FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yaniv, Y Lakatta, EG Maltsev, VA AF Yaniv, Yael Lakatta, Edward G. Maltsev, Victor A. TI From two competing oscillators to one coupled-clock pacemaker cell system SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE arrhythmias; coupled-clock pacemaker system; heart rate variability; mathematical modeling; sinoatrial node ID SINOATRIAL NODE CELLS; HEART-RATE-VARIABILITY; NONSELECTIVE CATION CHANNEL; PROTEIN-KINASE-II; L-TYPE CA2+; CARDIAC PACEMAKING; CALCIUM CLOCK; FUNNY CURRENT; SINUS NODE; AUTONOMIC MODULATION AB At the beginning of this century, debates regarding "what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells" dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., "M-clock") is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a "Ca2+-clock" rhythmically discharges diastolic local Ca2+ releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na/+Ca2+ exchanger) that prompts the surface membrane "M-clock" to ignite an AP Theoretical and experimental evidence has mounted to indicate that this clock "crosstalk" operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept. C1 [Yaniv, Yael] Technion IIT, Biomed Engn Fac, IL-3200003 Haifa, Israel. [Lakatta, Edward G.; Maltsev, Victor A.] NIA, Cardiovasc Sci Lab, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Yaniv, Y (reprint author), Technion IIT, Biomed Engn Fac, IL-3200003 Haifa, Israel. EM yaely@bm.technion.ac.il; lakattae@grc.nia.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; Technion V.P.R Fund-Mallat Family Research Fund; NSFC-ISF joint research program [398/14] FX This research was partially supported by the Intramural Research Program of the NIH, National Institute on Aging, by Technion V.P.R Fund-Mallat Family Research Fund (YY) and by NSFC-ISF joint research program, No. 398/14 (YY). NR 62 TC 11 Z9 11 U1 4 U2 27 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD FEB 13 PY 2015 VL 6 AR UNSP 28 DI 10.3389/fphys.2015.00028 PG 8 WC Physiology SC Physiology GA CB0DW UT WOS:000349296600001 PM 25741284 ER PT J AU Wakabayashi, KT Kiyatkin, EA AF Wakabayashi, Ken T. Kiyatkin, Eugene A. TI Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE high-speed amperometry; enzyme-based glucose sensors; nucleus accumbens; metabolism; cerebral blood flow; neural activity ID FREELY MOVING RATS; NATURAL AROUSING STIMULI; CENTRAL-NERVOUS-SYSTEM; CEREBRAL-BLOOD-FLOW; EXTRACELLULAR GLUCOSE; BRAIN TEMPERATURE; NEURONAL-ACTIVITY; CARDIOVASCULAR-RESPONSES; CONSCIOUS RATS; RAPID CHANGES AB The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8s; similar to 50 mu M or similar to 5% of baseline) followed by a larger, more prolonged tonic elevation (similar to 100 mu M or 10% of baseline, peak similar to 15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells. C1 [Wakabayashi, Ken T.; Kiyatkin, Eugene A.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU National Institute on Drug Abuse, Intramural Research Program FX This work was supported by the National Institute on Drug Abuse, Intramural Research Program. NR 86 TC 6 Z9 6 U1 1 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD FEB 12 PY 2015 VL 9 AR 42 DI 10.3389/fnins.2015.00042 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CG0LB UT WOS:000352957000002 PM 25729349 ER PT J AU Smith, SD Redman, M Dunleavy, K AF Smith, Stephen D. Redman, Mary Dunleavy, Kieron TI FDG PET-CT in follicular lymphoma: a case-based evidence review SO BLOOD LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; NON-HODGKINS-LYMPHOMA; FONDAZIONE ITALIANA LINFOMI; STANDARDIZED UPTAKE VALUES; MINIMAL RESIDUAL DISEASE; B-CELL LYMPHOMA; FOLL05 TRIAL; STANFORD-UNIVERSITY; RESPONSE ASSESSMENT; INITIAL TREATMENT AB A 52-year-old woman develops right neck lymphadenopathy in the absence of systemic symptoms. Excisional biopsy specimen shows grade 1-2 follicular lymphoma (FL). Physical examination reveals a cluster of 1- to 2-cm right cervical nodes but no other abnormalities. Lactate dehydrogenase is 400 U/L (normal: 140-210 U/L), beta-2 microglobulin is 4.1 mu g/mL (normal: 0-2.5 mu g/mL), and a complete blood count with differential is normal. 18-Fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) is performed, showing FDG-avid lymphadenopathy above and below the diaphragm, ranging in size from 1.2 to 6 cm. Three FDG-avid lymph nodes measure more than 3 cm. A single 6-cm pelvic node has a maximum standardized uptake value (SUVmax) of 22, and other SUVs range from 6 to 8. An absence of FDG marrow uptake is noted. How should these PET-CT findings be integrated into further evaluation, prognostication, and treatment recommendations for this patient with FL? Should repeat PET-CT be performed on completion of therapy? C1 [Smith, Stephen D.] Univ Washington, Sch Med, Dept Med, Div Med Oncol,Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Redman, Mary] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Dunleavy, Kieron] NCI, Lymphoid Malignancies Branch, Bethesda, MD 20892 USA. RP Smith, SD (reprint author), Seattle Canc Care Alliance, Box G3-200, Seattle, WA 98109 USA. EM ssmith50@u.washington.edu NR 51 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 12 PY 2015 VL 125 IS 7 BP 1078 EP 1082 DI 10.1182/blood-2014-11-537522 PG 5 WC Hematology SC Hematology GA CD1FB UT WOS:000350818800009 PM 25527711 ER PT J AU Kim, YC Zhang, AH Su, Y Rieder, SA Rossi, RJ Ettinger, RA Pratt, KP Shevach, EM Scott, DW AF Kim, Yong Chan Zhang, Ai-Hong Su, Yan Rieder, Sadiye Amcaoglu Rossi, Robert J. Ettinger, Ruth A. Pratt, Kathleen P. Shevach, Ethan M. Scott, David W. TI Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses SO BLOOD LA English DT Article ID LATENT TGF-BETA; FACTOR-VIII; HEMOPHILIA-A; SUPPRESSOR FUNCTION; IN-VITRO; IMMUNE-RESPONSES; GENE-EXPRESSION; RECEPTOR; FOXP3(+); ACTIVATION AB Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients. C1 [Kim, Yong Chan; Zhang, Ai-Hong; Su, Yan; Rossi, Robert J.; Pratt, Kathleen P.; Scott, David W.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Rieder, Sadiye Amcaoglu; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Rockville, MD USA. [Ettinger, Ruth A.] Puget Sound Blood Ctr, Res Inst, Seattle, WA 98104 USA. RP Scott, DW (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med MED, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM david.scott@usuhs.edu FU National Institutes of Health National Heart, Lung, and Blood Institue [RO1-HL061883-15]; Bayer; CSL Behring; National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health National Heart, Lung, and Blood Institue grant RO1-HL061883-15 (to D.W.S.), funding from Bayer and CSL Behring (to K.P.P.), and intramural support from the National Institute of Allergy and Infectious Diseases (to E.M.S.). NR 51 TC 21 Z9 22 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 12 PY 2015 VL 125 IS 7 BP 1107 EP 1115 DI 10.1182/blood-2014-04-566786 PG 9 WC Hematology SC Hematology GA CD1FB UT WOS:000350818800013 PM 25498909 ER PT J AU Iqbal, J Shen, YL Huang, X Liu, YY Wake, L Liu, CL Deffenbacher, K Lachel, CM Wang, C Rohr, J Guo, SP Smith, LM Wright, G Bhagavathi, S Dybkaer, K Fu, K Greiner, TC Vose, JM Jaffe, E Rimsza, L Rosenwald, A Ott, G Delabie, J Campo, E Braziel, RM Cook, JR Tubbs, RR Armitage, JO Weisenburger, DD Staudt, LM Gascoyne, RD McKeithan, TW Chan, WC AF Iqbal, Javeed Shen, Yulei Huang, Xin Liu, Yanyan Wake, Laura Liu, Cuiling Deffenbacher, Karen Lachel, Cynthia M. Wang, Chao Rohr, Joseph Guo, Shuangping Smith, Lynette M. Wright, George Bhagavathi, Sharathkumar Dybkaer, Karen Fu, Kai Greiner, Timothy C. Vose, Julie M. Jaffe, Elaine Rimsza, Lisa Rosenwald, Andreas Ott, German Delabie, Jan Campo, Elias Braziel, Rita M. Cook, James R. Tubbs, Raymond R. Armitage, James O. Weisenburger, Dennis D. Staudt, Louis M. Gascoyne, Randy D. McKeithan, Timothy W. Chan, Wing C. TI Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma SO BLOOD LA English DT Article ID GERMINAL CENTER; BURKITTS-LYMPHOMA; TUMOR-SUPPRESSOR; GASTRIC-CANCER; R-CHOP; SURVIVAL; PATHWAY; DIAGNOSIS; PROTEIN; GROWTH AB We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naive B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog(MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. C1 [Iqbal, Javeed; Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Bhagavathi, Sharathkumar; Fu, Kai; Greiner, Timothy C.; McKeithan, Timothy W.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68105 USA. [Smith, Lynette M.] Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE 68105 USA. [Wright, George; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dybkaer, Karen] Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark. [Vose, Julie M.; Armitage, James O.] Univ Nebraska Med Ctr, Dept Hematol Oncol, Omaha, NE 68105 USA. [Jaffe, Elaine] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rimsza, Lisa] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dr Margareta Fischer Bosch Inst Clin Pharmacol, Dept Clin Pathol, Stuttgart, Germany. [Delabie, Jan] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Clin Pathol, Portland, OR 97201 USA. [Cook, James R.; Tubbs, Raymond R.] Cleveland Clin, Robert J Tomsich Pathol & Lab Med Inst, Cleveland, OH 44106 USA. [Weisenburger, Dennis D.; McKeithan, Timothy W.; Chan, Wing C.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. RP Iqbal, J (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, LTC 11714,Zip 7760, Omaha, NE 68105 USA. EM jiqbal@unmc.edu; jochan@coh.org RI Campo, elias/O-7192-2016; OI Campo, elias/0000-0001-9850-9793; McKeithan, Timothy/0000-0003-2242-3074 FU National Institutes of Health National Cancer Institute [1U01CA157581-01]; Lymphoma Research Foundation; Leukemia & Lymphoma Society; University of Nebraska Medical Center (UNMC)-Clinical and Translational Research mentored Scholars program pilot grant FX This work was supported by a grant from the National Institutes of Health National Cancer Institute (1U01CA157581-01 [W.C.C.]) and is part of the Lymphoma/Leukemia Molecular profiling project (LLMPP). J.I. has received support from the Lymphoma Research Foundation, the Leukemia & Lymphoma Society, and the University of Nebraska Medical Center (UNMC)-Clinical and Translational Research mentored Scholars program pilot grant. NR 52 TC 21 Z9 22 U1 2 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 12 PY 2015 VL 125 IS 7 BP 1137 EP 1145 DI 10.1182/blood-2014-04-566778 PG 9 WC Hematology SC Hematology GA CD1FB UT WOS:000350818800016 PM 25498913 ER PT J AU He, JT Schepmoes, AA Shi, TJ Wu, CC Fillmore, TL Gao, YQ Smith, RD Qian, WJ Rodland, KD Liu, T Camp, DG Rastogi, A Tan, SH Yan, WS Mohamed, AA Huang, W Banerjee, S Kagan, J Srivastava, S McLeod, DG Srivastava, S Petrovics, G Dobi, A Srinivasan, A AF He, Jintang Schepmoes, Athena A. Shi, Tujin Wu, Chaochao Fillmore, Thomas L. Gao, Yuqian Smith, Richard D. Qian, Wei-Jun Rodland, Karin D. Liu, Tao Camp, David G., II Rastogi, Anshu Tan, Shyh-Han Yan, Wusheng Mohamed, Ahmed A. Huang, Wei Banerjee, Sreedatta Kagan, Jacob Srivastava, Sudhir McLeod, David G. Srivastava, Shiv Petrovics, Gyorgy Dobi, Albert Srinivasan, Alagarsamy TI Analytical platform evaluation for quantification of ERG in prostate cancer using protein and mRNA detection methods SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE ERG; Quantification; Biomarker; PRISM-SRM; MRM; Mass spectrometry; ELISA; Prostate cancer; Diagnosis ID TARGETED QUANTIFICATION; QUANTITATIVE PROTEOMICS; ONCOPROTEIN EXPRESSION; GENE-EXPRESSION; ANTIBODY-FREE; FUSION; STRATIFICATION; PROGRESSION; FREQUENCY; ONCOGENE AB Background: The established methods for detecting prostate cancer (CaP) are based on tests using PSA (blood), PCA3 (urine), and AMACR (tissue) as biomarkers in patient samples. The demonstration of ERG oncoprotein overexpression due to gene fusion in CaP has thus provided ERG as an additional biomarker. Based on this, we hypothesized that ERG protein quantification methods can be of use in the diagnosis of prostate cancer. Methods: An antibody-free assay for ERG3 protein detection was developed based on PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry. We utilized TMPRSS2-ERG positive VCaP and TMPRSS2-ERG negative LNCaP cells to simulate three different sample types (cells, tissue, and post-DRE urine sediment). Enzyme-linked immunosorbent assay (ELISA), western blot, NanoString, and qRT-PCR were also used in the analysis of these samples. Results: Recombinant ERG3 protein spiked into LNCaP cell lysates could be detected at levels as low as 20 pg by PRISM-SRM analysis. The sensitivity of the PRISM-SRM assay was approximately 10,000 VCaP cells in a mixed cell population model of VCaP and LNCaP cells. Interestingly, ERG protein could be detected in as few as 600 VCaP cells spiked into female urine. The sensitivity of the in-house ELISA was similar to the PRISM-SRM assay, with detection of 30 pg of purified recombinant ERG3 protein and 10,000 VCaP cells. On the other hand, qRT-PCR exhibited a higher sensitivity, as TMPRSS2-ERG transcripts were detected in as few as 100 VCaP cells, in comparison to NanoString methodologies which detected ERG from 10,000 cells. Conclusions: Based on this data, we propose that the detection of both ERG transcriptional products with RNA-based assays, as well as protein products of ERG using PRISM-SRM assays, may be of clinical value in developing diagnostic and prognostic assays for prostate cancer given their sensitivity, specificity, and reproducibility. C1 [He, Jintang; Schepmoes, Athena A.; Shi, Tujin; Wu, Chaochao; Gao, Yuqian; Smith, Richard D.; Qian, Wei-Jun; Rodland, Karin D.; Liu, Tao; Camp, David G., II] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Fillmore, Thomas L.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Rastogi, Anshu; Tan, Shyh-Han; Yan, Wusheng; Mohamed, Ahmed A.; Huang, Wei; Banerjee, Sreedatta; McLeod, David G.; Srivastava, Shiv; Petrovics, Gyorgy; Dobi, Albert; Srinivasan, Alagarsamy] Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Bethesda, MD 20814 USA. [Kagan, Jacob; Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [McLeod, David G.] Walter Reed Natl Mil Med Ctr, Urol Serv, Bethesda, MD USA. RP Srinivasan, A (reprint author), Uniformed Serv Univ Hlth Sci, Dept Surg, Ctr Prostate Dis Res, Bethesda, MD 20814 USA. EM asrinivasan@cpdr.org RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Tan, Shyh-Han/0000-0001-8250-7005 FU National Cancer Institute (NCI) Early Detection Research Network (EDRN) Interagency Agreement [ACN12003-001-00000]; National Institutes of Health [P41GM103493]; DoD/CDMRP/PCRP [PC073614]; NCI/EDRN [ACN12011-001-0]; Department of Energy and located at Pacific Northwest National Laboratory; Department of Energy [DE-AC05-76RL0 1830]; Center for Prostate Disease Research; Basic Science Research Program; Department of Surgery, at Uniformed Services University of the Health Sciences FX Portions of this work were supported by the National Cancer Institute (NCI) Early Detection Research Network (EDRN) Interagency Agreement ACN12003-001-00000 (to K.D.R. and D.G.C.) and National Institutes of Health grant P41GM103493 (to R.D.S.), as well as the DoD/CDMRP/PCRP grant PC073614 (to S.S.) and the NCI/EDRN ACN12011-001-0 (to S.S.). The experimental work described herein was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the Department of Energy under Contract DE-AC05-76RL0 1830, as well as The Center for Prostate Disease Research, under the Basic Science Research Program under the Department of Surgery, at the Uniformed Services University of the Health Sciences. NR 38 TC 7 Z9 8 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 12 PY 2015 VL 13 AR 54 DI 10.1186/s12967-015-0418-z PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC6VL UT WOS:000350507000003 PM 25889691 ER PT J AU Yi, CJ Wu, CO Tee, M Liu, CY Volpe, GJ Prince, MR Hundley, GW Gomes, AS van der Geest, RJ Heckbert, S Lima, JA Bluemke, DA AF Yi, Colin J. Wu, Colin O. Tee, Michael Liu, Chia-Ying Volpe, Gustavo J. Prince, Martin R. Hundley, Gregory W. Gomes, Antoinette S. van der Geest, Rob J. Heckbert, Susan Lima, Joao A. Bluemke, David A. TI The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA) SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Myocardium; Cardiovascular magnetic resonance; Risk factors ID DIFFUSE MYOCARDIAL FIBROSIS; CORONARY-HEART-DISEASE; CARDIAC FIBROSIS; FABRY DISEASE; PROFESSIONALS; CHOLESTEROL; FRAMINGHAM; STATEMENT; FAILURE; CALCIUM AB Background: Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T-1 mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis. Methods: CVD risk scores for 1208 subjects (men, 50.8%) ages 55-94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T-1 times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T-1, 12 and 25 minute post-gadolinium T-1, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001). Results: 25 minute post gadolinium T-1 time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e. g. native T-1 (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index. Conclusions: Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T-1 times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T-1 time. C1 [Yi, Colin J.; Tee, Michael; Liu, Chia-Ying; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Volpe, Gustavo J.; Lima, Joao A.; Bluemke, David A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Prince, Martin R.] Cornell Univ, Cornell MRI Facil, Ithaca, NY USA. [Hundley, Gregory W.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Gomes, Antoinette S.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [van der Geest, Rob J.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Heckbert, Susan] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI van der Geest, Rob/J-8193-2015; Prince, Martin/S-6850-2016; OI van der Geest, Rob/0000-0002-9084-5597; Bluemke, David/0000-0002-8323-8086; Prince, Martin/0000-0002-9883-0584 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95166, N01-HC-95169]; NIH research program FX This research was supported by contracts N01-HC-95159 through N01-HC-95166 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and the intramural NIH research program. Gadolinium contrast was provided without charge by Bayer Healthcare. We thank the other investigators, staff, and participants of the MESA and MESA-Lung Studies for their valuable contributions. A full list of participating MESA Investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 32 TC 4 Z9 4 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 FEB 12 PY 2015 VL 17 AR 15 DI 10.1186/s12968-015-0121-5 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CB9IQ UT WOS:000349945600004 PM 25827220 ER PT J AU Subramanian, V Knight, JS Parelkar, S Anguish, L Coonrod, SA Kaplan, MJ Thompson, PR AF Subramanian, Venkataraman Knight, Jason S. Parelkar, Sangram Anguish, Lynne Coonrod, Scott A. Kaplan, Mariana J. Thompson, Paul R. TI Design, Synthesis, and Biological Evaluation of Tetrazole Analogs of CI-Amidine as Protein Arginine Deiminase Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PEPTIDYLARGININE DEIMINASE; RHEUMATOID-ARTHRITIS; PROTEIN-ARGININE-DEIMINASE-4 PAD4; CITRULLINATED PROTEINS; IN-VITRO; MURINE MODELS; CL-AMIDINE; PATHOGENESIS AB Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiology of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isozyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isozyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isozymes. Importantly, one of the compounds, biphenyl tetrazole tert-butyl Cl-amidine (compound 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs. C1 [Subramanian, Venkataraman; Parelkar, Sangram; Thompson, Paul R.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. [Knight, Jason S.] Univ Michigan, Sch Med, Div Rheumatol, Ann Arbor, MI 48109 USA. [Anguish, Lynne; Coonrod, Scott A.] Cornell Univ, Coll Vet Med, Baker Inst Anim Hlth, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Kaplan, Mariana J.] NIAMSD, Bethesda, MD 20892 USA. RP Thompson, PR (reprint author), Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, 364 Plantat St, Worcester, MA 01605 USA. EM Paul.Thompson@umassmed.edu FU NIH [GM079357, GM110394]; NIAMS FX The authors are most grateful to Rose L. Szabady and Beth McCormick for providing the human neutrophils for the cytotoxicity studies. Financial support for this work was provided by NIH Grants GM079357 (P.R.T.) and GM110394 (P.R.T. and S.A.C.) and in part by the intramural research program at NIAMS. NR 60 TC 11 Z9 11 U1 3 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 12 PY 2015 VL 58 IS 3 BP 1337 EP 1344 DI 10.1021/jm501636x PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CB4BS UT WOS:000349573800024 PM 25559347 ER PT J AU Shungin, D Winkler, TW Croteau-Chonka, DC Ferreira, T Lockes, AE Magi, R Strawbridge, RJ Pers, TH Fischer, K Justice, AE Workalemahu, T Wu, JMW Buchkovich, ML Heard-Costa, NL Roman, TS Drong, AW Song, C Gustafsson, S Day, FR Esko, T Fall, T Kutalik, Z Luan, JA Randall, JC Scherag, A Vedantam, S Wood, AR Chen, J Fehrmann, R Karjalainen, J Kahali, B Liu, CT Schmidt, EM Absher, D Amin, N Anderson, D Beekman, M Bragg-Gresham, JL Buyske, S Demirkan, A Ehret, GB Feitosa, MF Goel, A Jackson, AU Johnson, T Kleber, ME Kristiansson, K Mangino, M Leach, IM Medina-Gomez, C Palmer, CD Pasko, D Pechlivaniss, S Peters, MJ Prokopenko, I Stancakova, A Sung, YJ Tanakam, T Teumer, A Van Vliet-Ostaptchouk, JV Yengo, L Zhang, WH Albrecht, E Arnlov, J Arscott, GM Bandinelli, S Barrett, A Bellis, C Bennett, AJ Berne, C Bluher, M Buhringer, S Bonnet, F Bottcher, Y Bruinenberg, M Carba, DB Caspersen, IH Clarke, R Daw, EW Deelen, J Deelman, E Delgado, G Doney, ASF Eklund, N Erdos, MR Estrada, K Eury, E Friedrichs, N Garcia, ME Giedraitis, V Gigante, B Go, AS Golay, A Grallert, H Grammer, TB Grassler, J Grewal, J Groves, CJ Haller, T Hallmans, G Hartman, CA Hassinen, M Hayward, C Heikkila, K Herzig, KH Helmer, Q Hillege, HL Holmen, O Hunt, SC Isaacs, A Ittermann, T James, AL Johansson, I Juliusdottir, T Kalafati, IP Kinnunen, L Koenig, W Kooner, IK Kratzer, W Lamina, C Leander, K Lee, NR Lichtner, P Lind, L Lindstrom, J Lobbens, S Lorentzon, M Mach, F Magnusson, PKE Mahajan, A McArdle, WL Menni, C Merger, S Mihailov, E Milani, L Mills, R Moayyeri, A Monda, KL Mooijaart, SP Muhleisen, TW Mulas, A Muller, G Muller-Nurasyid, M Nagaraja, R Nalls, MA Narisu, N Glorioso, N Nolte, IM Olden, M Rayner, NW Renstrom, F Ried, JS Robertson, NR Rose, LM Sanna, S Scharnagl, H Scholtens, S Sennblad, B Seufferlein, T Sitlani, CM Smith, AV Stirrups, K Stringhams, HM Sundstrom, J Swertz, MA Swift, AJ Syvanen, AC Tayo, BO Thorand, B Thorleifsson, G Tomaschitz, A Troffa, C van Oort, FVA Verweij, N Vonk, JM Waite, LL Wennauer, R Wilsgaard, T Wojczynski, MK Wong, A Zhang, QY Zhao, JH Brennan, EP Choi, M Eriksson, P Folkersen, L Franco-Cereceda, A Gharavi, AG Hedman, AK Hivert, MF Huang, JY Kanoni, S Karpe, F Keildson, S Kiryluk, K Liang, LM Lifton, RP Ma, BS McKnight, AJ McPherson, R Metspalu, A Min, JL Moffatt, MF Montgomery, GW Murabito, JM Nicholson, G Nyholt, DR Olsson, C Perry, JRB Reinmaa, E Salem, RM Sandholm, N Schadt, EE Scott, R Stolk, L Vallejo, EE Westra, HJ Zondervan, KT Amouyel, P Arveiler, D Bakker, SJL Beilby, J Bergman, RN Blangero, J Brown, MJ Burnier, M Campbell, H Chakravarti, A Chiness, PS Claudi-Boehmi, S Collins, FS Crawford, DC Danesh, J de Faire, U de Geusl, EJC Dorr, M Erbel, R Eriksson, JG Farrall, M Ferrannini, E Ferrieres, J Forouhi, NG Forrester, T Franco, OH Gansevoort, RT Gieger, C Gudnason, V Haiman, CA Harris, TB Hattersley, AT Heliovaara, M Hicks, AA Hingorani, AD Hoffmann, W Hofman, A Homuth, G Humphries, SE Hypponen, E Illig, T Jarvelin, MR Johansen, B Jousilahti, P Jula, AM Kaprio, J Kee, F Keinanen-Kiukaanniemi, SM Kooner, JS Kooperberg, C Kovacs, P Kraja, AT Kumari, M Kuulasmaa, K Kuusisto, J Lakka, TA Langenberg, C Le Marchand, L Lehtimaki, T Lyssenko, V Mannisto, S Marette, A Matise, TC McKenzie, CA McKnight, B Musk, AW Mohlenkamp, S Morris, AD Nelis, M Ohlsson, C Oldehinkel, AJ Ong, KK Palmer, LJ Penninx, BW Peters, A Pramstaller, PP Raitakari, OT Rankinen, T Rao, DC Rice, TK Ridker, PM Ritchie, MD Rudan, I Salomaa, V Samani, NJ Saramies, J Sarzynski, MA Schwarz, PEH Shuldiner, AR Staessen, JA Steinthorsdottir, V Stolk, RP Strauch, K Tonjes, A Tremblay, A Tremoli, E Vohl, MC Volker, U Vollenweider, P Wilson, JF Witteman, JC Adair, LS Bochud, M Boehm, BO Bornstein, SR Bouchard, C Cauchi, S Caulfield, MJ Chambers, JC Chasman, DI Cooper, RS Dedoussis, G Ferrucci, L Froguel, P Grabe, HJ Hamsten, A Hui, JN Hveem, K Jockel, KH Kivimaki, M Kuh, D Laakso, M Liu, YM Marz, W Munroe, PB Njolstad, I Oostra, BA Palmer, CNA Pedersen, NL Perola, M Perusse, L Peters, U Power, C Quertermous, T Rauramaa, R Rivadeneira, F Saaristo, TE Saleheen, D Sinisalo, J Slagboom, PE Snieder, H Spector, TD Thorsteinsdottir, UR Stumvoll, M Tuomilehto, J Uitterlinden, AG Uusitupa, M van der Harst, P Veronesi, G Walker, M Wareham, NJ Watkins, H Wichmann, HE Abecasis, GR Assimes, TL Berndt, SI Boehnkes, M Borecki, IB Deloukas, P Franke, L Frayling, TM Groop, LC Hunter, DJ Kaplan, RC O'Connell, JR Qi, L Schlessinger, D Strachan, DP Stefansson, K van Dujin, CM Willer, CJ Visscher, PM Yang, J Hirschhorn, JN Zillikens, MC McCarthy, MI Speliotes, EK North, KE Fox, CS Barroso, I Franks, PW Ingelsson, E Heid, IM Loos, RJF Cupples, LA Morris, AP Lindgren, CM Mohlke, KL AF Shungin, Dmitry Winkler, Thomas W. Croteau-Chonka, Damien C. Ferreira, Teresa Lockes, Adam E. Maegi, Reedik Strawbridge, Rona J. Pers, Tune H. Fischer, Krista Justice, Anne E. Workalemahu, Tsegaselassie Wu, Joseph M. W. Buchkovich, Martin L. Heard-Costa, Nancy L. Roman, Tamara S. Drong, Alexander W. Song, Ci Gustafsson, Stefan Day, Felix R. Esko, Tonu Fall, Tove Kutalik, Zoltan Luan, Jian'an Randall, Joshua C. Scherag, Andre Vedantam, Sailaja Wood, Andrew R. Chen, Jin Fehrmann, Rudolf Karjalainen, Juha Kahali, Bratati Liu, Ching-Ti Schmidt, Ellen M. Absher, Devin Amin, Najaf Anderson, Denise Beekman, Marian Bragg-Gresham, Jennifer L. Buyske, Steven Demirkan, Ayse Ehret, Georg B. Feitosa, Mary F. Goel, Anuj Jackson, Anne U. Johnson, Toby Kleber, Marcus E. Kristiansson, Kati Mangino, Massimo Leach, Irene Mateo Medina-Gomez, Carolina Palmer, Cameron D. Pasko, Dorota Pechlivaniss, Sonali Peters, Marjolein J. Prokopenko, Inga Stancakova, Alena Sung, Yun Ju Tanakam, Toshiko Teumer, Alexander Van Vliet-Ostaptchouk, Jana V. Yengo, Loic Zhang, Weihua Albrecht, Eva Arnlov, Johan Arscott, Gillian M. Bandinelli, Stefania Barrett, Amy Bellis, Claire Bennett, Amanda J. Berne, Christian Blueher, Matthias Buhringer, Stefan Bonnet, Fabrice Boettcher, Yvonne Bruinenberg, Marcel Carba, Delia B. Caspersen, Ida H. Clarke, Robert Daw, E. Warwick Deelen, Joris Deelman, Ewa Delgado, Graciela Doney, Alex S. F. Eklund, Niina Erdos, Michael R. Estrada, Karol Eury, Elodie Friedrichs, Nele Garcia, Melissa E. Giedraitis, Vilmantas Gigante, Bruna Go, Alan S. Golay, Alain Grallert, Harald Grammer, Tanja B. Graessler, Juergen Grewal, Jagvir Groves, Christopher J. Haller, Toomas Hallmans, Goran Hartman, Catharina A. Hassinen, Maija Hayward, Caroline Heikkila, Kauko Herzig, Karl-Heinz Helmer, Quinta Hillege, Hans L. Holmen, Oddgeir Hunt, Steven C. Isaacs, Aaron Ittermann, Till James, Alan L. Johansson, Ingegerd Juliusdottir, Thorhildur Kalafati, Ioanna-Panagiota Kinnunen, Leena Koenig, Wolfgang Kooner, Ishminder K. Kratzer, Wolfgang Lamina, Claudia Leander, Karin Lee, Nanette R. Lichtner, Peter Lind, Lars Lindstrom, Jaana Lobbens, Stephane Lorentzon, Mattias Mach, Francois Magnusson, Patrik K. E. Mahajan, Anubha McArdle, Wendy L. Menni, Cristina Merger, Sigrun Mihailov, Evelin Milani, Lili Mills, Rebecca Moayyeri, Alireza Monda, Ken L. Mooijaart, Simon P. Muehleisen, Thomas W. Mulas, Antonella Mueller, Gabriele Mueller-Nurasyid, Martina Nagaraja, Ramaiah Nalls, Michael A. Narisu, Narisu Glorioso, Nicola Nolte, Ilja M. Olden, Matthias Rayner, Nigel W. Renstrom, Frida Ried, Janina S. Robertson, Neil R. Rose, Lynda M. Sanna, Serena Scharnagl, Hubert Scholtens, Salome Sennblad, Bengt Seufferlein, Thomas Sitlani, Colleen M. Smith, Albert Vernon Stirrups, Kathleen Stringham, Heather M. Sundstrom, Johan Swertz, Morris A. Swift, Amy J. Syvanen, Ann-Christine Tayo, Bamidele O. Thorand, Barbara Thorleifsson, Gudmar Tomaschitz, Andreas Troffa, Chiara van Oort, Floor V. A. Verweij, Niek Vonk, Judith M. Waite, Lindsay L. Wennauer, Roman Wilsgaard, Tom Wojczynski, Mary K. Wong, Andrew Zhang, Qunyuan Zhao, Jing Hua Brennan, Eoin P. Choi, Murim Eriksson, Per Folkersen, Lasse Franco-Cereceda, Anders Gharavi, Ali G. Hedman, Asa K. Hivert, Marie-France Huang, Jinyan Kanoni, Stavroula Karpe, Fredrik Keildson, Sarah Kiryluk, Krzysztof Liang, Liming Lifton, Richard P. Ma, Baoshan McKnight, Amy J. McPherson, Ruth Metspalu, Andres Min, Josine L. Moffatt, Miriam F. Montgomery, Grant W. Murabito, Joanne M. Nicholson, George Nyholt, Dale R. Olsson, Christian Perry, John R. B. Reinmaa, Eva Salem, Rany M. Sandholm, Niina Schadt, Eric E. Scott, Robert A. Stolk, Lisette Vallejo, Edgar E. Westra, Harm-Jan Zondervan, Krina T. Amouyel, Philippe Arveiler, Dominique Bakker, Stephan J. L. Beilby, John Bergman, Richard N. Blangero, John Brown, Morris J. Burnier, Michel Campbell, Harry Chakravarti, Aravinda Chiness, Peter S. Claudi-Boehmi, Simone Collins, Francis S. Crawford, Dana C. Danesh, John de Faire, Ulf de Geusl, Eco J. C. Doerr, Marcus Erbel, Raimund Eriksson, Johan G. Farrall, Martin Ferrannini, Ele Ferrieres, Jean Forouhi, Nita G. Forrester, Terrence Franco, Oscar H. Gansevoort, Ron T. Gieger, Christian Gudnason, Vilmundur Haiman, Christopher A. Harris, Tamara B. Hattersley, Andrew T. Heliovaara, Markku Hicks, Andrew A. Hingorani, Aroon D. Hoffmann, Wolfgang Hofman, Albert Homuth, Georg Humphries, Steve E. Hyppoenen, Elina Illig, Thomas Jarvelin, Marjo-Riitta Johansen, Berit Jousilahti, Pekka Jula, Antti M. Kaprio, Jaakko Kee, Frank Keinanen-Kiukaanniemi, Sirkka M. Kooner, Jaspal S. Kooperberg, Charles Kovacs, Peter Kraja, Aldi T. Kumari, Meena Kuulasmaa, Kari Kuusisto, Johanna Lakka, Timo A. Langenberg, Claudia Le Marchand, Loic Lehtimaki, Terho Lyssenko, Valeriya Mannisto, Satu Marette, Andre Matise, Tara C. McKenzie, Colin A. McKnight, Barbara Musk, Arthur W. Mohlenkamp, Stefan Morris, Andrew D. Nelis, Mari Ohlsson, Claes Oldehinkel, Albertine J. Ong, Ken K. Palmer, Lyle J. Penninx, Brenda W. Peters, Annette Pramstaller, Peter P. Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rice, Treva K. Ridker, Paul M. Ritchie, Marylyn D. Rudan, Igor Salomaa, Veikko Samani, Nilesh J. Saramies, Jouko Sarzynski, Mark A. Schwarz, Peter E. H. Shuldiner, Alan R. Staessen, Jan A. Steinthorsdottir, Valgerdur Stolk, Ronald P. Strauch, Konstantin Toenjes, Anke Tremblay, Angelo Tremoli, Elena Vohl, Marie-Claude Voelker, Uwe Vollenweider, Peter Wilson, James F. Witteman, Jacqueline C. Adair, Linda S. Bochud, Murielle Boehm, Bernhard O. Bornstein, Stefan R. Bouchard, Claude Cauchi, Stephane Caulfield, Mark J. Chambers, John C. Chasman, Daniel I. Cooper, Richard S. Dedoussis, George Ferrucci, Luigi Froguel, Philippe Grabe, Hans-Joergen Hamsten, Anders Hui, Jennie Hveem, Kristian Joeckel, Karl-Heinz Kivimaki, Mika Kuh, Diana Laakso, Markku Liu, Yongmei Maerz, Winfried Munroe, Patricia B. Njolstad, Inger Oostra, Ben A. Palmer, Colin N. A. Pedersen, Nancy L. Perola, Markus Perusse, Louis Peters, Ulrike Power, Chris Quertermous, Thomas Rauramaa, Rainer Rivadeneira, Fernando Saaristo, Timo E. Saleheen, Danish Sinisalo, Juha Slagboom, P. Eline Snieder, Harold Spector, Tim D. Thorsteinsdottir, Unnur R. Stumvoll, Michael Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Math van der Harst, Pim Veronesi, Giovanni Walker, Mark Wareham, Nicholas J. Watkins, Hugh Wichmann, H-Erich Abecasis, Goncalo R. Assimes, Themistocles L. Berndt, Sonja I. Boehnkes, Michael Borecki, Ingrid B. Deloukas, Panos Franke, Lude Frayling, Timothy M. Groop, Leif C. Hunter, David J. Kaplan, Robert C. O'Connell, Jeffrey R. Qi, Lu Schlessinger, David Strachan, David P. Stefansson, Kari van Dujin, Cornelia M. Willer, Cristen J. Visscher, Peter M. Yang, Jian Hirschhorn, Joel N. Zillikens, M. Carola McCarthy, Mark I. Speliotes, Elizabeth K. North, Kari E. Fox, Caroline S. Barroso, Ines Franks, Paul W. Ingelsson, Erik Heid, Iris M. Loos, Ruth J. F. Cupples, L. Adrienne Morris, Andrew P. Lindgren, Cecilia M. Mohlke, Karen L. CA ADIPOGEN Consortium CARDIOGRAMplusC4D Consortium CKDGen Consortium GEFOS Consortium GENIE Consortium GLGC ICBP Int Endogene Consortium LifeLines Cohort Study MAGIC Investigators MuTHER Consortium PAGE Consortium ReproGen Consortium TI New genetic loci link adipose and insulin biology to body fat distribution SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; MESENCHYMAL STEM-CELLS; HUMAN HEIGHT; ADIPOGENIC DIFFERENTIATION; ABDOMINAL ADIPOSITY; SUSCEPTIBILITY LOCI; SEXUAL-DIMORPHISM; GLYCEMIC TRAITS; FALSE DISCOVERY; COMMON SNPS AB Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. C1 [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Med Unit, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Lund Univ, Ctr Diabet, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, S-20502 Malmo, Sweden. [Shungin, Dmitry; Johansson, Ingegerd] Umea Univ, Dept Oncol, S-90185 Umea, Sweden. [Winkler, Thomas W.; Olden, Matthias; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Croteau-Chonka, Damien C.; Buchkovich, Martin L.; Roman, Tamara S.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Croteau-Chonka, Damien C.; Hunter, David J.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Croteau-Chonka, Damien C.; Estrada, Karol; Ridker, Paul M.; Chasman, Daniel I.; Hunter, David J.; Qi, Lu] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ferreira, Teresa; Maegi, Reedik; Drong, Alexander W.; Randall, Joshua C.; Goel, Anuj; Prokopenko, Inga; Juliusdottir, Thorhildur; Mahajan, Anubha; Rayner, Nigel W.; Robertson, Neil R.; Hedman, Asa K.; Keildson, Sarah; Perry, John R. B.; Zondervan, Krina T.; Farrall, Martin; Watkins, Hugh; McCarthy, Mark I.; Ingelsson, Erik; Morris, Andrew P.; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Lockes, Adam E.; Bragg-Gresham, Jennifer L.; Jackson, Anne U.; Stringham, Heather M.; Abecasis, Goncalo R.; Boehnkes, Michael] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. [Maegi, Reedik; Fischer, Krista; Esko, Tonu; Haller, Toomas; Mihailov, Evelin; Milani, Lili; Metspalu, Andres; Reinmaa, Eva; Nelis, Mari; Perola, Markus; Morris, Andrew P.] