE PRODUCTION; METAANALYSIS; DISORDER; FACTORIAL; IL-6; PATHWAYS; IMPACT AB Background: The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro-inflammatory cytokines, which leads to an over activation of the hypothalamic-pituitary-adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti-inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. Methods: We evaluated, in the Set-Leanne vs. Eleciric Curreni Therapy for TreaLing Depression Clinical SLudy (SELECT-TDCS) fetal, whether the plasma levels of the soluble TNF recepLors 1 and 2 (sTNFRs) changed tiller anLiclepressanL LreaLmeni in a sample of 73 anLidepressanL-free paLienis with unipolar depressive disorder in an episode of aL leasL mocleraLe inLensiLy. Results: Although boat LDCS and set-Leanne exerLed anLiclepressanL effecfs. the plasma levels of sTNFRs did noi change over Lime regardless of Lhe infervenLion and clinical response. Also, baseline sTNFRs levels did noL predicL anLiclepressanL response. Limitations: Our negative findings could be a type LI error, as this trial did not use an equivalence design. Conclusions: To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment I esponse of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity. (C) 2015 Elsevier B.V. All rights reserved C1 [Brunoni, Andre R.; Sampaio-Junior, Bernardo; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Ctr Clin & Epidemiol Res, Sao Paulo, Brazil. [Brunoni, Andre R.; Sampaio-Junior, Bernardo; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Interdisciplinary Ctr Appl Neuromodulat CINA, Univ Hosp, Sao Paulo, Brazil. [Brunoni, Andre R.; Sampaio-Junior, Bernardo; Valiengo, Leandro] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, SIN, Sao Paulo, Brazil. [Brunoni, Andre R.; Sampaio-Junior, Bernardo; Valiengo, Leandro; Gattaz, Wagner F.] Univ Sao Paulo, Lab Neurosci LIM27, Dept & Inst Psychiat, Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Vieira, Erica L. M.] Fed Univ Minas Gerais UFMG, Sch Med, Interdisciplinary Lab Med Invest LIIM, Div Neurosci, Belo Horizonte, MG, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fortaleza, Ceara, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Translat Pychiatry Res Grp, Fac Med, Fortaleza, Ceara, Brazil. [Cho, Hyong Jin] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA 90024 USA. RP Brunoni, AR (reprint author), Inst Psiquiatria HC FMUSP, Serv EMT, R Dr Ovidio Pires Campos 785,2 Andar Ala Sul, BR-05403000 Sao Paulo, SP, Brazil. EM Brunoni@usp.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Cho, Hyong Jin/B-9934-2014; Lotufo, Paulo/A-9843-2008; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Cho, Hyong Jin/0000-0002-8629-8500; Lotufo, Paulo/0000-0002-4856-8450; Russowsky Brunoni, Andre/0000-0002-6310-3571 FU FAPESP (Sao Paulo Research Foundation) [2009/05728-7]; FAPEMIG; CNPq FX The funding sources played no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript. This study was partially funded by FAPESP (Sao Paulo Research Foundation, Grant number: 2009/05728-7), FAPEMIG and CNPq. NR 23 TC 1 Z9 1 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT 1 PY 2015 VL 185 BP 209 EP 213 DI 10.1016/j.jad.2015.07.006 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CP2RS UT WOS:000359725400030 PM 26241865 ER PT J AU Eguchi, T Prince, T Wegiel, B Calderwood, SK AF Eguchi, Taka Prince, Thomas Wegiel, Barbara Calderwood, Stuart K. TI Role and Regulation of Myeloid Zinc Finger Protein 1 in Cancer SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE MYELOID; ZINC; FINGER-1; CANCER; INVASION; SUMO; NUCLEAR BODY ID LEUKEMIA NUCLEAR-BODIES; SCAN DOMAIN; CHAPERONE CDC37; GENE-EXPRESSION; STEM-CELLS; C-MYC; MZF-1; PML; PHOSPHORYLATION; TRANSCRIPTION AB Myeloid zinc finger 1 (MZF1) belongs to the SCAN-Zinc Finger (SCAN-ZF) transcription factor family that has recently been implicated in a number of types of cancer. Although the initial studies concentrated on the role of MZF1 in myeloid differentiation and leukemia, the factor now appears to be involved in the etiology of major solid tumors such as lung, cervical, breast, and colorectal cancer. Here we discuss the regulation of MZF1 that mediated its recruitment and activation in cancer, concentrating on posttranslational modification by phosphorylation, and sumoylation, formation of promyelocytic leukemia nuclear bodies and its association with co-activators and co-repressors. J. Cell. Biochem. 116: 2146-2154, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Eguchi, Taka; Calderwood, Stuart K.] Harvard Univ, Dept Radiat Oncol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Prince, Thomas] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wegiel, Barbara] Harvard Univ, Dept Surg, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. RP Calderwood, SK (reprint author), 3 Blackfan Circle, Boston, MA 02115 USA. EM scalderw@bidmc.harvard.edu FU NIH [R0-1CA047407, R01CA119045, R0-1CA094397] FX Grant sponsor: NIH research; Grant numbers: R0-1CA047407, R01CA119045, R0-1CA094397. NR 59 TC 4 Z9 4 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT PY 2015 VL 116 IS 10 BP 2146 EP 2154 DI 10.1002/jcb.25203 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CP3UZ UT WOS:000359809400004 PM 25903835 ER PT J AU Choe, M Brusgard, JL Chumsri, S Bhandary, L Zhao, XF Lu, S Goloubeva, OG Polster, BM Fiskum, GM Girnun, GD Kim, MS Passaniti, A AF Choe, Moran Brusgard, Jessica L. Chumsri, Saranya Bhandary, Lekhana Zhao, Xianfeng Frank Lu, Song Goloubeva, Olga G. Polster, Brian M. Fiskum, Gary M. Girnun, Geoffrey D. Kim, Myoung Sook Passaniti, Antonino TI The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE BREAST CANCER; METABOLISM; GLYCOLYSIS; MITOCHONDRIAL RESPIRATION; TRANSCRIPTION ID EPITHELIAL-MESENCHYMAL TRANSITION; HISTONE DEACETYLASE SIRT6; ENERGY-METABOLISM; GENE-EXPRESSION; TUMOR; DIFFERENTIATION; PROLIFERATION; PROTEIN; LINES; TRANSFORMATION AB Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regulates glucose metabolism and promotes an oncogenic phenotype are not known. RUNX2 expression in luminal BC cells correlated with lower estrogen receptor- (ER) levels, anchorage-independent growth, expression of glycolytic genes, increased glucose uptake, and sensitivity to glucose starvation, but not to inhibitors of oxidative phosphorylation. Conversely, RUNX2 knockdown in triple-negative BC cells inhibited mammosphere formation and glucose dependence. RUNX2 knockdown resulted in lower LDHA, HK2, and GLUT1 glycolytic gene expression, but upregulation of pyruvate dehydrogenase-A1 (PDHA1) mRNA and enzymatic activity, which was consistent with lower glycolytic potential. The NAD-dependent histone deacetylase, SIRT6, a known tumor suppressor, was a critical regulator of these RUNX2-mediated metabolic changes. RUNX2 expression resulted in elevated pAkt, HK2, and PDHK1 glycolytic protein levels that were reduced by ectopic expression of SIRT6. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation (respiration). Overexpression of SIRT6 increased respiration in RUNX2-positive cells, but knockdown of SIRT6 in cells expressing low RUNX2 decreased respiration. RUNX2 repressed SIRT6 expression at both the transcriptional and post-translational levels and endogenous SIRT6 expression was lower in malignant BC tissues or cell lines that expressed high levels of RUNX2. These results support a hypothesis whereby RUNX2-mediated repression of the SIRT6 tumor suppressor regulates metabolic pathways that promote BC progression. J. Cell. Biochem. 116: 2210-2226, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Choe, Moran; Girnun, Geoffrey D.; Passaniti, Antonino] Univ Maryland, Dept Biochem & Mol Biol, Sch Med, Baltimore, MD 21201 USA. [Brusgard, Jessica L.; Passaniti, Antonino] Univ Maryland, Program Mol Med, Sch Med, Baltimore, MD 21201 USA. [Chumsri, Saranya; Bhandary, Lekhana] Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21201 USA. [Zhao, Xianfeng Frank; Lu, Song; Kim, Myoung Sook; Passaniti, Antonino] Univ Maryland, Dept Pathol, Sch Med, Baltimore, MD 21201 USA. [Zhao, Xianfeng Frank] Univ Calif San Diego, Dept Pathol, San Diego, CA 92161 USA. [Zhao, Xianfeng Frank] Univ Calif San Diego, VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Goloubeva, Olga G.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Polster, Brian M.; Fiskum, Gary M.] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Girnun, Geoffrey D.] SUNY Stony Brook, Dept Pathol, Med Ctr, Stony Brook, NY 11794 USA. [Choe, Moran] NCI, Lab Genitourinary Canc Pathogenesis, Bethesda, MD 20814 USA. [Passaniti, Antonino] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Vet Hlth Adm Res & Dev Serv, Baltimore, MD 21201 USA. RP Passaniti, A (reprint author), Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Pathol, BRB 9-045,655 W Baltimore St, Baltimore, MD 21201 USA. EM apass001@umaryland.edu FU VA Research and Development Service [I01 BX002205A]; State of Maryland University of Maryland Greenebaum Cancer Center; Department of Pathology; NIH [R01NS064978, P01HD16596-26A1] FX Grant sponsor: VA Research and Development Service; Grant number: Merit award I01 BX002205A (AP, MC); Grant sponsor: State of Maryland University of Maryland Greenebaum Cancer Center; Grant number: Cigarette Restitution Fund (AP, MC, GDG); Grant sponsor: Department of Pathology; Grant number: Institutional Funds (XFZ, SL); Grant sponsor: NIH; Grant number: R01NS064978 (BMP); Grant sponsor: NIH; Grant number: P01HD16596-26A1 (GMF, BMP). NR 55 TC 9 Z9 11 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT PY 2015 VL 116 IS 10 BP 2210 EP 2226 DI 10.1002/jcb.25171 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CP3UZ UT WOS:000359809400010 PM 25808624 ER PT J AU Faulkner, WB Memarzadeh, F Riskowski, G Kalbasi, A Chang, ACZ AF Faulkner, W. Brock Memarzadeh, Farhad Riskowski, Gerald Kalbasi, Ahmad Chang, Audrey Ching-Zu TI Effects of air exchange rate, particle size and injection place on particle concentrations within a reduced-scale room SO BUILDING AND ENVIRONMENT LA English DT Article DE Airborne disease transmission; Particulate concentrations; Air exchange; Aerobiology; Chamber measurements ID INDOOR ENVIRONMENTS; AIRBORNE TRANSMISSION; EXPIRATORY DROPLETS; VENTILATION SYSTEM; DEPOSITION RATES; HOSPITAL WARD; DISPERSION; TRANSPORT; TUBERCULOSIS; DOWNWARD AB Using aerobiology and engineering strategies to study particle movement in ventilated rooms is a powerful tool for understanding airborne disease transmission in healthcare facilities. More research is needed on movement of particles in ventilated rooms and more empirical data is needed to show effects Of air exchange rates on particulate movement within a simple ventilated space. Results from this study can provide data for more complex strategies like Computational Fluid Dynamics (CFD) to help design ventilation systems in healthcare facilities where airborne disease transmission is a concern. In this study, particles were injected into a reduced-scale chamber to measure particle mass concentrations at twelve locations throughout the ventilated space and at the ventilation exhaust. Experiments had three particle sizes (1.9, 5.4, and 7.9 mu m) of borosilicate glass, five levels of ventilation rate (nominally 2, 4, 6, 8 and 12 air changes per hour), and two injection locations (center and side). The ventilation system had one round inlet centered in one wall at 3/4 height and one outlet in the opposite wall. Three replications were conducted for each combination of variables for a total of 90 tests. Increasing ventilation rates reduced concentrations of 1.9 mu m particles in the occupied zone but had little effect on room concentrations of 5.4 and 7.9 mu m particles. Exit concentrations for 1.9 mu m particles were higher than for 5.4 and 7.9 mu m particles. For 1.9 mu m particles, average concentrations decreased linearly with increasing ventilation, while similar trends were not seen for the larger particles. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Faulkner, W. Brock; Riskowski, Gerald; Kalbasi, Ahmad] Texas A&M Univ, Biol & Agr Engn Dept, College Stn, TX USA. [Memarzadeh, Farhad] NIH, Div Tech Resources, Bethesda, MD 20892 USA. [Kalbasi, Ahmad] Univ Tehran, Food Engn, Karaj, Iran. [Chang, Audrey Ching-Zu] Natl Ilan Univ, Dept Food Sci, Ilan, Taiwan. RP Riskowski, G (reprint author), Texas A&M Univ, 2117 TAMU, College Stn, TX 77843 USA. EM Riskowski@tamu.edu NR 55 TC 0 Z9 1 U1 3 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-1323 EI 1873-684X J9 BUILD ENVIRON JI Build. Environ. PD OCT PY 2015 VL 92 BP 246 EP 255 DI 10.1016/j.buildenv.2015.04.034 PG 10 WC Construction & Building Technology; Engineering, Environmental; Engineering, Civil SC Construction & Building Technology; Engineering GA CN9YT UT WOS:000358807800023 ER PT J AU Ekenga, CC Parks, CG Sandler, DP AF Ekenga, Christine C. Parks, Christine G. Sandler, Dale P. TI Chemical exposures in the workplace and breast cancer risk: A prospective cohort study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; cohort studies; chemicals; occupational exposure ID ENDOCRINE-DISRUPTING CHEMICALS; OCCUPATIONAL-EXPOSURE; POLLUTANTS AB We investigated the relationship between workplace chemical exposures and breast cancer risk among women enrolled in the Sister Study, a prospective cohort study of US and Puerto Rican women. A total of 47,640 participants reported work outside of the home. Workplace exposure to eleven agents (acids, dyes or inks, gasoline or other petroleum products, glues or adhesives, lubricating oils, metals, paints, pesticides, soldering materials, solvents and stains or varnishes) was characterized based on self-reports of frequency and duration of use. Approximately 14% of the study population reported exposure to only one agent and 11% reported working with two or more of the 11 agents in their lifetime. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for each agent, adjusting for established breast cancer risk factors. During follow-up, 1,966 cases of breast cancer were reported. Although there were no significant associations between ever use of the eleven agents evaluated and breast cancer risk, women with cumulative exposure to gasoline or petroleum products at or above the highest quartile cutoff had an elevated risk of total (HR: 2.3, 95%CI: 1.1-4.9) and invasive (HR: 2.5, 95%CI: 1.1-5.9) breast cancer compared with women in the lowest quartile group (p(trend)=0.03). Workplace exposure to soldering materials was associated with an increased risk of premenopausal breast cancer (HR=1.8, 95% CI=1.1-3.0). Findings support the need for further studies to elucidate the role of occupational chemicals in breast cancer etiology. What's new? There has been widespread interest in the role of chemical exposures in the development of breast cancer, but few occupational studies have prospectively investigated breast cancer risk. The workplace is a setting where there is the potential for greater than background levels of exposure. Here, the authors investigate the association between workplace chemical exposures and incident breast cancer in 47,640 women enrolled in the Sister Study. They observe significant trends in breast cancer risk associated with increased gasoline/petroleum product use, suggesting that additional studies are warranted to examine the influence of occupational chemical exposures on breast cancer etiology. C1 [Ekenga, Christine C.; Parks, Christine G.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX Grant sponsor: Intramural Research Program of the NIH, National Institute of Environmental Health Sciences NR 28 TC 0 Z9 0 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2015 VL 137 IS 7 BP 1765 EP 1774 DI 10.1002/ijc.29545 PG 10 WC Oncology SC Oncology GA CM9FK UT WOS:000358012600025 PM 25846061 ER PT J AU Kim, E Rich, J Karoutas, A Tarlykov, P Cochet, E Malysheva, D Mamchaoui, K Ogryzko, V Pirozhkova, I AF Kim, Elena Rich, Jeremy Karoutas, Adam Tarlykov, Pavel Cochet, Emilie Malysheva, Daria Mamchaoui, Kamel Ogryzko, Vasily Pirozhkova, Iryna TI ZNF555 protein binds to transcriptional activator site of 4qA allele and ANT1: potential implication in Facioscapulohumeral dystrophy SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FSHD CANDIDATE GENE; BETA-SATELLITE DNA; MUSCULAR-DYSTROPHY; OXIDATIVE STRESS; DUX4 EXPRESSION; HUMAN MYOBLASTS; 4Q35 LOCUS; TANDEM DNA; IN-VIVO; MUSCLE AB Facioscapulohumeral dystrophy (FSHD) is an epi/genetic satellite disease associated with at least two satellite sequences in 4q35: (i) D4Z4 macrosatellite and (ii) beta-satellite repeats (BSR), a prevalent part of the 4qA allele. Most of the recent FSHD studies have been focused on a DUX4 transcript inside D4Z4 and its tandem contraction in FSHD patients. However, the D4Z4-contraction alone is not pathological, which would also require the 4qA allele. Since little is known about BSR, we investigated the 4qA BSR functional role in the transcriptional control of the FSHD region 4q35. We have shown that an individual BSR possesses enhancer activity leading to activation of the Adenine Nucleotide Translocator 1 gene (ANT1), a major FSHD candidate gene. We have identified ZNF555, a previously uncharacterized protein, as a putative transcriptional factor highly expressed in human primary myoblasts that interacts with the BSR enhancer site and impacts the ANT1 promoter activity in FSHD myoblasts. The discovery of the functional role of the 4qA allele and ZNF555 in the transcriptional control of ANT1 advances our understanding of FSHD pathogenesis and provides potential therapeutic targets. C1 [Kim, Elena; Rich, Jeremy; Karoutas, Adam; Cochet, Emilie; Malysheva, Daria; Pirozhkova, Iryna] Univ Paris 11, CNRS, UMR 8126, F-94408 Villejuif, France. [Tarlykov, Pavel] Natl Biotechnol Ctr, Astana 010000, Kazakhstan. [Cochet, Emilie; Ogryzko, Vasily] IRCIV Gustave Roussy, Prote Platform, F-94408 Villejuif, France. [Mamchaoui, Kamel] Univ Paris 06, INSERM, Therapie Malad Muscle Strie, UMR7215,Inst Myol,UM76,U974,CNRS, F-75013 Paris, France. [Ogryzko, Vasily] Univ Paris 11, INSERM, CNRS, UMR 8126, F-94408 Villejuif, France. RP Pirozhkova, I (reprint author), Univ Paris 11, CNRS, UMR 8126, F-94408 Villejuif, France. EM iryna.pirozhkova@gustaveroussy.fr RI Ogryzko, Vasily/M-6665-2015; OI Ogryzko, Vasily/0000-0002-8548-1389; Tarlykov, Pavel/0000-0003-2075-307X FU Association pour la Recherche sur le Cancer [SFI20121205936]; Taxe d'Apprentissage (Gustave Roussy, Villejuif, France) for AK/VO/IP; Erasmus program; CNRS Annual Funding [UMR8126] FX Association pour la Recherche sur le Cancer subvention no [SFI20121205936 to V.O.]; Taxe d'Apprentissage (Gustave Roussy, Villejuif, France) for AK/VO/IP; Erasmus program (to A.K.). Funding for open access charge: CNRS