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Strawbridge, Rona J.; Sennblad, Bengt; Eriksson, Per; Folkersen, Lasse; Hamsten, Anders] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden. [Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Estrada, Karol; Salem, Rany M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Pers, Tune H.; Esko, Tonu; Vedantam, Sailaja; Palmer, Cameron D.; Estrada, Karol; Salem, Rany M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.] Harvard Univ, Cambridge, MA 02142 USA. [Pers, Tune H.; Esko, Tonu; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Dept Genet, Boston, MA 02115 USA. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Justice, Anne E.; Monda, Ken L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Workalemahu, Tsegaselassie; Hunter, David J.; Qi, Lu; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Wu, Joseph M. W.; Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Heard-Costa, Nancy L.; Murabito, Joanne M.; Fox, Caroline S.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Song, Ci; Fall, Tove; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Song, Ci; Gustafsson, Stefan; Fall, Tove; Arnlov, Johan; Syvanen, Ann-Christine; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75185 Uppsala, Sweden. [Song, Ci; Gustafsson, Stefan; Fall, Tove; Arnlov, Johan; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Day, Felix R.; Luan, Jian'an; Zhao, Jing Hua; Scott, Robert A.; Forouhi, Nita G.; Langenberg, Claudia; Ong, Ken K.; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Kutalik, Zoltan] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland. [Kutalik, Zoltan; Johnson, Toby] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Kutalik, Zoltan; Johnson, Toby] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Randall, Joshua C.; Rayner, Nigel W.; Stirrups, Kathleen; Deloukas, Panos; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Scherag, Andre; Pechlivaniss, Sonali; Joeckel, Karl-Heinz] Univ Hosp Essen, IMIBE, D-45147 Essen, Germany. [Scherag, Andre] Jena Univ Hosp, CSCC, Clin Epidemiol Integrated Res & Treatment Ctr, D-07743 Jena, Germany. [Wood, Andrew R.; Pasko, Dorota; Perry, John R. B.; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Chen, Jin; Willer, Cristen J.] Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Fehrmann, Rudolf; Karjalainen, Juha; Swertz, Morris A.; Westra, Harm-Jan; van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Schmidt, Ellen M.; Willer, Cristen J.; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Absher, Devin; Waite, Lindsay L.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Amin, Najaf; Demirkan, Ayse; Isaacs, Aaron; Oostra, Ben A.; van Dujin, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Anderson, Denise] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6008, Australia. [Beekman, Marian; Buhringer, Stefan; Deelen, Joris; Helmer, Quinta; Mooijaart, Simon P.; Stolk, Lisette; Slagboom, P. Eline] Leiden Univ, Med Ctr, NCHA, NL-2300 RC Leiden, Netherlands. [Beekman, Marian; Deelen, Joris; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands. [Bragg-Gresham, Jennifer L.] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Demirkan, Ayse] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet c Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland. [Feitosa, Mary F.; Daw, E. Warwick; Zhang, Qunyuan; Kraja, Aldi T.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. [Johnson, Toby] Univ Lausanne, CHUV, Univ Inst Social & Preventat Med, CH-1005 Lausanne, Switzerland. [Kleber, Marcus E.; Delgado, Graciela; Grammer, Tanja B.; Smith, Albert Vernon; Maerz, Winfried] Heidelberg Univ, Dept Med Nephrol Hypertensiol Endocrinol Diabetol, Med Fac Mannheim, D-68187 Mannheim, Germany. [Kleber, Marcus E.; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med 2, D-89081 Ulm, Germany. [Kristiansson, Kati; Eklund, Niina; Kinnunen, Leena; Lindstrom, Jaana; Eriksson, Johan G.; Heliovaara, Markku; Jousilahti, Pekka; Jula, Antti M.; Kaprio, Jaakko; Kuulasmaa, Kari; Mannisto, Satu; Salomaa, Veikko; Perola, Markus; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Mangino, Massimo; Menni, Cristina; Moayyeri, Alireza; Perry, John R. B.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Leach, Irene Mateo; Hillege, Hans L.; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Medina-Gomez, Carolina; Peters, Marjolein J.; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Dujin, Cornelia M.; Zillikens, M. Carola] NCHA, NL-3015 GE Rotterdam, Netherlands. [Medina-Gomez, Carolina; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Dujin, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.; Zillikens, M. Carola] Erasmus MC Univ Med Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Prokopenko, Inga; Barrett, Amy; Bennett, Amanda J.; Groves, Christopher J.; Rayner, Nigel W.; Robertson, Neil R.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, Hammersmith Hosp, London W12 0NN, England. [Stancakova, Alena] Univ Eastern Finland, FI-70210 Kuopio, Finland. [Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Tanakam, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, UMR 8199, F-59019 Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] European Genom Inst Diabet, F-59000 Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Univ Lille 2, F-59000 Lille, France. [Zhang, Weihua; Grewal, Jagvir; Kooner, Ishminder K.; Mills, Rebecca; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England. [Zhang, Weihua; Grewal, Jagvir; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Albrecht, Eva; Grallert, Harald; Mueller-Nurasyid, Martina; Ried, Janina S.; Gieger, Christian; Strauch, Konstantin; Heid, Iris M.] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Studies, SE-79188 Falun, Sweden. [Arscott, Gillian M.; Beilby, John; Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA 6009, Australia. [Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy. [Bellis, Claire; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [Bellis, Claire] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Genom Res Ctr, Brisbane, Qld 4001, Australia. [Berne, Christian] Uppsala Univ, Dept Med Sci Endocrinol Diabet & Metab, S-75185 Uppsala, Sweden. [Blueher, Matthias; Boettcher, Yvonne; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Integrated Res & Treatment Ctr IFB Adipos Dis, D-04103 Leipzig, Germany. [Blueher, Matthias; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Buhringer, Stefan; Helmer, Quinta] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands. [Bonnet, Fabrice] Univ Rennes, Dept Endocrinol, INSERM, UMR991, F-35000 Rennes, France. [Bruinenberg, Marcel; Scholtens, Salome] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands. [Carba, Delia B.; Lee, Nanette R.] Univ San Carlos, USC Off Populat Studies Fdn Inc, Cebu 6000, Philippines. [Caspersen, Ida H.; Johansen, Berit] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway. [Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England. [Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England. [Deelman, Ewa] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Eklund, Niina; Kaprio, Jaakko; Perola, Markus; Groop, Leif C.] Univ Helsinki, Inst Mol Med, FI-00014 Helsinki, Finland. [Erdos, Michael R.; Narisu, Narisu; Swift, Amy J.; Chiness, Peter S.; Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Estrada, Karol] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Friedrichs, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden. [Gigante, Bruna; Leander, Karin; de Faire, Ulf] Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, S-17177 Stockholm, Sweden. [Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, CH-1211 Geneva, Switzerland. [Grallert, Harald; Illig, Thomas; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Grallert, Harald; Thorand, Barbara] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Graessler, Juergen; Schwarz, Peter E. H.; Bornstein, Stefan R.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany. [Hallmans, Goran] Umea Univ, Unit Nutr Res, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Hassinen, Maija; Lakka, Timo A.; Rauramaa, Rainer] Kuoplo Res Inst Exercise Med, FI-70100 Kuopio, Finland. [Hayward, Caroline] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, FI-00014 Helsinki, Finland. [Herzig, Karl-Heinz] Univ Oulu, Inst Biomed, FI-90014 Oulu, Finland. [Herzig, Karl-Heinz] Med Res Ctr Oulu, FI-90014 Oulu, Finland. [Herzig, Karl-Heinz] Oulu Univ Hosp, FI-90014 Oulu, Finland. [Herzig, Karl-Heinz; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland. [Helmer, Quinta] Vrije Univ Amsterdam, Fac Psychol & Educ, NL-1081 BT Amsterdam, Netherlands. [Hillege, Hans L.; Nolte, Ilja M.; Vonk, Judith M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway. [Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Dept Internal Med, Salt Lake City, UT 84108 USA. [Isaacs, Aaron; Oostra, Ben A.; van Dujin, Cornelia M.] Ctr Med Sytems Biol, NL-2300 RC Leiden, Netherlands. [Ittermann, Till; Hoffmann, Wolfgang] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [James, Alan L.] Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia. [Kalafati, Ioanna-Panagiota; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens 17671, Greece. [Kratzer, Wolfgang; Seufferlein, Thomas] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany. [Lamina, Claudia] Med Univ Innsbruck, Div Genet Epidemiol, Dept Med Genet Mol & Clin Pharmacol, A-6020 Innsbruck, Austria. [Lichtner, Peter] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. [Lind, Lars; Sundstrom, Johan] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden. [McArdle, Wendy L.; Min, Josine L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Merger, Sigrun; Claudi-Boehmi, Simone] Univ Ulm, Med Ctr, Div Endocrinol Diabet & Metab, D-89081 Ulm, Germany. [Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Moayyeri, Alireza] UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England. [Monda, Ken L.] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA. [Mooijaart, Simon P.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [Muehleisen, Thomas W.] Univ Bonn, Life Brain Ctr, Dept Genom, D-53127 Bonn, Germany. [Muehleisen, Thomas W.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Mulas, Antonella; Sanna, Serena] CNR, IRGB, I-09042 Cagliari, Sardinia, Italy. [Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat, D-81377 Munich, Germany. [Mueller-Nurasyid, Martina; Peters, Annette] Munich HeartAlliance, German Res Ctr Cardiovasc Res, Deutsch Forschungszentrum Herz Kreislauferkrankun, D-80636 Munich, Germany. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Nalls, Michael A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Glorioso, Nicola; Troffa, Chiara] Univ Sassari, Sch Med, Hypertens & Related Dis Ctr AOU, I-07100 Sassari, Italy. [Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Scharnagl, Hubert; Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria. [Sennblad, Bengt] Karolinska Inst, Sci Life Lab, S-17165 Stockholm, Sweden. [Sitlani, Colleen M.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [Stirrups, Kathleen; Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, S-75144 Uppsala, Sweden. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA. [Thorand, Barbara; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur R.; Stefansson, Kari] Amgen Inc, deCODE Genet, IS-101 Reykjavik, Iceland. [Tomaschitz, Andreas] Med Univ Graz, Dept Cardiol, A-8036 Graz, Austria. [van Oort, Floor V. A.] Erasmus MC Univ Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands. [Wennauer, Roman] Univ Ulm, Med Ctr, Dept Clin Chem, D-89081 Ulm, Germany. [Wilsgaard, Tom; Njolstad, Inger] UiT, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway. [Wong, Andrew; Ong, Ken K.; Kuh, Diana] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England. [Brennan, Eoin P.] Natl Univ Ireland Univ Coll Dublin, Diabet Complicat Res Ctr, Conway Inst, Sch Med & Med Sci, Dublin 4, Ireland. [Choi, Murim] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea. [Franco-Cereceda, Anders; Olsson, Christian] Karolinska Inst, Cardlothorac Surg Unit, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. [Gharavi, Ali G.; Kiryluk, Krzysztof] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom,Shanghai Inst Hematol, Shanghai 200025, Peoples R China. [Huang, Jinyan; Liang, Liming; Ma, Baoshan; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Karpe, Fredrik] OUH Trust, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LE, England. [Liang, Liming] Harvard Univ, Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06520 USA. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning, Peoples R China. [McKnight, Amy J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT9 7AB, Down, North Ireland. [McPherson, Ruth] Univ Ottawa, Inst Heart, Ottawa, ON K1Y 4W7, Canada. [Moffatt, Miriam F.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England. [Montgomery, Grant W.; Nyholt, Dale R.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Nicholson, George] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Nicholson, George] MRC Harwell, Harwell OX11 0QG, Berks, England. [Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [Sandholm, Niina] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, FI-00076 Helsinki, Finland. [Sandholm, Niina] Univ Helsinki, Cent Hosp, Div Nephrol, Dept Med, FI-00290 Helsinki, Finland. [Sandholm, Niina] Folkhalsan Inst Genet, Folkhalsan Res Ctr, FI-00290 Helsinki, Finland. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10580 USA. [Vallejo, Edgar E.] Tecnol Monterrey, Dept Comp Sci, Atizapan De Zaragoza 52926, Mexico. [Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford OX3 7BN, England. [Amouyel, Philippe] Univ Lille 2, Inst Pasteur Lille, INSERM, U744, F-59000 Lille, France. [Arveiler, Dominique] Univ Strasbourg, Fac Med, EA3430, Dept Epidemiol & Publ Hlth, Strasbourg, France. [Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands. [Beilby, John; Hui, Jennie] Univ Western Australia, Perth, WA 6009, Australia. [Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Burnier, Michel] Lausanne Univ Hosp CHUV, Dept Med, Serv Nephrol, CH-1005 Lausanne, Switzerland. [Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37203 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [de Geusl, Eco J. C.] Vrije Univ Amsterdam, NL-1081 BT Amsterdam, Netherlands. [de Geusl, Eco J. C.; Penninx, Brenda W.] Vrije Univ Amsterdam, Inst Hlth & Care Res, Inst Res Extramural Med, NL-1081 BT Amsterdam, Netherlands. [Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany. [Doerr, Marcus; Hoffmann, Wolfgang; Voelker, Uwe] Partner Site Greifswald, DZHK, D-17475 Greifswald, Germany. [Erbel, Raimund; Mohlenkamp, Stefan] Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, D-45122 Essen, Germany. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth, FI-00290 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FI-00290 Helsinki, Finland. [Ferrannini, Ele] Univ Pisa, Dept Internal Med, I-56100 Pisa, Italy. [Ferrieres, Jean] Toulouse Univ, Sch Med, Rangueil Hosp, Dept Cardiol, F-31400 Toulouse, France. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, UWI Solut Developing Countries, Kingston 7, Jamaica. [Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Hattersley, Andrew T.] Univ Exeter, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Hicks, Andrew A.; Pramstaller, Peter P.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, I-39100 Bolzano, Italy. [Hicks, Andrew A.; Pramstaller, Peter P.] Inst Univ Lubeck, D-23562 Lubeck, Germany. [Hingorani, Aroon D.] UCL, Inst Cardiovasc Sci, London WC1E 6BT, England. [Humphries, Steve E.] UCL, Ctr Cardiovasc Genet, Inst Cardiovasc Sci, London WC1E 6JJ, England. [Hyppoenen, Elina] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5000, Australia. [Hyppoenen, Elina] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5000, Australia. [Hyppoenen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia. [Hyppoenen, Elina; Power, Chris] UCL, Inst Child Hlth, London WC1N 1EH, England. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, FI-90101 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environ & Hlth, London W2 1PG, England. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, FI-90014 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, FI-90014 Oulu, Finland. [Kee, Frank] Queens Univ Belfast, UK Clin Res Collaborat Ctr Excellence Publ Hlth N, Belfast BT7 1NN, Antrim, North Ireland. [Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Inst Hlth Sci, Fac Med, FI-90014 Oulu, Finland. [Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Primary Hlth Care Gen Practice, FI-90220 Oulu, Finland. [Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. [Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Kumari, Meena; Langenberg, Claudia; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Kumari, Meena] Univ Essex, Dept Biol & Social Epidemiol, Colchester CO4 3SQ, Essex, England. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Med, FI-70210 Kuopio, Finland. [Kuusisto, Johanna; Lakka, Timo A.; Laakso, Markku; Rauramaa, Rainer] Univ Eastern Finland, FI-70210 Kuopio, Finland. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, FI-70211 Kuopio, Finland. [Lakka, Timo A.; Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-70210 Kuopio, Finland. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96813 USA. [Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Lyssenko, Valeriya] Steno Diabet Ctr AS, DK-2820 Gentofte, Denmark. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Lund Univ Diabet Ctr, S-22100 Malmo, Sweden. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, S-22100 Malmo, Sweden. [Marette, Andre] Univ Laval, Fac Med, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ G1V 0A6, Canada. [Marette, Andre; Vohl, Marie-Claude; Perusse, Louis] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ G1V 0A6, Canada. [Musk, Arthur W.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Palmer, Lyle J.] Univ Toronto, Toronto, ON M5G 1E2, Canada. [Lakka, Timo A.; Rauramaa, Rainer] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Penninx, Brenda W.] Vrije Univ Amsterdam, Dept Psychiat, NL-1081 BT Amsterdam, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland. [Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split 21000, Croatia. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Samani, Nilesh J.] Glenfield Gen Hosp, Natl Inst Hlth Res NIHR Leicester Cardiovasc Biom, Leicester LE3 9QP, Leics, England. [Saramies, Jouko] South Carelia Cent Hosp, Lappeenranta 53130, Finland. [Schwarz, Peter E. H.] Paul Langerhans Inst Dresden, German Ctr Diabet Res DZD, D-01307 Dresden, Germany. [Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Divis Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Program Personalized & Genom Med, Sch Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Staessen, Jan A.] Maastricht Univ, Dept Epidemiol, NL-6229 HA Maastricht, Netherlands. [Staessen, Jan A.] Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Louvain, Belgium. [Tremblay, Angelo; Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ G1V 0A6, Canada. [Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, I-20133 Milan, Italy. [Tremoli, Elena] Inst Ricovero & Cura Carattere Sci, Ctr Cardiol Monzi, I-20133 Milan, Italy. [Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ G1V 0A6, Canada. [Vollenweider, Peter] Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Vollenweider, Peter; Bochud, Murielle] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland. [Boehm, Bernhard O.] Imperial Coll London, Lee Kong Chian Sch Med, Singapore 637553, Singapore. [Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 637553, Singapore. [Boehm, Bernhard O.] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany. [Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Dept Clin Pharmacol, London EC1M 6BQ, England. [Grabe, Hans-Joergen] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany. [Grabe, Hans-Joergen] German Ctr Neurodegenerat Dis DZNE, D-17475 Greifswald, Germany. [Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, D-68163 Mannheim, Germany. [Oostra, Ben A.] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Saaristo, Timo E.] Finnish Diabet Assoc, FI-33680 Tampere, Finland. [Saaristo, Timo E.] Pirkanmaa Hosp Dist, FI-33521 Tampere, Finland. [Saleheen, Danish] Ctr Noncommunicable Dis, Karatchi, Pakistan. [Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, FI-00290 Helsinki, Finland. [Thorsteinsdottir, Unnur R.; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Tuomilehto, Jaakko] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid 28046, Spain. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Uusitupa, Math] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, FI-70211 Kuopio, Finland. [van der Harst, Pim] Interuniv Cardiol Inst Netherlands, Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Veronesi, Giovanni] Univ Insubria, EPIMED Res Ctr, Dept Clin & Expt Med, I-21100 Varese, Italy. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, D-85764 Munich, Germany. [Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Wichmann, H-Erich] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Visscher, Peter M.; Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Visscher, Peter M.; Yang, Jian] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia. [McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 OQQ, England. [Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 OQQ, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. RP Mohlke, KL (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. EM celi@well.ox.ac.uk; mohlke@med.unc.edu RI Colaus, PsyColaus/K-6607-2013; Grallert, Harald/B-3424-2013; Salumets, Andres/J-2278-2015; Bakker, Stephan/J-4023-2015; Singleton, Andrew/C-3010-2009; Fall, Tove/O-7226-2014; Meisinger, Christine/B-5358-2014; Visser, Jenny /F-8156-2011; Moayyeri, Alireza/N-3332-2014; Palmer, Colin/C-7053-2008; Boehm, Bernhard/F-8750-2015; Fehrmann, Rudolf/E-2551-2011; Kolcic, Ivana/E-2713-2017; Boban, Mladen/E-2777-2017; Stathopoulou, Maria/H-7324-2016; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Ormel, Johan/C-6094-2013; Karjalainen, Juha/P-8624-2016; Laan, Maris/A-4100-2011; Slagboom, P. Eline/R-4790-2016; Verweij, Niek/A-4499-2017; Erdmann, Jeanette/P-7513-2014; Franke, Andre/B-2151-2010; Magnusson, Patrik/C-4458-2017; Balcells, Susana/C-5222-2017; Leander, Karin/C-7261-2017; Yengo, Loic/D-2692-2017; Palmer, Lyle/K-3196-2014; Nato, Alejandro/J-3880-2016; Yang, Jian/A-5852-2010; Khusnutdinova, Elza/A-4810-2013; Matullo, Giuseppe/K-6383-2016; Deloukas, Panos/B-2922-2013; kinnunen, leena/B-7059-2012; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; d'Adamo, Adamo Pio/G-4064-2011; Schwarz, Peter/B-5127-2013; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Kronenberg, Florian/B-1736-2008; Sundstrom, Johan/A-6286-2009; Sarzynski, Mark/A-9798-2014; Thorand, Barbara/B-5349-2014; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Tregouet, David-Alexandre/E-3961-2016; Urreizti, Roser/M-6402-2014; Hypponen, Elina/B-2596-2014; Cauley, Jane/N-4836-2015; Bovet, Pascal/F-4477-2011; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Veronesi, Giovanni/E-3859-2010; Onland-Moret, N. 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Eline/0000-0002-2875-4723; Erdmann, Jeanette/0000-0002-4486-6231; Franke, Andre/0000-0003-1530-5811; Balcells, Susana/0000-0003-1211-1907; Leander, Karin/0000-0002-1404-9222; Yengo, Loic/0000-0002-4272-9305; Palmer, Lyle/0000-0002-1628-3055; Nato, Alejandro/0000-0002-8745-9046; Yang, Jian/0000-0003-2001-2474; Deloukas, Panos/0000-0001-9251-070X; kinnunen, leena/0000-0001-8739-4812; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; d'Adamo, Adamo Pio/0000-0001-9367-4909; Schwarz, Peter/0000-0001-6317-7880; Franke, Lude/0000-0002-5159-8802; Kronenberg, Florian/0000-0003-2229-1120; Sundstrom, Johan/0000-0003-2247-8454; Thorand, Barbara/0000-0002-8416-6440; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Urreizti, Roser/0000-0003-3617-7134; Hypponen, Elina/0000-0003-3670-9399; Cauley, Jane/0000-0003-0752-4408; Bovet, Pascal/0000-0002-0242-4259; Smith, Albert/0000-0003-1942-5845; Veronesi, Giovanni/0000-0002-4119-6615; Staessen, Jan/0000-0002-3026-1637; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457 FU British Heart Foundation [FS/14/55/30806, RG/08/008/25291, RG/08/014/24067, RG/10/12/28456, RG/13/2/30098]; Cancer Research UK [14136]; Chief Scientist Office [CZB/4/710]; Diabetes UK [12/0004470]; Intramural NIH HHS [Z01 HG000024-14]; Medical Research Council [G1000143, G0401527, G0601261, G0601463, G1001799, G9521010, MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UP_A620_1014, MC_UU_12011/1, MC_UU_12012/1, MC_UU_12013/1, MC_UU_12015/1, MC_UU_12015/2, MC_UU_12015/5, MC_UU_12019/1, MR/K006584/1, MR/K011480/1, MR/K013351/1, MR/L003120/1, MR/N01104X/1]; NCI NIH HHS [UM1 CA182910, UM1 CA182913]; NHGRI NIH HHS [U01 HG007376, U01 HG007416, U01 HG007419]; NHLBI NIH HHS [K01 HL116770, R00 HL094535, R01 HL109946, R01 HL117078, R01 HL117626, T32 HL007055, T32 HL069768]; NIA NIH HHS [R01 AG025941, R01 AG033193, R01 AG041517, U01 AG049505]; NIDA NIH HHS [R21 DA027040]; NIDDK NIH HHS [K23 DK080145, P30 DK020541, P30 DK020572, P30 DK040561, P30 DK072488, P30 DK079637, P60 DK020541, R01 DK062370, R01 DK072193, R01 DK075787, R01 DK078150, R01 DK089256, R01 DK093757, R01 DK107437, U01 DK062370]; NIGMS NIH HHS [P30 GM103341, T32 GM007092, T32 GM067553]; NIMHD NIH HHS [P20 MD006899]; Wellcome Trust [084766, 085235, 097117, 098017, 098381, 098498, 100574] NR 95 TC 165 Z9 166 U1 34 U2 215 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 12 PY 2015 VL 518 IS 7538 BP 187 EP U378 DI 10.1038/nature14132 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8SD UT WOS:000349190300030 PM 25673412 ER PT J AU Locke, AE Kahali, B Berndt, SI Justice, AE Pers, TH Felix, R Powell, C Vedantam, S Buchkovich, ML Yang, J Croteau-Chonka, DC Esko, T Fall, T Ferreira, T Gustafsson, S Kutalik, Z Luan, JA Magi, R Randall, JC Winkler, TW Wood, AR Workalemahu, T Faul, JD Smith, JA Zhao, JH Zhao, W Chen, J Fehrmann, R Hedman, AK Karjalainen, J Schmidt, EM Absher, D Amin, N Anderson, D Beekman, M Bolton, JL Bragg-Gresham, L Buyske, S Demirkan, A Deng, GH Ehret, GB Feenstra, B Feitosa, MF Fischer, K Goel, A Gong, J Jackson, AU Kanoni, S Kleber, ME Kristiansson, K Lim, U Lotay, V Mangino, M Leach, IM Medina-Gomez, C Medland, SE Nalls, MA Palmer, CD Pasko, D Pechlivanis, S Peters, MJ Prokopenko, I Shungin, D Stancakova, A Strawbridge, RJ Sung, YJ Tanaka, T Teumer, A Trompet, S van der Laan, SW van Settee, J Van Vliet-Ostaptchouk, JV Wang, ZM Yengo, L Zhang, WH Isaacs, A Albrecht, E Arnlov, J Arscott, GM Attwood, AP Bandinelli, S Barrett, A Bas, IN Bellis, C Bennett, AJ Berne, C Blagieva, R Bluher, M Bohringer, S Bonnycastle, LL Bottcher, Y Boyd, HA Bruinenberg, M Caspersen, IH Chen, YD Clarke, R Daw, EW de Craen, AJM Delgado, G Dimitriou, M Doney, ASF Eklund, N Estrada, K Eury, E Folkersen, L Fraser, RM Garcia, ME Geller, F Giedraitis, V Gigante, B Go, AS Golay, A Goodall, AH Gordon, SD Gorski, M Grabe, HJ Grallert, H Grammer, TB Grassler, J Gronberg, H Groves, CJ Gusto, G Haessler, J Hall, P Haller, T Hallmans, G Hartman, CA Hassinen, M Hayward, C Heard-Costa, NL Helmer, Q Hengstenberg, C Holmen, O Hottenga, JJ James, AL Jeff, JM Johansson, A Jolley, J Juliusdottir, T Kinnunen, L Koenig, W Koskenvuo, M Kratzer, W Laitinen, J Lamina, C Leander, K Lee, NR Lichtner, P Lind, L Lindstrom, J Lo, KS Lobbens, S Lorbeer, R Lu, YC Mach, F Magnusson, PKE Mahajan, A McArdle, WL McLachlan, S Menni, C Merger, S Mihailov, E Milani, L Moayyeri, A Monda, KL Morken, MA Mulas, A Muller, G Muller-Nurasyid, M Musk, AW Nagaraja, R Nothen, MM Nolte, IM Pilz, S Rayner, NW Renstrom, F Rettig, R Ried, JS Ripke, S Robertson, NR Rose, LM Sanna, S Scharnagl, H Scholtens, S Schumacher, FR Scott, WR Seufferlein, T Shi, JX Smith, AV Smolonska, J Stanton, AV Steinthorsdottir, V Stirrups, K Stringham, HM Sundstrom, J Swertz, MA Swift, AJ Syvanen, AC Tan, ST Tayo, BO Thorand, B Thorleifsson, G Tyrer, JP Uh, HW Vandenput, L Verhulst, FC Vermeulen, SH Verweij, N Vonk, JM Waite, LL Warren, HR Waterworth, D Weedon, MN Wilkens, LR Willenborg, C Wilsgaard, T Wojczynski, MK Wong, A Wrightl, AF Zhang, QY Brennan, EP Choi, M Dastani, Z Drong, AW Eriksson, P Franco-Cereceda, A Gadin, JR Gharavi, AG Goddard, ME Handsaker, RE Huang, JY Karpe, F Kathiresan, S Keildson, S Kiryluk, K Kubo, M Lee, JY Liang, L Lifton, RP Ma, BS McCarroll, SA McKnight, AJ Min, JL Moffatt, MF Montgomery, GW Murabito, JM Nicholson, G Nyholt, DR Okada, Y Perry, JRB Dorajoo, R Reinmaa, E Salem, RM Sandholm, N Scott, RA Stolk, L Takahashi, A Tanaka, T van 't Hooft, FM Vinkhuyzen, AAE Westra, HJ Zheng, W Zondervan, KT Heath, AC Arveiler, D Bakker, SJL Beilby, J Bergman, RN Blangero, J Bovet, P Campbell, H Caulfield, MJ Cesana, G Chakravarti, A Chasman, DI Chines, PS Collins, FS Crawford, DC Cupples, LA Cusi, D Danesh, J de Faire, U den Ruijter, HM Dominiczak, AF Erbel, R Erdmann, J Eriksson, JG Farrall, M Felix, SB Ferrannini, E Ferrieres, J Ford, I Forouhi, NG Forrester, T Franco, OH Gansevoort, RT Gejman, PV Gieger, C Gottesman, O Gudnason, V Gyllensten, U Hall, AS Harris, TB Hattersley, AT Hicks, AA Hindorff, LA Hingorani, AD Hofman, A Homuth, G Hovingh, GK Humphries, SE Hunt, SC Hypponen, E Illig, T Jacobs, KB Jarvelin, MR Jockel, KH Johansen, B Jousilahti, P Jukema, JW Jula, AM Kaprio, J Kastelein, JJP Keinanen-Kiukaanniemi, SM Kiemeney, LA Knekt, P Kooner, JS Kooperberg, C Kovacs, P Kraja, AT Kumari, M Kuusisto, J Lakka, TA Langenberg, C Le Marchand, L Lehtimaki, T Lyssenko, V Mannisto, S Marette, A Matise, TC McKenzie, CA McKnight, B Moll, FL Morris, AD Morris, AP Murray, JC Nelis, M Ohlsson, C Oldehinkel, AJ Ong, KK Madden, PAF Pasterkamp, G Peden, JF Peters, A Postma, DS Pramstaller, PP Price, JF Qi, L Raitakari, OT Rankinen, T Rao, DC Rice, TK Ridker, PM Rioux, JD Ritchie, MD Rudan, I Salomaa, V Samani, NJ Saramines, J Sarzynski, MA Schunkert, H Schwarz, PEH Sever, P Shuldiner, AR Sinisalo, J Stolk, RP Strauch, K Tonjes, A Tregouet, DA Tremblay, A Tremoli, E Virtamo, J Vohl, MC Volker, U Waeber, G Willemsen, G Witteman, JC Zillikens, MC Adair, LS Amouyel, P Asselbergs, FW Assimes, TL Bochud, M Boehm, BO Boerwinkle, E Bornstein, SR Bottinger, EP Bouchard, C Cauchi, S Chambers, JC Chanock, SJ Cooper, RS de Bakker, PIW Dedoussis, G Ferrucci, L Franks, PW Froguel, P Groop, LC Haiman, CA Hamsten, A Hui, JN Hunter, DJ Hveem, K Kaplan, RC Kivimaki, M Kuh, D Laakso, M Liu, YM Martin, NG Marz, W Melbve, M Metspalu, A Moebus, S Munroe, PB Njolstad, I Oostra, BA Palmer, CNA Pedersen, NL Perola, M Perusse, L Peters, U Power, C Quertermous, T Rauramaa, R Rivadeneira, F Saaristo, TE Saleheen, D Sattar, N Schadt, EE Schlessinger, D Slagboom, PE Snieder, H Spector, TD Thorsteinsdottir, UR Stumvoll, M Tuomilehto, J Uitterlinden, AG Uusitupa, M van der Harst, P Walker, M Wallaschofski, H Wareham, NJ Watkins, H Weir, DR Wichmann, HE Wilson, JF Zanen, P Borecki, IB Deloukas, P Fox, CS Heid, IM O'Connell, JR Strachan, DP Stefansson, K van Duijri, CM Abecasis, GR Franke, L Frayling, TM McCarthy, MI Visscher, PM Scherag, A Willer, CJ Boehnke, M Mohlke, KL Lindgren, CM Beckmann, JS Barroso, I North, KE Ingelsson, E Hirschhorn, JN Loos, RJF Speliotes, EK AF Locke, Adam E. Kahali, Bratati Berndt, Sonja I. Justice, Anne E. Pers, Tune H. Day, Felix R. Powell, Corey Vedantam, Sailaja Buchkovich, Martin L. Yang, Jian Croteau-Chonka, Damien C. Esko, Tonu Fall, Tove Ferreira, Teresa Gustafsson, Stefan Kutalik, Zoltan Luan, Jian'an Maegi, Reedik Randall, Joshua C. Winkler, Thomas W. Wood, Andrew R. Workalemahu, Tsegaselassie Faul, Jessica D. Smith, Jennifer A. Zhao, Jing Hua Zhao, Wei Chen, Jin Fehrmann, Rudolf Hedman, Asa K. Karjalainen, Juha Schmidt, Ellen M. Absher, Devin Amin, Najaf Anderson, Denise Beekman, Marian Bolton, Jennifer L. Bragg-Gresham, L. Buyske, Steven Demirkan, Ayse Deng, Guohong Ehret, Georg B. Feenstra, Bjarke Feitosa, Mary F. Fischer, Krista Goel, Anuj Gong, Jian Jackson, Anne U. Kanoni, Stavroula Kleber, Marcus E. Kristiansson, Kati Lim, Unhee Lotay, Vaneet Mangino, Massimo Leach, Irene Mateo Medina-Gomez, Carolina Medland, Sarah E. Nalls, Michael A. Palmer, Cameron D. Pasko, Dorota Pechlivanis, Sonali Peters, Marjolein J. Prokopenko, Inga Shungin, Dmitry Stancakova, Alena Strawbridge, Rona J. Sung, Yun Ju Tanaka, Toshiko Teumer, Alexander Trompet, Stella van der Laan, Sander W. van Settee, Jessica Van Vliet-Ostaptchouk, Jana V. Wang, Zhaoming Yengo, Loic Zhang, Weihua Isaacs, Aaron Albrecht, Eva Arnlov, Johan Arscott, Gillian M. Attwood, Antony P. Bandinelli, Stefania Barrett, Amy Bas, Isabelita N. Bellis, Claire Bennett, Amanda J. Berne, Christian Blagieva, Roza Blueher, Matthias Bohringer, Stefan Bonnycastle, Lori L. Boettcher, Yvonne Boyd, Heather A. Bruinenberg, Marcel Caspersen, Ida H. Chen, Yii-Der Ida Clarke, Robert Daw, E. Warwick de Craen, Anton J. M. Delgado, Graciela Dimitriou, Maria Doney, Alex S. F. Eklund, Niina Estrada, Karol Eury, Elodie Folkersen, Lasse Fraser, Ross M. Garcia, Melissa E. Geller, Frank Giedraitis, Vilmantas Gigante, Bruna Go, Alan S. Golay, Alain Goodall, Alison H. Gordon, Scott D. Gorski, Mathias Grabe, Hans-Joergen Grallert, Harald Grammer, Tanja B. Graessler, Jurgen Gronberg, Henrik Groves, Christopher J. Gusto, Gaeelle Haessler, Jeffrey Hall, Per Haller, Toomas Hallmans, Goran Hartman, Catharina A. Hassinen, Maija Hayward, Caroline Heard-Costa, Nancy L. Helmer, Qinta Hengstenberg, Christian Holmen, Oddgeir Hottenga, Jouke-Jan James, Alan L. Jeff, Janina M. Johansson, Asa Jolley, Jennifer Juliusdottir, Thorhildur Kinnunen, Leena Koenig, Wolfgang Koskenvuo, Markku Kratzer, Wolfgang Laitinen, Jaana Lamina, Claudia Leander, Karin Lee, Nanette R. Lichtner, Peter Lind, Lars Lindstrom, Jaana Lo, Ken Sin Lobbens, Stephane Lorbeer, Roberto Lu, Yingchang Mach, Francois Magnusson, Patrik K. E. Mahajan, Anubha McArdle, Wendy L. McLachlan, Stela Menni, Cristina Merger, Sigrun Mihailov, Evelin Milani, Lili Moayyeri, Alireza Monda, Keri L. Morken, Mario A. Mulas, Antonella Mueller, Gabriele Mueller-Nurasyid, Martina Musk, Arthur W. Nagaraja, Ramaiah Noethen, Markus M. Nolte, Ilja M. Pilz, Stefan Rayner, Nigel W. Renstrom, Frida Rettig, Rainer Ried, Janina S. Ripke, Stephan Robertson, Neil R. Rose, Lynda M. Sanna, Serena Scharnagl, Hubert Scholtens, Salome Schumacher, Fredrick R. Scott, William R. Seufferlein, Thomas Shi, Jianxin Smith, Albert Vernon Smolonska, Joanna Stanton, Alice V. Steinthorsdottir, Valgerdur Stirrups, Kathleen Stringham, Heather M. Sundstrom, Johan Swertz, Morris A. Swift, Amy J. Syvanen, Ann-Christine Tan, Sian-Tsung Tayo, Bamidele O. Thorand, Barbara Thorleifsson, Gudmar Tyrer, Jonathan P. Uh, Hae-Won Vandenput, Liesbeth Verhulst, Frank C. Vermeulen, Sita H. Verweij, Niek Vonk, Judith M. Waite, Lindsay L. Warren, Helen R. Waterworth, Dawn