Annual Funding [UMR8126]. NR 72 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 30 PY 2015 VL 43 IS 17 BP 8227 EP 8242 DI 10.1093/nar/gkv721 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CY4UR UT WOS:000366404600017 PM 26184877 ER PT J AU Li, W Lee, MH Henderson, L Tyagi, R Bachani, M Steiner, J Campanac, E Hoffman, DA von Geldern, G Johnson, K Maric, D Morris, HD Lentz, M Pak, K Mammen, A Ostrow, L Rothstein, J Nath, A AF Li, Wenxue Lee, Myoung-Hwa Henderson, Lisa Tyagi, Richa Bachani, Muzna Steiner, Joseph Campanac, Emilie Hoffman, Dax A. von Geldern, Gloria Johnson, Kory Maric, Dragan Morris, H. Douglas Lentz, Margaret Pak, Katherine Mammen, Andrew Ostrow, Lyle Rothstein, Jeffrey Nath, Avindra TI Human endogenous retrovirus-K contributes to motor neuron disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID REVERSE-TRANSCRIPTASE ACTIVITY; HUMAN TISSUES; EXPRESSION; GENE; DEGENERATION; PROTEIN; SERUM; MICE; ALS; DETERMINANT AB The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis. C1 [Li, Wenxue; Lee, Myoung-Hwa; Henderson, Lisa; Tyagi, Richa; von Geldern, Gloria; Maric, Dragan; Nath, Avindra] Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Bachani, Muzna] Natl Inst Neurol Disorders & Stroke, Neurotherapeut Unit, NIH, Bethesda, MD 20892 USA. [Campanac, Emilie; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. [Johnson, Kory] Natl Inst Neurol Disorders & Stroke, Bioinformat Unit, NIH, Bethesda, MD 21042 USA. [Morris, H. Douglas] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 21042 USA. [Lentz, Margaret] NIAID, Integrated Res Facil, NIH, Frederick, MD 21042 USA. [Pak, Katherine; Mammen, Andrew] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Lab Muscle Stem Cell & Gene Regulat, NIH, Bethesda, MD 21042 USA. [Ostrow, Lyle; Rothstein, Jeffrey] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 28217 USA. RP Nath, A (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Neurological Disorders and Stroke, National Institute of Arthritis, Musculoskeletal and Skin Diseases; NICHD of the NIH; Robert Packard Center for ALS Research FX Funding: This work was supported by funds from the National Institute of Neurological Disorders and Stroke, National Institute of Arthritis, Musculoskeletal and Skin Diseases, and the NICHD of the NIH and the Robert Packard Center for ALS Research. NR 48 TC 30 Z9 30 U1 3 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 30 PY 2015 VL 7 IS 307 AR 307ra153 DI 10.1126/scitranslmed.aac8201 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8EY UT WOS:000365233500006 PM 26424568 ER PT J AU Woolhouse, MEJ Rambaut, A Kellam, P AF Woolhouse, Mark E. J. Rambaut, Andrew Kellam, Paul TI Lessons from Ebola: Improving infectious disease surveillance to inform outbreak management SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID WEST-AFRICA; TRANSMISSION; INFLUENZA; EPIDEMIC; ORIGIN; STRATEGIES AB The current Ebola virus disease outbreak in West Africa has revealed serious shortcomings in national and international capacity to detect, monitor, and respond to infectious disease outbreaks as they occur. Recent advances in diagnostics, risk mapping, mathematical modeling, pathogen genome sequencing, phylogenetics, and phylogeography have the potential to improve substantially the quantity and quality of information available to guide the public health response to outbreaks of all kinds. C1 [Woolhouse, Mark E. J.; Rambaut, Andrew] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge CB10 1RQ, England. [Kellam, Paul] UCL, Div Infect & Immun, London WC1E 6BT, England. RP Woolhouse, MEJ (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland. EM mark.woolhouse@ed.ac.uk FU Wellcome Trust [WT098608]; EU; UK Department of Health; Health Innovation Challenge Fund [HICF-T5-344] FX Funding: This work was supported by a Wellcome Trust Strategic Award (VIZIONS), with additional support from an EU Horizon 2020 grant (COMPARE), the UK Department of Health, the Wellcome Trust (grant no. WT098608), and the Health Innovation Challenge Fund (HICF-T5-344). NR 45 TC 8 Z9 8 U1 5 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 30 PY 2015 VL 7 IS 307 AR 307rv5 DI 10.1126/scitranslmed.aab0191 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CW8EY UT WOS:000365233500001 PM 26424572 ER PT J AU Patel, EU Manucci, J Kahle, EM Lingappa, JR Morrow, RA Piwowar-Manning, E James, A Maluzi, KF Cheeba, MM Gray, G Delany-Moretlwe, S Inambao, M Vwalika, B Quinn, TC Laeyendecker, O AF Patel, Eshan U. Manucci, Jordyn Kahle, Erin M. Lingappa, Jairam R. Morrow, Rhoda Ashley Piwowar-Manning, Estelle James, Anelet Maluzi, Kwitaka F. Cheeba, Maina M. Gray, Glenda Delany-Moretlwe, Sinead Inambao, Mubiana Vwalika, Bellington Quinn, Thomas C. Laeyendecker, Oliver TI Precision of the Kalon Herpes Simplex Virus Type 2 IgG ELISA: an international inter-laboratory assessment SO BMC INFECTIOUS DISEASES LA English DT Article DE Herpes; HSV-2; Kalon; Precision; Reproducibility; Accuracy; Sensitivity; Specificity; Zambia; South Africa ID LINKED IMMUNOSORBENT ASSAYS; HPTN 071 POPART; SEROLOGICAL ASSAYS; GENITAL HERPES; PERFORMANCE; ANTIBODIES; HSV-2; HIV; TRANSMISSION; PREVENTION AB Background: The commercial Kalon HSV-2 IgG ELISA is currently recommended for research use in sub-Saharan Africa because of its superior accuracy compared to other serologic assays. However, there are no data on key precision parameters of Kalon such as inter-operator variation, repeatability, and reproducibility, thus contributing to a barrier for its acceptance and use in clinical trials in sub-Saharan Africa. We evaluated the analytical and field precision of the Kalon HSV-2 IgG ELISA. Methods: A total of 600 HIV-infected and uninfected serum samples from South Africa and Zambia, previously tested by the gold standard University of Washington HSV western blot (UW-WB), were tested using Kalon by two technologists in an United States reference laboratory. Aliquots of 183 samples were retested using Kalon by an on-site technologist in a South African laboratory and a Zambian laboratory. Results: Intra-assay variation was below 10 %. Intra-assay, intra-laboratory, and inter-laboratory correlation and agreement were significantly high (p < 0.01). In comparison to the UW-WB, accurate performance of Kalon was reproducible by each operator and laboratory. Receiver operating characteristic curve analysis indicated high selectivity of Kalon in the overall study population (area under the curve = 0.95, 95% CI = 0.92-0.97). Discussion: Kalon is a robust assay with high precision and reproducibility. Accordingly, operator errorlikely does not contribute to the variability observed in Kalon's specificity throughout sera from sub-Saharan Africa. Conclusions: In populations with optimal diagnostic accuracy, Kalon is a reliable stand-alone method for on-site HSV-2 IgG antibody detection. C1 [Patel, Eshan U.; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Lab Immunoregulat, Div Intramural Res, NIH, Baltimore, MD 15097 USA. [Manucci, Jordyn; Quinn, Thomas C.; Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Kahle, Erin M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lingappa, Jairam R.] Univ Washington, Dept Med, Dept Global Hlth, Seattle, WA 98195 USA. [Lingappa, Jairam R.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Morrow, Rhoda Ashley] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Morrow, Rhoda Ashley] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Piwowar-Manning, Estelle] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [James, Anelet] Univ Stellenbosch, Dept Paediat & Child Hlth, ZA-7600 Stellenbosch, South Africa. [Maluzi, Kwitaka F.; Cheeba, Maina M.] Zambart, Lusaka, Zambia. [Gray, Glenda] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Delany-Moretlwe, Sinead] Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Delany-Moretlwe, Sinead] Univ Witwatersrand, Johannesburg, South Africa. [Inambao, Mubiana; Quinn, Thomas C.] Zambia Emory Res Project, Ndola, Zambia. [Inambao, Mubiana; Quinn, Thomas C.] Ndola Cent Hosp, Ndola, Zambia. [Vwalika, Bellington] Zambia Emory Res Project, Lusaka, Zambia. [Laeyendecker, Oliver] NIAID, NIH, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] NIAID, SOM, JHU, Baltimore, MD 21205 USA. RP Laeyendecker, O (reprint author), NIAID, Lab Immunoregulat, Div Intramural Res, NIH, Baltimore, MD 15097 USA. EM olaeyen1@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760; Patel, Eshan/0000-0003-2174-5004 FU Division of Intramural Research, NIH; Bill and Melinda Gates Foundation [26469]; HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of the NIH, Dept. of Health and Human Services (DHHS) [UM1AI068613]; NIH (NIAID) [P01 AI030731] FX Funding was provided by the Division of Intramural Research, NIH, and research grants from the Bill and Melinda Gates Foundation (Grant ID #26469). The research was also supported by the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the NIH, Dept. of Health and Human Services (DHHS) (UM1AI068613) and the NIH (NIAID Grant P01 AI030731). The views expressed by the authors do not necessarily reflect the views of NIAID, Johns Hopkins University, the University of Washington, Stellenbosch University, University of the Witwatersrand, the Fred Hutchinson Cancer Research Center, or the Zambia-Emory Research Project. NR 30 TC 0 Z9 0 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 30 PY 2015 VL 15 AR 398 DI 10.1186/s12879-015-1130-6 PG 9 WC Infectious Diseases SC Infectious Diseases GA CS7GN UT WOS:000362252200007 PM 26423888 ER PT J AU Shin, HJ Rashid, MA Cartner, LK Bokesch, HR Wilson, JA McMahon, JB Gustafson, KR AF Shin, Hee Jae Rashid, Mohammad A. Cartner, Laura K. Bokesch, Heidi R. Wilson, Jennifer A. McMahon, James B. Gustafson, Kirk R. TI Stellettapeptins A and B, HIV-inhibitory cyclic depsipeptides from the marine sponge Stelletta sp. (vol 56, pg 4215, 2015) SO TETRAHEDRON LETTERS LA English DT Correction C1 [Shin, Hee Jae; Rashid, Mohammad A.; Cartner, Laura K.; Bokesch, Heidi R.; Wilson, Jennifer A.; McMahon, James B.; Gustafson, Kirk R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Cartner, Laura K.; Bokesch, Heidi R.