Weedon, Michael N. Wilkens, Lynne R. Willenborg, Christina Wilsgaard, Tom Wojczynski, Mary K. Wong, Andrew Wrightl, Alan F. Zhang, Qunyuan Brennan, Eoin P. Choi, Murim Dastani, Zari Drong, Alexander W. Eriksson, Per Franco-Cereceda, Anders Gadin, Jesper R. Gharavi, Ali G. Goddard, Michael E. Handsaker, Robert E. Huang, Jinyan Karpe, Fredrik Kathiresan, Sekar Keildson, Sarah Kiryluk, Krzysztof Kubo, Michiaki Lee, Jong-Young Liang, Liming Lifton, Richard P. Ma, Baoshan McCarroll, Steven A. McKnight, Amy J. Min, Josine L. Moffatt, Miriam F. Montgomery, Grant W. Murabito, Joanne M. Nicholson, George Nyholt, Dale R. Okada, Yukinori Perry, John R. B. Dorajoo, Rajkumar Reinmaa, Eva Salem, Rany M. Sandholm, Niina Scott, Robert A. Stolk, Lisette Takahashi, Atsushi Tanaka, Toshihiro van 't Hooft, Ferdinand M. Vinkhuyzen, Anna A. E. Westra, Harm-Jan Zheng, Wei Zondervan, Krina T. Heath, Andrew C. Arveiler, Dominique Bakker, Stephan J. L. Beilby, John Bergman, Richard N. Blangero, John Bovet, Pascal Campbell, Harry Caulfield, Mark J. Cesana, Giancarlo Chakravarti, Aravinda Chasman, Daniel I. Chines, Peter S. Collins, Francis S. Crawford, Dana C. Cupples, L. Adrienne Cusi, Daniele Danesh, John de Faire, Ulf den Ruijter, Hester M. Dominiczak, Anna F. Erbel, Raimund Erdmann, Jeanette Eriksson, Johan G. Farrall, Martin Felix, Stephan B. Ferrannini, Ele Ferrieres, Jean Ford, Ian Forouhi, Nita G. Forrester, Terrence Franco, Oscar H. Gansevoort, Ron T. Gejman, Pablo V. Gieger, Christian Gottesman, Omri Gudnason, Vilmundur Gyllensten, Ulf Hall, Alistair S. Harris, Tamara B. Hattersley, Andrew T. Hicks, Andrew A. Hindorff, Lucia A. Hingorani, Aroon D. Hofman, Albert Homuth, Georg Hovingh, G. Kees Humphries, Steve E. Hunt, Steven C. Hypponen, Elina Illig, Thomas Jacobs, Kevin B. Jarvelin, Marjo-Riitta Joeckel, Karl-Heinz Johansen, Berit Jousilahti, Pekka Jukema, J. Wouter Jula, Antti M. Kaprio, Jaakko Kastelein, John J. P. Keinanen-Kiukaanniemi, Sirkka M. Kiemeney, Lambertus A. Knekt, Paul Kooner, Jaspal S. Kooperberg, Charles Kovacs, Peter Kraja, Aldi T. Kumari, Meena Kuusisto, Johanna Lakka, Timo A. Langenberg, Claudia Le Marchand, Laic Lehtimaki, Terho Lyssenko, Valeriya Mannisto, Satu Marette, Andre Matise, Tara C. McKenzie, Colin A. McKnight, Barbara Moll, Frans L. Morris, Andrew D. Morris, Andrew P. Murray, Jeffrey C. Nelis, Mari Ohlsson, Claes Oldehinkel, Albertine J. Ong, Ken K. Madden, Pamela A. F. Pasterkamp, Gerard Peden, John F. Peters, Annette Postma, Dirkje S. Pramstaller, Peter P. Price, Jackie F. Qi, Lu Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rice, Treva K. Ridker, Paul M. Rioux, John D. Ritchie, Marylyn D. Rudan, Igor Salomaa, Veikko Samani, Nilesh J. Saramines, Jouko Sarzynski, Mark A. Schunkert, Heribert Schwarz, Peter E. H. Sever, Peter Shuldiner, Alan R. Sinisalo, Juha Stolk, Ronald P. Strauch, Konstantin Toenjes, Anke Tregouet, David-Alexandre Tremblay, Angelo Tremoli, Elena Virtamo, Jarmo Vohl, Marie-Claude Voelker, Uwe Waeber, Gerard Willemsen, Gonneke Witteman, Jacqueline C. Zillikens, M. Carola Adair, Linda S. Amouyel, Philippe Asselbergs, Folkert W. Assimes, Themistocles L. Bochud, Murielle Boehm, Bernhard O. Boerwinkle, Eric Bornstein, Stefan R. Bottinger, Erwin P. Bouchard, Claude Cauchi, Stephane Chambers, John C. Chanock, Stephen J. Cooper, Richard S. de Bakker, Paul I. W. Dedoussis, George Ferrucci, Luigi Franks, Paul W. Froguel, Philippe Groop, Leif C. Haiman, Christopher A. Hamsten, Anders Hui, Jennie Hunter, David J. Hveem, Kristian Kaplan, Robert C. Kivimaki, Mika Kuh, Diana Laakso, Markku Liu, Yongmei Martin, Nicholas G. Maerz, Winfried Melbve, Mads Metspalu, Andres Moebus, Susanne Munroe, Patricia B. Njolstad, Inger Oostra, Ben A. Palmer, Colin N. A. Pedersen, Nancy L. Perola, Markus Perusse, Louis Peters, Ulrike Power, Chris Quertermous, Thomas Rauramaa, Rainer Rivadeneira, Fernando Saaristo, Timo E. Saleheen, Danish Sattar, Naveed Schadt, Eric E. Schlessinger, David Slagboom, P. Eline Snieder, Harold Spector, Tim D. Thorsteinsdottir, Unnu R. Stumvoll, Michael Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti van der Harst, Pim Walker, Mark Wallaschofski, Henri Wareham, Nicholas J. Watkins, Hugh Weir, David R. Wichmann, H-Erich Wilson, James F. Zanen, Pieter Borecki, Ingrid B. Deloukas, Panos Fox, Caroline S. Heid, Iris M. O'Connell, Jeffrey R. Strachan, David P. Stefansson, Kari van Duijri, Cornelia M. Abecasis, Goncalo R. Franke, Lude Frayling, Timothy M. McCarthy, Mark I. Visscher, Peter M. Scherag, Andre Willer, Cristen J. Boehnke, Michael Mohlke, Karen L. Lindgren, Cecilia M. Beckmann, Jacques S. Barroso, Ines North, Kari E. Ingelsson, Erik Hirschhorn, Joel N. Loos, Ruth J. F. Speliotes, Elizabeth K. CA LifeLines Cohort Study ADIPOGen Consortium AGEN-BMI Working Grp CARDIOGRAMplusC4D Consortium CKDGen Consortium GLGC ICBP MAGIC Investigators MuTHER Consortium MIGen Consortium PAGE Consortium ReproGen Consortium GENIE Consortium Int Endogene Consortium TI Genetic studies of body mass index yield new insights for obesity biology SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; PROVIDES INSIGHTS; GLYCEMIC TRAITS; HUMAN HEIGHT; LOCI; METAANALYSIS; VARIANTS; EXPRESSION; PATHWAYS; ARCHITECTURE AB Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. C1 [Locke, Adam E.; Bragg-Gresham, L.; Jackson, Anne U.; Stringham, Heather M.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Powell, Corey; Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Powell, Corey; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Berndt, Sonja I.; Wang, Zhaoming; Jacobs, Kevin B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Justice, Anne E.; Monda, Keri L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Palmer, Cameron D.; Estrada, Karol; Handsaker, Robert E.; Kathiresan, Sekar; McCarroll, Steven A.; Salem, Rany M.; Lindgren, Cecilia M.; Hirschhorn, Joel N.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Pers, Tune H.; Esko, Tonu; Handsaker, Robert E.; McCarroll, Steven A.; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Day, Felix R.; Luan, Jian'an; Zhao, Jing Hua; Scott, Robert A.; Forouhi, Nita G.; Langenberg, Claudia; Ong, Ken K.; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge CB2 0QQ, England. [Buchkovich, Martin L.; Croteau-Chonka, Damien C.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Yang, Jian; Vinkhuyzen, Anna A. E.; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Yang, Jian; Visscher, Peter M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4012, Australia. [Croteau-Chonka, Damien C.; Qi, Lu; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Esko, Tonu; Maegi, Reedik; Fischer, Krista; Haller, Toomas; Mihailov, Evelin; Milani, Lili; Reinmaa, Eva; Morris, Andrew P.; Nelis, Mari; Metspalu, Andres; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Fall, Tove; Gronberg, Henrik; Hall, Per; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Fall, Tove; Gustafsson, Stefan; Hedman, Asa K.; Arnlov, Johan; Syvanen, Ann-Christine; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75185 Uppsala, Sweden. [Fall, Tove; Gustafsson, Stefan; Hedman, Asa K.; Arnlov, Johan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Ferreira, Teresa; Maegi, Reedik; Randall, Joshua C.; Hedman, Asa K.; Goel, Anuj; Prokopenko, Inga; Juliusdottir, Thorhildur; Mahajan, Anubha; Rayner, Nigel W.; Robertson, Neil R.; Drong, Alexander W.; Keildson, Sarah; Perry, John R. B.; Zondervan, Krina T.; Farrall, Martin; Morris, Andrew P.; Watkins, Hugh; McCarthy, Mark I.; Lindgren, Cecilia M.; Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Kutalik, Zoltan] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland. [Kutalik, Zoltan; Beckmann, Jacques S.] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Kutalik, Zoltan; Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Randall, Joshua C.; Rayner, Nigel W.; Stirrups, Kathleen; Deloukas, Panos; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Winkler, Thomas W.; Gorski, Mathias; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Wood, Andrew R.; Pasko, Dorota; Weedon, Michael N.; Perry, John R. B.; Frayling, Timothy M.] Univ Exeter, Univ Exeter Med Sch, Exeter EX1 2LU, Devon, England. [Workalemahu, Tsegaselassie; Qi, Lu; Franks, Paul W.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA. [Smith, Jennifer A.; Zhao, Wei] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Chen, Jin; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Fehrmann, Rudolf; Karjalainen, Juha; Smolonska, Joanna; Swertz, Morris A.; Westra, Harm-Jan; van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Schmidt, Ellen M.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Absher, Devin; Waite, Lindsay L.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Amin, Najaf; Demirkan, Ayse; Isaacs, Aaron; Oostra, Ben A.; van Duijri, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Anderson, Denise] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Perth, WA 6008, Australia. [Beekman, Marian; Bohringer, Stefan; Helmer, Qinta; Uh, Hae-Won; Stolk, Lisette; Slagboom, P. Eline] Leiden Univ, Med Ctr, NCHA, NL-2300 RC Leiden, Netherlands. [Beekman, Marian; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands. [Bolton, Jennifer L.; Fraser, Ross M.; McLachlan, Stela; Campbell, Harry; Price, Jackie F.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Bragg-Gresham, L.] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Demirkan, Ayse] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. [Deng, Guohong; Zhang, Weihua; Scott, William R.; Tan, Sian-Tsung; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England. [Deng, Guohong] Univ London Imperial Coll Sci Technol & Med, Dept Gastroenterol & Hepatol, London W2 1PG, England. [Deng, Guohong] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing, Peoples R China. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. [Ehret, Georg B.; Mach, Francois] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva, Switzerland. [Feenstra, Bjarke; Boyd, Heather A.; Geller, Frank] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Feitosa, Mary F.; Daw, E. Warwick; Wojczynski, Mary K.; Zhang, Qunyuan; Kraja, Aldi T.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovacular Med, Oxford OX3 9DU, England. [Gong, Jian; Haessler, Jeffrey; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Kanoni, Stavroula; Stirrups, Kathleen; Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Kleber, Marcus E.; Delgado, Graciela; Grammer, Tanja B.; Maerz, Winfried] Heidelberg Univ, Dept Med Nephrol Hypertensiol Endocrinol Diabetol, Med Fac Mannheim, D-68187 Mannheim, Germany. [Kleber, Marcus E.; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med 2, D-89081 Ulm, Germany. [Kristiansson, Kati; Eklund, Niina; Kinnunen, Leena; Lindstrom, Jaana; Eriksson, Johan G.; Jousilahti, Pekka; Jula, Antti M.; Kaprio, Jaakko; Knekt, Paul; Mannisto, Satu; Salomaa, Veikko; Virtamo, Jarmo; Perola, Markus; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Lim, Unhee; Wilkens, Lynne R.; Le Marchand, Laic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96813 USA. [Lotay, Vaneet; Jeff, Janina M.; 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. [Mangino, Massimo; Menni, Cristina; Moayyeri, Alireza; Perry, John R. B.; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Leach, Irene Mateo; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Medina-Gomez, Carolina; Peters, Marjolein J.; Franco, Oscar H.; Hofman, Albert; Zillikens, M. Carola; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijri, Cornelia M.] NCHA, NL-3015 GE Rotterdam, Netherlands. [Medina-Gomez, Carolina; Franco, Oscar H.; Hofman, Albert; Witteman, Jacqueline C.; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijri, Cornelia M.] Erasmus MC Univ Med Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Stolk, Lisette; Zillikens, M. Carola; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Medland, Sarah E.; Gordon, Scott D.; Montgomery, Grant W.; Nyholt, Dale R.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Nalls, Michael A.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Pechlivanis, Sonali; Joeckel, Karl-Heinz; Moebus, Susanne; Scherag, Andre] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol IMIBE, D-45147 Essen, Germany. [Prokopenko, Inga; Barrett, Amy; Bennett, Amanda J.; Groves, Christopher J.; Rayner, Nigel W.; Robertson, Neil R.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Skane Univ Hosp, Dept Clin Sci, Genet & Mol Epidemiol Unit, S-20502 Malmo, Sweden. [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, S-90185 Umea, Sweden. [Stancakova, Alena] Univ Eastern Finland, FI-70210 Kuopio, Finland. [Strawbridge, Rona J.; Folkersen, Lasse; Eriksson, Per; Gadin, Jesper R.; van 't Hooft, Ferdinand M.; Hamsten, Anders] Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden. [Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands. [Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [van der Laan, Sander W.; den Ruijter, Hester M.; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Heart & Lungs, Expt Cardiol Lab, NL-3584 CX Utrecht, Netherlands. [van Settee, Jessica; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Wang, Zhaoming; Jacobs, Kevin B.] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Smith, Albert Vernon; Cauchi, Stephane; Froguel, Philippe] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, UMR 8199, F-59019 Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Smith, Albert Vernon; Cauchi, Stephane; Froguel, Philippe] European Genom Inst Diabet, F-59000 Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Univ Lille 2, F-59000 Lille, France. [Zhang, Weihua; Scott, William R.; Jarvelin, Marjo-Riitta; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Isaacs, Aaron; Oostra, Ben A.; van Duijri, Cornelia M.] Ctr Med Sytems Biol, NL-2300 RC Leiden, Netherlands. [Albrecht, Eva; Grallert, Harald; Mueller-Nurasyid, Martina; Ried, Janina S.; Gieger, Christian; Strauch, Konstantin; Heid, Iris M.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Arnlov, Johan] Dalarna Univ, Sch Hlth & Social Studies, SE-79188 Falun, Sweden. [Arscott, Gillian M.; Beilby, John; Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA 6009, Australia. [Attwood, Antony P.; Jolley, Jennifer] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England. [Attwood, Antony P.; Jolley, Jennifer] NHS Blood & Transplant, Cambridge CB2 0PT, England. [Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy. [Bas, Isabelita N.; Lee, Nanette R.] Univ San Carlos, USC Off Populat Studies Fdn Inc, Cebu 6000, Philippines. [Bellis, Claire; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [Bellis, Claire] Queensland Univ Technol, Genom Res Ctr, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Berne, Christian] Uppsala Univ, Dept Med Sci Endocrinol Diabet & Metab, S-75185 Uppsala, Sweden. [Blagieva, Roza; Merger, Sigrun] Univ Ulm, Med Ctr, Div Endocrinol Diabet & Metab, D-89081 Ulm, Germany. [Blueher, Matthias; Boettcher, Yvonne; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, Integrated Res & Treatment Ctr IFB Adipos Dis, D-04103 Leipzig, Germany. [Blueher, Matthias; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Bohringer, Stefan; Helmer, Qinta; Uh, Hae-Won] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands. [Bonnycastle, Lori L.; Morken, Mario A.; Swift, Amy J.; Chines, Peter S.; Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Bruinenberg, Marcel; Scholtens, Salome] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, NL-9700 RB Groningen, Netherlands. [Caspersen, Ida H.; Johansen, Berit] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway. [Chen, Yii-Der Ida] Univ Calif Los Angeles, Dept Pediat, Torrance, CA 90502 USA. [Chen, Yii-Der Ida] Los Angeles Biomed Res Inst, Transgen Inst, Torrance, CA 90502 USA. [Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England. [Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England. [Dimitriou, Maria; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens 17671, Greece. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Eklund, Niina; Kaprio, Jaakko; Groop, Leif C.; Perola, Markus] Univ Helsinki, Inst Mol Med, FI-00014 Helsinki, Finland. [Estrada, Karol; Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Estrada, Karol; Ripke, Stephan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden. [Gigante, Bruna; Leander, Karin; de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-17177 Stockholm, Sweden. [Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, CH-1211 Geneva, Switzerland. [Goodall, Alison H.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Goodall, Alison H.; Samani, Nilesh J.] Glenfield Gen Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Gorski, Mathias] Univ Hosp Regensburg, Dept Nephrol, D-93053 Regensburg, Germany. [Grabe, Hans-Joergen] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany. [Grabe, Hans-Joergen] German Ctr Neurodegenerat Dis DZNE, D-17475 Greifswald, Germany. [Grallert, Harald; Illig, Thomas; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Grallert, Harald; Thorand, Barbara] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Graessler, Jurgen; Schwarz, Peter E. H.; Bornstein, Stefan R.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany. [Gusto, Gaeelle] Inst Inter Reg Sante, F-37520 La Riche, France. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Unit Nutr Res, S-90187 Umea, Sweden. [Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Hassinen, Maija; Lakka, Timo A.; Rauramaa, Rainer] Kuoplo Res Inst Exercise Med, Kuopio 70100, Finland. [Hayward, Caroline; Wrightl, Alan F.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Heard-Costa, Nancy L.; Murabito, Joanne M.; Cupples, L. Adrienne; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Helmer, Qinta] Vrije Univ Amsterdam, Fac Psychol & Educ, NL-1081 BT Amsterdam, Netherlands. [Hengstenberg, Christian; Mueller-Nurasyid, Martina; Peters, Annette; Schunkert, Heribert] Munich Heart Alliance, German Res Ctr Cardiovasc Res, Deutsch Forschungszentrum Herz Kreislauferkrankun, D-80636 Munich, Germany. [Hengstenberg, Christian; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80636 Munich, Germany. [Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway. [Hottenga, Jouke-Jan; Willemsen, Gonneke] Vrije Univ Amsterdam, NL-1081 BT Amsterdam, Netherlands. [James, Alan L.] Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia. [Johansson, Asa; Gyllensten, Ulf] Univ Western Australia, Sch Med & Pharmacol, Crawley 6009, Australia. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol, SciLifeLab, Rudbeck Lab, SE-75185 Uppsala, Sweden. [Koskenvuo, Markku; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, FI-00014 Helsinki, Finland. [Kratzer, Wolfgang; Seufferlein, Thomas] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany. [Laitinen, Jaana] Finnish Inst Occupat Hlth, FI-90100 Oulu, Finland. [Lamina, Claudia] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Lichtner, Peter] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. [Lind, Lars; Sundstrom, Johan] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Lo, Ken Sin; Rioux, John D.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lorbeer, Roberto] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [McArdle, Wendy L.; Min, Josine L.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Moayyeri, Alireza] UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England. [Monda, Keri L.] Amgen Inc, Ctr Observat Res, Newbury Pk, CA 91320 USA. [Mulas, Antonella; Sanna, Serena] CNR, IRGB, I-09042 Cagliari, Sardinia, Italy. [Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01307 Dresden, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Lab Genet, Baltimore, MD 21224 USA. [Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Nolte, Ilja M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Inst Res Extramural Med, Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands. [Pilz, Stefan] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, A-8036 Graz, Austria. [Rettig, Rainer] Univ Med Greifswald, Inst Physiol, D-17495 Karlsburg, Germany. [Ripke, Stephan; McCarroll, Steven A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Rose, Lynda M.; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Scharnagl, Hubert; Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria. [Schumacher, Fredrick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Shi, Jianxin] NCI, Bethesda, MD 20892 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [Smolonska, Joanna; Vonk, Judith M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Stanton, Alice V.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnu R.; Stefansson, Kari] Amgen Inc, deCODE Genet, IS-101 Reykjavik, Iceland. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, S-75144 Uppsala, Sweden. [Tan, Sian-Tsung; Moffatt, Miriam F.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA. [Thorand, Barbara; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany. [Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Cambridge CB2 0QQ, England. [Tyrer, Jonathan P.] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden. [Verhulst, Frank C.] Erasmus MC Univ Med Ctr, Dept Child & Adolescent Psychiat Psychol, NL-3000 CB Rotterdam, Netherlands. [Vermeulen, Sita H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6500 HB Nijmegen, Netherlands. [Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6500 HB Nijmegen, Netherlands. [Warren, Helen R.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Dept Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Waterworth, Dawn] GlaxoSmithKline, Genet, King Of Prussia, PA 19406 USA. [Willenborg, Christina; Erdmann, Jeanette] Partner Site Hamburg Lubeck Kiel, German Ctr Cardiovasc Res, D-23562 Lubeck, Germany. [Willenborg, Christina; Erdmann, Jeanette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany. [Wilsgaard, Tom; Njolstad, Inger] UiT, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway. [Wong, Andrew; Ong, Ken K.; Kuh, Diana] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England. [Brennan, Eoin P.] Natl Univ Ireland Univ Coll Dublin, Sch Med & Med Sci, Diabet Complicat Res Ctr, Conway Inst, Dublin 4, Ireland. [Choi, Murim] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Epidemiol, Montreal, PQ H3T 1E2, Canada. [Dastani, Zari] McGill Univ, Lady Davis Inst, Dept Biostat, Montreal, PQ H3T 1E2, Canada. [Franco-Cereceda, Anders] Karolinska Inst, Cardiothoracic Surg Unit, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. [Gharavi, Ali G.; Kiryluk, Krzysztof] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Bundoora, Vic 3083, Australia. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic 3010, Australia. [Huang, Jinyan; Liang, Liming; Ma, Baoshan; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Huang, Jinyan] Shanghai Jiao Tong Univ, State Key Lab Med Genom, Shanghai Inst Hematol, Rui Jin Hosp,Sch Med, Shanghai 200030, Peoples R China. [Karpe, Fredrik] OUH Trust, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LE, England. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa 2300045, Japan. [Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do 363951, Chungbuk, South Korea. [Liang, Liming] Harvard Univ, Dept Biostat, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06520 USA. [Ma, Baoshan] Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning, Peoples R China. [McKnight, Amy J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT9 7AB, Down, North Ireland. [Murabito, Joanne M.] Boston Univ, Sch Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Nicholson, George] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Nicholson, George] MRC Harwell, Harwell OX11 0QG, Berks, England. [Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [Okada, Yukinori; Takahashi, Atsushi] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan. [Okada, Yukinori; Tanaka, Toshihiro] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo 1138510, Japan. [Dorajoo, Rajkumar] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. [Sandholm, Niina] Aalto Univ, Dept Biomed Engn & Computat Sci, Sch Sci, FI-00076 Helsinki, Finland. [Sandholm, Niina] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, FI-00290 Helsinki, Finland. [Sandholm, Niina] Folkhalsan Res Ctr, Folkhalsan Inst Genet, FI-00290 Helsinki, Finland. [Tanaka, Toshihiro] RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa 2300045, Japan. [Tanaka, Toshihiro] Tokyo Med & Dent Univ, Bioresource Res Ctr, Div Dis Divers, Tokyo 1138510, Japan. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN 37075 USA. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37075 USA. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37075 USA. [Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Oxford OX3 7BN, England. [Heath, Andrew C.; Madden, Pamela A. F.; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Arveiler, Dominique] Univ Strasbourg, Fac Med, Dept Epidemiol & Publ Hlth, EA3430, Strasbourg, France. [Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands. [Beilby, John; Hui, Jennie] Univ Western Australia, Nedlands, WA 6009, Australia. [Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Bovet, Pascal; Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland. [Bovet, Pascal; Bochud, Murielle] Univ Lausanne, CH-1010 Lausanne, Switzerland. [Bovet, Pascal; Bochud, Murielle] Minist Hlth, Victoria, Seychelles. [Cesana, Giancarlo] Univ Milan, I-20126 Bicocca, Italy. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37203 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Cusi, Daniele] Univ Milan, Dept Hlth Sci, I-20142 Milan, Italy. [Cusi, Daniele] Fdn Filarete, I-20139 Milan, Italy. [Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [den Ruijter, Hester M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands. [Dominiczak, Anna F.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Erbel, Raimund] Univ Hosp Essen, Clin Cardiol, West German Heart Ctr, D-45147 Essen, Germany. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00290 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FIN-00290 Helsinki, Finland. [Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany. [Felix, Stephan B.; Voelker, Uwe; Wallaschofski, Henri] Partner Site Greifswald, DZHK, D-17475 Greifswald, Germany. [Ferrannini, Ele] Univ Pisa, Dept Internal Med, I-56100 Pisa, Italy. [Ferrannini, Ele] Univ Pisa, Inst Clin Physiol, Natl Res Council, I-56124 Pisa, Italy. [Ferrieres, Jean] Toulouse Univ, Sch Med, Ranguell Hosp, Dept Cardiol, F-31400 Toulouse, France. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, UWI Solut Developing Countries, Kingston 7, Jamaica. [Gejman, Pablo V.] NorthShore Univ HealthSyst, Evanston, IL 60201 USA. [Gejman, Pablo V.] Univ Chicago, Chicago, IL 60637 USA. [Hall, Alistair S.] Univ Leeds, Leeds MRC Med Bioinformat Ctr, Leeds LS2 9LU, W Yorkshire, England. [Hattersley, Andrew T.] Univ Exeter, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Hicks, Andrew A.; Pramstaller, Peter P.] Bolzano EURAC, European Acad Bozen, Ctr Biomed, I-39100 Bolzano, Italy. [Hicks, Andrew A.; Pramstaller, Peter P.] Inst Univ Lubeck, D-23562 Lubeck, Germany. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Hingorani, Aroon D.; Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, London WC1E 6BT, England. [Hovingh, G. Kees; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Humphries, Steve E.] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London WC1E 6JJ, England. [Hunt, Steven C.] Univ Utah, Dept Internal Med, Cardiovasc Genet Div, Salt Lake City, UT 84108 USA. [Hypponen, Elina] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5000, Australia. [Hypponen, Elina] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5000, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA 5000, Australia. [Hypponen, Elina; Power, Chris] UCL, Inst Child Hlth, London WC1N 1EH, England. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, FI-90101 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC Hlth Protect Agcy HPA, Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, FI-90220 Oulu, Finland. Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland. [Jarvelin, Marjo-Riitta; Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Inst Hlth Sci, FI-90014 Oulu, Finland. [Jukema, J. Wouter; Asselbergs, Folkert W.; van der Harst, Pim] Interuniv Cardiol Inst Netherlands ICIN, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Jukema, J. Wouter; Asselbergs, Folkert W.; van der Harst, Pim] Interuniv Cardiol Inst Netherlands ICIN, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands ICIN, NL-3501 DG Utrecht, Netherlands. [Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Primary Hlth Care Gen Practice, FI-90220 Oulu, Finland. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands. [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. [Kumari, Meena; Langenberg, Claudia; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Kumari, Meena] Univ Essex, Dept Biol & Social Epidemiol, Colchester CO4 3SQ, Essex, England. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Med, FI-70210 Kuopio, Finland. [Kuusisto, Johanna; Lakka, Timo A.; Laakso, Markku; Rauramaa, Rainer] Univ Eastern Finland, FI-70210 Kuopio, Finland. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Dept Physiol, FI-70211 Kuopio, Finland. [Lakka, Timo A.; Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, FI-70210 Kuopio, Finland. [Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Lyssenko, Valeriya] Steno Diabet Ctr AS, DK-2820 Gentofte, Denmark. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Lund Univ Diabet Ctr, S-22100 Malmo, Sweden. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, S-22100 Malmo, Sweden. [Marette, Andre] Univ Laval, Fac Med, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ G1V 0A6, Canada. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Moll, Frans L.] Univ Med Ctr Utrecht, Dept Surg, NL-3584 CX Utrecht, Netherlands. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Peden, John F.] Illumina Inc, Cambridge CB10 1XL, England. [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Med & TB, Groningen, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland. [Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Rudan, Igor] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split 21000, Croatia. [Saramines, Jouko] South Carelia Cent Hosp, Lappeenranta 53130, Finland. [Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, D-01307 Dresden, Germany. [Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London W2 1PG, England. [Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, FI-00290 Helsinki, Finland. [Tregouet, David-Alexandre] Univ Paris 06, Sorbonne Univ, UMR S 1166, F-75013 Paris, France. [Tregouet, David-Alexandre] Univ Paris 06, INSERM, UMR S 1166, Team Genom & Physiopathol Cardiovasc Dis, F-75013 Paris, France. [Tregouet, David-Alexandre] ICAN, F-75013 Paris, France. [Tremblay, Angelo; Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ G1V 0A6, Canada. [Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, I-20133 Milan, Italy. [Tremoli, Elena] Inst Ricoveroe Cura & Carattere Sci, Ctr Cardiol Monzino, I-20133 Milan, Italy. [Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ G1V 0A6, Canada. [Waeber, Gerard] Univ Hosp CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Waeber, Gerard] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Amouyel, Philippe] Inst Pasteur, F-59000 Lille, France. [Amouyel, Philippe] INSERM, U744, F-59000 Lille, France. [Amouyel, Philippe] Univ Lille 2, F-59000 Lille, France. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, NL-3584 CX Utrecht, Netherlands. [Assimes, Themistocles L.; Melbve, Mads; Quertermous, Thomas] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Boehm, Bernhard O.] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, Singapore 637553, Singapore. [Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 637553, Singapore. [Boehm, Bernhard O.] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89081 Ulm, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [de Bakker, Paul I. W.] Harvard Univ, Dept Med, Div Genet, Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands. [Hui, Jennie] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, D-68163 Mannheim, Germany. [Melbve, Mads] Univ Copenhagen, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Oostra, Ben A.] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Saaristo, Timo E.] Finnish Diabet Assoc, FI-33680 Tampere, Finland. [Saaristo, Timo E.] Pirkanmaa Hosp Dist, FI-33521 Tampere, Finland. [Saleheen, Danish] Ctr Noncommunicable Dis, Karatchi, Pakistan. [Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Sattar, Naveed] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Div Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10580 USA. [Thorsteinsdottir, Unnu R.; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Tuomilehto, Jaakko] Univ Hosp La Paz IdiPaz, Inst Hlth Res, Madrid 28046, Spain. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, FI-70210 Kuopio, Finland. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, D-85764 Munich, Germany. [Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Wichmann, H-Erich] Helmholtz Zentrum Munchen, Inst Epidemiol 1, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany. [Zanen, Pieter] Univ Med Ctr Utrecht, Dept Pulmonol, NL-3584 CX Utrecht, Netherlands. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England. [McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Scherag, Andre] Jena Univ Hosp, Clin Epidemiol Integrated Res & Treatment Ctr, CSCC, D-07743 Jena, Germany. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Speliotes, EK (reprint author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM joelh@broadinstitute.org; ruth.loos@mssm.edu; espeliot@med.umich.edu RI Beckmann, Jacques S /A-9772-2008; Leander, Karin/C-7261-2017; Yengo, Loic/D-2692-2017; Palmer, Lyle/K-3196-2014; Kolcic, Ivana/E-2713-2017; Boban, Mladen/E-2777-2017; Stathopoulou, Maria/H-7324-2016; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Schwarz, Peter/B-5127-2013; Ramos , Rafel/D-9627-2016; Johnson, Andrew/G-6520-2013; Franke, Lude/P-7036-2016; Ormel, Johan/C-6094-2013; Karjalainen, Juha/P-8624-2016; Laan, Maris/A-4100-2011; Slagboom, P. Eline/R-4790-2016; Verweij, Niek/A-4499-2017; Erdmann, Jeanette/P-7513-2014; Franke, Andre/B-2151-2010; Magnusson, Patrik/C-4458-2017; Johansson, Asa/G-5270-2011; Bovet, Pascal/F-4477-2011; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; Nato, Alejandro/J-3880-2016; Yang, Jian/A-5852-2010; Matullo, Giuseppe/K-6383-2016; Deloukas, Panos/B-2922-2013; kinnunen, leena/B-7059-2012; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Kessler, Thorsten/O-7426-2015; Prokopenko, Inga/H-3241-2014; Kronenberg, Florian/B-1736-2008; Sundstrom, Johan/A-6286-2009; Tanaka, Toshihiro/J-9310-2014; Sarzynski, Mark/A-9798-2014; Thorand, Barbara/B-5349-2014; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Tregouet, David-Alexandre/E-3961-2016; Vermeulen, H.H.M./L-4716-2015; Hypponen, Elina/B-2596-2014; Salumets, Andres/J-2278-2015; Bakker, Stephan/J-4023-2015; Rioux, John/A-9599-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Huang, Jiaxing/B-7521-2009; Ripatti, Samuli/H-9446-2014; Mattace- Raso, Francesco/L-2541-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Singleton, Andrew/C-3010-2009; Moayyeri, Alireza/N-3332-2014; Palmer, Colin/C-7053-2008; Boehm, Bernhard/F-8750-2015; Fehrmann, Rudolf/E-2551-2011; Colaus, PsyColaus/K-6607-2013; Grallert, Harald/B-3424-2013; Fall, Tove/O-7226-2014; Kiemeney, Lambertus/D-3357-2009; de Bakker, Paul/B-8730-2009; Meisinger, Christine/B-5358-2014; Visser, Jenny /F-8156-2011 OI Wain, Louise/0000-0003-4951-1867; Medland, Sarah/0000-0003-1382-380X; Kaprio, Jaakko/0000-0002-3716-2455; Lawlor, Debbie A/0000-0002-6793-2262; Hattersley, Andrew/0000-0001-5620-473X; Sinisalo, Juha/0000-0002-0169-5137; Lahti, Jari/0000-0002-4310-5297; Kleber, Marcus/0000-0003-0663-7275; Ganna, Andrea/0000-0002-8147-240X; Peters, Annette/0000-0001-6645-0985; Medina-Gomez, Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760; Marmot, Michael/0000-0002-2431-6419; Eriksson, Johan/0000-0002-2516-2060; Prabhakaran, Dorairaj/0000-0002-3172-834X; Falhammar, Henrik/0000-0002-5622-6987; Evans, David/0000-0003-0663-4621; Assimes, Themistocles/0000-0003-2349-0009; Ouwehand, Willem/0000-0002-7744-1790; Folkersen, Lasse/0000-0003-0708-9530; Smith, Jennifer/0000-0002-3575-5468; ruggiero, daniela/0000-0003-3898-7827; Buyske, Steven/0000-0001-8539-5416; Vandenput, Liesbeth/0000-0002-1712-6131; Karpe, Fredrik/0000-0002-2751-1770; Maxwell, Alexander P./0000-0002-6110-7253; Vinkhuyzen, Anna/0000-0003-3352-0603; Ramos , Rafel/0000-0001-7970-5537; Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685; Kuulasmaa, Kari/0000-0003-2165-1411; Karasik, David/0000-0002-8826-0530; Hedman, Asa/0000-0001-5413-204X; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; rossing, peter/0000-0002-1531-4294; Nothen, Markus/0000-0002-8770-2464; Goessling, Wolfram/0000-0001-9972-1569; Mannisto, Satu/0000-0002-8668-3046; Lakka, Timo/0000-0002-9199-2871; Gigante, Bruna/0000-0003-4508-7990; van der Laan, Sander W./0000-0001-6888-1404; Humphries, Stephen E/0000-0002-8221-6547; Adeyemo, Adebowale/0000-0002-3105-3231; Org, Elin/0000-0003-1451-9375; Esko, Tonu/0000-0003-1982-6569; Arora, Pankaj/0000-0003-2420-3550; Hosseini, Mohsen/0000-0003-3626-9928; Sandholm, Niina/0000-0003-4322-6942; Kristiansson, Kati/0000-0003-4688-107X; Tryggvadottir, Laufey/0000-0001-8067-9030; Locke, Adam/0000-0001-6227-198X; Gieger, Christian/0000-0001-6986-9554; Strawbridge, Rona/0000-0001-8506-3585; Menni, Cristina/0000-0001-9790-0571; Goddard, Michael/0000-0001-9917-7946; Melzer, David/0000-0002-0170-3838; TREMOLI, ELENA/0000-0002-0929-6106; Magi, Reedik/0000-0002-2964-6011; Fuchsberger, Christian/0000-0002-5918-8947; Mulas, Antonella/0000-0002-6856-1483; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Fraser, Ross/0000-0003-0488-2592; Beckmann, Jacques S /0000-0002-9741-1900; Leander, Karin/0000-0002-1404-9222; Yengo, Loic/0000-0002-4272-9305; Palmer, Lyle/0000-0002-1628-3055; Kolcic, Ivana/0000-0001-7918-6052; Stathopoulou, Maria/0000-0003-4376-2083; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Franks, Paul/0000-0002-0520-7604; McCarroll, Steven/0000-0002-6954-8184; Beekman, Marian/0000-0003-0585-6206; Stanton, Alice/0000-0002-4961-165X; Schwarz, Peter/0000-0001-6317-7880; Ramos , Rafel/0000-0001-8146-5288; Franke, Lude/0000-0002-5159-8802; Laan, Maris/0000-0002-8519-243X; Slagboom, P. Eline/0000-0002-2875-4723; Erdmann, Jeanette/0000-0002-4486-6231; Franke, Andre/0000-0003-1530-5811; Day, Felix/0000-0003-3789-7651; Asselta, Rosanna/0000-0001-5351-0619; Seshadri, Sudha/0000-0001-6135-2622; Bush, William/0000-0002-9729-6519; Peters, Marjolein/0000-0003-3167-9063; Zgaga, Lina/0000-0003-4089-9703; Shungin, Dmitry/0000-0001-7900-5856; Johansson, Asa/0000-0002-2915-4498; Bovet, Pascal/0000-0002-0242-4259; Smith, Albert/0000-0003-1942-5845; Nato, Alejandro/0000-0002-8745-9046; Yang, Jian/0000-0003-2001-2474; Deloukas, Panos/0000-0001-9251-070X; kinnunen, leena/0000-0001-8739-4812; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Kronenberg, Florian/0000-0003-2229-1120; Sundstrom, Johan/0000-0003-2247-8454; Tanaka, Toshihiro/0000-0001-6201-9784; Thorand, Barbara/0000-0002-8416-6440; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Hypponen, Elina/0000-0003-3670-9399; Salumets, Andres/0000-0002-1251-8160; Bakker, Stephan/0000-0003-3356-6791; Rioux, John/0000-0001-7560-8326; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Moayyeri, Alireza/0000-0002-9143-2161; Palmer, Colin/0000-0002-6415-6560; Fehrmann, Rudolf/0000-0002-7516-315X; Kiemeney, Lambertus/0000-0002-2368-1326; de Bakker, Paul/0000-0001-7735-7858; FU British Heart Foundation [FS/14/55/30806, RG/08/008/25291, RG/08/014/24067, RG/10/12/28456]; Cancer Research UK [14136]; Chief Scientist Office [CZB/4/672, CZB/4/710]; Medical Research Council [G0401527, G0601261, G1000143, G1001799, G9521010, MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UU_12012/1, MC_UU_12013/1, MC_UU_12015/1, MC_UU_12015/2, MC_UU_12015/5, MC_UU_12019/1, MR/K006584/1, MR/K013351/1, MR/L003120/1, MR/N01104X/1]; NCATS NIH HHS [TL1 TR001066, UL1 TR000124, UL1 TR001067]; NCI NIH HHS [UM1 CA182910, UM1 CA182913]; NHGRI NIH HHS [U01 HG007376, U01 HG007416, U01 HG007419]; NHLBI NIH HHS [K01 HL116770, P30 HL107251, R01 HL109946, R01 HL117078, R01 HL117626, T32 HL007055, T32 HL007824]; NIA NIH HHS [R01 AG033193, R01 AG025941, R01 AG041517, U01 AG009740, U01 AG049505]; NIDA NIH HHS [R21 DA027040]; NIDDK NIH HHS [K23 DK080145, P30 DK020541, P30 DK020572, P30 DK063491, P30 DK072488, P60 DK020541, R01 DK062370, R01 DK072193, R01 DK075787, R01 DK078150, R01 DK089256, R01 DK093757, U01 DK062370]; NIGMS NIH HHS [P30 GM103341, T32 GM080178]; NIMHD NIH HHS [P20 MD006899]; NINDS NIH HHS [R01 NS017950]; Wellcome Trust [084766, 085235, 097117, 098017, 098381, 100574] NR 73 TC 431 Z9 435 U1 64 U2 323 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 12 PY 2015 VL 518 IS 7538 BP 197 EP U401 DI 10.1038/nature14177 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8SD UT WOS:000349190300031 PM 25673413 ER PT J AU Chen, YH Du, WL Hagemeijer, MC Takvorian, PM Pau, C Cali, A Brantner, CA Stempinski, ES Connelly, PS Ma, HC Jiang, P Wimmer, E Altan-Bonnet, G Altan-Bonnet, N AF Chen, Ying-Han Du, WenLi Hagemeijer, Marne C. Takvorian, Peter M. Pau, Cyrilla Cali, Ann Brantner, Christine A. Stempinski, Erin S. Connelly, Patricia S. Ma, Hsin-Chieh Jiang, Ping Wimmer, Eckard Altan-Bonnet, Gregoire Altan-Bonnet, Nihal TI Phosphatidylserine Vesicles Enable Efficient En Bloc Transmission of Enteroviruses SO CELL LA English DT Article ID CELLULAR MEMBRANES; VIRUS ENTRY; ANNEXIN-V; POLIOVIRUS; PROTEIN; CELLS; REPLICATION; RECOGNITION; MACROPINOCYTOSIS; AUTOPHAGOSOMES AB A central paradigm within virology is that each viral particle largely behaves as an independent infectious unit. Here, we demonstrate that clusters of enteroviral particles are packaged within phosphatidylserine (PS) lipid-enriched vesicles that are non-lytically released from cells and provide greater infection efficiency than free single viral particles. We show that vesicular PS lipids are co-factors to the relevant enterovirus receptors in mediating subsequent infectivity and transmission, in particular to primary human macrophages. We demonstrate that clustered packaging of viral particles within vesicles enables multiple viral RNA genomes to be collectively transferred into single cells. This study reveals a novel mode of viral transmission, where enteroviral genomes are transmitted from cell-to-cell en bloc in membrane-bound PS vesicles instead of as single independent genomes. This has implications for facilitating genetic cooperativity among viral quasispecies as well as enhancing viral replication. C1 [Chen, Ying-Han; Du, WenLi; Hagemeijer, Marne C.; Altan-Bonnet, Nihal] NHLBI, Lab Host Pathogen Dynam, NIH, Bethesda, MD 20892 USA. [Chen, Ying-Han; Takvorian, Peter M.; Pau, Cyrilla; Cali, Ann] Rutgers State Univ, Federated Dept Biol Sci, Newark, NJ 07102 USA. [Brantner, Christine A.; Stempinski, Erin S.; Connelly, Patricia S.] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Ma, Hsin-Chieh; Jiang, Ping; Wimmer, Eckard] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Altan-Bonnet, Gregoire] Mem Sloan Kettering Canc Ctr, Program Computat Biol & Immunol, New York, NY 10065 USA. RP Altan-Bonnet, N (reprint author), NHLBI, Lab Host Pathogen Dynam, NIH, Bethesda, MD 20892 USA. EM nihal.altan-bonnet@nih.gov OI Brantner, Christine/0000-0001-8172-901X FU NIH; [AI091985-01A1]; [AI083408]; [AI15122] FX The authors would like to thank Yasmine Belkaid, Konstantin Chumakov, Ana Maria Cuervo, James Hogle, Gerald Feldman, Jennifer Jones, Jennifer Lippincott-Schwartz, Sanford Simon, Radek Dobrowolski, Wilma Friedman, Ellie Ehrenfeld and members of the Altan-Bonnet lab for fruitful discussions. The authors would like to especially thank Wen-Chin Tseng for help in constructing the graphical cartoons. The authors also thank Frank Macaluso and Geoffrey Perumal of the Albert Einstein College of Medicine Analytical Imaging facility for technical support. A.C., P.T., and C.P. were supported by grant AI091985-01A1; G.A.B. was supported by grant AI083408; H.M., P.J., and E.W. were supported by grant AI15122; and Y.C., W.D., M.H., C.B., P.C., E.S., and N.A.B. were supported by intramural NIH funds. NR 49 TC 38 Z9 38 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 12 PY 2015 VL 160 IS 4 BP 619 EP 630 DI 10.1016/j.cell.2015.01.032 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CA8ZE UT WOS:000349208800007 PM 25679758 ER PT J AU McDermott, DH Gao, JL Liu, Q Siwicki, M Martens, C Jacobs, P Velez, D Yim, E Bryke, CR Hsu, N Dai, ZY Marquesen, MM Stregevsky, E Kwatemaa, N Theobald, N Priel, DAL Pittaluga, S Raffeld, MA Calvo, KR Maric, I Desmond, R Holmes, KL Kuhns, DB Balabanian, K Bachelerie, F Porcella, SF Malech, HL Murphy, PM AF McDermott, David H. Gao, Ji-Liang Liu, Qian Siwicki, Marie Martens, Craig Jacobs, Paejonette Velez, Daniel Yim, Erin Bryke, Christine R. Hsu, Nancy Dai, Zunyan Marquesen, Martha M. Stregevsky, Elina Kwatemaa, Nana Theobald, Narda Priel, Debra A. Long Pittaluga, Stefania Raffeld, Mark A. Calvo, Katherine R. Maric, Irina Desmond, Ronan Holmes, Kevin L. Kuhns, Douglas B. Balabanian, Karl Bachelerie, Francoise Porcella, Stephen F. Malech, Harry L. Murphy, Philip M. TI Chromothriptic Cure of WHIM Syndrome SO CELL LA English DT Article ID CXCR4 ANTAGONIST PLERIXAFOR; CHEMOKINE RECEPTORS; HEMATOPOIETIC STEM; PROGENITOR CELLS; IN-VIVO; MYELOKATHEXIS; SURVIVAL/ANTIAPOPTOSIS; HYPOGAMMAGLOBULINEMIA; GRANULOCYTOPENIA; DESENSITIZATION AB Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that re-populated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wildtype or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation. C1 [McDermott, David H.; Gao, Ji-Liang; Liu, Qian; Siwicki, Marie; Jacobs, Paejonette; Velez, Daniel; Yim, Erin; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Martens, Craig; Porcella, Stephen F.] NIAID, Res Technol Branch, NIH, Hamilton, MT 59840 USA. [Stregevsky, Elina; Holmes, Kevin L.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Hsu, Nancy; Dai, Zunyan] Quest Diagnost, Chantilly, VA 20151 USA. [Marquesen, Martha M.; Kwatemaa, Nana; Theobald, Narda; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Priel, Debra A. Long; Kuhns, Douglas B.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Clin Serv Program, Frederick, MD 21701 USA. [Pittaluga, Stefania; Raffeld, Mark A.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Calvo, Katherine R.; Maric, Irina] NIH, Div Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Desmond, Ronan] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Desmond, Ronan] Tallaght Hosp, Dept Haematol, Dublin 24, Ireland. [Balabanian, Karl; Bachelerie, Francoise] Univ Paris 11, Lab Excellence Res Medicat & Innovat Therapeut, INSERM UMR S996, F-92140 Clamart, France. [Bryke, Christine R.; Hsu, Nancy] Beth Israel Deaconess Med Ctr, Dept Cytogenet, Boston, MA 02215 USA. [Dai, Zunyan] Emory Univ, Sch Med, Dept Human Genet, Decatur, GA 30030 USA. RP Murphy, PM (reprint author), NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM pmm@nih.gov RI Balabanian, Karl/I-2990-2016; BACHELERIE, FRANCOISE/F-8823-2013; OI McDermott, David/0000-0001-6978-0867; Malech, Harry/0000-0001-5874-5775 FU Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), NIH; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), NIH and was funded in part with federal funds from the National Cancer Institute, NIH under contract HHSN261200800001E. We thank Hongwei Zhang for flow cytometry advice, Carolyn Boscia for help with graphics, and the research subjects for their participation in the study. A provisional patent on CXCR4 knockdown as a method to enhance HSC engraftment has been filed by the US government with D. H. M., Q. L., M. S., J.G., H. L. M., and P. M. M. as inventors. NR 34 TC 31 Z9 32 U1 1 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 12 PY 2015 VL 160 IS 4 BP 686 EP 699 DI 10.1016/j.cell.2015.01.014 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CA8ZE UT WOS:000349208800012 PM 25662009 ER PT J AU Lutskiy, MY Avneri-Katz, S Zhu, N Itsko, M Ronen, Z Arnusch, CJ Kasher, R AF Lutskiy, Marina-Yamit Avneri-Katz, Shani Zhu, Ni Itsko, Mark Ronen, Zeev Arnusch, Christopher J. Kasher, Roni TI A microbiology-based assay for quantification of bacterial early stage biofilm formation on reverse-osmosis and nanofiltration membranes SO SEPARATION AND PURIFICATION TECHNOLOGY LA English DT Article DE Biofilm-growth; Reverse-osmosis; Nanofiltration; Biofouling; Bacterial initial attachment ID TECHNOLOGY; ADHESION AB Membrane-based water treatment and purification technologies are crucial globally, and are especially essential in areas that suffer from a shortage of water. In the source water bacteria are ubiquitous and "microbial attachment and growth on membranes is a major problem associated with these technologies. Here we describe an assay to quantify early stage biofilm growth on reverse-osmosis (RO) and nanofiltration (NF) polyamide membranes. The adherence and growth of Klebsiella oxytoca on RO and NF membranes was monitored over time under static conditions, with repeated removal of planktonic bacteria, and this assay was effective in showing especially the early stages of bacterial attachment and growth. Comparison of bacterial growth on NF270, SW30, TM820-400, and LE-400 membranes showed only slight differences, and in all cases the bacterial growth rate accelerated between 5 and 10 h of incubation time. The average surface growth rate was 1.3 x 10(6) CFU/(cm(2) x h) during 5-10 h of incubation, and was measured by counting colony-forming units (CFU) after detachment of bacteria from the membranes. Fluorescence microscopy confirmed early stage biofilm growth between 5 and 10 h of incubation time. This assay will be useful to assess the susceptibility of membranes to bacterial attachment and subsequent biofilm growth and will be especially useful in screening novel antimicrobial and anti-biofilm membrane coatings and modifications and gaining insight into the mode of action of surface-tethered antimicrobial agents. Since initial irreversible adhesion is a critical step in the development of biofilms and hence biofouling on membranes, a deeper understanding of the process may lead to novel strategies for biofilm prevention. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lutskiy, Marina-Yamit; Avneri-Katz, Shani; Zhu, Ni; Itsko, Mark; Arnusch, Christopher J.; Kasher, Roni] Ben Gurion Univ Negev, Jacob Blaustein Inst Desert Res, Zuckerberg Inst Water Res, Dept Desalinat & Water Treatment, IL-84990 Sede Boqer, Israel. [Itsko, Mark] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Ronen, Zeev] Ben Gurion Univ Negev, Jacob Blaustein Inst Desert Res, Zuckerberg Inst Water Res, Dept Hydrol & Environm Microbiol, IL-84990 Sede Boqer, Israel. RP Kasher, R (reprint author), Ben Gurion Univ Negev, Jacob Blaustein Inst Desert Res, Zuckerberg Inst Water Res, Dept Desalinat & Water Treatment, Sde Boqer Campus, IL-84990 Sede Boqer, Israel. EM kasher@bgu.ac.il FU Massachusetts Institute of Technology - BenGurion University (MIT-BGU); Israeli Ministry of Science and Technology for the fellowship of Advancement of Women in Science [3-8736]; Water Authority of Israel FX The authors wish to thank the Water Authority of Israel for providing the 2012-2013 PhD student fellowship Grant (M.-Y.L.). The authors thank the Massachusetts Institute of Technology - BenGurion University (MIT-BGU) student exchange program for financing a scholarship and travel expenses (N.Z.), and the Israeli Ministry of Science and Technology for the 2012 fellowship of Advancement of Women in Science (No. 3-8736, M.-Y.L.). The authors thank Dr. Ehud Banin (Bar-Ilan University, Israel) and Dr. Moshe Herzberg (Ben-Gurion University of the Negev, Israel) for fruitful scientific discussions. NR 26 TC 5 Z9 5 U1 2 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5866 EI 1873-3794 J9 SEP PURIF TECHNOL JI Sep. Purif. Technol. PD FEB 12 PY 2015 VL 141 BP 214 EP 220 DI 10.1016/j.seppur.2014.12.003 PG 7 WC Engineering, Chemical SC Engineering GA CA9WE UT WOS:000349274700026 ER PT J AU Carter, BD Abnet, CC Feskanich, D Freedman, ND Hartge, P Lewis, CE Ockene, JK Prentice, RL Speizer, FE Thun, MJ Jacobs, EJ AF Carter, Brian D. Abnet, Christian C. Feskanich, Diane Freedman, Neal D. Hartge, Patricia Lewis, Cora E. Ockene, Judith K. Prentice, Ross L. Speizer, Frank E. Thun, Michael J. Jacobs, Eric J. TI Smoking and Mortality - Beyond Established Causes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BREAST-CANCER RISK; CIGARETTE-SMOKING; PROSTATE-CANCER; PROSPECTIVE COHORT; NURSES HEALTH; RENAL-FAILURE; UNITED-STATES; ASSOCIATION; ALCOHOL; DISEASE AB BACKGROUND Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. METHODS We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. RESULTS During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. CONCLUSIONS A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.) C1 [Carter, Brian D.; Thun, Michael J.; Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Abnet, Christian C.; Freedman, Neal D.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Feskanich, Diane; Speizer, Frank E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Feskanich, Diane; Speizer, Frank E.] Harvard Univ, Sch Med, Boston, MA USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA USA. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Carter, BD (reprint author), Amer Canc Soc, Natl Home Off, 250 Williams St NW, Atlanta, GA 30303 USA. EM brian.carter@cancer.org RI Freedman, Neal/B-9741-2015; Abnet, Christian/C-4111-2015 OI Freedman, Neal/0000-0003-0074-1098; Abnet, Christian/0000-0002-3008-7843 FU American Cancer Society FX Funded by the American Cancer Society. NR 37 TC 115 Z9 117 U1 7 U2 52 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 FEB 12 PY 2015 VL 372 IS 7 BP 631 EP 640 DI 10.1056/NEJMsa1407211 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CA8CK UT WOS:000349143900007 PM 25671255 ER PT J AU Tao-Cheng, JH Pham, A Yang, Y Winters, CA Gallant, PE Reese, TS AF Tao-Cheng, J. -H. Pham, A. Yang, Y. Winters, C. A. Gallant, P. E. Reese, T. S. TI SYNTAXIN 4 IS CONCENTRATED ON PLASMA MEMBRANE OF ASTROCYTES SO NEUROSCIENCE LA English DT Article DE syntaxin 4; syntaxin 1; exocytosis; electron microscopy; synapse; astroglia ID PROTEIN EXPRESSION; GLUTAMATE RELEASE; FUSION; SNARE; TRAFFICKING; VESICLES; SNAP-25; IMMUNOGOLD; TRANSPORT; NEURONS AB Syntaxins are a family of transmembrane proteins that participate in SNARE complexes to mediate membrane fusion events including exocytosis. Different syntaxins are thought to participate in exocytosis in different compartments of the nervous system such as the axon, the soma/dendrites or astrocytes. It is well known that exocytosis of synaptic vesicles at axonal presynaptic terminals involves syntaxin 1 but distributions of syntaxins on neuronal somal and dendritic, postsynaptic or astroglial plasma membranes are less well characterized. Here, we use pre-embedding immunogold labeling to compare the distribution of two plasma membrane-enriched syntaxins (1 and 4) in dissociated rat hippocampal cultures as well as in perfusion-fixed mouse brains. Comparison of Western blots of neuronal cultures, consisting of a mixture of hippocampal neurons and glia, with glial cultures, consisting of mostly astrocytes, shows that syntaxin 1 is enriched in neuronal cultures, whereas syntaxin 4 is enriched in glial cultures. Electron microscopy (EM)-immunogold labeling shows that syntaxin 1 is most abundant at the plasma membranes of axons and terminals, while syntaxin 4 is most abundant at astroglial plasma membranes. This differential distribution was evident even at close appositions of membranes at synapses, where syntaxin 1 was localized to the plasma membrane of the presynaptic terminal, including that at the active zone, while syntaxin 4 was localized to nearby peri-synaptic astroglial processes. These results show that syntaxin 4 is available to support exocytosis in astroglia. Published by Elsevier Ltd. on behalf of IBRO. C1 [Tao-Cheng, J. -H.] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Pham, A.; Yang, Y.; Winters, C. A.; Gallant, P. E.; Reese, T. S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Tao-Cheng, JH (reprint author), 49 Convent Dr,Room 3A50, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU NIH, NINDS FX We thank Virginia Crocker and Rita Azzam for expert EM technical support, and Dr. Ayse Dosemeci for helpful discussions. Supported by the Intramural Research Program of the NIH, NINDS. NR 33 TC 2 Z9 2 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD FEB 12 PY 2015 VL 286 BP 264 EP 271 DI 10.1016/j.neuroscience.2014.11.054 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AZ1YL UT WOS:000348031200023 PM 25485479 ER PT J AU Miller, CA Hsu, LY Ta, A Conn, H Winkler, S Arai, AE AF Miller, Christopher A. Hsu, Li-Yueh Ta, Allison Conn, Hannah Winkler, Susanne Arai, Andrew E. TI Quantitative pixel-wise measurement of myocardial blood flow: The impact of surface coil-related field inhomogeneity and a comparison of methods for its correction SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Cardiovascular magnetic resonance; Perfusion; Myocardial blood flow; Quantification; Field inhomogeneity; Surface coil intensity correction ID CARDIAC MAGNETIC-RESONANCE; CORONARY-ARTERY-DISEASE; INTENSITY CORRECTION; PERFUSION ANALYSIS; PHASED-ARRAY; MRI; QUANTIFICATION; HUMANS; ACCURACY; IMAGES AB Background: Surface coil-related field inhomogeneity potentially confounds pixel-wise quantitative analysis of perfusion CMR images. This study assessed the effect of surface coil-related field inhomogeneity on the spatial variation of pixel-wise myocardial blood flow (MBF), and assessed its impact on the ability of MBF quantification to differentiate ischaemic from remote coronary territories. Two surface coil intensity correction (SCIC) techniques were evaluated: 1) a proton density-based technique (PD-SCIC) and; 2) a saturation recovery steady-state free precession-based technique (SSFP-SCIC). Methods: 26 subjects (18 with significant CAD and 8 healthy volunteers) underwent stress perfusion CMR using a motion-corrected, saturation recovery SSFP dual-sequence protocol. A proton density (PD)-weighted image was acquired at the beginning of the sequence. Surface coil-related field inhomogeneity was approximated using a third-order surface fit to the PD image or a pre-contrast saturation prepared SSFP image. The estimated intensity bias field was subsequently applied to the image series. Pixel-wise MBF was measured from mid-ventricular stress images using the two SCIC approaches and compared to measurements made without SCIC. Results: MBF heterogeneity in healthy volunteers was higher using SSFP-SCIC (24.8 +/- 4.1%) compared to PD-SCIC (20.8 +/- 3.0%; p = 0.009), however heterogeneity was significantly lower using either SCIC technique compared to analysis performed without SCIC (36.2 +/- 6.3%). In CAD patients, the difference in MBF between remote and ischaemic territories was minimal when analysis was performed without SCIC (0.06 +/- 0.91 mL/min/kg), and was substantially lower than with either PD-SCIC (0.50 +/- 0.63 mL/min/kg; p = 0.013) or with SSFP-SCIC (0.63 +/- 0.89 mL/min/kg; p = 0.005). In 6 patients, MBF quantified without SCIC was artifactually higher in the stenosed coronary territory compared to the remote territory. PD-SCIC and SSFP-SCIC had similar differences in MBF between remote and ischaemic territories (p = 0.145). Conclusions: This study demonstrates that surface coil-related field inhomogeneity can confound pixel-wise MBF quantification. Whilst a PD-based SCIC led to a more homogenous correction than a saturation recovery SSFP-based technique, this did not result in an appreciable difference in the differentiation of ischaemic from remote coronary territories and thus either method could be applied. C1 [Miller, Christopher A.; Hsu, Li-Yueh; Ta, Allison; Conn, Hannah; Winkler, Susanne; Arai, Andrew E.] NHLBI, Dept Hlth & Human Serv, Adv Cardiovasc Imaging Lab, NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Dept Hlth & Human Serv, Adv Cardiovasc Imaging Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM araia@nih.gov FU National Institute for Health Research, UK [NIHR-DRF-2010-03-98] FX CAM was supported by a Fellowship from the National Institute for Health Research, UK (NIHR-DRF-2010-03-98). NR 19 TC 1 Z9 1 U1 0 U2 3 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 FEB 11 PY 2015 VL 17 AR 11 DI 10.1186/s12968-015-0117-1 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CB9IP UT WOS:000349945500002 PM 25827156 ER PT J AU Costa, VD Tran, VL Turchi, J Averbeck, BB AF Costa, Vincent D. Tran, Valery L. Turchi, Janita Averbeck, Bruno B. TI Reversal Learning and Dopamine: A Bayesian Perspective SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Bayesian; dopamine; haloperidol; L-DOPA; reinforcement learning; reversal learning ID PREFRONTAL CORTEX; PARKINSONS-DISEASE; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; FRONTAL-CORTEX; IN-VIVO; LESIONS; DISCRIMINATION; REINFORCEMENT; SENSITIVITY AB Reversal learning has been studied as the process of learning to inhibit previously rewarded actions. Deficits in reversal learning have been seen after manipulations of dopamine and lesions of the orbitofrontal cortex. However, reversal learning is often studied in animals that have limited experience with reversals. As such, the animals are learning that reversals occur during data collection. We have examined a task regime in which monkeys have extensive experience with reversals and stable behavioral performance on a probabilistic two-arm bandit reversal learning task. We developed a Bayesian analysis approach to examine the effects of manipulations of dopamine on reversal performance in this regime. We find that the analysis can clarify the strategy of the animal. Specifically, at reversal, the monkeys switch quickly from choosing one stimulus to choosing the other, as opposed to gradually transitioning, which might be expected if they were using a naive reinforcement learning (RL) update of value. Furthermore, we found that administration of haloperidol affects the way the animals integrate prior knowledge into their choice behavior. Animals had a stronger prior on where reversals would occur on haloperidol than on levodopa (L-DOPA) or placebo. This strong prior was appropriate, because the animals had extensive experience with reversals occurring in the middle of the block. Overall, we find that Bayesian dissection of the behavior clarifies the strategy of the animals and reveals an effect of haloperidol on integration of prior information with evidence in favor of a choice reversal. C1 [Costa, Vincent D.; Tran, Valery L.; Turchi, Janita; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov OI Costa, Vincent/0000-0002-5412-8945 FU National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. NR 31 TC 12 Z9 12 U1 2 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 11 PY 2015 VL 35 IS 6 BP 2407 EP 2416 DI 10.1523/JNEUROSCI.1989-14.2015 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CB5RZ UT WOS:000349686500009 PM 25673835 ER PT J AU Astarita, G Avanesian, A Grimaldi, B Realini, N Justinova, Z Panlilio, LV Basit, A Goldberg, SR Piomelli, D AF Astarita, Giuseppe Avanesian, Agnesa Grimaldi, Benedetto Realini, Natalia Justinova, Zuzana Panlilio, Leight V. Basit, Abdul Goldberg, Steven R. Piomelli, Daniele TI Methamphetamine Accelerates Cellular Senescence through Stimulation of De Novo Ceramide Biosynthesis SO PLOS ONE LA English DT Article ID KAPPA-B; SPHINGOLIPID METABOLISM; BETA-GALACTOSIDASE; ENDOTHELIAL-CELLS; MASS-SPECTROMETRY; MOUSE-BRAIN; DNA-BINDING; TNF-ALPHA; RAT; APOPTOSIS AB Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanism underlying these findings remains unknown. Here we used functional lipidomics and transcriptomics experiments to study abnormalities in lipid metabolism in select regions of the brain and, to a greater extent, peripheral organs and tissues of rats that self-administered methamphetamine. Experiments in various cellular models (primary mouse fibroblasts and myotubes) allowed us to investigate the molecular mechanisms of systemic inflammation and cellular aging related to methamphetamine abuse. We report now that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P-450, and involves the recruitment of nuclear factor-kappa B (NF-kappa B) to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of NF-kappa B signaling and ceramide formation prevent methamphetamine-induced senescence and systemic inflammation in rats self-administering the drug, attenuating their health deterioration. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments. C1 [Astarita, Giuseppe; Avanesian, Agnesa] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. [Grimaldi, Benedetto; Realini, Natalia; Basit, Abdul; Piomelli, Daniele] Italian Inst Technol, Genoa, Italy. [Justinova, Zuzana; Panlilio, Leight V.; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Baltimore, MD USA. [Justinova, Zuzana] Univ Maryland, Sch Med, MPRC, Dept Psychiat, Baltimore, MD 21201 USA. [Piomelli, Daniele] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92717 USA. RP Piomelli, D (reprint author), Italian Inst Technol, Genoa, Italy. EM piomelli@uci.edu RI Justinova, Zuzana/A-9109-2011; OI Justinova, Zuzana/0000-0001-5793-7484; Basit, Abdul/0000-0002-1164-5520; Grimaldi, Benedetto/0000-0002-2589-9302 FU National Institute on Drug Abuse [RC2 DA028902]; National Institute on Drug Abuse, NIH, DHHS FX These studies were funded by the National Institute on Drug Abuse (RC2 DA028902 to D. P.) and by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 3 Z9 4 U1 4 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 11 PY 2015 VL 10 IS 2 AR e0116961 DI 10.1371/journal.pone.0116961 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB3RF UT WOS:000349545300028 PM 25671639 ER PT J AU Roychoudhuri, R Lefebvre, F Honda, M Pan, L Ji, Y Klebanoff, CA Nichols, CN Fourati, S Hegazy, AN Goulet, JP Gattinoni, L Nabel, GJ Gilliet, M Cameron, M Restifo, NP Sekaly, RP Flatz, L AF Roychoudhuri, Rahul Lefebvre, Francois Honda, Mitsuo Pan, Li Ji, Yun Klebanoff, Christopher A. Nichols, Carmen N. Fourati, Slim Hegazy, Ahmed N. Goulet, Jean-Philippe Gattinoni, Luca Nabel, Gary J. Gilliet, Michel Cameron, Mark Restifo, Nicholas P. Sekaly, Rafick P. Flatz, Lukas TI Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation SO VACCINE LA English DT Article DE CD8; Memory T cells; T cell memory; Prime-boost vaccination; LCMV vector; Adenovirus vector ID INTERLEUKIN-7 RECEPTOR; EFFECTOR; EXPRESSION; VACCINE; GENERATION; SUBSETS; LYMPHOCYTES; ANTIGEN; FATES; BET AB The generation of CD8(+) T-cell memory is a major aim of vaccination. While distinct subsets of CD8(+) T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8(+) T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (T-EFF), effector memory (T-EM) and central memory (T-CM) CD8(+) T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8(+) T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order T-N > T-CM > T-EM > T-EFF Strikingly, when we compared global differences in gene expression between T-N, T-CM, T-EM and T-EFF cells with known transcriptional changes that result when CD8(+) T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from T-N > T-CM > T-EM > T-EFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Roychoudhuri, Rahul; Honda, Mitsuo; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Lefebvre, Francois; Pan, Li; Nichols, Carmen N.; Fourati, Slim; Goulet, Jean-Philippe; Cameron, Mark; Sekaly, Rafick P.] Vaccine & Gene Therapy Inst, Port St Lucie, FL 34987 USA. [Ji, Yun; Klebanoff, Christopher A.; Gattinoni, Luca; Restifo, Nicholas P.] NCI, Natl Inst Bethesda, Bethesda, MD 20892 USA. [Hegazy, Ahmed N.] Univ Oxford, Nuffield Dept Clin Med, Translat Gastroenterol Unit, Oxford, England. [Gilliet, Michel; Flatz, Lukas] Univ Hosp CHUV, Dept Dermatol, CH-1011 Lausanne, Switzerland. [Flatz, Lukas] Kantonsspital, Inst Immunobiol, St Gallen, Switzerland. RP Flatz, L (reprint author), Inst Immunobiol, Rorschacher Str 95, CH-9007 St Gallen, Switzerland. EM roychoudhuri@mail.nih.gov; rpsekaly@vgtifl.org; lukas.flatz@gmail.com RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Roychoudhuri, Rahul/A-7442-2010; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Roychoudhuri, Rahul/0000-0002-5392-1853; Fourati, Slim/0000-0001-6609-7587; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural Research Programs of the US National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Cancer Institute; Stiftung Propter Homines; Vaduz; Principality of Liechtenstein; Fondation Leenaards; Medic Foundatio; European Molecular Biology Organization (EMBO) long-term fellowship [ALTF 116-2012]; Marie Curie fellowship [FP7-PEOPLE-2012-IEF, 330621]; Wellcome Trust FX We thank S. Perfetto, E. Lugli, M. Vernez, A. Bergthaler and G. Fabozzi, D.C. Macallan and G.E. Griffin for helpful insights and discussion. We also thank R. Nguyen and D. Ambrozak for their expertise with FACS sorting. This research was supported by the Intramural Research Programs of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases and National Cancer Institute. L.F. is supported by the Stiftung Propter Homines, Vaduz, Principality of Liechtenstein, the Fondation Leenaards and the Medic Foundation. A.N.H. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 116-2012) and a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, Proposal 330621). R.R. is supported by a Fellowship from the Wellcome Trust. NR 41 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 11 PY 2015 VL 33 IS 7 BP 914 EP 923 DI 10.1016/j.vaccine.2014.10.007 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CB3AU UT WOS:000349500900012 PM 25446821 ER PT J AU Zhou, CK Pfeiffer, RM Cleary, SD Hoffman, HJ Levine, PH Chu, LW Hsing, AW Cook, MB AF Zhou, Cindy Ke Pfeiffer, Ruth M. Cleary, Sean D. Hoffman, Heather J. Levine, Paul H. Chu, Lisa W. Hsing, Ann W. Cook, Michael B. TI Relationship Between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; ENDOGENOUS SEX-HORMONES; ANDROGEN RECEPTOR GENE; MALE BALDING PATTERNS; EARLY-ONSET BALDNESS; GROWTH-FACTOR AXIS; INSULIN-RESISTANCE; ALOPECIA; HAIR; MEN AB Purpose Male pattern baldness and prostate cancer appear to share common pathophysiologic mechanisms. However, results from previous studies that assess their relationship have been inconsistent. Therefore, we investigated the association of male pattern baldness at age 45 years with risks of overall and subtypes of prostate cancer in a large, prospective cohortthe Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods We included 39,070 men from the usual care and screening arms of the trial cohort who had no cancer diagnosis (excluding nonmelanoma skin cancer) at the start of follow-up and recalled their hair-loss patterns at age 45 years. Hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards regression models with age as the time metric. Results During follow-up (median, 2.78 years), 1,138 incident prostate cancer cases were diagnosed, 571 of which were aggressive (biopsy Gleason score 7, and/or clinical stage III or greater, and/or fatal). Compared with no baldness, frontal plus moderate vertex baldness at age 45 years was not significantly associated with overall (HR, 1.19; 95% CI, 0.98 to 1.45) or nonaggressive (HR, 0.97; 95% CI, 0.72 to 1.30) prostate cancer risk but was significantly associated with increased risk of aggressive prostate cancer (HR, 1.39; 95% CI, 1.07 to 1.80). Adjustment for covariates did not substantially alter these estimates. Other classes of baldness were not significantly associated with overall or subtypes of prostate cancer. Conclusion Our analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms. C1 [Zhou, Cindy Ke; Pfeiffer, Ruth M.; Cook, Michael B.] NCI, Bethesda, MD 20892 USA. [Zhou, Cindy Ke; Cleary, Sean D.; Hoffman, Heather J.; Levine, Paul H.] George Washington Univ, Washington, DC USA. [Chu, Lisa W.; Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7-E106,MSC 9774, Bethesda, MD 20892 USA. EM cookmich@mail.nih.gov RI Zhou, Cindy /H-2165-2015; Cook, Michael/A-5641-2009 OI Zhou, Cindy /0000-0003-4814-4305; Cook, Michael/0000-0002-0533-7302 FU Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Supported by the Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 68 TC 9 Z9 9 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2015 VL 33 IS 5 BP 419 EP U63 DI 10.1200/JCO.2014.55.4279 PG 11 WC Oncology SC Oncology GA CF3OK UT WOS:000352458200011 PM 25225425 ER PT J AU Lei, J Rudolph, A Moysich, KB Rafiq, S Behrens, S Goode, EL Pharoah, PP Seibold, P Fasching, PA Andrulis, IL Kristensen, VN Couch, FJ Hamann, U Hooning, MJ Nevanlinna, H Eilber, U Bolla, MK Dennis, J Wang, Q Lindblom, A Mannermaa, A Lambrechts, D Garcia-Closas, M Hall, P Chenevix-Trench, G Shah, M Luben, R Haeberle, L Ekici, AB Beckmann, MW Knight, JA Glendon, G Tchatchou, S Alnaes, GIG Borresen-Dale, AL Nord, S Olson, JE Hallberg, E Vachon, C Torres, D Ulmer, HU Rudiger, T Jager, A van Deurzen, CH Tilanus-Linthorst, MM Muranen, TA Aittomaki, K Blomqvist, C Margolin, S Kosma, VM Hartikainen, JM Kataja, V Hatse, S Wildiers, H Smeets, A Figueroa, J Chanock, SJ Lissowska, J Li, J Humphreys, K Phillips, KA Linn, S Cornelissen, S van den Broek, SAJ Kang, D Choi, JY Park, SK Yoo, KY Hsiung, CN Wu, PE Hou, MF Shen, CY Teo, SH Taib, NAM Yip, CH Ho, GF Matsuo, K Ito, H Iwata, H Tajima, K Dunning, AM Benitez, J Czene, K Sucheston, LE Maishman, T Tapper, WJ Eccles, D Easton, DF Schmidt, MK Chang-Claude, J AF Lei, Jieping Rudolph, Anja Moysich, Kirsten B. Rafiq, Sajjad Behrens, Sabine Goode, Ellen L. Pharoah, Paul Pd Seibold, Petra Fasching, Peter A. Andrulis, Irene L. Kristensen, Vessela N. Couch, Fergus J. Hamann, Ute Hooning, Maartje J. Nevanlinna, Heli Eilber, Ursula Bolla, Manjeet K. Dennis, Joe Wang, Qin Lindblom, Annika Mannermaa, Arto Lambrechts, Diether Garcia-Closas, Montserrat Hall, Per Chenevix-Trench, Georgia Shah, Mitul Luben, Robert Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Alnaes, Grethe I. Grenaker Borresen-Dale, Anne-Lise Nord, Silje Olson, Janet E. Hallberg, Emily Vachon, Celine Torres, Diana Ulmer, Hans-Ulrich Ruediger, Thomas Jager, Agnes van Deurzen, Carolien Hm Tilanus-Linthorst, Madeleine Ma Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Margolin, Sara Kosma, Veli-Matti Hartikainen, Jaana M. Kataja, Vesa Hatse, Sigrid Wildiers, Hans Smeets, Ann Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Li, Jingmei Humphreys, Keith Phillips, Kelly-Anne Linn, Sabine Cornelissen, Sten van den Broek, Sandra Alexandra J. Kang, Daehee Choi, Ji-Yeob Park, Sue K. Yoo, Keun-Young Hsiung, Chia-Ni Wu, Pei-Ei Hou, Ming-Feng Shen, Chen-Yang Teo, Soo Hwang Taib, Nur Aishah Mohd Yip, Cheng Har Ho, Gwo Fuang Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Dunning, Alison M. Benitez, Javier Czene, Kamila Sucheston, Lara E. Maishman, Tom Tapper, William J. Eccles, Diana Easton, Douglas F. Schmidt, Marjanka K. Chang-Claude, Jenny CA KConFab Invest TI Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy SO BREAST CANCER RESEARCH LA English DT Article ID REGULATORY T-CELLS; GENOME-WIDE ASSOCIATION; TUMOR-INFILTRATING LYMPHOCYTES; ANTITUMOR IMMUNITY; SUPPRESSOR-CELLS; PREDICT RESPONSE; PROGRESSION; ADJUVANT; OUTCOMES; SYSTEM AB Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P < 10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction < 10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity. Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer. C1 [Lei, Jieping; Rudolph, Anja; Behrens, Sabine; Seibold, Petra; Eilber, Ursula; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Moysich, Kirsten B.; Sucheston, Lara E.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Rafiq, Sajjad; Maishman, Tom; Tapper, William J.; Eccles, Diana] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England. [Goode, Ellen L.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Pharoah, Paul Pd; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Luben, Robert; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Pharoah, Paul Pd; Shah, Mitul; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Fasching, Peter A.; Haeberle, Lothar; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr Franconia, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Kings Coll Circle 1, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Kristensen, Vessela N.; Alnaes, Grethe I. Grenaker; Borresen-Dale, Anne-Lise; Nord, Silje] Oslo Univ Hosp, Dept Genet, Inst Canc Res, Radiumhosp, N-0310 Oslo, Norway. [Kristensen, Vessela N.; Alnaes, Grethe I. Grenaker; Borresen-Dale, Anne-Lise; Nord, Silje] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0450 Oslo, Norway. [Kristensen, Vessela N.] Akershus Univ Hosp, Div Med, Dept Clin Mol Biol EpiGen, N-1478 Lorenskog, Norway. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Hamann, Ute; Torres, Diana] German Canc Res Ctr, Div Mol Genet Breast Canc, D-69120 Heidelberg, Germany. [Hooning, Maartje J.; Jager, Agnes] Erasmus MC Canc Inst, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.; Aittomaki, Kristiina; Blomqvist, Carl] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Kataja, Vesa] Univ Eastern Finland, Sch Med, Inst Clin Med, Oncol, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Lambrechts, Diether] VRC, VIB, B-3000 Leuven, Belgium. [Lambrechts, Diether; Hatse, Sigrid] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium. [Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, Div Breast Canc Res, Inst Canc Res, London SW3 6JB, England. [Hall, Per; Li, Jingmei; Humphreys, Keith] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota 11001000, Colombia. [Goode, Ellen L.; Ulmer, Hans-Ulrich] Frauenklinik Stadtklinik Baden Baden, D-7570 Baden Baden, Germany. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, D-76133 Karlsruhe, Germany. [van Deurzen, Carolien Hm] Erasmus Univ, Med Ctr, Dept Pathol, NL-3075 EA Rotterdam, Netherlands. [Tilanus-Linthorst, Madeleine Ma] Erasmus MC Canc Inst, Dept Surg Oncol, NL-3075 EA Rotterdam, Netherlands. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, FI-00029 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, FI-00029 Hus Helsinki, Finland. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden. [Kataja, Vesa] Jyvaskyla Cent Hosp, Jyvaskyla 40620, Finland. [Hatse, Sigrid; Wildiers, Hans; Smeets, Ann] Univ Hosp Leuven, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium. [Lissowska, Jolanta] Ctr Canc, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, PL-02781 Warsaw, Poland. [Li, Jingmei] Genome Inst Singapore, Human Genet, Singapore 138672, Singapore. [Li, Jingmei] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Phillips, Kelly-Anne] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Phillips, Kelly-Anne] Univ Melbourne, Peter MacCallum Dept Oncol, Melbourne, Vic 3002, Australia. [Linn, Sabine; Cornelissen, Sten; van den Broek, Sandra Alexandra J.; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Mol Pathol, NL-1006 BE Amsterdam, Netherlands. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 151742, South Korea. [Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. [Hsiung, Chia-Ni; Wu, Pei-Ei; Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Wu, Pei-Ei; Shen, Chen-Yang] Acad Sinica, Taiwan Biobank, Taipei 115, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung 807, Taiwan. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichung 40402, Taiwan. [Teo, Soo Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya 47500, Selangor, Malaysia. [Teo, Soo Hwang; Taib, Nur Aishah Mohd; Yip, Cheng Har] Univ Malaya, Breast Canc Res Unit, Fac Med, Canc Res Inst, Kuala Lumpur 59100, Malaysia. [Ho, Gwo Fuang] Univ Malaya, Dept Oncol, Fac Med, Kuala Lumpur 59100, Malaysia. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med SciencesLembah Pantai, Fukuoka 8128582, Japan. [Ito, Hidemi] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Chikusa Ku, Nagoya, Aichi 4648681, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Chikusa Ku, Nagoya, Aichi 4648681, Japan. [Tajima, Kazuo] Mie Univ Hosp, Epidemiol Ctr Dis Control & Prevent, Tsu, Mie 5148507, Japan. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genotyping Unit, Ctr Nacl Genotipado CEGEN, Human Canc Genet Programme, Madrid 28029, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia 46010, Spain. [Schmidt, Marjanka K.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, NL-1006 BE Amsterdam, Netherlands. RP Chang-Claude, J (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM j.chang-claude@dkfz-heidelberg.de RI U-ID, Kyushu/C-5291-2016; Andrulis, Irene/E-7267-2013; HO, GWO FUANG/B-8634-2010; Nord, Silje/R-5212-2016; Hartikainen, Jaana/E-6256-2015; Li, Jingmei/I-2904-2012; Garcia-Closas, Montserrat /F-3871-2015; Knight, Julia/A-6843-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014 OI Dunning, Alison Margaret/0000-0001-6651-7166; Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Nord, Silje/0000-0002-3271-5356; Rafiq, Sajjad/0000-0003-4873-4540; Phillips, Kelly-Anne/0000-0002-0475-1771; Luben, Robert/0000-0002-5088-6343; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; FU European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; CR-UK [C1287/A10118, C1287/A12014]; European Union [BM0606]; Dutch Cancer Society [NKI 2007-3839, 4363]; BBMRI-NL; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society, The Nordic Cancer Union; Sigrid Juselius Foundation; KARBAC; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; Stichting tegen Kanker [232-2008, 196-2010]; Deutsche Krebshilfe e.V. [70-2892-BRI, 106332, 108253, 108419]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; NIH [CA128978, CA116167, CA176785, CA116201]; Norwegian Research council [155218/V40, 175240/S10]; FUGE-NFR [181600/V11]; Swizz Bridge Award; National Cancer Institute (USA) [UM1 CA164920]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Agency for Science, Technology and Research of Singapore; US National Institute of Health (NIH); Susan G Komen Breast Cancer Foundation; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NHMRC; National Breast Cancer Foundation, Cancer Australia; National Institute of Health (USA); Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National medical Research Council, Singapore [NMRC/CG/SERI/2010]; National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Funding Breast Cancer Campaign [NOV210PR62] FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: Kyriaki Michailidou, (BCAC), Andrew Berchuck (OCAC), Rosalind A Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Andrew Lee, Ed Dicks, Graig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiSre and Frederic Robidoux and the staff of the McGill University and Gnome Qubec Innovation Centre, Stig E. Bojesen, Sune F Nielsen, Borge G Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M Cunningham, Sharon A Windebank, Christopher A Hilker, Jeffret Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCS would like to thank Annegien Broeks, Emiel Rutgers, Laura vanat Veer, Richard van Hien, Frans Hogervorst, Senno Verhoef. HEBCS would like to thank Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen and Irja Erkki KBCP thanks Eija Myohanen and Helena Kemilainen. LMBC thanks Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. MARIE thanks Judith Heinz, Nadia Obi, Alina Vrieling, Muhabbet Celik, Til Olchers and Stefan Nickels. NBCS would like to thank the following clinical collaborators: Professor Per Eystein Lonning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), Professor Emeritus Sophie D Foss, MD (National Resource Centre for Long-term Studies after Cancer, Rikshospitalet-Radiumhospitalet Cancer Clinic Montebello, Oslo, Norway), Head physician Tone Ikdahl, MD (Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr Lars Ottestad, MD (Department of Genetics and Department of Oncology, Oslo University Hospital Radiumhospitalet), Dr Marit Muri Holmen, MD (Department of Radiology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr Vilde Haakensen, MD (Department of Genetics and Department of Oncology, Oslo University Hospital Radiumhospitalet and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Professor Bjorn Naume, MD (Division of Cancer Medicine and Radiotherapy, Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Professor Eiliv Lund (Department of Community Medicine, Faculty of Health Sciences, University of Tromso - The Arctic University of Norway, Tromso, Norway), Associate Professor slaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Professor Inger Torhild Gram, MD (Department of Community Medicine, Faculty of Health Sciences, University of Tromso and Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromso, Norway), Professor Emeritus Rolf Karesen, MD (Department of Breast and Endocrine Surgery, Institute for Clinical Medicine, Ullevaal Hospital, Oslo University Hospital and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Dr.; Ellen Schlichting, MD (Department for Breast and Endocrine Surgery, Oslo University Hospital Ullevaal, Oslo, Norway), Professor Toril Sauer, MD (Department of Pathology at Akershus University hospital, Lorenskog, Norway), Dr Olav Engebrten, MD (Institute for Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr Margit Riis, MD (Department of Surgery, Akershus University Hospital and Department of Clinical Molecular Biology (EpiGen), Institute of Clinical Medicine, Akershus University Hospital, University of Oslo, Lorenskog, Norway). OFBCR thanks Teresa Selander and Nayana Weerasooriya. PBCS thanks Louise Brinton, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner, RBCS would like to thank Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk and the Erasmus MC Family Cancer Clinic. SASBAC would like to thank the Swedish Medical Research Counsel. SEARCH thanks Craig Luccarini, Caroline Baynes, Don Conroy, Anne Stafford, Sue Irvine, Barbara Perkins, Val Rhenius. SKKDKFZS thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to the study. kConFab/AOCS wish to thank Heather Thorne, Eveline Niedermayr, Charmaine Smith, Sandra Picken, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the kConFab Follow Up Study for their contributions to this resource, and the many families who contribute to kConFab. MYBRCA thanks Phuah Sze Yee, Peter Kang, Kang In Nee, Kavitta Sivanandan, Shivaani Mariapun, Yoon Sook-Yee, Daphne Lee and Teh Yew Ching for DNA extraction and patient recruitment. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The BCAC is funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST program (BM0606). The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The work of the BBCC study was partly funded by ELAN-Fond of the University Hospital of Erlangen. The HEBCS study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. Financial support for KARBAC study was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation.; The KBCP study was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. The LMBC study is supported by the Stichting tegen Kanker (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BRI, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MCBCS study was supported by the NIH grants CA128978, CA116167, CA176785 and NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and the Breast Cancer Research Foundation and a generous gift from the David F and Margaret T Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. The NBCS study was supported by grants from the Norwegian Research council, 155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and a Swizz Bridge Award to ALBD. The OFBCR study was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The PBCS study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS study was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G Komen Breast Cancer Foundation. The SEARCH study is funded by a program grant from Cancer Research UK (C490/A10124)] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SKKDKFZS study is supported by the German Cancer Research Center. The kConFab study is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The kConFab follow-up study has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA). KAP is a National Breast Cancer Foundation Fellow (Australia). The HERPACC study was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The MYBRCA study is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010).; The SEBCS study was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). The TWBCS study is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The POSH study was supported by Funding Breast Cancer Campaign (NOV210PR62) and Cancer Research UK (C1275/A9896). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. Douglas F Easton is a Principal Research Fellow of Cancer Research UK. The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 3 Z9 3 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD FEB 10 PY 2015 VL 17 AR 18 DI 10.1186/s13058-015-0522-2 PG 13 WC Oncology SC Oncology GA CE7YQ UT WOS:000352058300001 PM 25849327 ER PT J AU Tamrat, R Peralta, CA Tajuddin, SM Evans, MK Zonderman, AB Crews, DC AF Tamrat, Ruth Peralta, Carmen A. Tajuddin, Salman M. Evans, Michele K. Zonderman, Alan B. Crews, Deidra C. TI Apolipoprotein L1, income and early kidney damage SO BMC NEPHROLOGY LA English DT Article DE APOL1; Chronic kidney disease; Socioeconomic status; African American; Renal; Albuminuria ID AFRICAN-AMERICANS; APOL1 VARIANTS; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; FUNCTION DECLINE; RENAL-DISEASE; UNITED-STATES; CYSTATIN C; RISK; ASSOCIATION AB Background: The degree to which genetic or environmental factors are associated with early kidney damage among African Americans (AAs) is unknown. Methods: Among 462 AAs in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, we examined the cross-sectional association between apolipoprotein L1 (APOL1) risk variants and income with: 1) mildly reduced eGFR (<75 mL/min/1.73 m(2), creatinine-cystatin C equation) and 2) elevated urine albumin-to-creatinine ratio (ACR) (>= 17 in men and >= 25 mg/g in women). High risk APOL1 status was defined by 2 copies of high-risk variants; low risk if 0 or 1 copy. Income groups were dichotomized as < $ 14,000/year (lowest income group) or >= $ 14,000/year. Logistic regression models were adjusted for age, sex, and % European ancestry. Results: Overall, participants' mean age was 47 years and 16% (n = 73) had high risk APOL1 status. Mean eGFR was 99 mL/min/1.73 m(2). Mildly reduced eGFR was prevalent among 11% (n = 51). The lowest income group had higher adjusted odds (aOR) of mildly reduced eGFR than the higher income group (aOR 1.8, 95% CI 1.2-2.7). High-risk APOL1 was not significantly associated with reduced eGFR (aOR 1.5, 95% CI 0.9-2.5). Among 301 participants with ACR data, 7% (n = 21) had elevated ACR. Compared to low-risk, persons with high-risk APOL1 had higher odds of elevated ACR (aOR 3.8, 95% CI 2.0-7.3). Income was not significantly associated with elevated ACR (aOR 1.8, 95% CI 0.7-4.5). There were no significant interactions between APOL1 and income. Conclusions: Both genetic and socioeconomic factors may be important determinants of early kidney damage among AAs. C1 [Tamrat, Ruth; Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Tajuddin, Salman M.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Crews, Deidra C.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Crews, Deidra C.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Crews, Deidra C.] Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, Div Nephrol, Baltimore, MD 21224 USA. RP Crews, DC (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. EM dcrews1@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778; Tajuddin, Salman M./0000-0002-7919-8528 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); Robert Wood Johnson Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K23DK097184]; Gilbert S. Omenn Anniversary Fellowship of the Institute of Medicine FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). Dr. Crews was supported by the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, grant K23DK097184 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, and the Gilbert S. Omenn Anniversary Fellowship of the Institute of Medicine. NR 32 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 10 PY 2015 VL 16 AR 14 DI 10.1186/s12882-015-0008-6 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CD3ET UT WOS:000350961400001 PM 25884165 ER PT J AU Yao, C Chen, BH Joehanes, R Otlu, B Zhang, XL Liu, CY Huan, TX Tastan, O Cupples, LA Meigs, JB Fox, CS Freedman, JE Courchesne, P O'Donnell, CJ Munson, PJ Keles, S Levy, D AF Yao, Chen Chen, Brian H. Joehanes, Roby Otlu, Burcak Zhang, Xiaoling Liu, Chunyu Huan, Tianxiao Tastan, Oznur Cupples, L. Adrienne Meigs, James B. Fox, Caroline S. Freedman, Jane E. Courchesne, Paul O'Donnell, Christopher J. Munson, Peter J. Keles, Sunduz Levy, Daniel TI Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease Phenotypes SO CIRCULATION LA English DT Article DE cardiovascular disease; gene expression/regulation network; genetic variation ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; SMOKING-BEHAVIOR; LOCI; VARIANTS; RISK; CYTOSCAPE; DISCOVERY; TRAITS; MODELS AB Background-Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. Methods and Results-We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P <= 5x10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. Conclusions-Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD. C1 [Yao, Chen; Chen, Brian H.; Joehanes, Roby; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Cupples, L. Adrienne; Fox, Caroline S.; Courchesne, Paul; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Framingham Heart Study, NIH, Bethesda, MD 20892 USA. [Yao, Chen; Chen, Brian H.; Joehanes, Roby; Zhang, Xiaoling; Liu, Chunyu; Huan, Tianxiao; Courchesne, Paul; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Joehanes, Roby; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Otlu, Burcak] Middle E Tech Univ, Dept Chem Engn, TR-06531 Ankara, Turkey. [Tastan, Oznur] Bilkent Univ, Dept Comp Engn, Ankara, Turkey. [Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. [Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Keles, Sunduz] Univ Wisconsin Madison, Dept Stat, Madison, WI USA. [Keles, Sunduz] Univ Wisconsin Madison, Dept Biostat & Med Informat, Madison, WI USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Populat Sci Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM LevyD@nih.gov FU National Institutes of Health [N01-HC-25195, U01 HG007019]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Information Technology, National Institutes of Health, Bethesda, MD; Bilim Akademisi, The Science Academy, Turkey, under the BAGEP program; L'Oreal-UNESCO under the UNESCO-L'Oreal National Fellowships Program for Young Women in Life Sciences; Scientific and Technological Research Council of Turkey (TUBITAK) [2211-C]; [K24 DK080140] FX The FHS is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD, and a National Institutes of Health grant (U01 HG007019). Dr Tastan acknowledges support from Bilim Akademisi, The Science Academy, Turkey, under the BAGEP program and support from L'Oreal-UNESCO under the UNESCO-L'Oreal National Fellowships Program for Young Women in Life Sciences. B.O. is supported by The Scientific and Technological Research Council of Turkey (TUBITAK, 2211-C PhD Scholarship). J.B. Meigs is supported by K24 DK080140. NR 50 TC 16 Z9 17 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 10 PY 2015 VL 131 IS 6 BP 536 EP U247 DI 10.1161/CIRCULATIONAHA.114.010696 PG 211 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CA9EM UT WOS:000349223600010 PM 25533967 ER PT J AU Datta, M Via, LE Kamoun, WS Liu, C Chen, W Seano, G Weiner, DM Schimel, D England, K Martin, JD Gao, X Xu, L Barry, CE Jain, RK AF Datta, Meenal Via, Laura E. Kamoun, Walid S. Liu, Chong Chen, Wei Seano, Giorgio Weiner, Danielle M. Schimel, Daniel England, Kathleen Martin, John D. Gao, Xing Xu, Lei Barry, Clifton E., III Jain, Rakesh K. TI Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antiangiogenesis; hypoxia; host-directed therapy; Mycobacterium tuberculosis; rabbit model ID ANTITUBERCULOSIS DRUGS; TUMOR VASCULATURE; SOLID TUMORS; CANCER; DISEASES; NANOMEDICINE; CHEMOTHERAPY; ANGIOGENESIS; STRATEGIES; INFECTION AB Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens. C1 [Datta, Meenal; Kamoun, Walid S.; Liu, Chong; Chen, Wei; Seano, Giorgio; Martin, John D.; Gao, Xing; Xu, Lei; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Datta, Meenal; Kamoun, Walid S.; Liu, Chong; Chen, Wei; Seano, Giorgio; Martin, John D.; Gao, Xing; Xu, Lei; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA. [Via, Laura E.; Weiner, Danielle M.; Schimel, Daniel; England, Kathleen; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Martin, John D.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Rondebosch, 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@mail.nih.gov; jain@steele.mgh.harvard.edu RI Barry, III, Clifton/H-3839-2012; Martin, John/L-6892-2016; Seano, Giorgio/R-6611-2016 OI Martin, John/0000-0002-9828-8203; Seano, Giorgio/0000-0002-7294-302X FU Bill and Melinda Gates Foundation; American Cancer Society; Children's Tumor Foundation; Susan G. Komen Foundation [PDF14301739]; Grand Challenges in Global Health Program; Intramural Research Program of the NIH/National Institute of Allergy and Infectious Diseases; Korean Ministry of Health and Welfare; [P01CA080214] FX We thank Carolyn Smith for outstanding technical support of the immunohistochemistry studies, and Drs. Matija Snuderl and Rehka Samuel for their scientific input. We thank all of the participants who enrolled in the study, as well as the staff of the International Tuberculosis Research Center, Asan Medical Center, Pusan National University Hospital, and the National Medical Center for their assistance with this work. We acknowledge Seokyong Eum for his service as a pathologist for this study. This study was supported, in part, by Grant P01CA080214 (to R.K.J.) and by grants from the Bill and Melinda Gates Foundation (to R.K.J.), from the American Cancer Society (to L.X.), from the Children's Tumor Foundation (to L.X.), and from the Susan G. Komen Foundation [Grant PDF14301739 (to G.S.)]; through the Grand Challenges in Global Health Program to Douglas Young, Imperial College (to C.E.B.); by the Intramural Research Program of the NIH/National Institute of Allergy and Infectious Diseases (C.E.B.); and by the Korean Ministry of Health and Welfare. NR 33 TC 33 Z9 33 U1 3 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 10 PY 2015 VL 112 IS 6 BP 1827 EP 1832 DI 10.1073/pnas.1424563112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8XL UT WOS:000349204200054 PM 25624495 ER PT J AU Kiss, JE Brambilla, D Glynn, SA Mast, AE Spencer, BR Stone, M Kleinman, SH Cable, RG AF Kiss, Joseph E. Brambilla, Donald Glynn, Simone A. Mast, Alan E. Spencer, Bryan R. Stone, Mars Kleinman, Steven H. Cable, Ritchard G. CA Natl Heart Lung Blood Inst NHLBI TI Oral Iron Supplementation After Blood Donation A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID STATUS EVALUATION RISE; RESTLESS LEGS SYNDROME; SERUM FERRITIN; LOW HEMOGLOBIN; DONORS; DEFICIENCY; WOMEN; RECOVERY; STORES; PICA AB IMPORTANCE Although blood donation is allowed every 8 weeks in the United States, recovery of hemoglobin to the currently accepted standard (12.5 g/dL) is frequently delayed, and some donors become anemic. OBJECTIVE To determine the effect of oral iron supplementation on hemoglobin recovery time (days to recovery of 80% of hemoglobin removed) and recovery of iron stores in iron-depleted ("low ferritin," <= 26 ng/mL) and iron-replete ("higher ferritin," >26 ng/mL) blood donors. DESIGN, SETTING, AND PARTICIPANTS Randomized, nonblinded clinical trial of blood donors stratified by ferritin level, sex, and age conducted in 4 regional blood centers in the United States in 2012. Included were 215 eligible participants aged 18 to 79 years who had not donated whole blood or red blood cells within 4 months. INTERVENTIONS One tablet of ferrous gluconate (37.5mg of elemental iron) daily or no iron for 24 weeks (168 days) after donating a unit of whole blood (500 mL). MAIN OUTCOMES AND MEASURES Time to recovery of 80% of the postdonation decrease in hemoglobin and recovery of ferritin level to baseline as a measure of iron stores. RESULTS The mean baseline hemoglobin levels were comparable in the iron and no-iron groups and declined from a mean (SD) of 13.4 (1.1) g/dL to 12.0 (1.2) g/dL after donation in the low-ferritin group and from 14.2 (1.1) g/dL to 12.9 (1.2) g/dL in the higher-ferritin group. Compared with participants who did not receive iron supplementation, those who received iron supplementation had shortened time to 80% hemoglobin recovery in both the low-ferritin and higher-ferritin groups. Recovery of iron stores in all participants who received supplements took a median of 76 days (IQR, 20-126); for participants not taking iron, median recovery time was longer than 168 days (IQR, 147-> 168 days; P < .001). Without iron supplements, 67% of participants did not recover iron stores by 168 days. 168) [GRAPHICS] CONCLUSIONS AND RELEVANCE Among blood donors with normal hemoglobin levels, low-dose iron supplementation, compared with no supplementation, reduced time to 80% recovery of the postdonation decrease in hemoglobin concentration in donors with low ferritin (<= 26 ng/mL) or higher ferritin (>26 ng/mL). Copyright 2015 American Medical Association. All rights reserved. C1 [Kiss, Joseph E.] Inst Transfus Med, Pittsburgh, PA 15213 USA. [Brambilla, Donald] RTI, Rockville, MD USA. [Glynn, Simone A.] NHLBI, Bethesda, MD 20892 USA. [Mast, Alan E.] BloodCtr Wisconsin, Milwaukee, WI USA. [Spencer, Bryan R.] Amer Red Cross, Dedham, MA USA. [Stone, Mars] Blood Syst Res Inst, San Francisco, CA USA. [Kleinman, Steven H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Cable, Ritchard G.] Amer Red Cross, Farmington, CT USA. RP Kiss, JE (reprint author), Inst Transfus Med, 3636 Blvd Allies, Pittsburgh, PA 15213 USA. EM jkiss@itxm.org FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100001I, HHSN268201100002I, HHSN268201100003I, HHSN268201100004I, HHSN268201100005I, HHSN268201100006I] FX This work was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201100001I, HHSN268201100002I, HHSN268201100003I, HHSN268201100004I, HHSN268201100005I, and HHSN268201100006I. NR 24 TC 18 Z9 18 U1 0 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 10 PY 2015 VL 313 IS 6 BP 575 EP 583 DI 10.1001/jama.2015.119 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AZ UT WOS:000349070700017 PM 25668261 ER PT J AU Kieburtz, K Tilley, BC Elm, JJ Babcock, D Hauser, R Ross, GW Augustine, AH Augustine, EU Aminoff, MJ Bodis-Wollner, IG Boyd, J Cambi, F Chou, K Christine, CW Cines, M Dahodwala, N Derwent, L Dewey, RB Hawthorne, K Houghton, DJ Kamp, C Leehey, M Lew, MF Liang, GSL Luo, ST Mari, Z Morgan, JC Parashos, S Perez, A Petrovitch, H Rajan, S Reichwein, S Roth, JT Schneider, JS Shannon, KM Simon, DK Simuni, T Singer, C Sudarsky, L Tanner, CM Umeh, CC Williams, K Wills, AM AF Kieburtz, Karl Tilley, Barbara C. Elm, Jordan J. Babcock, Debra Hauser, Robert Ross, G. Webster Augustine, Alicia H. Augustine, Erika U. Aminoff, Michael J. Bodis-Wollner, Ivan G. Boyd, James Cambi, Franca Chou, Kelvin Christine, Chadwick W. Cines, Michelle Dahodwala, Nabila Derwent, Lorelei Dewey, Richard B., Jr. Hawthorne, Katherine Houghton, David J. Kamp, Cornelia Leehey, Maureen Lew, Mark F. Liang, Grace S. Lin Luo, Sheng T. Mari, Zoltan Morgan, John C. Parashos, Sotirios Perez, Adriana Petrovitch, Helen Rajan, Suja Reichwein, Sue Roth, Jessie Tatsuno Schneider, Jay S. Shannon, Kathleen M. Simon, David K. Simuni, Tanya Singer, Carlos Sudarsky, Lewis Tanner, Caroline M. Umeh, Chizoba C. Williams, Karen Wills, Anne-Marie CA Writing Grp NINDS Exploratory TI Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID UNITED-STATES; QUESTIONNAIRE; MINOCYCLINE; LEVODOPA; QUALITY; TESTS AB IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1: 1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P <.01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. Copyright 2015 American Medical Association. All rights reserved. C1 [Kieburtz, Karl; Augustine, Alicia H.; Augustine, Erika U.; Kamp, Cornelia] Univ Rochester, Rochester, NY 14642 USA. [Tilley, Barbara C.; Luo, Sheng T.; Perez, Adriana; Rajan, Suja] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Elm, Jordan J.] Med Univ S Carolina, Charleston, SC USA. [Babcock, Debra] NIH, Bethesda, MD 20892 USA. [Hauser, Robert] Univ S Florida, Tampa, FL USA. [Ross, G. Webster; Petrovitch, Helen] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Aminoff, Michael J.; Christine, Chadwick W.; Roth, Jessie Tatsuno] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bodis-Wollner, Ivan G.