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Shin, Hee Jae] Korea Inst Ocean Sci & Technol, Marine Nat Prod Lab, Ansan 426744, South Korea. [Rashid, Mohammad A.] Univ Dhaka, Dept Pharmaceut Chem, Dhaka 1000, Bangladesh. RP Gustafson, KR (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick Natl Lab Canc Res, Bldg 562,Room 201, Frederick, MD 21702 USA. EM shinhj@kiost.ac; rashidma@univdhaka.edu; gustafki@mail.nih.gov NR 1 TC 1 Z9 1 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD SEP 30 PY 2015 VL 56 IS 40 BP 5482 EP 5482 DI 10.1016/j.tetlet.2015.08.034 PG 1 WC Chemistry, Organic SC Chemistry GA CT1CC UT WOS:000362533900027 ER PT J AU Mizumoto, K Endo, A Chowell, G Miyamatsu, Y Saitoh, M Nishiura, H AF Mizumoto, Kenji Endo, Akira Chowell, Gerardo Miyamatsu, Yuichiro Saitoh, Masaya Nishiura, Hiroshi TI Real-time characterization of risks of death associated with the Middle East respiratory syndrome (MERS) in the Republic of Korea, 2015 SO BMC MEDICINE LA English DT Article DE Case fatality ratio; Fatal outcome; Middle East respiratory syndrome; Risk factors; Statistical model; South Korea ID CASE-FATALITY RATIO; EMERGING INFECTIOUS-DISEASES; HONG-KONG; EPIDEMIOLOGIC ASSESSMENT; INFLUENZA; SPREAD; VIRUS AB Background: An outbreak of the Middle East respiratory syndrome (MERS), comprising 185 cases linked to healthcare facilities, occurred in the Republic of Korea from May to July 2015. Owing to the nosocomial nature of the outbreak, it is particularly important to gain a better understanding of the epidemiological determinants characterizing the risk of MERS death in order to predict the heterogeneous risk of death in medical settings. Methods: We have devised a novel statistical model that identifies the risk of MERS death during the outbreak in real time. While accounting for the time delay from illness onset to death, risk factors for death were identified using a linear predictor tied to a logit model. We employ this approach to (1) quantify the risks of death and (2) characterize the temporal evolution of the case fatality ratio (CFR) as case ascertainment greatly improved during the course of the outbreak. Results: Senior persons aged 60 years or over were found to be 9.3 times (95 % confidence interval (CI), 5.3-16.9) more likely to die compared to younger MERS cases. Patients under treatment were at a 7.8-fold (95 % CI, 4.0-16.7) significantly higher risk of death compared to other MERS cases. The CFR among patients aged 60 years or older under treatment was estimated at 48.2 % (95 % CI, 35.2-61.3) as of July 31, 2015, while the CFR among other cases was estimated to lie below 15 %. From June 6, 2015, onwards, the CFR declined 0.3-fold (95 % CI, 0.1-1.1) compared to the earlier epidemic period, which may perhaps reflect enhanced case ascertainment following major contact tracing efforts. Conclusions: The risk of MERS death was significantly associated with older age as well as treatment for underlying diseases after explicitly adjusting for the delay between illness onset and death. Because MERS outbreaks are greatly amplified in the healthcare setting, enhanced infection control practices in medical facilities should strive to shield risk groups from MERS exposure. C1 [Mizumoto, Kenji] Univ Tokyo, Grad Sch Arts & Sci, Meguro Ku, Tokyo 1538902, Japan. [Endo, Akira; Miyamatsu, Yuichiro; Saitoh, Masaya; Nishiura, Hiroshi] Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Miyamatsu, Yuichiro; Saitoh, Masaya; Nishiura, Hiroshi] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Saitoh, Masaya] Inst Stat Math, Tachikawa, Tokyo, Japan. RP Nishiura, H (reprint author), Univ Tokyo, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM nishiurah@m.u-tokyo.ac.jp OI Nishiura, Hiroshi/0000-0003-0941-8537 FU Japan Society for the Promotion of Science (JSPS) KAKENHI [26670308, 26700028]; Japan Agency for Medical Research and Development; Tokyo Society of Medical Sciences; Japan Science and Technology Agency (JST) CREST program; RISTEX program for Science of Science, Technology and Innovation Policy; Division of International Epidemiology and Population Studies; Fogarty International Center, United States National Institutes of Health; Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services; NSF, joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases programme [1414374]; United Kingdom Biotechnology and Biological Sciences Research Council [BB/M008894/1]; NSF-IIS [1518939] FX HN received funding support from the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 26670308 and 26700028, Japan Agency for Medical Research and Development, the Tokyo Society of Medical Sciences, the Japan Science and Technology Agency (JST) CREST program and RISTEX program for Science of Science, Technology and Innovation Policy. GC acknowledges financial support from the Division of International Epidemiology and Population Studies, The Fogarty International Center, United States National Institutes of Health, funded in part by the Office of Pandemics and Emerging Threats at the United States Department of Health and Human Services, as well as support from grants NSF grant 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases programme, United Kingdom Biotechnology and Biological Sciences Research Council grant BB/M008894/1 and NSF-IIS Grant#1518939. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 8 Z9 8 U1 0 U2 5 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 SEP 30 PY 2015 VL 13 AR 228 DI 10.1186/s12916-015-0468-3 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CS3AD UT WOS:000361942600001 PM 26420593 ER PT J AU Marsh, JW Wee, BA Tyndall, JDA Lott, WB Bastidas, RJ Caldwell, HD Valdivia, RH Kari, L Huston, WM AF Marsh, James W. Wee, Bryan A. Tyndall, Joel D. A. Lott, William B. Bastidas, Robert J. Caldwell, Harlan D. Valdivia, Raphael H. Kari, L. Huston, Wilhelmina M. TI A Chlamydia trachomatis strain with a chemically generated amino acid substitution (P370L) in the cthtrA gene shows reduced elementary body production SO BMC MICROBIOLOGY LA English DT Article DE Chlamydia; HtrA; Genetics; Heat shock; Intracellular ID OBLIGATE INTRACELLULAR PATHOGEN; ESCHERICHIA-COLI; HTRA PROTEASE; CHAPERONE; DEGP; VIRULENCE; IDENTIFICATION; DETERMINANTS; MUTAGENESIS; ACTIVATION AB Background: Chlamydia (C.) trachomatis is the most prevalent bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Genetic approaches to investigate C. trachomatis have been only recently developed due to the organism's intracellular developmental cycle. HtrA is a critical stress response serine protease and chaperone for many bacteria and in C. trachomatis has been previously shown to be important for heat stress and the replicative phase of development using a chemical inhibitor of the CtHtrA activity. In this study, chemically-induced SNVs in the cthtrA gene that resulted in amino acid substitutions (A240V, G475E, and P370L) were identified and characterized. Methods: SNVs were initially biochemically characterized in vitro using recombinant protein techniques to confirm a functional impact on proteolysis. The C. trachomatis strains containing the SNVs with marked reductions in proteolysis were investigated in cell culture to identify phenotypes that could be linked to CtHtrA function. Results: The strain harboring the SNV with the most marked impact on proteolysis (cthtrA(P370L)) was detected to have a significant reduction in the production of infectious elementary bodies. Conclusions: This provides genetic evidence that CtHtrA is critical for the C. trachomatis developmental cycle. C1 [Marsh, James W.; Wee, Bryan A.; Lott, William B.; Huston, Wilhelmina M.] Queensland Univ Technol, IHBI, Kelvin Grove, Qld 4059, Australia. [Tyndall, Joel D. A.] Univ Otago, Natl Sch Pharm, Dunedin 9054, New Zealand. [Bastidas, Robert J.; Valdivia, Raphael H.] Duke Univ, Med Ctr, Ctr Microbial Pathogenesis, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Caldwell, Harlan D.; Kari, L.] NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT USA. RP Huston, WM (reprint author), Queensland Univ Technol, IHBI, 60 Musk Ave, Kelvin Grove, Qld 4059, Australia. EM w.huston@qut.edu.au RI Marsh, James/F-1037-2016; Lott, William/J-1062-2012; OI Marsh, James/0000-0003-4681-1012; Lott, William/0000-0001-7118-7560; Tyndall, Joel/0000-0003-0783-1635 FU NHMRC [553020]; ARC; Wesley Research Institute; NHMRC Peter Doherty Fellowship; Queensland University of Technology; Institute of Health and Biomedical Innovation FX Most of the work on Chlamydia HtrA in the Huston group has been supported by NHMRC Project Grant 553020 and an ARC Linkage Project in Conjunction with The Wesley Research Institute. WH has previously received support from an NHMRC Peter Doherty Fellowship. Queensland University of Technology and Institute of Health and Biomedical Innovation funding supported several components of this study. JM wishes to acknowledge the technical and experimental support from Amba Lawrence throughout the experimental work of this study. NR 37 TC 1 Z9 1 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD SEP 30 PY 2015 VL 15 AR 194 DI 10.1186/s12866-015-0533-2 PG 13 WC Microbiology SC Microbiology GA CS7FY UT WOS:000362250700002 PM 26424482 ER PT J AU Stamatakis, E Rogers, K Ding, D Berrigan, D Chau, J Hamer, M Bauman, A AF Stamatakis, Emmanuel Rogers, Kris Ding, Ding Berrigan, David Chau, Josephine Hamer, Mark Bauman, Adrian TI All-cause mortality effects of replacing sedentary time with physical activity and sleeping using an isotemporal substitution model: a prospective study of 201,129 mid-aged and older adults SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Physical activity; Sedentary behaviour; Mortality; Longitudinal; Isotemporal substitution; Prevention; Sitting; Screen time; Mortality; Epidemiology; Sleeping; Public health; Population cohort ID POSTPRANDIAL GLUCOSE; SITTING TIME; RISK; POPULATION; VALIDITY; DISEASE; INTERVENTION; METAANALYSIS; RELIABILITY; INACTIVITY AB Background: Sedentary behaviour, sleeping, and physical activity are thought to be independently associated with health outcomes but it is unclear whether these associations are due to the direct physiological effects of each behaviour or because, across a finite 24-hour day, engagement in one behavior requires displacement of another. The aim of this study was to examine the replacement effects of sedentary behaviour (total sitting, television/computer screen time combined), sleeping, standing, walking, and moderate-to-vigorous physical activity on all-cause mortality using isotemporal substitution modelling. Methods: Longitudinal analysis (4.22 +/- 0.9 years follow-up/849,369 person-years) of 201,129 participants of the 45 and Up study aged >= 45 years from New South Wales, Australia. Results: Seven thousand four hundred and sixty deaths occurred over follow-up. There were beneficial associations for replacing total sitting time with standing (per-hour HR: 95 % CI: 0.95, 0.94-0.96), walking (0.86, 0.81-0.90), moderate-to-vigorous physical activity (0.88, 0.85-0.90), and sleeping in those sleeping <= 7 h/day (0.94, 0.90-0.98). Similar associations were noted for replacing screen time. Replacing one hour of walking or moderate-to-vigorous physical activity with any other activity class was associated with an increased mortality risk by 7-18 %. Excluding deaths in the first 24 months of the follow up and restricting analyses to those who were healthy at baseline did not materially change the above observations. Conclusion: Although replacing sedentary behaviour with walking and moderate-to-vigorous physical activity are associated with the lowest mortality risk, replacements with equal amounts of standing and sleeping (in low sleepers only) are also linked to substantial mortality risk reductions. C1 [Stamatakis, Emmanuel; Chau, Josephine; Bauman, Adrian] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Stamatakis, Emmanuel] Univ Sydney, Fac Hlth Sci, Exercise & Sport Sci, Sydney, NSW 2006, Australia. [Stamatakis, Emmanuel; Hamer, Mark] UCL, Dept Epidemiol & Publ Hlth, Phys Act Res Grp, UCL PARG, London, England. [Rogers, Kris; Chau, Josephine; Bauman, Adrian] Univ Sydney, Sydney Sch Publ Hlth, Prevent Res Collaborat, Sydney, NSW 2006, Australia. [Ding, Ding] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Berrigan, David] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hamer, Mark] Univ Loughborough, Natl Ctr Sport & Exercise Med, Loughborough, Leics, England. RP Stamatakis, E (reprint author), Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. EM emmanuel.stamatakis@sydney.edu.au OI Hamer, Mark/0000-0002-8726-7992 FU Australian National Health and Medical Research Council Program [301200]; UK National Institute for Health Research Career Development Fellowship FX These analyses were supported by Australian National Health and Medical Research Council Program Grant #301200 and by a UK National Institute for Health Research Career Development Fellowship (ES). NR 34 TC 15 Z9 15 U1 4 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD SEP 30 PY 2015 VL 12 AR 121 DI 10.1186/s12966-015-0280-7 PG 10 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA CS2YK UT WOS:000361937700002 PM 26419654 ER PT J AU Pulcini, S Staines, HM Lee, AH Shafik, SH Bouyer, G Moore, CM Daley, DA Hoke, MJ Altenhofen, LM Painter, HJ Mu, JB Ferguson, DJP Llinas, M Martin, RE Fidock, DA Cooper, RA Krishna, S AF Pulcini, Serena Staines, Henry M. Lee, Andrew H. Shafik, Sarah H. Bouyer, Guillaume Moore, Catherine M. Daley, Daniel A. Hoke, Matthew J. Altenhofen, Lindsey M. Painter, Heather J. Mu, Jianbing Ferguson, David J. P. Llinas, Manuel Martin, Rowena E. Fidock, David A. Cooper, Roland A. Krishna, Sanjeev TI Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities SO SCIENTIFIC REPORTS LA English DT Article ID TRANSMEMBRANE PROTEIN PFCRT; XENOPUS-LAEVIS OOCYTES; MALARIA PARASITES; ARTEMISININ RESISTANCE; ANTIMALARIAL; POLYMORPHISMS; MECHANISM; METAANALYSIS; PIPERAQUINE; EXPRESSION AB Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs. C1 [Pulcini, Serena; Staines, Henry M.; Bouyer, Guillaume; Moore, Catherine M.; Krishna, Sanjeev] Univ London, Inst Infect & Immun, London SW17 0RE, England. [Lee, Andrew H.; Fidock, David A.] Columbia Univ, Dept Microbiol & Immunol, Med Ctr, New York, NY 10032 USA. [Shafik, Sarah H.; Martin, Rowena E.] Australian Natl Univ, Res Sch Biol, Canberra, ACT 2601, Australia. [Bouyer, Guillaume] Univ Paris 06, Sorbonne Univ, Integrat Biol Marine Models, UMR 8227,Comparat Physiol Erythrocytes,Stn Biol R, Roscoff, France. [Bouyer, Guillaume] CNRS, Integrat Biol Marine Models, Comparat Physiol Erythrocytes, UMR 8227,Stn Biol Roscoff, Roscoff, France. [Daley, Daniel A.; Hoke, Matthew J.; Cooper, Roland A.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. [Altenhofen, Lindsey M.; Painter, Heather J.; Llinas, Manuel] Penn State Univ, Dept Biochem & Mol Biol, State Coll, PA 16802 USA. [Altenhofen, Lindsey M.; Painter, Heather J.; Llinas, Manuel] Penn State Univ, Ctr Malaria Res, State Coll, PA 16802 USA. [Mu, Jianbing] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ferguson, David J. P.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. [Fidock, David A.] Columbia Univ, Dept Med, Med Ctr, Div Infect Dis, New York, NY 10032 USA. [Cooper, Roland A.] Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA 94901 USA. RP Krishna, S (reprint author), Univ London, Inst Infect & Immun, London SW17 0RE, England. EM s.krishna@sgul.ac.uk RI Staines, Henry/B-6281-2009; Martin, Rowena/C-9992-2009; OI Staines, Henry/0000-0001-5890-3040; Ferguson, David/0000-0001-5045-819X FU European Community's Seventh Framework Programme (Marie Curie) [215281-2, 304948]; NIH [R01 AI50234, R01 AI071121]; Australian National Health and Medical Research Council [1007035, 1053082]; Burroughs Wellcome Fund - Investigators in Pathogenesis of Infectious Disease award [1007041.02] FX This work was supported by the European Community's Seventh Framework Programme, FP7/2007-2013 (Marie Curie-funded Initial Training Network InterMal, 215281-2 to SK and NanoMal, 304948 to SK and HMS), the NIH (R01 AI50234 to DAF and R01 AI071121 to RAC), the Australian National Health and Medical Research Council (Grant 1007035 and Fellowship 1053082 to REM) and the Burroughs Wellcome Fund - Investigators in Pathogenesis of Infectious Disease award (1007041.02 to ML). NR 71 TC 7 Z9 7 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 30 PY 2015 VL 5 AR 14552 DI 10.1038/srep14552 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS3FY UT WOS:000361958500002 PM 26420308 ER PT J AU Caqueo-Urizar, A Boyer, L Baumstarck, K Gilman, SE AF Caqueo-Urizar, Alejandra Boyer, Laurent Baumstarck, Karine Gilman, Stephen E. TI The relationships between patients' and caregivers' beliefs about the causes of schizophrenia and clinical outcomes in Latin American countries SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Causal beliefs; Caregivers; Health outcomes; Symptoms; Attitudes towards medication ID SERIOUS MENTAL ILLNESSES; MIDDLE-INCOME COUNTRIES; NEGATIVE SYNDROME SCALE; EXPRESSED EMOTION; FAMILY-MEMBERS; HEALTH; POVERTY; RELATIVES; MODELS; HELP AB Beliefs about the causes of schizophrenia are thought to impact treatment outcomes. We investigated 3 theoretically opposing belief systems (biological, psychosocial, magical-religious) in relation to the severity of positive and negative symptoms and to attitudes towards medications. We recruited 253 patients with schizophrenia and their primary caregivers from public mental health clinics in Bolivia, Chile, and Peru. We assessed patients' and caregivers' beliefs about the causes of schizophrenia, which were used as predictors of symptom severity and medication attitudes in linear regression analyses. Patients' scores on biological, psychosocial, and magical-religious beliefs were positively correlated with one another, indicating that these domains were not, as anticipated, "opposing". Patients with higher levels of biological and psychosocial beliefs had significantly lower levels of positive and negative symptoms; in contrast, higher levels of magical-religious beliefs were associated with increased positive symptoms and less favorable attitudes towards medications. Patients' belief systems are significant predictors of symptom severity and medication attitudes. Research is needed on the extent to which psychotherapeutic treatments for schizophrenia should bolster patients' beliefs in the biological and psychosocial domains and weaken beliefs in the magical-religious domain; this research should also attend to the ethical considerations involved in intervening on belief systems cross-culturally. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Caqueo-Urizar, Alejandra] Univ Tarapaca, Arica, Chile. [Caqueo-Urizar, Alejandra; Gilman, Stephen E.] Harvard Univ, Dept Social & Behav Sci, Sch Publ Hlth, Boston, MA 02115 USA. [Boyer, Laurent; Baumstarck, Karine] Aix Marseille Univ, Chron Dis & Qual Life Res Unit, EA Publ Hlth 3279, F-13005 Marseille, France. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Caqueo-Urizar, A (reprint author), Univ Tarapaca, Dept Filosofia & Psicol, Ave 18 Septiembre 2222, Arica, Chile. EM acaqueo@uta.cl; Laurent.BOYER@ap-hm.fr; karine.baumstarck@univ-amu.fr; stephen.gilman@nih.gov RI Gilman, Stephen/E-7632-2010; Boyer, Laurent/E-5728-2016 OI Gilman, Stephen/0000-0002-8331-6419; Boyer, Laurent/0000-0003-1229-6622 FU CONICYT; BECAS-CHILE Postdoctorado en el Extranjero [74140004]; Convenio de De-sempenio UTA-MINEDUC; Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was funded in part by CONICYT and BECAS-CHILE Postdoctorado en el Extranjero (74140004), the Convenio de De-sempenio UTA-MINEDUC, and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 54 TC 1 Z9 1 U1 6 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2015 VL 229 IS 1-2 BP 440 EP 446 DI 10.1016/j.psychres.2015.06.033 PG 7 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600063 PM 26188641 ER PT J AU Haass-Koffler, CL Aoun, EG Swift, RM de la Monte, SM Kenna, GA Leggio, L AF Haass-Koffler, C. L. Aoun, E. G. Swift, R. M. de la Monte, S. M. Kenna, G. A. Leggio, L. TI Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID GROWTH-HORMONE SECRETAGOGUE; EVOLVING-IMPACT; FOOD-INTAKE; RECEPTOR; DEPENDENCE; RESISTIN; SYSTEM; EXPRESSION; RAT; PHARMACOTHERAPY AB Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n = 45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P = not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P = NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving. C1 [Haass-Koffler, C. L.; Leggio, L.] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD 20892 USA. [Haass-Koffler, C. L.; Leggio, L.] NIDA, NIH, Bethesda, MD 20892 USA. [Haass-Koffler, C. L.; Leggio, L.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. [Aoun, E. G.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Swift, R. M.; Kenna, G. A.] Brown Univ, Dept Psychiat & Human Behav, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Swift, R. M.] Vet Affairs Med Ctr, Providence, RI USA. [de la Monte, S. M.] Brown Univ, Rhode Isl Hosp, Dept Pathol, Providence, RI 02903 USA. [de la Monte, S. M.] Brown Univ, Rhode Isl Hosp, Dept Neurol, Providence, RI 02903 USA. [de la Monte, S. M.] Brown Univ, Rhode Isl Hosp, Dept Neurosurg, Providence, RI 02903 USA. [de la Monte, S. M.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr 10CRC 15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Leggio, Lorenzo/M-2972-2016 FU NIAAA Division of Intramural Clinical and Biological Research; National Institute on Drug Abuse; NIAAA [5T32AA007459-28]; National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R21-AA019709] FX We acknowledge the technical support from Samuel Fricchione and the nursing support from Tamara Sequeira and Julia Nadeau at the Brown University Center for Alcohol and Addiction Studies; and the technical support from Valerie Zabala and Ming Tong at the Rhode Island Hospital and Chetram Deochand and Rosa Yu at the Brown University. The current work of LL is supported by the NIAAA Division of Intramural Clinical and Biological Research and the Intramural Research Program of the National Institute on Drug Abuse. The work of CLH-K is supported by an NIAAA training grant, Grant #5T32AA007459-28. The parent study was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Grant #R21-AA019709, awarded to LL while he was at the Brown University. NR 57 TC 5 Z9 5 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP 29 PY 2015 VL 5 AR e646 DI 10.1038/tp.2015.140 PG 6 WC Psychiatry SC Psychiatry GA DA2YO UT WOS:000367663300001 PM 26418274 ER PT J AU Wiers, CE Shumay, E Volkow, ND Frieling, H Kotsiari, A Lindenmeyer, J Walter, H Bermpohl, F AF Wiers, C. E. Shumay, E. Volkow, N. D. Frieling, H. Kotsiari, A. Lindenmeyer, J. Walter, H. Bermpohl, F. TI Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID COGNITIVE BIAS MODIFICATION; DOPAMINE TRANSPORTER GENE; HUMAN BRAIN; USE DISORDERS; ADDICTION; DEPENDENCE; BLOOD; RELAPSE; TISSUE; REWARD AB In alcohol-dependent (AD) patients, alcohol cues induce strong activations in brain areas associated with alcohol craving and relapse, such as the nucleus accumbens (NAc) and amygdala. However, little is known about the influence of depressive symptoms, which are common in AD patients, on the brain's reactivity to alcohol cues. The methylation state of the dopamine transporter gene (DAT) has been associated with alcohol dependence, craving and depression, but its influence on neural alcohol cue reactivity has not been tested. Here, we compared brain reactivity to alcohol cues in 38 AD patients and 17 healthy controls (HCs) using functional magnetic resonance imaging and assessed the influence of depressive symptoms and peripheral DAT methylation in these responses. We show that alcoholics with low Beck's Depression Inventory scores (n = 29) had higher cue-induced reactivity in NAc and amygdala than those with mild/moderate depression scores (n = 9), though subjective perception of craving was higher in those with mild/moderate depression scores. We corroborated a higher DAT methylation in AD patients than HCs, and showed higher DAT methylation in AD patients with mild/moderate than low depression scores. Within the AD cohort, higher methylation predicted craving and, at trend level (P = 0.095), relapse 1 year after abstinence. Finally, we show that amygdala cue reactivity correlated with craving and DAT methylation only in AD patients with low depression scores. These findings suggest that depressive symptoms and DAT methylation are associated with alcohol craving and associated brain processes in alcohol dependence, which may have important consequences for treatment. Moreover, peripheral DAT methylation may be a clinically relevant biomarker in AD patients. C1 [Wiers, C. E.; Shumay, E.; Volkow, N. D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD 20892 USA. [Volkow, N. D.] NIDA, NIH, Bethesda, MD 20892 USA. [Frieling, H.; Kotsiari, A.] Hannover Med Sch, Dept Psychiat Socialpsychiat & Psychotherapy, Hannover, Germany. [Lindenmeyer, J.] Salus Clin, Lindow, Germany. [Walter, H.; Bermpohl, F.] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Walter, H.; Bermpohl, F.] Humboldt Univ, Berlin Sch Mind & Brain, D-10099 Berlin, Germany. RP Wiers, CE (reprint author), NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. EM corinde.wiers@nih.gov RI Frieling, Helge/C-5299-2015; Walter, Henrik/O-2612-2013 OI Frieling, Helge/0000-0001-5146-9720; FU German Federal Ministry of Education and Research [BMBF-01KR1207C]; German Research Foundation (Deutsche Forschungsgemeinschaft) [DFG_FOR_1617: WA 1539/7-1] FX We thank Samantha Cunningham for helpful comments on earlier versions of the manuscript, and Elizabeth Cabrera and Emily Skarda for proofreading. This study was supported by grants from the German Federal Ministry of Education and Research (BMBF-01KR1207C) and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG_FOR_1617: grant WA 1539/7-1). NR 50 TC 2 Z9 2 U1 4 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP 29 PY 2015 VL 5 AR e648 DI 10.1038/tp.2015.141 PG 8 WC Psychiatry SC Psychiatry GA DA2YO UT WOS:000367663300003 PM 26418276 ER PT J AU Shinnar, S Cnaan, A Hu, FM Clark, P Dlugos, D Hirtz, DG Masur, D Mizrahi, EM Moshe, SL Glauser, TA AF Shinnar, Shlomo Cnaan, Avital Hu, Fengming Clark, Peggy Dlugos, Dennis Hirtz, Deborah G. Masur, David Mizrahi, Eli M. Moshe, Solomon L. Glauser, Tracy A. CA Childhood Absence Epilepsy Study TI Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial SO NEUROLOGY LA English DT Article ID INITIAL MONOTHERAPY; VALPROIC ACID; ETHOSUXIMIDE; LAMOTRIGINE; DIAGNOSIS; ATTENTION; REMISSION; PROGNOSIS; MODEL; EEG AB Objective:To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE).Methods:Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE.Results:As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs (p = -0.0009), as was the duration of the shortest burst on the baseline EEG (p = 0.037). Failure to respond to initial treatment (p < 0.001) but not treatment assignment was associated with a higher rate of GTCs. Among patients initially assigned to ethosuximide, 94% (15/16) with GTCs experienced initial therapy failure (p < 0.0001). A similar but more modest effect was noted in those initially treated with valproate (p = 0.017) and not seen in those initially treated with lamotrigine.Conclusions:The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs. C1 [Shinnar, Shlomo; Masur, David; Moshe, Solomon L.] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY 10467 USA. [Cnaan, Avital; Hu, Fengming] Childrens Natl Hlth Syst, Washington, DC USA. [Clark, Peggy; Glauser, Tracy A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Clark, Peggy; Glauser, Tracy A.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Dlugos, Dennis] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hirtz, Deborah G.] NINDS, Bethesda, MD 20892 USA. [Mizrahi, Eli M.] Baylor Coll Med, Houston, TX 77030 USA. RP Shinnar, S (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY 10467 USA. EM sshinnar@aol.com FU NIH [U01-NS045911, U01-NS045803] FX Supported by NIH (U01-NS045911 and U01-NS045803). NR 15 TC 7 Z9 8 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 29 PY 2015 VL 85 IS 13 BP 1108 EP 1114 DI 10.1212/WNL.0000000000001971 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CX4CC UT WOS:000365644800005 PM 26311751 ER PT J AU Espeland, MA Brinton, RD Manson, JE Yaffe, K Hugenschmidt, C Vaughan, L Craft, S Edwards, BJ Casanova, R Masaki, K Resnick, SM AF Espeland, Mark A. Brinton, Roberta Diaz Manson, JoAnn E. Yaffe, Kristine Hugenschmidt, Christina Vaughan, Leslie Craft, Suzanne Edwards, Beatrice J. Casanova, Ramon Masaki, Kamal Resnick, Susan M. CA WHIMS-MRI2 Study Grp TI Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes SO NEUROLOGY LA English DT Article ID HEALTH INITIATIVE MEMORY; CONJUGATED EQUINE ESTROGENS; WHIMS-MRI; COGNITIVE PERFORMANCE; MAGNETIC-RESONANCE; INSULIN-RESISTANCE; WOMEN; GLUCOSE; DEMENTIA; RISK AB Objective:To examine whether the effect of postmenopausal hormone therapy (HT) on brain volumes in women aged 65-79 years differs depending on type 2 diabetes status during postintervention follow-up of a randomized controlled clinical trial.Methods:The Women's Health Initiative randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without 2.5 mg/day medroxyprogesterone acetate) or placebo for an average of 5.6 years. A total of 1,402 trial participants underwent brain MRI 2.4 years after the trials; these were repeated in 699 women 4.7 years later. General linear models were used to assess the interaction between diabetes status and HT assignment on brain volumes.Results:Women with diabetes at baseline or during follow-up who had been assigned to HT compared to placebo had mean decrement in total brain volume of -18.6 mL (95% confidence interval [CI] -29.6, -7.6). For women without diabetes, this mean decrement was -0.4 (95% CI -3.8, 3.0) (interaction p = 0.002). This interaction was evident for total gray matter (p < 0.001) and hippocampal (p = 0.006) volumes. It was not evident for changes in brain volumes over follow-up or for ischemic lesion volumes and was not influenced by diabetes duration or oral medications.Conclusions:For women aged 65 years or older who are at increased risk for brain atrophy due to type 2 diabetes, prescription of postmenopausal HT is associated with lower gray matter (total and hippocampal) volumes. Interactions with diabetes and insulin resistance may explain divergent findings on how estrogen influences brain volume among older women. C1 [Espeland, Mark A.; Casanova, Ramon] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Hugenschmidt, Christina; Craft, Suzanne] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Vaughan, Leslie] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Brinton, Roberta Diaz] Univ So Calif, Dept Pharmacol, Los Angeles, CA USA. [Brinton, Roberta Diaz] Univ So Calif, Dept Pharmaceut Sci, Los Angeles, CA USA. [Brinton, Roberta Diaz] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Brinton, Roberta Diaz] Univ So Calif, Dept Neurol, Los Angeles, CA USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Div Prevent Med, Sch Med, Boston, MA 02115 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Edwards, Beatrice J.] Univ Texas MD Anderson Canc Ctr, Dept Internal Med, Houston, TX 77030 USA. [Masaki, Kamal] Univ Hawaii Manoa, Dept Geriatr Med, Honolulu, HI 96822 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Espeland, MA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. EM mespelan@wakehealth.edu FU National Heart, Lung, and Blood Institute of the NIH, U.S. Department of Health and Human Services; Wyeth Pharmaceuticals, Inc., St. Davids, PA; [HHSN268200464221C]; [N01-WH-4-4221] FX The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute of the NIH, U.S. Department of Health and Human Services. Contracts HHSN268200464221C and N01-WH-4-4221 provided additional support. The Women's Health Initiative Memory Study was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA. NR 40 TC 3 Z9 5 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 29 PY 2015 VL 85 IS 13 BP 1131 EP 1138 DI 10.1212/WNL.0000000000001816 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CX4CC UT WOS:000365644800008 PM 26163429 ER PT J AU Johnson, B Hallett, M Slobounov, S AF Johnson, Brian Hallett, Mark Slobounov, Semyon TI Follow-up evaluation of oculomotor performance with fMRI in the subacute phase of concussion SO NEUROLOGY LA English DT Article ID TRAUMATIC BRAIN-INJURY; CLOSED-HEAD INJURY; EYE-MOVEMENT AB Objective:To expand on our previous study by performing a follow-up testing session in the subacute phase of injury for participants recently diagnosed with a concussion.Methods:A battery of oculomotor tests were administered to participants 30 days postconcussion while simultaneous fMRI was performed.Results:Three of the 7 oculomotor tasks (antisaccade, self-paced saccade, and memory-guided saccade) administered showed significant differences between the recently concussed group compared with normal volunteers. However, performance in these 3 tasks did show improvement from the acute phase of injury. The fMRI analysis revealed significant differences in brain activation patterns compared with normal volunteers, with the concussed group still demonstrating increased and larger areas of activation. Similar to the oculomotor performance, the fMRI analysis showed that at 30 days postinjury, the concussed group more closely mirrored that of the normal volunteer group compared with at 7 days following insult.Conclusions:Even at 30 days postinjury, and despite being clinically asymptomatic, advanced techniques are able to detect subtle lingering alterations in the concussed brain. Therefore, progressive neuroimaging techniques such as fMRI in conjunction with assessment of oculomotor performance may be beneficial in clinical management of concussion. C1 [Johnson, Brian; Slobounov, Semyon] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Slobounov, Semyon] Penn State Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA USA. [Hallett, Mark; Slobounov, Semyon] NINDS, NIH, Bethesda, MD 20892 USA. RP Slobounov, S (reprint author), Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. EM sms18@psu.edu NR 10 TC 3 Z9 3 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 29 PY 2015 VL 85 IS 13 BP 1163 EP 1166 DI 10.1212/WNL.0000000000001968 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA CX4CF UT WOS:000365645100002 PM 26320202 ER PT J AU Ghitza, UE AF Ghitza, Udi E. TI Commentary: Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder SO FRONTIERS IN PSYCHIATRY LA English DT Editorial Material DE posttraumatic stress disorder; childhood; brain development; precision medicine; genetics; addiction; opioid-related disorders; substance use disorders C1 [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. RP Ghitza, UE (reprint author), NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. EM ghitzau@nida.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD SEP 29 PY 2015 VL 6 AR 136 DI 10.3389/fpsyt.2015.00136 PG 3 WC Psychiatry SC Psychiatry GA CW4VZ UT WOS:000364996000001 PM 26483705 ER PT J AU Leshchenko, VV Kuo, PY Jiang, ZW Weniger, MA Overbey, J Dunleavy, K Wilson, WH Wiestner, A Parekh, S AF Leshchenko, Violetta V. Kuo, Pei-Yu Jiang, Zewei Weniger, Marc A. Overbey, Jessica Dunleavy, Kieron Wilson, Wyndham H. Wiestner, Adrian Parekh, Samir TI Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma SO ONCOTARGET LA English DT Article DE Mantle cell lymphoma; Noxa; methylation; Bortezomib; Resistance ID PROTEASOME INHIBITOR BORTEZOMIB; ACUTE MYELOID-LEUKEMIA; NON-HODGKINS-LYMPHOMA; DNA METHYLATION; QUANTITATIVE-ANALYSIS; MASS-SPECTROMETRY; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; CANCER-CELLS; PHASE-II AB Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients. C1 [Leshchenko, Violetta V.; Kuo, Pei-Yu; Jiang, Zewei; Parekh, Samir] Icahn Sch Med Mt Sinai, Div Hematol & Med Oncol, New York, NY 10029 USA. [Weniger, Marc A.