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Boyd, James] Univ Vermont, Burlington, VT 05405 USA. [Cambi, Franca] Univ Kentucky, Lexington, KY 40506 USA. [Chou, Kelvin] Univ Michigan, Ann Arbor, MI 48109 USA. [Cines, Michelle] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Dahodwala, Nabila; Reichwein, Sue] Univ Penn, Philadelphia, PA 19104 USA. [Derwent, Lorelei] Univ Calgary, Calgary, AB, Canada. [Dewey, Richard B., Jr.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Hawthorne, Katherine; Lew, Mark F.] Univ So Calif, Los Angeles, CA USA. [Houghton, David J.] Ochsner Med Ctr, New Orleans, LA USA. [Leehey, Maureen] Univ Colorado Denver, Aurora, CO USA. [Liang, Grace S. Lin; Tanner, Caroline M.] Parkinsons Inst & Clin Ctr, Sunnyvale, CA USA. [Mari, Zoltan] Johns Hopkins Univ, Baltimore, MD USA. [Morgan, John C.] Georgia Regents Univ, Augusta, GA USA. [Parashos, Sotirios] Struthers Parkinsons Ctr, Golden Valley, MN USA. [Schneider, Jay S.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Shannon, Kathleen M.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Simon, David K.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Simuni, Tanya; Williams, Karen] Northwestern Univ, Chicago, IL 60611 USA. [Singer, Carlos] Univ Miami, Miami, FL USA. [Sudarsky, Lewis; Umeh, Chizoba C.; Wills, Anne-Marie] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kieburtz, K (reprint author), Univ Rochester, Ctr Human Expt Therapeut, 265 Crittenden Blvd,POB 694, Rochester, NY 14642 USA. EM karl.kieburtz@chet.rochester.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [U01NS43128] FX Financial support for the LS-1 study was provided by National Institute of Neurological Disorders and Stroke (NINDS) grant U01NS43128. NR 31 TC 28 Z9 29 U1 3 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 10 PY 2015 VL 313 IS 6 BP 584 EP 593 DI 10.1001/jama.2015.120 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AZ UT WOS:000349070700018 ER PT J AU Gadalla, SM Wang, T Haagenson, M Spellman, SR Lee, SJ Williams, KM Wong, JY De Vivo, I Savage, SA AF Gadalla, Shahinaz M. Wang, Tao Haagenson, Michael Spellman, Stephen R. Lee, Stephanie J. Williams, Kirsten M. Wong, Jason Y. De Vivo, Immaculata Savage, Sharon A. TI Association Between Donor Leukocyte Telomere Length and Survival After Unrelated Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; RISK-FACTORS; CHILDREN; SENESCENCE; PATHOPHYSIOLOGY; RECIPIENTS; FAILURE; PROGRAM; AGE AB IMPORTANCE Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity. OBJECTIVE To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia. DESIGN, PARTICIPANTS, AND SETTING The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013. EXPOSURES Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution. MAIN OUTCOMES AND MEASURES Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up. RESULTS Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P = .009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30). CONCLUSIONS AND RELEVANCE Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival. Copyright 2015 American Medical Association. All rights reserved. C1 [Gadalla, Shahinaz M.; Savage, Sharon A.] NCI, Clin Genet Branch, NIH, Rockville, MD 20850 USA. [Wang, Tao; Lee, Stephanie J.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant hRes, Milwaukee, WI 53226 USA. [Wang, Tao; Lee, Stephanie J.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Haagenson, Michael; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Williams, Kirsten M.] George Washington Univ, Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders,Childrens Natl Med Ctr, Washington, DC 20037 USA. [Williams, Kirsten M.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wong, Jason Y.; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Wong, Jason Y.; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Wong, Jason Y.; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. RP Gadalla, SM (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E-534, Rockville, MD 20850 USA. EM gadallas@mail.nih.gov RI Savage, Sharon/B-9747-2015; OI Savage, Sharon/0000-0001-6006-0740; Wong, Jason/0000-0002-8167-540X FU Public Health Service from the National Cancer Institute [U24-CA76518]; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases, Health Resources; Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; National Institutes of Health [2R01 CA082838]; Intramural Research Program of the National Cancer Institute FX The study was supported by Public Health Service grant U24-CA76518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases, Health Resources (Drs Wang and Lee and Messrs Haagenson and Spellman), and grant HHSH234200637015C from the Services Administration, grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research (Dr Wang and Messrs Haagenson and Spellman), grant 2R01 CA082838 from the National Institutes of Health (Dr De Vivo), and the Intramural Research Program of the National Cancer Institute (Drs Gadalla and Savage). NR 36 TC 13 Z9 13 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 10 PY 2015 VL 313 IS 6 BP 594 EP 602 DI 10.1001/jama.2015.7 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AZ UT WOS:000349070700019 PM 25668263 ER PT J AU Kiss, JE Brambilla, D Glynn, SA Mast, AE Spencer, BR Stone, M Kleinman, SH Cable, RG AF Kiss, Joseph E. Brambilla, Donald Glynn, Simone A. Mast, Alan E. Spencer, Bryan R. Stone, Mars Kleinman, Steven H. Cable, Ritchard G. CA Natl Heart Lung Blood Inst NHLBI TI Oral Iron Supplementation After Blood Donation A Randomized Clinical Trial (vol 313, pg 575, 2015) SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Correction C1 [Kiss, Joseph E.] Inst Transfus Med, Pittsburgh, PA 15213 USA. [Brambilla, Donald] RTI, Rockville, MD USA. [Glynn, Simone A.] NHLBI, Bethesda, MD 20892 USA. [Mast, Alan E.] BloodCtr Wisconsin, Milwaukee, WI USA. [Spencer, Bryan R.] Amer Red Cross, Dedham, MA USA. [Stone, Mars] Blood Syst Res Inst, San Francisco, CA USA. [Kleinman, Steven H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Cable, Ritchard G.] Amer Red Cross, Farmington, CT USA. RP Kiss, JE (reprint author), Inst Transfus Med, 3636 Blvd Allies, Pittsburgh, PA 15213 USA. EM jkiss@itxm.org NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 10 PY 2015 VL 313 IS 6 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AZ UT WOS:000349070700016 ER PT J AU Gabriel, EE Sachs, MC Gilbert, PB AF Gabriel, Erin E. Sachs, Michael C. Gilbert, Peter B. TI Comparing and combining biomarkers as principle surrogates for time-to-event clinical endpoints SO STATISTICS IN MEDICINE LA English DT Article DE causal inference; surrogate endpoint evaluation; survival analysis; accuracy measures; multivariate principal stratification ID VACCINE TRIALS; MARKERS AB Principal surrogate endpoints are useful as targets for phase I and II trials. In many recent trials, multiple post-randomization biomarkers are measured. However, few statistical methods exist for comparison of or combination of biomarkers as principal surrogates, and none of these methods to our knowledge utilize time-to-event clinical endpoint information. We propose a Weibull model extension of the semi-parametric estimated maximum likelihood method that allows for the inclusion of multiple biomarkers in the same risk model as multivariate candidate principal surrogates. We propose several methods for comparing candidate principal surrogates and evaluating multivariate principal surrogates. These include the time-dependent and surrogate-dependent true and false positive fraction, the time-dependent and the integrated standardized total gain, and the cumulative distribution function of the risk difference. We illustrate the operating characteristics of our proposed methods in simulations and outline how these statistics can be used to evaluate and compare candidate principal surrogates. We use these methods to investigate candidate surrogates in the Diabetes Control and Complications Trial. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Gabriel, Erin E.; Gilbert, Peter B.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Sachs, Michael C.] NCI, Biometr Res Branch, Washington, DC USA. [Gilbert, Peter B.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Gabriel, EE (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. EM egabriel@fhcrc.org OI Gabriel, Erin/0000-0002-0504-8404 FU NIAID NIH HHS [UM1 AI068635, R37 AI054165] NR 20 TC 2 Z9 2 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD FEB 10 PY 2015 VL 34 IS 3 BP 381 EP 395 DI 10.1002/sim.6349 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AY6XC UT WOS:000347705100002 PM 25352131 ER PT J AU Felix, AS Sherman, ME Hewitt, SM Gunja, MZ Yang, HP Cora, RL Boudreau, V Ylaya, K Lissowska, J Brinton, LA Wentzensen, N AF Felix, Ashley S. Sherman, Mark E. Hewitt, Stephen M. Gunja, Munira Z. Yang, Hannah P. Cora, Renata L. Boudreau, Vicky Ylaya, Kris Lissowska, Jolanta Brinton, Louise A. Wentzensen, Nicolas TI Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers SO FRONTIERS IN ONCOLOGY LA English DT Article DE molecular etiology; prognosis; gynecologic cancer; cell-cycle ID REGULATORY PROTEINS; CLINICOPATHOLOGICAL PARAMETERS; SUBCELLULAR-LOCALIZATION; PROGNOSTIC-SIGNIFICANCE; P27(KIP1) EXPRESSION; PROMOTER METHYLATION; HUMAN-PAPILLOMAVIRUS; POOR-PROGNOSIS; INHIBITOR P27; CARCINOMA AB Aberrant expression of cyclin-dependent kinase (CDK) inhibitors is implicated in the carcinogenesis of many cancers, including ovarian and endometrial cancers. We examined associations between CDK inhibitor expression, cancer risk factors, tumor characteristics, and survival outcomes among ovarian and endometrial cancer patients enrolled in a population-based case-control study. Expression (negative vs. positive) of three CDK inhibitors (p16, p21, and p27) and ki67 was examined with immunohistochemical staining of tissue microarrays. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (Cis) for associations between biomarkers, risk factors, and tumor characteristics. Survival outcomes were only available for ovarian cancer patients and examined using Kaplan Meier plots and Cox proportional hazards regression. Among ovarian cancer patients (n=175), positive p21 expression was associated with endometrioid tumors (OR = 12.22, 95% Cl = 1.45-102.78) and higher overall survival (logrank p= 0.002). In Cox models adjusted for stage, grade, and histology, the association between p21 expression and overall survival was borderline significant (hazard ratio = 0.65, 95% CI = 0.42-1.05). Among endometrial cancer patients (n= 289), positive p21 expression was inversely associated with age (OR > 65 years of age= 0.25, 95% Cl = 0.07-0.84) and current smoking status (OR: 0.33, 95% Cl 0.15, 0.72) compared to negative expression. Our study showed heterogeneity in expression of cell-cycle proteins associated with risk factors and tumor characteristics of gynecologic cancers. Future studies to assess these markers of etiological classification and behavior may be warranted. C1 [Felix, Ashley S.; Gunja, Munira Z.; Yang, Hannah P.; Cora, Renata L.; Boudreau, Vicky; Brinton, Louise A.; Wentzensen, Nicolas] NCI, Hormonaland Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ylaya, Kris] NCI, Tissue Array Res Program, NIH, Bethesda, MD 20892 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. RP Felix, AS (reprint author), NCI, Hormonaland Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,7E214, Bethesda, MD 20892 USA. EM ashley.felix@nih.gov RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Hewitt, Stephen/0000-0001-8283-1788 FU National Cancer Institute FX This research was supported (in part) by the Intramural Research Program of the National Cancer Institute. NR 46 TC 4 Z9 5 U1 1 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD FEB 9 PY 2015 VL 5 AR 25 DI 10.3389/fonc.2015.00025 PG 11 WC Oncology SC Oncology GA CO3QS UT WOS:000359074400001 PM 25709969 ER PT J AU Liu, JJ Green, P Mann, JJ Rapoport, SI Sublette, ME AF Liu, Joanne J. Green, Pnina Mann, J. John Rapoport, Stanley I. Sublette, M. Elizabeth TI Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease SO BRAIN RESEARCH LA English DT Review DE Polyunsaturated fatty acids; Lipid metabolism; Brain; Depression; Bipolar disorder; Schizophrenia ID ALPHA-LINOLENIC ACID; RAT FRONTAL-CORTEX; OMEGA-3-FATTY-ACID DOCOSAHEXAENOIC ACID; MAJOR DEPRESSIVE DISORDER; N-3 PUFA DEPRIVATION; PROLIFERATOR-ACTIVATED RECEPTORS; DEFICIT-HYPERACTIVITY-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; CAPILLARY ENDOTHELIAL-CELLS; HUMAN 5-HT7(A) RECEPTORS AB Essential polyunsaturated fatty acids (PUPAS) have profound effects on brain development and function. Abnormalities of PUPA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer's disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUPA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUPA utilization, highlighting their relevance to neuropsychiatric disease. (C) 2014 Elsevier B.V. All rights reserved. C1 [Liu, Joanne J.; Mann, J. John; Sublette, M. Elizabeth] New York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USA. [Liu, Joanne J.] New York Med Coll, Valhalla, NY 10595 USA. [Green, Pnina] Tel Aviv Univ, Felsenstein Med Res Ctr, Lab Metab Res, Petah Tiqwa, Israel. [Mann, J. John; Sublette, M. Elizabeth] Columbia Univ, Dept Psychiat, New York, NY USA. [Mann, J. John] Columbia Univ, Dept Radiol, New York, NY USA. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Sublette, ME (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Unit 42, New York, NY 10032 USA. EM es2316@columbia.edu RI Sublette, M/A-8391-2009 OI Sublette, M/0000-0001-7378-4262 FU Intramural Program of the National Institute on Aging; NIMH [MH079033] FX Work by Dr. Rapoport was supported entirely by the Intramural Program of the National Institute on Aging. Work by Dr. Sublette was supported in part by NIMH MH079033. NR 546 TC 19 Z9 19 U1 2 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD FEB 9 PY 2015 VL 1597 BP 220 EP 246 DI 10.1016/j.brainres.2014.11.059 PG 27 WC Neurosciences SC Neurosciences & Neurology GA CD2TA UT WOS:000350930700021 PM 25498862 ER PT J AU Wang, H Yu, CJ Gao, X Welte, T Muscarella, AM Tian, L Zhao, H Zhao, Z Du, SY Tao, JN Lee, B Westbrook, TF Wong, STC Jin, X Rosen, JM Osborne, CK Zhang, XHF AF Wang, Hai Yu, Cuijuan Gao, Xia Welte, Thomas Muscarella, Aaron M. Tian, Lin Zhao, Hong Zhao, Zhen Du, Shiyu Tao, Jianning Lee, Brendan Westbrook, Thomas F. Wong, Stephen T. C. Jin, Xin Rosen, Jeffrey M. Osborne, C. Kent Zhang, Xiang H. -F. TI The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells SO CANCER CELL LA English DT Article ID MESENCHYMAL STEM-CELLS; GENE-EXPRESSION; EXTRACELLULAR-MATRIX; MOLECULAR PORTRAITS; ESTROGEN-RECEPTOR; TUMOR-CELLS; METASTASIS; THERAPY; REVEALS; GROWTH AB Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironnnent niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. C1 [Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Osborne, C. Kent; Zhang, Xiang H. -F.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Tian, Lin; Westbrook, Thomas F.; Wong, Stephen T. C.; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H. -F.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Wong, Stephen T. C.; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H. -F.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Tian, Lin; Westbrook, Thomas F.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Muscarella, Aaron M.] Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA. [Zhang, Xiang H. -F.] Baylor Coll Med, McNair Med Inst, Houston, TX 77030 USA. [Zhao, Hong; Zhao, Zhen; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Weill Cornell Med Coll, NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. [Zhao, Hong; Zhao, Zhen; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Weill Cornell Med Coll, Dept Syst Med & Bioengn, Houston, TX 77030 USA. [Zhao, Zhen] Southeast Univ, Sch Med, Dept Radiol, Nanjing 210018, Peoples R China. [Du, Shiyu] China Japan Friendship Hosp, Dept Gastroenterol, Beijing 100029, Peoples R China. [Wong, Stephen T. C.] Houston Methodist Hosp, Dept Radiol, Houston, TX 77459 USA. [Jin, Xin] Eli & Edythe L Broad Inst, Canc Program, Cambridge, MA 02142 USA. RP Zhang, XHF (reprint author), Baylor Coll Med, Lester & Sue Smith Breast Ctr, One Baylor Plaza, Houston, TX 77030 USA. EM xiangz@bcm.edu FU NCI [CA151293, CA183878]; Breast Cancer Research Foundation; U.S. Department of Defense DAMD [W81XWH-13-1-0195, CA149196-04, W81XWH-13-1-0296]; McNair Medical Institute; NIH [U54CA149196, CA148761]; John S. Dunn Research Foundation; Ting Tsung and Wei Fong Chao Foundation FX We thank Dr. Max Wicha and S. Liu for generously providing us with the immortalized human MSC cells; Dr. Robin L. Anderson for 4T1.2 cells; Baylor Breast Center Pathology Core for technical assistance; and D. Weiss, I.S. Kim, H.C. Lo, and Z. Duan for helpful discussions. X. H.-F. Z. is supported by NCI CA151293, CA183878, Breast Cancer Research Foundation, U.S. Department of Defense DAMD W81XWH-13-1-0195, a Pilot Award of CA149196-04, and McNair Medical Institute. H.W. is supported by U.S. Department of Defense DAMD W81XWH-13-1-0296. H. Z. and S.T.C.W. are supported by NIH grant U54CA149196, John S. Dunn Research Foundation, and Ting Tsung and Wei Fong Chao Foundation. Studies with the p53 null tumors were supported by NIH grant CA148761 to J.M.R. C.K.O. is a member on the advisory boards for Genentech, Novartis, Nanostring, AstraZeneca, and Pfizer. NR 49 TC 39 Z9 39 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD FEB 9 PY 2015 VL 27 IS 2 BP 193 EP 210 DI 10.1016/j.ccell.2014.11.017 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CB3GC UT WOS:000349515200008 PM 25600338 ER PT J AU Walz, AL Ooms, A Gadd, S Gerhard, DS Smith, MA Auvil, JMG Meerzaman, D Chen, QR Hsu, CH Yan, CH Nguyen, C Hu, Y Bowlby, R Brooks, D Ma, Y Mungall, AJ Moore, RA Schein, J Marra, MA Huff, V Dome, JS Chi, YY Mullighan, CG Ma, J Wheeler, DA Hampton, OA Jafari, N Ross, N Gastier-Foster, JM Perlman, EJ AF Walz, Amy L. Ooms, Ariadne Gadd, Samantha Gerhard, Daniela S. Smith, Malcolm A. Auvil, Jamie M. Guidry Meerzaman, Daoud Chen, Qing-Rong Hsu, Chih Hao Yan, Chunhua Cu Nguyen Hu, Ying Bowlby, Reanne Brooks, Denise Ma, Yussanne Mungall, Andrew J. Moore, Richard A. Schein, Jacqueline Marra, Marco A. Huff, Vicki Dome, Jeffrey S. Chi, Yueh-Yun Mullighan, Charles G. Ma, Jing Wheeler, David A. Hampton, Oliver A. Jafari, Nadereh Ross, Nicole Gastier-Foster, Julie M. Perlman, Elizabeth J. TI Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors SO CANCER CELL LA English DT Article ID DICER1 MUTATIONS; MICRORNA BIOGENESIS; SOMATIC MUTATIONS; GENETIC-VARIATION; MAMMALIAN KIDNEY; IN-VIVO; CANCER; TUMORIGENESIS; PHENOTYPE; ALIGNMENT AB We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death. C1 [Walz, Amy L.] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Div Hematol Oncol & Transplantat, Chicago, IL 60611 USA. [Ooms, Ariadne] Erasmus MC, Josephine Nefkens Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands. [Gadd, Samantha; Perlman, Elizabeth J.] Northwestern Univ, Feinberg Sch Med, Lurie Childrens Hosp, Dept Pathol & Lab Med, Chicago, IL 60611 USA. [Gadd, Samantha; Perlman, Elizabeth J.] Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Gerhard, Daniela S.; Auvil, Jamie M. Guidry] NCI, Off Canc Genom, Bethesda, MD 20892 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Meerzaman, Daoud; Chen, Qing-Rong; Hsu, Chih Hao; Yan, Chunhua; Cu Nguyen; Hu, Ying] NCI, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Bowlby, Reanne; Brooks, Denise; Ma, Yussanne; Mungall, Andrew J.; Moore, Richard A.; Schein, Jacqueline; Marra, Marco A.] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Huff, Vicki] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Dome, Jeffrey S.] Childrens Natl Med Ctr, Div Pediat Hematol Oncol, Washington, DC 20010 USA. [Chi, Yueh-Yun] Univ Florida, Dept Biostat, Gainesville, FL 32610 USA. [Mullighan, Charles G.; Ma, Jing] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Wheeler, David A.; Hampton, Oliver A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Jafari, Nadereh] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Ross, Nicole; Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA. RP Perlman, EJ (reprint author), Northwestern Univ, Feinberg Sch Med, Lurie Childrens Hosp, Dept Pathol & Lab Med, Chicago, IL 60611 USA. EM eperlman@luriechildrens.org RI Marra, Marco/B-5987-2008; OI Mullighan, Charles/0000-0002-1871-1850 FU NCI [U10 CA98543, T32 CA079447]; NCI, National Institutes of Health (NIH) [HHSN261200800001E]; NIH [U10CA42326, U10CA98543, U24 CA114766, UO1CA88131]; American and Lebanese Syrian Associated Charities of St. Jude FX The TARGET initiative is supported by NCI Grant U10 CA98543. Work performed under contracts from the NCI, National Institutes of Health (NIH), within HHSN261200800001E includes specimen processing (the COG Biopathology Center), WGS (CGI), WXS (Baylor College of Medicine), miRNA-seq, RNA sequencing, and target capture sequencing (British Columbia Cancer Agency Genome Sciences Center). 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 USA government. We thank Patee Gesuwan and Leandro Hermida and the Data Coordinating Center for their support. We also thank the Clinical Applications of Core Technology Laboratory of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital for performing the copy number analysis and the Northwestern University Genomic Core facility for performing the methylation analysis. This work is also supported by NCI T32 CA079447 (A.L.W.), NIH U10CA42326 (E.J.P.), U10CA98543 (J.S.D., E.J.P.), U24 CA114766, UO1CA88131 (E.J.P.), and the American and Lebanese Syrian Associated Charities of St. Jude (J.M., C.G.M.). We are grateful for the expertise of Karen Novik and Laura Monovich, Patricia Beezhold, Donna Kersey, Debbie-Payne Turner, Mary McNulty; and Yvonne Moyer. This work would not be possible without the dedication of all the experts within the many clinical disciplines at the local institutions and centrally within the COG and the National Wilms Tumor Study Group. NR 60 TC 30 Z9 31 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD FEB 9 PY 2015 VL 27 IS 2 BP 286 EP 297 DI 10.1016/j.ccell.2015.01.003 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CB3GC UT WOS:000349515200014 PM 25670082 ER PT J AU Ratto-Kim, S de Souza, MS Currier, JR Karasavvas, N Sidney, J Rolland, M Valencia-Micolta, A Madnote, S Sette, A Nitayaphan, S Pitisuttuthum, P Kaewkungwal, J Rerks-Ngarm, S O'Connell, R Michael, N Robb, ML Marovich, M Kim, JH AF Ratto-Kim, Silvia de Souza, Mark S. Currier, Jeffrey R. Karasavvas, Nicos Sidney, John Rolland, Morgane Valencia-Micolta, Anais Madnote, Sirinan Sette, Alessandro Nitayaphan, Sorachai Pitisuttuthum, Punnee Kaewkungwal, Jaranit Rerks-Ngarm, Supachai O'Connell, Robert Michael, Nelson Robb, Merlin L. Marovich, Mary Kim, Jerome H. TI Identification of Immunodominant CD4-Restricted Epitopes Co-Located with Antibody Binding Sites in Individuals Vaccinated with ALVAC-HIV and AIDSVAX B/E SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; THAI ADULTS; SUBTYPE-B; TRIAL; V2; IMMUNOGENICITY; EFFICACY; ENVELOPE; SAFETY; LOOP AB We performed fine epitope mapping of the CD4+ responses in the ALVAC-HIV-AIDSVAX B/E prime-boost regimen in the Thai Phase III trial (RV144). Non-transformed Env-specific T cell lines established from RV144 vaccinees were used to determine the fine epitope mapping of the V2 and C1 responses and the HLA class II restriction. Data showed that there are two CD4+ epitopes contained within the V2 loop: one encompassing the alpha 4 beta 7 integrin binding site (AA179-181) and the other nested between two previously described genetic sieve signatures (AA169, AA181). There was no correlation between the frequencies of CD4+ fine epitope responses and binding antibody. C1 [Ratto-Kim, Silvia; Currier, Jeffrey R.; Rolland, Morgane; Valencia-Micolta, Anais; Michael, Nelson; Robb, Merlin L.; Kim, Jerome H.] Walter Reed Army Inst Res, United States Mil HIV Res Program, Silver Spring, MD 20910 USA. [de Souza, Mark S.; Karasavvas, Nicos; Madnote, Sirinan; O'Connell, Robert] US Army Med Component, Armed Forces Res Inst Med Sci, United States Mil HIV Res Program, Bangkok, Thailand. [Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Nitayaphan, Sorachai] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Pitisuttuthum, Punnee] Mahidol Univ, Fac Trop Med, Vaccine Trials Ctr, Bangkok 10400, Thailand. [Kaewkungwal, Jaranit] Mahidol Univ, Fac Trop Med, Ctr Excellence Biomed & Publ Hlth Informat, Bangkok 11000, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Nonthaburi 11000, Thailand. [Marovich, Mary] NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Ratto-Kim, S (reprint author), Walter Reed Army Inst Res, United States Mil HIV Res Program, Silver Spring, MD 20910 USA. EM sratto-kim@hivresearch.org FU Henry M. Jackson Foundation [W81XWH-07-2-0067]; U.S. Department of Defense FX This work was funded by the cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U.S. Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed herein are those of the authors and should not be construed to represent the positions of the U.S. Army or Department of Defense. NR 16 TC 5 Z9 5 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 9 PY 2015 VL 10 IS 2 AR e0115582 DI 10.1371/journal.pone.0115582 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7UO UT WOS:000349123100004 PM 25665096 ER PT J AU Johnen, VM Neubert, FX Buch, ER Verhagen, LM O'Reilly, J Mars, RB Rushworth, MFS AF Johnen, Vanessa M. Neubert, Franz-Xaver Buch, Ethan R. Verhagen, Lennart M. O'Reilly, Jill Mars, Rogier B. Rushworth, Matthew F. S. TI Causal manipulation of functional connectivity in a specific neural pathway during behaviour and at rest SO ELIFE LA English DT Article DE Resting-state connectivity; functional connectivity; premotor cortex; fMRI; TMS; plasticity ID VENTRAL PREMOTOR CORTEX; PRIMARY MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; TRACTOGRAPHY-BASED PARCELLATION; PAIRED ASSOCIATIVE STIMULATION; TRAUMATIC BRAIN-INJURY; HUMAN PARIETAL CORTEX; MACAQUE MONKEY; FRONTAL-CORTEX; MR-IMAGES AB Correlations in brain activity between two areas (functional connectivity) have been shown to relate to their underlying structural connections. We examine the possibility that functional connectivity also reflects short-term changes in synaptic efficacy. We demonstrate that paired transcranial magnetic stimulation (TMS) near ventral premotor cortex (PMv) and primary motor cortex (M1) with a short 8ms inter-pulse interval evoking synchronous pre- and post-synaptic activity and which strengthens interregional connectivity between the two areas in a pattern consistent with Hebbian plasticity, leads to increased functional connectivity between PMv and M1 as measured with functional magnetic resonance imaging (fMRI). Moreover, we show that strengthening connectivity between these nodes has effects on a wider network of areas, such as decreasing coupling in a parallel motor programming stream. A control experiment revealed that identical TMS pulses at identical frequencies caused no change in fMRI-measured functional connectivity when the inter-pulse-interval was too long for Hebbian-like plasticity. C1 [Johnen, Vanessa M.; Neubert, Franz-Xaver; Verhagen, Lennart M.; Mars, Rogier B.; Rushworth, Matthew F. S.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Buch, Ethan R.] NINDS, Human Cort Physiol & Neurorehabilitat Sect, NIH, Bethesda, MD 20814 USA. [Buch, Ethan R.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Verhagen, Lennart M.; Mars, Rogier B.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Ctr Cognit Neuroimaging, NL-6500 HB Nijmegen, Netherlands. [O'Reilly, Jill; Mars, Rogier B.; Rushworth, Matthew F. S.] Univ Oxford, Funct Magnet Resonance Imaging Brain FMRIB Ctr, John Radcliffe Hosp, Oxford OX3 9DU, England. RP Johnen, VM (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. EM vanessa.johnen@psy.ox.ac.uk RI Verhagen, Lennart/D-1070-2013 OI Verhagen, Lennart/0000-0003-3207-7929 FU Wellcome Trust; Medical Research Council (MRC); Christopher Welch Scholarship FX Wellcome Trust Matthew FS Rushworth; Medical Research Council (MRC) Matthew FS Rushworth; Christopher Welch Scholarship Franz-Xaver Neubert NR 81 TC 4 Z9 4 U1 5 U2 9 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 9 PY 2015 VL 4 AR e04585 DI 10.7554/eLife.04585 PG 50 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CB2MD UT WOS:000349460700002 ER PT J AU Weiss, DJ Mappin, B Dalrymple, U Bhatt, S Cameron, E Hay, SI Gething, PW AF Weiss, Daniel J. Mappin, Bonnie Dalrymple, Ursula Bhatt, Samir Cameron, Ewan Hay, Simon I. Gething, Peter W. TI Re-examining environmental correlates of Plasmodium falciparum malaria endemicity: a data-intensive variable selection approach SO MALARIA JOURNAL LA English DT Article DE Plasmodium falciparum; Malaria mapping; Africa ID LAND-COVER; IDENTIFICATION; POPULATION; WATER AB Background: Malaria risk maps play an increasingly important role in disease control planning, implementation, and evaluation. The construction of these maps using modern geospatial techniques relies on covariate grids: continuous surfaces quantifying environmental factors that partially explain spatial heterogeneity in malaria endemicity. Although crucial, past variable selection processes for this purpose have often been subjective and ad-hoc, with many covariates used in modeling with little quantitative justification. Methods: This research consists of an extensive covariate construction and selection process for predicting Plasmodium falciparum parasite rates (PfPR) in Africa for years 2000-2012. First, a literature review was conducted to establish a comprehensive list of covariates used for malaria mapping. Second, a library of covariate data was assembled to reflect this list, a process that included the construction of multiple, temporally dynamic datasets. Third, the resulting set of covariates was leveraged to create more than 50 million possible covariate terms via factorial combinations of different spatial and temporal aggregations, transformations, and pairwise interactions. Fourth, the expanded set of covariates was reduced via successive selection criteria to yield a robust covariate subset that was assessed using an out-of-sample validation approach. Results: The final covariate subset included predominately dynamic covariates and it substantially out-performed earlier sets used by the Malaria Atlas Project (MAP) for creating global malaria risk maps, with the pseudo-R-2 value for the out-of-sample validation increasing from 0.43 to 0.52. Dynamic covariates improved the model, with 17 of the 20 new covariates consisting of monthly or annual products, but the selected covariates were typically interaction terms that included both dynamic and synoptic datasets. Thus the interplay between normal (i.e., long-term averages) and immediate conditions may be key for characterizing environmental controls on parasite rate. Conclusions: This analysis represents the first effort to systematically audit covariate utility for malaria mapping and then derive an objective, empirically based set of environmental covariates for modeling PfPR. The new covariates produce more reliable representations of malaria risk patterns and how they are changing through time, and these covariates will be used to characterize spatially and temporally varying environmental conditions affecting PfPR within a geostatistical-modeling framework, thus building upon previous research by MAP that produced global malaria maps for 2007 and 2010. C1 [Weiss, Daniel J.; Mappin, Bonnie; Dalrymple, Ursula; Bhatt, Samir; Cameron, Ewan; Hay, Simon I.; Gething, Peter W.