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Overbey, Jessica] Icahn Sch Med Mt Sinai, Dept Hlth Sci & Policy, New York, NY 10029 USA. [Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Parekh, S (reprint author), Icahn Sch Med Mt Sinai, Div Hematol & Med Oncol, New York, NY 10029 USA. EM samir.parekh@mssm.edu FU Chemotherapy Foundation; Gabrielle's Angel Foundation; Leukemia and Lymphoma Society Translational Research Project Grant; National Institutes of Health [R21 5R21CA169487]; Paul Calabresi Career Development Award [K12-CA132783-01] FX This project was funded in part by the Chemotherapy Foundation (SP), Gabrielle's Angel Foundation (SP), Leukemia and Lymphoma Society Translational Research Project Grant (SP), National Institutes of Health Grant R21 5R21CA169487 (SP), and Paul Calabresi Career Development Award K12-CA132783-01 (SP). NR 22 TC 5 Z9 5 U1 2 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 29 PY 2015 VL 6 IS 29 BP 27332 EP 27342 DI 10.18632/oncotarget.2903 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9UE UT WOS:000363161300068 PM 25714012 ER PT J AU Liu, ZH Lam, N Thiele, CJ AF Liu, Zhihui Lam, Norris Thiele, Carol J. TI Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription SO ONCOTARGET LA English DT Article DE CASZ1; tumor suppressor; NuRD complex; DNA repair protein; cofactors ID TUMOR-SUPPRESSOR GENE; EMBRYONIC STEM-CELLS; TEMPORAL IDENTITY; MI-2/NURD COMPLEX; NERVOUS-SYSTEM; CHROMATIN; CASTOR; DROSOPHILA; DIFFERENTIATION; EXPRESSION AB The zinc finger transcription factor CASZ1 has been found to control neural fate-determination in flies, regulate murine and frog cardiac development, control murine retinal cell progenitor expansion and function as a tumor suppressor gene in humans. However, the molecular mechanism by which CASZ1 regulates gene transcription to exert these diverse biological functions has not been described. Here we identify co-factors that are recruited by CASZ1b to regulate gene transcription using co-immunoprecipitation (co-IP) and mass spectrometry assays. We find that CASZ1b binds to the nucleosome remodeling and histone deacetylase (NuRD) complex, histones and DNA repair proteins. Mutagenesis of the CASZ1b protein assay demonstrates that the N-terminus of CASZ1b is required for NuRD binding, and a poly(ADP-ribose) binding motif in the CASZ1b protein is required for histone H3 and DNA repair proteins binding. The N-terminus of CASZ1b fused to an artificial DNA-binding domain (GAL4DBD) causes a significant repression of transcription (5xUAS-luciferase assay), which could be blocked by treatment with an HDAC inhibitor. Realtime PCR results show that the transcriptional activity of CASZ1b mutants that abrogate NuRD or histone H3/DNA binding is significantly decreased. This indicates a model in which CASZ1b binds to chromatin and recruits NuRD complexes to orchestrate epigenetic-mediated transcriptional programs. C1 [Liu, Zhihui; Lam, Norris; Thiele, Carol J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Liu, ZH (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM liuzhihu@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. NR 44 TC 2 Z9 2 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 29 PY 2015 VL 6 IS 29 BP 27628 EP 27640 DI 10.18632/oncotarget.4733 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9UE UT WOS:000363161300088 PM 26296975 ER PT J AU Brusgard, JL Choe, M Chumsri, S Renoud, K MacKerell, AD Sudol, M Passaniti, A AF Brusgard, Jessica L. Choe, Moran Chumsri, Saranya Renoud, Keli MacKerell, Alexander D., Jr. Sudol, Marius Passaniti, Antonino TI RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells SO ONCOTARGET LA English DT Article DE breast cancer; transcription factors; tumorspheres; therapeutics ID EPITHELIAL-MESENCHYMAL TRANSITION; YES-ASSOCIATED PROTEIN; TRANSCRIPTION FACTOR; PROSTATE-CANCER; PREDICTIVE-VALUE; GENE-EXPRESSION; MAMMARY-GLAND; STEM-CELLS; GROWTH; PROLIFERATION AB Intratumoral heterogeneity and treatment resistance drive breast cancer (BC) metastasis and recurrence. The RUNX2 transcription factor is upregulated in early stage luminal BC. However, the precise mechanism by which RUNX2 regulates an oncogenic phenotype in luminal BCs remains an enigma. We show that RUNX2 is predictive of poor overall survival in BC patients. RUNX2 associated with the TAZ transcriptional co-activator to promote a tumorigenic phenotype that was inhibited by knockdown of TAZ. RUNX2 increased endogenous TAZ translocation to the nucleus, which was prevented by inhibiting RUNX2. RUNX2/TAZ interaction was associated with ectodomain shedding of an oncogenic soluble E-Cadherin fragment (sE-Cad), which is known to cooperate with human epidermal growth factor receptor-2 (HER2/ErbB2) to increase BC growth. Neutralizing E-Cadherin antibodies or TAZ knockdown reduced the levels of sE-Cad in RUNX2-expressing BC cells and inhibited tumorsphere formation. RUNX2 expression also increased HER2-mediated tumorsphere size, which was reduced after treatment with the HER2-targeting agents Herceptin and lapatinib. These data support a novel role for RUNX2 in promoting an oncogenic phenotype in luminal BC in the context of TAZ, sE-Cad, and HER2. Using this signaling pathway to monitor BC cell oncogenic activity will accelerate the discovery of new therapeutic modalities to treat BC patients. C1 [Brusgard, Jessica L.] Univ Maryland, Sch Med, Program Mol Med, Baltimore, MD 21201 USA. [Chumsri, Saranya] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Brusgard, Jessica L.; Choe, Moran; Renoud, Keli] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [MacKerell, Alexander D., Jr.] Univ Maryland, Sch Med, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Sudol, Marius] Natl Univ Singapore, Dept Physiol, Mechanobiol Inst, Singapore 117548, Singapore. [Passaniti, Antonino] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Passaniti, Antonino] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Passaniti, Antonino] Vet Hlth Adm Res & Dev Serv, Baltimore, MD USA. [Chumsri, Saranya] Mayo Clin, Dept Hematol Oncol, Jacksonville, FL 32224 USA. [Choe, Moran] NCI, Lab Genitourinary Canc Pathogenesis, Bethesda, MD 20892 USA. RP Passaniti, A (reprint author), Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. EM apass001@umaryland.edu FU VA Merit Review Award [I01BX002205A]; Cigarette Restitution Funds (CRF) of State of Maryland; Gudelsky Foundation Funds from University of Maryland Greenebaum Cancer Center FX We thank Dr. Anne Hamburger for her kind gift of lapatinib, Dr. Chen-Yong Lin at Georgetown University for a gift of anti-FLAG antibody, and Dr. Hancai Dan for the gift of NF kappa B. Luciferase reporter plasmid. We also would like to thank Dr. Toni Antalis for the gift of o-Phenanthroline. A VA Merit Review Award I01BX002205A (AP; JLB), the Cigarette Restitution Funds (CRF) of the State of Maryland, and the Gudelsky Foundation Funds from the University of Maryland Greenebaum Cancer Center (AP) supported this project. NR 69 TC 6 Z9 7 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 29 PY 2015 VL 6 IS 29 BP 28132 EP 28150 DI 10.18632/oncotarget.4654 PG 19 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9UE UT WOS:000363161300124 PM 26320173 ER PT J AU Kwilas, AR Ardiani, A Dirmeier, U Wottawah, C Schlom, J Hodge, JW AF Kwilas, Anna R. Ardiani, Andressa Dirmeier, Ulrike Wottawah, Cornelia Schlom, Jeffery Hodge, James W. TI A poxviral-based cancer vaccine targeting the transcription factor twist inhibits primary tumor growth and metastases in a model of metastatic breast cancer and improves survival in a spontaneous prostate cancer model SO ONCOTARGET LA English DT Article DE twist; vaccine; metastasis; TRICOM; immunotherapy ID EPITHELIAL-MESENCHYMAL TRANSITION; CADHERIN GENE-EXPRESSION; SQUAMOUS-CELL CARCINOMA; PHASE-II; TRANSGENIC MOUSE; DENDRITIC CELLS; LUNG-CANCER; CASTRATION; TRIAL; IMMUNOTHERAPY AB Several transcription factors play a role in the alteration of gene expression that occurs during cancer metastasis. Twist expression has been shown to be associated with the hallmarks of the metastatic process, as well as poor prognosis and drug resistance in many tumor types. However, primarily due to their location within the cell and the lack of a hydrophobic groove required for drug attachment, transcription factors such as Twist are difficult to target with conventional therapies. An alternative therapeutic strategy is a vaccine comprised of a Modified vaccinia Ankara (MVA), incorporating the Twist transgene and a TRIad of COstimulatory Molecules (B7-1, ICAM-1, LFA-3; TRICOM). Here we characterize an MVA-TWIST/TRICOM vaccine that induced both CD4+ and CD8+ Twist-specific T-cell responses in vivo. In addition, administration of this vaccine reduced both the primary tumor growth and metastasis in the 4T1 model of metastatic breast cancer. In the TRAMP transgenic model of spontaneous prostate cancer, MVA-TWIST/TRICOM alone significantly improved survival, and when combined with the androgen receptor antagonist enzalutamide, the vaccine further improved survival. These studies thus provide a rationale for the use of active immunotherapy targeting transcription factors involved in the metastatic process and for the combination of cancer vaccines with androgen deprivation. C1 [Kwilas, Anna R.; Ardiani, Andressa; Schlom, Jeffery; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dirmeier, Ulrike; Wottawah, Cornelia] Bavarian Nord, Martinsried, Germany. [Dirmeier, Ulrike; Wottawah, Cornelia] Bavarian Nord, Mountain View, CA USA. RP Hodge, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 61 TC 3 Z9 3 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 29 PY 2015 VL 6 IS 29 BP 28194 EP 28210 DI 10.18632/oncotarget.4442 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9UE UT WOS:000363161300129 PM 26317648 ER EF