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Hay, Simon I.] Fogarty Int Ctr, NIH, Bethesda, MD USA. RP Weiss, DJ (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg, Oxford, England. EM daniel.weiss@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Mappin, Bonnie/0000-0002-1205-719X; Gething, Peter/0000-0001-6759-5449 FU Bill and Melinda Gates Foundation [OPP1068048]; 943 Senior Research Fellowship from the Wellcome Trust [095066]; RAPIDD program of the Science & 945 Technology Directorate, Department of Homeland Security; Fogarty 946 International Center, National Institutes of Health, USA FX PWG is a Medical Research Council Career Development Fellow (#K00669X) and 940 receives support from the Bill and Melinda Gates Foundation (#OPP1068048) 941 that also supports DJW, BM, UD, SB, and EC. SIH is funded by a 943 Senior Research Fellowship from the Wellcome Trust (#095066) and 944 acknowledges funding support from the RAPIDD program of the Science & 945 Technology Directorate, Department of Homeland Security, and the Fogarty 946 International Center, National Institutes of Health, USA. NR 40 TC 15 Z9 15 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD FEB 7 PY 2015 VL 14 AR 68 DI 10.1186/s12936-015-0574-x PG 18 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CB7HQ UT WOS:000349798000001 PM 25890035 ER PT J AU Coren, LV Trivett, MT Jain, S Ayala, VI Del Prete, GQ Ohlen, C Ott, DE AF Coren, Lori V. Trivett, Matthew T. Jain, Sumiti Ayala, Victor I. Del Prete, Gregory Q. Ohlen, Claes Ott, David E. TI Potent restriction of HIV-1 and SIVmac239 Replication by African Green Monkey TRIM5 alpha SO RETROVIROLOGY LA English DT Article DE HIV; SIV; TRIM5 alpha; Restriction factor; Cumulative restriction ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; TO-CELL TRANSMISSION; SIMIAN IMMUNODEFICIENCY; RETROVIRAL RESTRICTION; REVERSE TRANSCRIPTION; RING DOMAIN; ANTIRETROVIRAL ACTIVITY; RHESUS TRIM5-ALPHA; TRIM5 PROTEINS AB Background: The TRIM5 alpha protein is a principal restriction factor that contributes to an HIV-1 replication block in rhesus macaque CD4(+) T cells by preventing reverse transcription. HIV-1 restriction is induced in human CD4(+) T cells by expression of rhesus TRIM5 alpha as well as those of other old world monkeys. While TRIM5 alpha restriction has been extensively studied in single-round infection assays, fewer studies have examined restriction after extended viral replication. Results: To examine TRIM5 alpha restriction of replication, we studied the ability of TRIM5 alpha proteins from African green monkey (AgmTRIM5 alpha) and gorilla (gorTRIM5 alpha) to restrict HIV-1 and SIVmac239 replication. These xenogeneic TRIM5 alpha genes were transduced into human Jurkat-CCR5 cells (JR5), which were then exposed to HIV-1 or SIVmac239. In our single-round infection assays, AgmTRIM5 alpha showed a relatively modest 4- to 10-fold restriction of HIV-1 and SIVmac239, while gorTRIM5 alpha produced a 2- and 3-fold restriction of HIV-1 and SIVmac239, respectively, consistent with the majority of previously published single-round studies. To assess the impact of these modest effects on infection, we tested restriction in replication systems initiated with either cell-free or cell-to-cell challenges. AgmTRIM5 alpha powerfully restricted both HIV-1 and SIVmac239 replication 14 days after cell-free infection, with a >= 3-log effect. Moreover, expression of AgmTRIM5 alpha restricted HIV-1 and SIVmac239 replication by 2-logs when co-cultured with infected JR5 cells for 12 days. In contrast, neither expression of gorTRIM5 alpha nor rhesus TRIM5 alpha induced significant resistance when co-cultured with infected cells. Follow up experiments showed that the observed differences between replication and infection were not due to assembly defects as xenogeneic TRIM5 alpha expression had no effect on either virion production or specific infectivity. Conclusions: Our results indicate that AgmTRIM5 alpha has a much greater effect on extended replication than on any single infection event, suggesting that AgmTRIM5 alpha restriction acts cumulatively, building up over many rounds of replication. Furthermore, AgmTRIM5 alpha was able to potently restrict both HIV-1 and SIV replication in a cell-to-cell infection challenge. Thus, AgmTRIM5 alpha is unique among the TRIM5 alpha species tested to date, being able to restrict even at the high multiplicities of infection presented by mixed culture with nonrestrictive infected cells. C1 [Coren, Lori V.; Trivett, Matthew T.; Jain, Sumiti; Ayala, Victor I.; Del Prete, Gregory Q.; Ohlen, Claes; Ott, David E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Ott, DE (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. EM ottde@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Theodora Hatziioannou for the African green monkey and gorilla TRIM5 alpha genes, Hans-Peter Kleim for the Phoenix RD114 clone 22 packaging cell line, Francois-Loic Cosset for the GAE-SFFV-GFP-WPRE lentiviral vector DNA, and Rob Gorelick for helpful advice. The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: Cat# 12271 Anti-rhTRIM5 alpha (3 F1-1-9), deposited by Tom Hope and Wes Sundquist; Cat# 3444 pSIVAgmTan-1 plasmid, deposited by Marcelo Soares and Beatrice Hahn; rhTRIM5 alpha gene, deposited by Joseph Sodroski and Matt Stremlau; Cat# 10072; 2 F12 SIV p27 hybridoma, Cat# 1547, deposited by Niels Pedersen. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 86 TC 1 Z9 1 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 7 PY 2015 VL 12 AR 11 DI 10.1186/s12977-015-0137-9 PG 14 WC Virology SC Virology GA CC2IQ UT WOS:000350169100001 PM 25809491 ER PT J AU Suzman, R Beard, JR Boerma, T Chatterji, S AF Suzman, Richard Beard, John R. Boerma, Ties Chatterji, Somnath TI Health in an ageing world-what do we know? SO LANCET LA English DT Editorial Material C1 [Suzman, Richard] NIA, Div Behav & Social Res, NIH, Bethesda, MD 20892 USA. [Beard, John R.] WHO, Dept Ageing & Life Course, CH-1211 Geneva, Switzerland. [Boerma, Ties; Chatterji, Somnath] WHO, Dept Hlth Stat & Informat Syst, CH-1211 Geneva, Switzerland. RP Chatterji, S (reprint author), WHO, Dept Hlth Stat & Informat Syst, CH-1211 Geneva, Switzerland. EM chatterjis@who.int RI Beard, John/K-9621-2014 OI Beard, John/0000-0002-8557-0242 FU World Health Organization [001] NR 13 TC 26 Z9 26 U1 3 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 7 PY 2015 VL 385 IS 9967 BP 484 EP 486 DI 10.1016/S0140-6736(13)61489-0 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CA9AV UT WOS:000349213600006 PM 25468156 ER PT J AU Lee, DW Kochenderfer, JN Stetler-Stevenson, M Cui, YZK Delbrook, C Feldman, SA Fry, TJ Orentas, R Sabatino, M Shah, NN Steinberg, SM Stroncek, D Tschemia, N Yuan, C Zhang, H Zhang, L Rosenberg, SA Wayne, AS Mackall, CL AF Lee, Daniel W. Kochenderfer, James N. Stetler-Stevenson, Maryalice Cui, Yongzhi K. Delbrook, Cindy Feldman, Steven A. Fry, Terry J. Orentas, Rimas Sabatino, Marianna Shah, Nirali N. Steinberg, Seth M. Stroncek, Dave Tschemia, Nick Yuan, Constance Zhang, Hua Zhang, Ling Rosenberg, Steven A. Wayne, Alan S. Mackall, Crystal L. TI T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial SO LANCET LA English DT Article ID C-REACTIVE PROTEIN; PEDIATRIC-PATIENTS; SURVIVAL; TRANSPLANTATION; CLOFARABINE; MANAGEMENT; CANCER AB Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 x 106 CAR-transduced T cells per kg (dose 1), 3 x 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defi ned as 1 x 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3.0-36.3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. C1 [Lee, Daniel W.; Cui, Yongzhi K.; Delbrook, Cindy; Fry, Terry J.; Orentas, Rimas; Shah, Nirali N.; Zhang, Hua; Zhang, Ling; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Kochenderfer, James N.] NCI, Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice; Yuan, Constance] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Feldman, Steven A.; Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Off Clin Director, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Sabatino, Marianna; Stroncek, Dave] NIH, Dept Transfus Med, Cell Proc Sect, Bethesda, MD 20892 USA. [Tschemia, Nick] Univ Nevada, Sch Med, Med Student Training Program, NIH, Reno, NV 89557 USA. [Wayne, Alan S.] Univ So Calif, Childrens Hosp Los Angeles, Keck Sch Med, Childrens Ctr Canc & Blood Dis,Div Hematol Oncol, Los Angeles, CA USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Rm 1W-3750,10 Ctr Dr MSC 1104, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU Intramural Research Program of the National Cancer Institute; St Baldrick's Foundation Scholar Award; Stand Up To Cancer-St Baldrick's-National Cancer Institute Pediatric Dream Team Translational Cancer Research Gran FX This work was supported, in part, by the Intramural Research Program of the National Cancer Institute. DWL's work is also supported by a St Baldrick's Foundation Scholar Award. Research was also supported by a Stand Up To Cancer-St Baldrick's-National Cancer Institute Pediatric Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a programme of the Entertainment Industry Foundation administered by the American Association for Cancer Research. We would like to thank Laurence Cooper for supplying the CD19-CAR anti-idiotype antibody, Mario Roederer, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, for assistance in design of T-cell subset panels and analysis, and Linda Weaver who worked on standardisation of methodology. NR 34 TC 323 Z9 339 U1 29 U2 104 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 7 PY 2015 VL 385 IS 9967 BP 517 EP 528 DI 10.1016/S0140-6736(14)61403-3 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CA9AV UT WOS:000349213600030 PM 25319501 ER PT J AU Handel, A Lebarbenchon, C Stallknecht, D Rohani, P AF Handel, Andreas Lebarbenchon, Camille Stallknecht, David Rohani, Pejman TI Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses (vol 281, 20133051, 2014) SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Correction C1 [Handel, Andreas] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. [Stallknecht, David] Univ Georgia, Coll Publ Hlth, Dept Populat Hlth, Athens, GA 30602 USA. [Lebarbenchon, Camille] Univ Reunion Isl, St Denis 97715, Reunion. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Handel, A (reprint author), Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. NR 1 TC 0 Z9 0 U1 2 U2 15 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD FEB 7 PY 2015 VL 282 IS 1800 AR 20142902 DI 10.1098/rspb.2014.2902 PG 1 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA AW6XM UT WOS:000346409000012 ER PT J AU Wang, FK Ito, Y Wei, Y AF Wang, Fengkang Ito, Yoichiro Wei, Yun TI Recent Progress on Countercurrent Chromatography Modeling SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE separation process; predict; peak; countercurrent chromatography; model ID CENTRIFUGAL PARTITION CHROMATOGRAPHY; STATIONARY-PHASE; LIQUID NATURE; ELUTION; APPARATUS; COLUMNS; FISH AB As countercurrent chromatography is becoming an established method in chromatography for many kinds of products, it is becoming increasingly important to model the process and to be able to predict the peaks for a given process. The CCC industries are looking for rapid methods to analyze the processes of countercurrent chromatography and select a suitable solvent system. In this paper, recent progress is reviewed in the development and demonstration of several types of models of countercurrent chromatography. Literature lists a number of countercurrent chromatography (CCC) models that can predict the retention time and, to a certain extent, the peak width of a solute eluting from a CCC column, such as cell model, CCD model, CSTRs model, probabilistic model, temperature dependence plate model, physical models, and so forth. C1 [Wang, Fengkang; Wei, Yun] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, 15 Beisanhuan East Rd, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU National Natural Science Foundation of China (NSFC) [21075007]; Program for New Century Excellent Talents in University [NCET-11-0563]; Special Fund for Agro-Scientific Research in the Public Interest [200803022, 201103027]; Beijing Nova Program Interdisciplinary [Z141107001814114]; Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT1205] FX This work was supported by National Natural Science Foundation of China (NSFC, Grant No. 21075007), Program for New Century Excellent Talents in University (NCET-11-0563), Special Fund for Agro-Scientific Research in the Public Interest (project 200803022 & 201103027), Beijing Nova Program Interdisciplinary (Z141107001814114), and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT1205). NR 31 TC 3 Z9 3 U1 3 U2 36 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1082-6076 EI 1520-572X J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD FEB 7 PY 2015 VL 38 IS 3 SI SI BP 415 EP 421 DI 10.1080/10826076.2014.941268 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AR9QN UT WOS:000343909800009 PM 25580072 ER PT J AU Ben-Shachar, R Koelle, K AF Ben-Shachar, Rotem Koelle, Katia TI Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections SO Journal of the Royal Society Interface LA English DT Article DE dengue; mathematical model; viral dynamics; immune response; cytokine storm; disease severity ID NECROSIS-FACTOR-ALPHA; ANTIBODY-DEPENDENT ENHANCEMENT; ORIGINAL ANTIGENIC SIN; NATURAL-KILLER-CELLS; DYNAMICS IN-VIVO; HEMORRHAGIC-FEVER; VIRUS-INFECTION; DISEASE SEVERITY; T-CELLS; INTERFERON-GAMMA AB In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm. C1 [Ben-Shachar, Rotem] Duke Univ, Program Computat Biol & Bioinformat, Durham, NC 27708 USA. [Koelle, Katia] Duke Univ, Dept Biol, Durham, NC USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ben-Shachar, R (reprint author), Duke Univ, Program Computat Biol & Bioinformat, Durham, NC 27708 USA. EM rotem.ben.shachar@duke.edu RI Barley, Kamal/F-9579-2011 OI Barley, Kamal/0000-0003-1874-9813 FU National Science Foundation [NSF-EF-08-27416]; James S. McDonnell Foundation; RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was funded by National Science Foundation grant no. NSF-EF-08-27416 and by a Complex Systems grant to K.K. from the James S. McDonnell Foundation. K.K. was further supported by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 76 TC 4 Z9 4 U1 1 U2 8 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD FEB 6 PY 2015 VL 12 IS 103 AR UNSP 20140886 DI 10.1098/rsif.2014.0886 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CG6FY UT WOS:000353394100003 ER PT J AU Nguyen, D Rubinstein, L Takebe, N Miele, L Tomaszewski, JE Ivy, P Doroshow, JH Yang, SX AF Dat Nguyen Rubinstein, Larry Takebe, Naoko Miele, Lucio Tomaszewski, Joseph E. Ivy, Percy Doroshow, James H. Yang, Sherry X. TI Notch1 phenotype and clinical stage progression in non-small cell lung cancer SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE Lung cancer; N1-ICD; Notch1; NSCLC; Stage ID EPITHELIAL-MESENCHYMAL TRANSITION; INTRACELLULAR DOMAIN; SIGNALING PATHWAY; ADENOCARCINOMA; EXPRESSION; HYPOXIA; RELEASE; AGENTS AB Background: Notch1 transmembrane receptor is activated through ligand-binding-triggered proteolytic cleavages and, upon release, the intracellular domain (N1-ICD) translocates into the nucleus and modulates target gene transcriptions. Notch activation has been implicated in tumorigenesis in an increasing number of human malignancies including non-small cell lung cancer (NSCLC). However, Notch1 in distinct expression patterns and activation status with tumor progression remains to be defined in NSCLC. Methods: Notch1 and activated Notch1, N1-ICD, were examined by immunohistochemistry in 58 cases of stage I to IV NSCLC tumors. Association between Notch1 or N1-ICD expression and clinicopathological factors was assessed via correlation coefficient r statistics. P-values are two-sided. Results: Detectable tumor Notch1, predominantly localized to the membrane and cytoplasm, was observed in 29 cases (50%, 95% Blyth-Still-Casella confidence interval 37 - 63%). It was negatively associated with stage (r = -0.43, P < 0.001) and nodal status (r = -0.33, P = 0.01), but not tumor size. In contrast, nuclear N1-ICD expression level was low and found in 12% of NSCLC patients, neither significantly associated with stage nor nodal status. Upon Notch1 activation in vitro, a mostly extra-nuclear staining was substantially turned into the nuclear signal in cancer cells. Conclusions: Notch1 in the largely inactivated phenotype is inversely associated with clinical stage progression in NSCLC. Notch1, rather than activated N1-ICD, may be a context-dependent restrictive factor to nodal metastasis. C1 [Dat Nguyen; Yang, Sherry X.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Rubinstein, Larry] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Takebe, Naoko; Ivy, Percy] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Miele, Lucio] Louisiana State Univ, Hlth Sci Ctr, Stanley Scott Canc Ctr, New Orleans, LA USA. [Miele, Lucio] Louisiana Canc Res Consortium, New Orleans, LA USA. [Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Yang, SX (reprint author), NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM Sherry.Yang@nih.gov FU Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States FX The Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States in part supported this work. We are grateful to Dr. Mark Sherman for his review of H&E stain of undifferentiated carcinoma of the ovary. NR 34 TC 11 Z9 11 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD FEB 6 PY 2015 VL 8 AR 9 DI 10.1186/s13045-014-0104-2 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA CD3BG UT WOS:000350952200001 PM 25653136 ER PT J AU Song, Y Hua, L Shapiro, BA Wang, JTL AF Song, Yang Hua, Lei Shapiro, Bruce A. Wang, Jason T. L. TI Effective alignment of RNA pseudoknot structures using partition function posterior log-odds scores SO BMC BIOINFORMATICS LA English DT Article DE RNA secondary structure including pseudoknots; Structural alignment; Dynamic programming algorithm ID MULTIPLE SEQUENCE ALIGNMENT; SECONDARY STRUCTURE PREDICTION; TURNIP CRINKLE VIRUS; PAIRWISE ALIGNMENT; WEB SERVER; TRANSLATIONAL ENHANCER; TERTIARY INTERACTIONS; RIBOSOME-BINDING; MESSENGER-RNA; 3D STRUCTURES AB Background: RNA pseudoknots play important roles in many biological processes. Previous methods for comparative pseudoknot analysis mainly focus on simultaneous folding and alignment of RNA sequences. Little work has been done to align two known RNA secondary structures with pseudoknots taking into account both sequence and structure information of the two RNAs. Results: In this article we present a novel method for aligning two known RNA secondary structures with pseudoknots. We adopt the partition function methodology to calculate the posterior log-odds scores of the alignments between bases or base pairs of the two RNAs with a dynamic programming algorithm. The posterior log-odds scores are then used to calculate the expected accuracy of an alignment between the RNAs. The goal is to find an optimal alignment with the maximum expected accuracy. We present a heuristic to achieve this goal. The performance of our method is investigated and compared with existing tools for RNA structure alignment. An extension of the method to multiple alignment of pseudoknot structures is also discussed. Conclusions: The method described here has been implemented in a tool named RKalign, which is freely accessible on the Internet. As more and more pseudoknots are revealed, collected and stored in public databases, we anticipate a tool like RKalign will play a significant role in data comparison, annotation, analysis, and retrieval in these databases. C1 [Song, Yang; Hua, Lei; Wang, Jason T. L.] Univ Hts, New Jersey Inst Technol, Dept Comp Sci, Bioinformat Program, Newark, NJ 07102 USA. [Shapiro, Bruce A.] NCI, Computat RNA Struct Grp, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. RP Wang, JTL (reprint author), Univ Hts, New Jersey Inst Technol, Dept Comp Sci, Bioinformat Program, Newark, NJ 07102 USA. EM wangj@njit.edu FU National Science Foundation [IIS-0707571]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We are grateful to the handling editor and anonymous reviewers for their constructive suggestions, which helped improve both the presentation and content of this paper. We thank the developers of CARNA for providing this robust and user-friendly tool on the web. We also thank Drs. Usman Roshan and Kaizhong Zhang for useful conversations. This research was supported in part by the National Science Foundation under Grant No. IIS-0707571 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 61 TC 0 Z9 0 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 6 PY 2015 VL 16 AR 39 DI 10.1186/s12859-015-0464-9 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA CB8XE UT WOS:000349914700001 PM 25727492 ER PT J AU Pourhoseini, S Seth, RK Das, S Dattaroy, D Kadiiska, MB Xie, G Michelotti, GA Nagarkatti, M Diehl, AM Chatterjee, S AF Pourhoseini, Sahar Seth, Ratanesh Kumar Das, Suvarthi Dattaroy, Diptadip Kadiiska, Maria B. Xie, Guanhua Michelotti, Gregory A. Nagarkatti, Mitzi Diehl, Anna Mae Chatterjee, Saurabh TI Upregulation of miR21 and Repression of Grhl3 by Leptin Mediates Sinusoidal Endothelial Injury in Experimental Nonalcoholic Steatohepatitis SO PLOS ONE LA English DT Article ID FATTY LIVER-DISEASE; HEPATIC STELLATE CELLS; PORTAL-HYPERTENSION; MICRORNAS; PROGRESSION; FIBROSIS; DYSFUNCTION; EXPRESSION; NAFLD; MECHANISMS AB Sinusoidal endothelial dysfunction (SED) has been found to be an early event in nonalcoholic steatohepatitis (NASH) progression but the molecular mechanisms underlying its causation remains elusive. We hypothesized that adipokine leptin worsens sinusoidal injury by decreasing functionally active nitric oxide synthase 3 (NOS) 3 via miR21. Using rodent models of NASH, and transgenic mice lacking leptin and leptin receptor, results showed that hyperleptinemia caused a 4-5 fold upregulation of hepatic miR21 as assessed by qRTPCR. The upregulation of miR21 led to a time-dependent repression of its target protein Grhl3 levels as shown by western blot analyses. NOS3-p/NOS3 ratio which is controlled by Grhl3 was significantly decreased in NASH models. SED markers ICAM-1, VEGFR-2, and E-selectin as assessed by immunofluorescence microscopy were significantly up regulated in the progressive phases of NASH. Lack of leptin or its receptor in vivo, reversed the upregulation of miR21 and restored the levels of Grhl3 and NOS3-p/NOS3 ratio coupled with decreased SED dysfunction markers. Interestingly, leptin supplementation in mice lacking leptin, significantly enhanced miR21 levels, decreased Grhl3 repression and NOS3 phosphorylation. Leptin supplementation in isolated primary endothelial cells, Kupffer cells and stellate cells showed increased mir21 expression in stellate cells while sinusoidal injury was significantly higher in all cell types. Finally miR21 KO mice showed increased NOS3-p/NOS3 ratio and reversed SED markers in the rodent models of NASH. The experimental results described here show a close association of leptin-induced miR21 in aiding sinusoidal injury in NASH. C1 [Pourhoseini, Sahar; Seth, Ratanesh Kumar; Das, Suvarthi; Dattaroy, Diptadip; Chatterjee, Saurabh] Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. [Kadiiska, Maria B.] Inst Environm Hlth Sci, Free Rad Metab Grp, Res Triangle Pk, NC 27709 USA. [Xie, Guanhua; Michelotti, Gregory A.; Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC 27707 USA. [Nagarkatti, Mitzi] Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29209 USA. RP Chatterjee, S (reprint author), Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. EM schatt@mailbox.sc.edu RI Seth, Ratanesh/M-3700-2016; OI Seth, Ratanesh/0000-0002-7078-0052; Nagarkatti, Mitzi/0000-0002-5977-5615 FU NIH [4R00ES019875-02, R01DK053792, P20GM103641, R01AT006888, R01ES019313]; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX This work has been supported by NIH pathway to Independence Award (4R00ES019875-02 to Saurabh Chatterjee), NIH R01 (R01DK053792 to Anna Mae Diehl) NIH grants (P20GM103641, R01AT006888, R01ES019313 to Mitzi Nagarkatti) and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 5 Z9 5 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 6 PY 2015 VL 10 IS 2 AR e0116780 DI 10.1371/journal.pone.0116780 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GK UT WOS:000349444900065 PM 25658689 ER PT J AU Wilson, MM Anderson, DE Bernstein, HD AF Wilson, Marlena M. Anderson, D. Eric Bernstein, Harris D. TI Analysis of the Outer Membrane Proteome and Secretome of Bacteroides fragilis Reveals a Multiplicity of Secretion Mechanisms SO PLOS ONE LA English DT Article ID GRAM-NEGATIVE BACTERIA; BINDING-PROTEIN; DEMYELINATING DISEASE; SURFACE-PROTEINS; SIGNAL PEPTIDES; DNA INVERSIONS; GENE SEQUENCE; CELL-ENVELOPE; IDENTIFICATION; EXPRESSION AB Bacteroides fragilis is a widely distributed member of the human gut microbiome and an opportunistic pathogen. Cell surface molecules produced by this organism likely play important roles in colonization, communication with other microbes, and pathogenicity, but the protein composition of the outer membrane (OM) and the mechanisms used to transport polypeptides into the extracellular space are poorly characterized. Here we used LC-MS/MS to analyze the OM proteome and secretome of B. fragilis NCTC 9343 grown under laboratory conditions. Of the 229 OM proteins that we identified, 108 are predicted to be lipoproteins, and 61 are predicted to be TonB-dependent transporters. Based on their proximity to genes encoding TonB-dependent transporters, many of the lipoprotein genes likely encode proteins involved in nutrient or small molecule uptake. Interestingly, protease accessibility and biotinylation experiments indicated that an unusually large fraction of the lipoproteins are cell-surface exposed. We also identified three proteins that are members of a novel family of autotransporters, multiple potential type I protein secretion systems, and proteins that appear to be components of a type VI secretion apparatus. The secretome consisted of lipoproteins and other proteins that might be substrates of the putative type I or type VI secretion systems. Our proteomic studies show that B. fragilis differs considerably from well-studied Gram-negative bacteria such as Escherichia coli in both the spectrum of OM proteins that it produces and the range of secretion strategies that it utilizes. C1 [Wilson, Marlena M.; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Anderson, D. Eric] NIDDK, Adv Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 13 Z9 13 U1 4 U2 33 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 6 PY 2015 VL 10 IS 2 AR e0117732 DI 10.1371/journal.pone.0117732 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB2GK UT WOS:000349444900211 PM 25658944 ER PT J AU Welbourn, S Kao, S Du Pont, KE Andrew, AJ Berndsen, CE Strebel, K AF Welbourn, Sarah Kao, Sandra Du Pont, Kelly E. Andrew, Amy J. Berndsen, Christopher E. Strebel, Klaus TI Positioning of Cysteine Residues within the N-terminal Portion of the BST-2/Tetherin Ectodomain Is Important for Functional Dimerization of BST-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 VIRUS RELEASE; CELL-SURFACE; MOLECULAR-CLONING; PARTICLE RELEASE; VPU; TETHERIN; PROTEIN; LOCALIZATION; RESTRICTION; INHIBITION AB BST-2/tetherin is a cellular host factor capable of restricting the release of a variety of enveloped viruses, including HIV-1. Structurally, BST-2 consists of an N-terminal cytoplasmic domain, a transmembrane domain, an ectodomain, and a C-terminal membrane anchor. The BST-2 ectodomain encodes three cysteine residues in its N-terminal half, each of which can contribute to the formation of cysteine-linked dimers. We previously reported that any one of the three cysteine residues is sufficient to produce functional BST-2 dimers. Here we investigated the importance of cysteine positioning on the ectodomain for functional dimerization of BST-2. Starting with a cysteine-free monomeric form of BST-2, individual cysteine residues were reintroduced at various locations throughout the ectodomain. The resulting BST-2 variants were tested for expression, dimerization, surface presentation, and inhibition of HIV-1 virus release. We found significant flexibility in the positioning of cysteine residues, although the propensity to form cysteine-linked dimers generally decreased with increasing distance from the N terminus. Interestingly, all BST-2 variants, including the one lacking all three ectodomain cysteines, retained the ability to form non-covalent dimers, and all of the BST-2 variants were efficiently expressed at the cell surface. Importantly, not all BST-2 variants capable of forming cysteine-linked dimers were functional, suggesting that cysteine-linked dimerization of BST-2 is necessary but not sufficient for inhibiting virus release. Our results expose new structural constraints governing the functional dimerization of BST-2, a property essential to its role as a restriction factor tethering viruses to the host cell. C1 [Welbourn, Sarah; Kao, Sandra; Andrew, Amy J.; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Du Pont, Kelly E.; Berndsen, Christopher E.] James Madison Univ, Dept Chem & Biochem, Harrisonburg, VA 22807 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Rm 310,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov OI Berndsen, Christopher/0000-0002-4285-4341 FU Intramural Research Program of the NIAID, National Institutes of Health [1 ZO1 AI000669]; Canadian Institutes of Health Research; Research Corporation Development Award [7957]; James Madison University Program of Grants for Faculty Assistance; 4-VA organization FX This work was supported in part by the Intramural Research Program of the NIAID, National Institutes of Health Grant 1 ZO1 AI000669.; Supported by a postdoctoral fellowship from the Canadian Institutes of Health Research.; Supported by Research Corporation Development Award 7957, the James Madison University Program of Grants for Faculty Assistance, and the 4-VA organization. NR 34 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2015 VL 290 IS 6 BP 3740 EP 3751 DI 10.1074/jbc.M114.617639 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CB2KL UT WOS:000349456000045 PM 25525265 ER PT J AU Weisz, A Ridge, CD Mazzola, EP Ito, Y AF Weisz, Adrian Ridge, Clark D. Mazzola, Eugene P. Ito, Yoichiro TI Preparative separation and identification of novel subsidiary colors of the color additive D&C Red No. 33 (Acid Red 33) using spiral high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE D&C Red No. 33; Spiral high-speed counter-current chromatography; NMR spectra of dye impurities; 5-Amino-3-biphenyl-3-ylazo-4-hydroxy-naphthalene-2,7-disulfonic acid; 5-Amino-4-hydroxy-6-phenyl-3-phenylazo-naphthalene-2,7-disulfonic acid; 5-Amino-4-hydroxy-3,6-bis-phenylazo-naphthalene-2,7-disulfonic acid ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SOLID-PHASE MICROEXTRACTION; TUBING SUPPORT ROTOR; MASS-SPECTROMETRY; PHLOXINE-B; NOS. 27; QUINOLINE YELLOW; BASE EQUILIBRIA; AZO-HYDRAZONE; 5 TARTRAZINE AB Three low-level subsidiary color impurities (A, B, and C) often present in batches of the color additive D&C Red No. 33 (R33, Acid Red 33, Colour Index No. 17200) were separated from a portion of R33 by spiral high-speed counter-current chromatography (HSCCC). The separation involved use of a very polar solvent system, 1-BuOH/5 mM aq. (NH4)(2)SO4. Addition of ammonium sulfate to the lower phase forced partition of the components into the upper phase, thereby eliminating the need to add a hydrophobic counterion as was previously required for separations of components from sulfonated dyes. The very polar solvent system used would not have been retained in a conventional multi-layer coil HSCCC instrument, but the spiral configuration enabled retention of the stationary phase, and thus, the separation was possible. A 1 g portion of R33 enriched in A, B, and C was separated using the upper phase of the solvent system as the mobile phase. The retention of the stationary phase was 38.1%, and the separation resulted in 4.8 mg of A of >90% purity, 18.3 mg of B of >85% purity, and 91 mg of C of 65-72% purity. A second separation of a portion of the C mixture resulted in 7 mg of C of >94% purity. The separated impurities were identified by high-resolution mass spectrometry and NMR spectroscopic techniques as follows: 5-amino-3-bipheny1-3-ylazo-4-hydroxy-naphthalene2,7-disulfonic acid, A; 5-amino-4-hydroxy-6-pheny1-3-phenylazo-naphthalene-2,7-disulfonic acid, B; and 5-amino-4-hydroxy-3,6-bis-phenylazo-naphthalene-2,7-disulfonic acid, C. The isomers A and B are compounds reported for the first time. Application of the spiral HSCCC method resulted in the additional benefit of yielding 930 mg of the main component of R33, 5-amino-4-hydroxy-3-phenylazo-naphthalene2,7-disulfonic acid, of >97% purity. Published by Elsevier B.V. C1 [Weisz, Adrian] US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ridge, Clark D.; Mazzola, Eugene P.] US FDA, Off Regulatory Sci, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Weisz, A (reprint author), US FDA, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM adrian.weisz@fda.hhs.gov FU Intramural NIH HHS [ZIA HL005107-07] NR 48 TC 3 Z9 3 U1 2 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 6 PY 2015 VL 1380 BP 120 EP 129 DI 10.1016/j.chroma.2014.12.072 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CA4RW UT WOS:000348893100015 PM 25591404 ER PT J AU Hickman, HD AF Hickman, Heather D. TI There goes the macrophage neighborhood SO SCIENCE LA English DT Editorial Material ID SUBCAPSULAR SINUS MACROPHAGES; CD8(+) T-CELLS; DENDRITIC CELLS; LYMPH-NODES; B-CELLS; VIRUS C1 NIH, Bethesda, MD 20892 USA. RP Hickman, HD (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM hhickman@mail.nih.gov FU Intramural NIH HHS NR 12 TC 0 Z9 0 U1 1 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 6 PY 2015 VL 347 IS 6222 BP 609 EP 610 DI 10.1126/science.aaa6919 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8CX UT WOS:000349145200021 PM 25657230 ER PT J AU Lecchi, A Razzari, C Paoletta, S Dupuis, A Nakamura, L Ohlmann, P Gachet, C Jacobson, KA Zieger, B Cattaneo, M AF Lecchi, Anna Razzari, Cristina Paoletta, Silvia Dupuis, Arnaud Nakamura, Lea Ohlmann, Philippe Gachet, Christian Jacobson, Kenneth A. Zieger, Barbara Cattaneo, Marco TI Identification of a new dysfunctional platelet P2Y(12) receptor variant associated with bleeding diathesis SO BLOOD LA English DT Article ID LIGHT TRANSMISSION AGGREGOMETRY; DRUG-INDUCED DEFECTS; ADENOSINE-DIPHOSPHATE; RICH PLASMA; PATIENT; ADP; AGGREGATION; MUTATION; COMPLEX; PROTEIN AB Defects of the platelet P2Y(12) receptor (P2Y(12)R) for adenosine diphosphate (ADP) are associated with increased bleeding risk. The study of molecular abnormalities associated with inherited qualitative defects of the P2Y(12)R protein is useful to unravel structure-function relationships of the receptor. We describe the case of 2 brothers, sons of first cousins, with lifelong history of abnormal bleeding, associated with dysfunctional P2Y(12)R and a previously undescribed missense mutation in the encoding gene. ADP (4-20 mu M)-induced aggregation of patients' platelets was markedly reduced and rapidly reversible. Other agonists induced borderline-normal aggregation. Inhibition of vasodilator-stimulated phosphoprotein phosphorylation and prostaglandin E-1-induced increase in cyclic adenosine monophosphate (cAMP) by ADP was impaired, whereas inhibition of cAMP increase by epinephrine was normal. [H-3]PSB-0413, a selective P2Y(12)R antagonist, bound to a normal number of binding sites; however, its affinity, and that of the agonists ADP and 2-methylthio-adenosine-5'-diphosphate, was reduced. Patients' DNA showed a homozygous c.847T>A substitution that changed the codon for His-187 to Gln (p.His187Gln). Crystallographic data and molecular modeling studies indicated that His187 in transmembrane 5 is important for agonist and nucleotide antagonist binding and located in a region undergoing conformational changes. These studies delineate a region of P2Y(12)R required for normal function after ADP binding. C1 [Lecchi, Anna] Osped Maggiore Policlin, Fdn Ist Ricovero & Cura Carattere Sci Ca Granda, Angelo Bianchi Bonomi Hemophilia & Thrombosis Ctr, Milan, Italy. [Razzari, Cristina; Cattaneo, Marco] Univ Milan, Osped San Paolo, Dipartimento Sci Salute, Div Med 3, I-20142 Milan, Italy. [Paoletta, Silvia; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Dupuis, Arnaud; Ohlmann, Philippe; Gachet, Christian] Univ Strasbourg, Unite Mixte Rech S949, Etab Francais Sang Alsace, Strasbourg, France. [Nakamura, Lea; Zieger, Barbara] Univ Med Ctr Freiburg, Dept Pediat & Adolescent Med, Freiburg, Germany. RP Cattaneo, M (reprint author), Univ Milan, Osped San Paolo, Unita Med 3, Via Rudini 8, I-20142 Milan, Italy. EM marco.cattaneo@unimi.it RI Jacobson, Kenneth/A-1530-2009; Gachet, Christian/H-9156-2016; OI Jacobson, Kenneth/0000-0001-8104-1493; Cattaneo, Marco/0000-0002-7343-4534 FU National Institutes of Health National Institute of Diabetes and Digestive Kidney Diseases Intramural Research Program FX This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive Kidney Diseases Intramural Research Program (K.A.J. and S.P.). NR 31 TC 12 Z9 13 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 5 PY 2015 VL 125 IS 6 BP 1006 EP 1013 DI 10.1182/blood-2013-07-517896 PG 8 WC Hematology SC Hematology GA CD1ES UT WOS:000350817700019 PM 25428217 ER PT J AU Fennell, TR Morgan, DL Watson, SL Dhungana, S Waidyanatha, S AF Fennell, Timothy R. Morgan, Daniel L. Watson, Scott L. Dhungana, Suraj Waidyanatha, Suramya TI Systemic uptake, albumin and hemoglobin binding of [C-14]2,3-butanedione administered by intratracheal instillation in male Harlan Sprague Dawley rats and oropharyngeal aspiration in male B6C3F(1)/N mice SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE 2,3-Butanedione; Hemoglobin binding; Albumin binding; Systemic uptake ID INHALATION DOSIMETRY; BUTTER FLAVORANT; DIACETYL; METHYLGLYOXAL; PROTEINS; MODEL; 2,3-BUTANEDIONE; BRONCHIOLITIS; HYPERGLYCEMIA; ACETALDEHYDE AB 2,3-Butanedione (BD) is a reactive diketone in artificial butter flavors that is thought to cause bronchiolitis obliterans in workers in microwave popcorn manufacturing. Bronchiolitis obliterans is generally not diagnosed until irreversible damage has occurred; therefore a biomarker of early exposure is needed. The potential systemic uptake of BD from inhalation exposure has not been evaluated. The objective here was to evaluate the systemic exposure of BD and binding to hemoglobin and albumin. [C-14]BD was administered to male Harlan Sprague Dawley rats (100 mg/kg, intratracheal instillation) and B6C3F(1/N) mice (157 mg/kg, oropharyngeal aspiration). Blood and plasma was collected 24 h after administration and analyzed for C-14 content. At 24 h, 0.88 +/- 0.07% of the administered dose was in rat blood, 0.66 +/- 0.06% in rat plasma, 0.38 +/- 0.13% in mouse blood and 0.17 +/- 0.05% in mouse plasma. Albumin binding in rats was 269 +/- 24.2 ng equiv./mg, which accounts for 38% of the radioactivity in plasma. In mice, binding was 85.0 +/- 22.3 ng equiv./mg albumin, which accounts for 51% of the radioactivity in plasma. The binding to hemoglobin in rats was 38.2 +/- 17.6 ng equiv./mg, and to globin was 29.1 +/- 3.96 ng equiv./mg. In mice, the binding to hemoglobin was 16.2 +/- 9.0 ng equiv./mg. The site(s) of adduction on hemoglobin and albumin was investigated by mass spectrometry. In rat globin, arginine adducts were detected at R-30 and R-104 of the beta chain in vitro and in vivo. In rat albumin, adducts were detected in vitro on R-219/221, R-360, and R-368, and in vivo on a variety of arginine residues. This study demonstrated that BD enters the systemic circulation and reacts with arginine on hemoglobin and albumin. These results indicate that hemoglobin and albumin adducts may be useful as biomarkers of BD exposure in humans. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Fennell, Timothy R.; Watson, Scott L.; Dhungana, Suraj] RTI Int, Res Triangle Pk, NC USA. [Morgan, Daniel L.; Waidyanatha, Suramya] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Waidyanatha, S (reprint author), NIEHS, Program Operat Branch, Div Natl Toxicol Program, POB 12233,MD K2-07, Res Triangle Pk, NC 27709 USA. EM waidyanathas@niehs.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services [N01-ES-75563 (HHSN29120077563)] FX This work was performed for the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, under contract No. N01-ES-75563 (HHSN29120077563). NR 23 TC 2 Z9 2 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD FEB 5 PY 2015 VL 227 BP 112 EP 119 DI 10.1016/j.cbi.2014.12.029 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA CC1GE UT WOS:000350088400014 PM 25559854 ER PT J AU Maier, R Moser, G Chen, GB Ripke, S Coryell, W Potash, JB Scheftner, WA Shi, JX Weissman, MM Hultman, CM Landen, M Levinson, DF Kendler, KS Smoller, JW Wray, NR Lee, SH AF Maier, Robert Moser, Gerhard Chen, Guo-Bo Ripke, Stephan Coryell, William Potash, James B. Scheftner, William A. Shi, Jianxin Weissman, Myrna M. Hultman, Christina M. Landen, Mikael Levinson, Douglas F. Kendler, Kenneth S. Smoller, Jordan W. Wray, Naomi R. Lee, S. Hong CA Psychiat Genomics Consortium TI Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RESTRICTED MAXIMUM-LIKELIHOOD; AVERAGE INFORMATION; GENETIC RISK; LOCI; SELECTION; TRAITS; MODELS; IDENTIFICATION; POPULATION AB Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk. C1 [Maier, Robert; Moser, Gerhard; Chen, Guo-Bo; Wray, Naomi R.; Lee, S. Hong] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Coryell, William; Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Scheftner, William A.] Rush Univ, Dept Psychiat, Med Ctr, Chicago, IL 60612 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Weissman, Myrna M.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Weissman, Myrna M.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hultman, Christina M.; Landen, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Landen, Mikael] Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, S-41345 Gothenburg, Sweden. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Kendler, Kenneth S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. RP Lee, SH (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. EM hong.lee@uq.edu.au RI Hansen, Thomas Folkmann/O-5965-2014; Lohoff, Falk/M-7951-2016; BELLIVIER, FRANK/H-5197-2012; McQuillin, Andrew/C-1623-2008; Lesch, Klaus-Peter/J-4906-2013; Wray, Naomi/C-8639-2015; Ruderfer, Douglas/M-5795-2016; Scherer, Stephen /B-3785-2013; Lee, Sang Hong/A-2569-2011; Kuntsi, Jonna/G-9750-2011; Franke, Barbara/D-4836-2009; Moser, Gerhard/H-7054-2012; Collier, David/D-1649-2011; Zhang, Peng/N-2920-2014; Mattheisen, Manuel/B-4949-2012; Breen, Gerome/A-5540-2010; Melle, Ingrid /B-4858-2011; Schumacher, Johannes/F-4970-2015 OI Yu, Timothy/0000-0003-2988-7701; Thapar, Anita/0000-0002-3689-737X; Etain, Bruno/0000-0002-5377-1488; de Geus, Eco/0000-0001-6022-2666; Chen, Guo-Bo/0000-0001-5475-8237; Cormand, Bru/0000-0001-5318-4382; Betancur, Catalina/0000-0002-3327-4804; Jamain, Stephane/0000-0002-4321-4100; Weissman, Myrna/0000-0003-3490-3075; Hansen, Thomas Folkmann/0000-0001-6703-7762; Kent, Lindsey/0000-0002-5315-3399; Anney, Richard/0000-0002-6083-407X; Bruggeman, Richard/0000-0002-3238-8471; Nothen, Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Oliveira, Guiomar/0000-0002-7049-1277; McQuillin, Andrew/0000-0003-1567-2240; Lesch, Klaus-Peter/0000-0001-8348-153X; Bergen, Sarah/0000-0002-5888-0034; Backlund, Lena/0000-0001-9399-5024; Zammit, Stanley/0000-0002-2647-9211; McMahon, Francis/0000-0002-9469-305X; Hamilton, Steven/0000-0001-8106-6260; Gallagher, Louise/0000-0001-9462-2836; Tozzi, Federica/0000-0002-3536-2920; Myin-Germeys, Inez/0000-0002-3731-4930; Wray, Naomi/0000-0001-7421-3357; Ruderfer, Douglas/0000-0002-2365-386X; Scherer, Stephen /0000-0002-8326-1999; Lee, Sang Hong/0000-0001-9701-2718; Franke, Barbara/0000-0003-4375-6572; Moser, Gerhard/0000-0003-3104-5730; Collier, David/0000-0003-4087-1559; Zhang, Peng/0000-0003-1182-1392; Mattheisen, Manuel/0000-0002-8442-493X; Breen, Gerome/0000-0003-2053-1792; Melle, Ingrid /0000-0002-9783-548X; Schumacher, Johannes/0000-0001-9217-6457 FU Australian Research Council [FT0991360, DE130100614]; National Health and Medical Research Council [613608, 1011506, 1047956, 1080157]; National Institute of Mental Health (NIMH) [U01 MH085520]; Stanley Center for Psychiatric Research; Sylvan Herman Foundation; Karolinska Institutet, Karolinska University Hospital; Swedish Research Council; Stockholm County Council; Soderstrom Konigska Foundation; Netherlands Scientific Organization [NWO 645-000-003]; Netherlands Scientific Organization (NOW) [480-05-003]; NIMH R01 [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]; [NIMH R01 MH077139] FX This study was supported by the Australian Research Council (FT0991360 and DE130100614) and the National Health and Medical Research Council (613608, 1011506, 1047956, and 1080157). The Psychiatric Genomics Consortium is supported by National Institute of Mental Health (NIMH) grant U01 MH085520. We acknowledge the funding that supported the Swedish schizophrenia study (NIMH R01 MH077139), the Stanley Center for Psychiatric Research, the Sylvan Herman Foundation, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, the Stockholm County Council, the Soderstrom Konigska Foundation, and the Netherlands Scientific Organization (NWO 645-000-003). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003). The GenRED GWAS project was supported by NIMH R01 grants MH061686 (D.F.L.), MH059542 (W.C.), MH075131 (W.B. Lawson), MH059552 (J.B.P.), MH059541 (W.A.S.), and MH060912 (M.M.W.). NR 45 TC 38 Z9 38 U1 6 U2 43 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 FEB 5 PY 2015 VL 96 IS 2 BP 283 EP 294 DI 10.1016/j.ajhg.2014.12.006 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CA9WY UT WOS:000349276700010 PM 25640677 ER PT J AU Diaz-Ruiz, A Gonzalez-Freire, M Ferrucci, L Bernier, M de Cabo, R AF Diaz-Ruiz, Alberto Gonzalez-Freire, Marta Ferrucci, Luigi Bernier, Michel de Cabo, Rafael TI SIRT1 Synchs Satellite Cell Metabolism with Stem Cell Fate SO CELL STEM CELL LA English DT Editorial Material AB Metabolic reprogramming of muscle stem cells modulates myogenic cell fate. In this issue of Cell Stem Cell, Ryall et al. (2015) show that SIRT1, a NAD(+)- dependent histone deacetylase, acts as an epigenetic regulator that connects changes in satellite cell metabolism with changes in the transcriptional machinery toward myogenic commitment. C1 [Diaz-Ruiz, Alberto; Gonzalez-Freire, Marta; Ferrucci, Luigi; Bernier, Michel; de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM deCaboRa@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Bernier, Michel/0000-0002-5948-368X; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS NR 10 TC 2 Z9 3 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 5 PY 2015 VL 16 IS 2 BP 103 EP 104 DI 10.1016/j.stem.2015.01.006 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CB2KC UT WOS:000349455000001 PM 25658362 ER PT J AU Ryall, JG Dell'Orso, S Derfoul, A Juan, A Zare, H Feng, XS Clermont, D Koulnis, M Gutierrez-Cruz, G Fulco, M Sartorelli, V AF Ryall, James G. Dell'Orso, Stefania Derfoul, Assia Juan, Aster Zare, Hossein Feng, Xuesong Clermont, Daphney Koulnis, Miroslav Gutierrez-Cruz, Gustavo Fulco, Marcella Sartorelli, Vittorio TI The NAD(+)-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells SO CELL STEM CELL LA English DT Article ID SATELLITE CELLS; SELF-RENEWAL; TRANSCRIPTION FACTORS; REGENERATION; DIFFERENTIATION; MYOGENESIS; QUIESCENT; SIRTUINS; ACETYLATION; NICHE AB Stem cells undergo a shift in metabolic substrate utilization during specification and/or differentiation, a process that has been termed metabolic reprogramming. Here, we report that during the transition from quiescence to proliferation, skeletal muscle stem cells experience a metabolic switch from fatty acid oxidation to glycolysis. This reprogramming of cellular metabolism decreases intracellular NAD(+) levels and the activity of the histone deacetylase SIRT1, leading to elevated H4K16 acetylation and activation of muscle gene transcription. Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in SCs. Moreover, mice with muscle-specific inactivation of the SIRT1 deacetylase domain display reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes. Overall, these findings reveal how metabolic cues can be mechanistically translated into epigenetic modifications that regulate skeletal muscle stem cell biology. C1 [Ryall, James G.; Dell'Orso, Stefania; Derfoul, Assia; Juan, Aster; Zare, Hossein; Feng, Xuesong; Clermont, Daphney; Koulnis, Miroslav; Gutierrez-Cruz, Gustavo; Fulco, Marcella; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20829 USA. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20829 USA. EM sartorev@mail.nih.gov OI Ryall, James/0000-0003-4702-1143 FU Overseas Biomedical Research Fellowship from the National Health & Medical Research Council of Australia; Intramural Research Program of NIAMS at the NIH FX We thank Yansong Gu (University of Washington, Seattle) for sharing the Sirt1 floxed mice, Kristina Zaal (Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS]) for help in evaluating Pax7+/MyoD+ immunofluorescence staining, and Jim Simone (Flow Cytometry Section, NIAMS) for help with FACS. J.G.R. was supported, in part, via an Overseas Biomedical Research Fellowship from the National Health & Medical Research Council of Australia. This work was supported by the Intramural Research Program of NIAMS at the NIH. NR 56 TC 50 Z9 52 U1 8 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 5 PY 2015 VL 16 IS 2 BP 171 EP 183 DI 10.1016/j.stem.2014.12.004 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CB2KC UT WOS:000349455000013 PM 25600643 ER PT J AU Wu, D Minton, AP AF Wu, Di Minton, Allen P. TI Quantitative Characterization of Nonspecific Self- and Hetero-Interactions of Proteins in Nonideal Solutions via Static Light Scattering SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRIMETHYLAMINE-N-OXIDE; INTERMOLECULAR INTERACTIONS; ASSOCIATING PROTEINS; RIBONUCLEASE; MIXTURES; DISSOCIATION AB The dependence of static light scattering upon the compositions of solutions including hen egg white ovalbumin, hen egg white ovomucoid, ribonuclease A, and binary mixtures of these proteins at total concentrations of up to about 40 g/L were measured at different values of the pH and ionic strength. At the pH values of measurement, ovalbumin and ovomucoid have a net negative charge and ribonuclease A has a net positive charge. The observed dependence of scattering intensity upon solution composition may be accounted for by an extension of previously formulated equivalent hard particle models that allows for the presence of both repulsive interactions between like species and attractive interactions between unlike species in mixtures of positively and negatively charged proteins. C1 [Wu, Di; Minton, Allen P.] NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIH, Bldg 8,Room 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Dr. Xiao-nan Zhao (NIDDK) for the electrophoresis experiments and thank Dr. Peter McPhie (NTH) for a critical reading of the draft manuscript. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 32 TC 4 Z9 4 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD FEB 5 PY 2015 VL 119 IS 5 BP 1891 EP 1898 DI 10.1021/jp510918d PG 8 WC Chemistry, Physical SC Chemistry GA CA7ZT UT WOS:000349137000011 PM 25580677 ER PT J AU Huang, R Xu, YF Wan, W Shou, X Qian, JL You, ZY Liu, B Chang, CM Zhou, TH Lippincott-Schwartz, J Liu, W AF Huang, Rui Xu, Yinfeng Wan, Wei Shou, Xin Qian, Jiali You, Zhiyuan Liu, Bo Chang, Chunmei Zhou, Tianhua Lippincott-Schwartz, Jennifer Liu, Wei TI Deacetylation of Nuclear LC3 Drives Autophagy Initiation under Starvation SO MOLECULAR CELL LA English DT Article ID MICROTUBULE-ASSOCIATED PROTEIN-1; SMOOTH-MUSCLE-CELLS; LIGHT-CHAIN 3; ENDOPLASMIC-RETICULUM; STRUCTURAL BASIS; MAMMALIAN-CELLS; COMPLEX; ATG8; ACETYLTRANSFERASE; PHOSPHORYLATION AB Shuttling of macromolecules between different cellular compartments helps regulate the timing and extent of different cellular activities. Here, we report that LC3, a key initiator of autophagy that cycles between the nucleus and cytoplasm, becomes selectively activated in the nucleus during starvation through deacetylation by the nuclear deacetylase Sirt1. Deacetylation of LC3 at K49 and K51 by Sirt1 allows LC3 to interact with the nuclear protein DOR and return to the cytoplasm with DOR, where it is able to bind Atg7 and other autophagy factors and undergo phosphatidylethanolamine conjugation to preautophagic membranes. The association of deacetylated LC3 with autophagic factors shifts LC3's distribution from the nucleus toward the cytoplasm. Thus, an acetylation-deacetylation cycle ensures that LC3 effectively redistributes in an activated form from nucleus to cytoplasm, where it plays a central role in autophagy to enable the cell to cope with the lack of external nutrients. C1 [Huang, Rui; Xu, Yinfeng; Wan, Wei; Shou, Xin; Qian, Jiali; You, Zhiyuan; Liu, Bo; Chang, Chunmei; Zhou, Tianhua; Liu, Wei] Zhejiang Univ, Sch Med, Program Mol & Cell Biol, Dept Biochem & Mol Biol, Hangzhou 310058, Zhejiang, Peoples R China. [Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Liu, Wei] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou 310003, Zhejiang, Peoples R China. RP Liu, W (reprint author), Zhejiang Univ, Sch Med, Program Mol & Cell Biol, Dept Biochem & Mol Biol, Hangzhou 310058, Zhejiang, Peoples R China. EM liuwei666@zju.edu.cn FU National Basic Research Program of China [2011CB910100, 2013CB910200]; National Natural Science Foundation of China [31171288, 31271431] FX We are grateful to the Imaging Center of Zhejiang University School of Medicine for their assistance in confocal microscopy and electron microscopy. We thank Hong Liu, Tingting Song (Zhejiang University), and Jingjing Tong (Tsinghua University) for other technical support and members of Dr. Liu's lab for helpful discussions. This study was supported by the National Basic Research Program of China (2011CB910100 and 2013CB910200) and National Natural Science Foundation of China (31171288 and 31271431). NR 41 TC 59 Z9 60 U1 4 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD FEB 5 PY 2015 VL 57 IS 3 BP 456 EP 466 DI 10.1016/j.molcel.2014.12.013 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CB3TD UT WOS:000349550700009 PM 25601754 ER PT J AU Do, R Stitziel, NO Won, HH Jorgensen, AB Duga, S Merlini, PA Kiezun, A Farrall, M Goel, A Zuk, O Guella, I Asselta, R Lange, LA Peloso, GM Auer, PL Girelli, D Martinelli, N Farlow, DN DePristo, MA Roberts, R Stewart, AFR Saleheen, D Danesh, J Epstein, SE Sivapalaratnam, S Hovingh, GK Kastelein, JJ Samani, NJ Schunkert, H Erdmann, J Shah, SH Kraus, WE Davies, R Nikpay, M Johansen, CT Wang, J Hegele, RA Hechter, E Marz, W Kleber, ME Huang, J Johnson, AD Li, MY Burke, GL Gross, M Liu, YM Assimes, TL Heiss, G Lange, EM Folsom, AR Taylor, HA Olivieri, O Hamsten, A Clarke, R Reilly, DF Yin, W Rivas, MA Donnelly, P Rossouw, JE Psaty, BM Herrington, DM Wilson, JG Rich, SS Bamshad, MJ Tracy, RP Cupples, LA Rader, DJ Reilly, MP Spertus, JA Cresci, S Hartiala, J Tang, WHW Hazen, SL Allayee, H Reiner, AP Carlson, CS Kooperberg, C Jackson, RD Boerwinkle, E Lander, ES Schwartz, SM Siscovick, DS McPherson, R Tybjaerg-Hansen, A Abecasis, GR Watkins, H Nickerson, DA Ardissino, D Sunyaev, SR O'Donnell, CJ Altshuler, D Gabriel, S Kathiresan, S AF Do, Ron Stitziel, Nathan O. Won, Hong-Hee Jorgensen, Anders Berg Duga, Stefano Merlini, Pier Angelica Kiezun, Adam Farrall, Martin Goel, Anuj Zuk, Or Guella, Illaria Asselta, Rosanna Lange, Leslie A. Peloso, Gina M. Auer, Paul L. Girelli, Domenico Martinelli, Nicola Farlow, Deborah N. DePristo, Mark A. Roberts, Robert Stewart, Alexander F. R. Saleheen, Danish Danesh, John Epstein, Stephen E. Sivapalaratnam, Suthesh Hovingh, G. Kees Kastelein, John J. Samani, Nilesh J. Schunkert, Heribert Erdmann, Jeanette Shah, Svati H. Kraus, William E. Davies, Robert Nikpay, Majid Johansen, Christopher T. Wang, Jian Hegele, Robert A. Hechter, Eliana Marz, Winfried Kleber, Marcus E. Huang, Jie Johnson, Andrew D. Li, Mingyao Burke, Greg L. Gross, Myron Liu, Yongmei Assimes, Themistocles L. Heiss, Gerardo Lange, Ethan M. Folsom, Aaron R. Taylor, Herman A. Olivieri, Oliviero Hamsten, Anders Clarke, Robert Reilly, Dermot F. Yin, Wu Rivas, Manuel A. Donnelly, Peter Rossouw, Jacques E. Psaty, Bruce M. Herrington, David M. Wilson, James G. Rich, Stephen S. Bamshad, Michael J. Tracy, Russell P. Cupples, L. Adrienne Rader, Daniel J. Reilly, Muredach P. Spertus, John A. Cresci, Sharon Hartiala, Jaana Tang, W. H. Wilson Hazen, Stanley L. Allayee, Hooman Reiner, Alex P. Carlson, Christopher S. Kooperberg, Charles Jackson, Rebecca D. Boerwinkle, Eric Lander, Eric S. Schwartz, Stephen M. Siscovick, David S. McPherson, Ruth Tybjaerg-Hansen, Anne Abecasis, Goncalo R. Watkins, Hugh Nickerson, Deborah A. Ardissino, Diego Sunyaev, Shamil R. O'Donnell, Christopher J. Altshuler, David Gabriel, Stacey Kathiresan, Sekar CA NHLBI Exome Sequencing Project TI Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SINGLE NUCLEOTIDE POLYMORPHISMS; OF-FUNCTION MUTATIONS; HEART-DISEASE; RECEPTOR; VARIANTS; HYPERCHOLESTEROLEMIA; TRIGLYCERIDES; CHOLESTEROL AB Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance(1,2). When MI occurs early in life, genetic inheritance is a major component to risk(1). Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (<= 50 years inmales and <= 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol(16). Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase(15,17) and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. C1 [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Do, Ron; Won, Hong-Hee; Peloso, Gina M.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Do, Ron; Won, Hong-Hee; Kiezun, Adam; Zuk, Or; Peloso, Gina M.; Farlow, Deborah N.; DePristo, Mark A.; Hechter, Eliana; Folsom, Aaron R.; Lander, Eric S.; Sunyaev, Shamil R.; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Cambridge Ctr 7, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Stitziel, Nathan O.; Cresci, Sharon] Washington Univ, Div Cardiovasc, Dept Med, Sch Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63110 USA. [Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Mol Genet Sect, Dept Clin Biochem KB3011, DK-1165 Copenhagen, Denmark. [Jorgensen, Anders Berg; Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth Sci, DK-1165 Copenhagen, Denmark. [Duga, Stefano; Guella, Illaria; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, I-20122 Milan, Italy. [Merlini, Pier Angelica] Osped Niguarda Ca Granda, Div Cardiol, I-20162 Milan, Italy. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX1 2J, England. [Lange, Leslie A.; Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Auer, Paul L.; Folsom, Aaron R.; Reiner, Alex P.; Carlson, Christopher S.; Kooperberg, Charles; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Girelli, Domenico; Martinelli, Nicola; Olivieri, Oliviero] Univ Verona, Dept Med, Sch Med, I-37129 Verona, Italy. [Roberts, Robert; Stewart, Alexander F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON K1Y 4W7, Canada. [Saleheen, Danish; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Epstein, Stephen E.] MedStar Hlth Res Inst, Cardiovasc Res Inst, Hyattsville, MD 20782 USA. [Sivapalaratnam, Suthesh; Hovingh, G. Kees; Kastelein, John J.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Samani, Nilesh J.] Glenfield Gen Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Schunkert, Heribert] Tech Univ Munich, DZHK German Res Ctr Cardiovasc Res, Munich Heart Alliance, Deutsch Herzzentrum Munchen, D-13347 Berlin, Germany. [Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23562 Lubeck, Germany. [Shah, Svati H.] Duke Univ, Ctr Human Genet, Durham, NC 27708 USA. [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Dept Cardiol, Durham, NC 27708 USA. [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Ctr Genom Med, Durham, NC 27708 USA. [Davies, Robert; Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON K1Y 4W7, Canada. [Johansen, Christopher T.; Wang, Jian; Hegele, Robert A.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada. [Hegele, Robert A.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, Robarts Res Inst, London, ON N6A 3K7, Canada. [Marz, Winfried; Kleber, Marcus E.] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, D-68167 Mannheim, Germany. [Marz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, A-8036 Graz, Austria. [Marz, Winfried] Synlab Acad, D-68259 Mannheim, Germany. [Huang, Jie; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Johnson, Andrew D.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA 01702 USA. [Li, Mingyao] Univ Penn, Dept Biostat & Epidemiol, Sch Med, Philadelphia, PA 19104 USA. [Burke, Greg L.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA. [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27106 USA. [Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Lange, Ethan M.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden. [Hamsten, Anders] Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford OX1 2JD, England. [Clarke, Robert] Univ Oxford, Epidemiol Studies Unit, Oxford OX1 2JD, England. [Reilly, Dermot F.; Yin, Wu] Merck Sharp & Dohme Corp, Rahway, NJ 08889 USA. [Rivas, Manuel A.; Donnelly, Peter; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 2JD, England. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20824 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Herrington, David M.] Wake Forest Sch Med, Sect Cardiol & Publ Hlth Sci, Winston Salem, NC 27106 USA. [Wilson, James G.] Jackson State Univ, Med Ctr, Univ Mississippi, Jackson Heart Study, Jackson, MS 39217 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22904 USA. [Bamshad, Michael J.] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA. [Bamshad, Michael J.] Seattle Childrens Hosp, Seattle, WA 98105 USA. [Bamshad, Michael J.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Spertus, John A.] Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Cresci, Sharon] Washington Univ, Dept Genet, St Louis, MO 63130 USA. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hartiala, Jaana; Allayee, Hooman] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA. [Tang, W. H. Wilson; Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44195 USA. [Reiner, Alex P.; Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Siscovick, David S.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Tybjaerg-Hansen, Anne] Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen N, Denmark. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MO 48109 USA. [Ardissino, Diego] Parma Hosp, Dept Cardiol, I-43100 Parma, Italy. [Sunyaev, Shamil R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; de Bakker, Paul/B-8730-2009; Hegele, Robert/G-3301-2011; Martinelli, Nicola/J-5622-2016; Johnson, Andrew/G-6520-2013; Erdmann, Jeanette/P-7513-2014; OI Turner, Emily/0000-0001-9040-9229; de Bakker, Paul/0000-0001-7735-7858; Martinelli, Nicola/0000-0001-6465-5119; Erdmann, Jeanette/0000-0002-4486-6231; Stewart, Alexandre/0000-0003-2673-9164; Asselta, Rosanna/0000-0001-5351-0619; Seshadri, Sudha/0000-0001-6135-2622; Stitziel, Nathan/0000-0002-4963-8211; Duga, Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Kleber, Marcus/0000-0003-0663-7275 FU National Heart, Lung, and Blood Institute (NHLBI); National Human Genome Research Institute (NHGRI) of the US National Institutes of Health (NIH); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, T32HL007604, T32HL007208]; NHGRI [5U54HG003067-11]; NIH [P01 HL076491, P01 HL098055]; Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq; Canadian Institutes of Health Research; NIH/NHLBI [K08HL114642]; Foundation for Barnes-Jewish Hospital; [RFPS-2007-3-644382] FX The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the National Human Genome Research Institute (NHGRI) of the US National Institutes of Health (NIH) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for the exome sequencing project (ESP) was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Exome sequencing in the ATVB, PROCARDIS, and Ottawa studies was supported by NHGRI 5U54HG003067-11 to E.S.L. and S.G. Cleveland Clinic GeneBank was supported by NIH grants P01 HL076491 and P01 HL098055. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. N.O.S. is supported, in part, by a career development award from the NIH/NHLBI K08HL114642 and by The Foundation for Barnes-Jewish Hospital. N.O.S. was supported by award number T32HL007604 from the NHLBI. G.M.P was supported by award number T32HL007208 from the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, NHGRI, or NIH. The Italian ATVB Study was supported by a grant from RFPS-2007-3-644382. A full listing of acknowledgements is provided in the Supplementary Information. NR 48 TC 90 Z9 91 U1 6 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 5 PY 2015 VL 518 IS 7537 BP 102 EP + DI 10.1038/nature13917 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7LE UT WOS:000349098000040 PM 25487149 ER PT J AU Marrazzo, JM Ramjee, G Richardson, BA Gomez, K Mgodi, N Nair, G Palanee, T Nakabiito, C van der Straten, A Noguchi, L Hendrix, CW Dai, JY Ganesh, S Mkhize, B Taljaard, M Parikh, UM Piper, J Masse, B Grossman, C Rooney, J Schwartz, JL Watts, H Marzinke, MA Hillier, SL McGowan, IM Chirenje, ZM AF Marrazzo, Jeanne M. Ramjee, Gita Richardson, Barbra A. Gomez, Kailazarid Mgodi, Nyaradzo Nair, Gonasagrie Palanee, Thesla Nakabiito, Clemensia van der Straten, Ariane Noguchi, Lisa Hendrix, Craig W. Dai, James Y. Ganesh, Shayhana Mkhize, Baningi Taljaard, Marthinette Parikh, Urvi M. Piper, Jeanna Masse, Benoit Grossman, Cynthia Rooney, James Schwartz, Jill L. Watts, Heather Marzinke, Mark A. Hillier, Sharon L. McGowan, Ian M. Chirenje, Z. Mike CA VOICE Study Team TI Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIRETROVIRAL PROPHYLAXIS; PREVENTION; TRIALS; TRANSMISSION; MICROBICIDE; ADHERENCE; GEL AB BACKGROUND Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. METHODS We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. RESULTS Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 personyears. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P = 0.004). We observed no significant differences in the frequencies of other adverse events. CONCLUSIONS None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. C1 [Marrazzo, Jeanne M.] Univ Washington, Seattle, WA 98104 USA. [Richardson, Barbra A.; Dai, James Y.; Masse, Benoit] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Ramjee, Gita; Ganesh, Shayhana] MRC, HIV Prevent Res Unit, Durban, South Africa. [Nair, Gonasagrie] Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. [Palanee, Thesla] Witwatersrand Reprod Hlth & HIV Res Inst, Johannesburg, South Africa. [Mkhize, Baningi] Perinatal HIV Res Unit, Johannesburg, South Africa. [Taljaard, Marthinette] AURUM Inst, Klerksdorp, South Africa. [Gomez, Kailazarid] FHI 360, Durham, NC USA. [Mgodi, Nyaradzo; Chirenje, Z. Mike] Univ Zimbabwe Univ Calif San Francisco Res Progra, Harare, Zimbabwe. [Nakabiito, Clemensia] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [van der Straten, Ariane] Res Triangle Inst RTI Int, Womens Global Hlth Imperat, San Francisco, CA USA. [Noguchi, Lisa; Parikh, Urvi M.; Hillier, Sharon L.; McGowan, Ian M.] Univ Pittsburgh, Med Ctr, Magee Womens Res Inst, Pittsburgh, PA USA. [Hendrix, Craig W.; Marzinke, Mark A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Piper, Jeanna] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Grossman, Cynthia] NIMH, NIH, Bethesda, MD 20892 USA. [Watts, Heather] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Rooney, James] Gilead Sci Inc, Foster City, CA 94404 USA. [Schwartz, Jill L.] CONRAD, Arlington, VA USA. [Masse, Benoit] Univ Montreal, Ctr Hosp Univ St Justine, Montreal, PQ, Canada. RP Marrazzo, JM (reprint author), Univ Washington, Harborview Med Ctr, Div Infect Dis, 325 9th Ave,Mailbox 359932, Seattle, WA 98104 USA. EM jmm2@uw.edu OI Masse, Benoit/0000-0002-4944-8098; Cranston, Ross/0000-0002-2687-6217; Marrazzo, Jeanne/0000-0002-9277-7364 FU Gilead Sciences FX Dr. Hendrix reports receiving grant support from Gilead Sciences, and Dr. Rooney, being an employee of and holding stock options in Gilead Sciences. Dr. Rooney also reports pending patents related to the use of tenofovir for prevention of genital herpes simplex virus infection (US 13/700,710 and WO 2011/156416). NR 19 TC 241 Z9 248 U1 4 U2 28 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 FEB 5 PY 2015 VL 372 IS 6 BP 509 EP 518 DI 10.1056/NEJMoa1402269 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CA8CH UT WOS:000349143600005 PM 25651245 ER PT J AU Saver, JL Starkman, S Eckstein, M Stratton, SJ Pratt, FD Hamilton, S Conwit, R Liebeskind, DS Sung, G Kramer, I Moreau, G Goldweber, R Sanossian, N AF Saver, Jeffrey L. Starkman, Sidney Eckstein, Marc Stratton, Samuel J. Pratt, Franklin D. Hamilton, Scott Conwit, Robin Liebeskind, David S. Sung, Gene Kramer, Ian Moreau, Gary Goldweber, Robert Sanossian, Nerses CA FAST-MAG Investigators Coordinator TI Prehospital Use of Magnesium Sulfate as Neuroprotection in Acute Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE ISCHEMIC-STROKE; HEALTH-CARE PROFESSIONALS; TRIAL; THERAPY; FIELD; ASSOCIATION; METHODOLOGY; GUIDELINES; MANAGEMENT AB Background Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents. Methods We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). Results Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (+/- SD) age was 69 +/- 13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7 +/- 1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P = 0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P = 1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P = 0.95) or all serious adverse events. Conclusions Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. C1 [Saver, Jeffrey L.; Starkman, Sidney; Liebeskind, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Comprehens Stroke Ctr, Los Angeles, CA 90095 USA. [Saver, Jeffrey L.; Starkman, Sidney; Liebeskind, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Starkman, Sidney; Pratt, Franklin D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Emergency Med, Los Angeles, CA 90095 USA. [Eckstein, Marc] Univ So Calif, Keck Sch Med, Dept Emergency Med, Los Angeles, CA 90033 USA. [Sung, Gene; Sanossian, Nerses] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Eckstein, Marc] Presbyterian Intercommun Hosp, Los Angeles Fire Dept, Los Angeles, CA USA. [Pratt, Franklin D.] Presbyterian Intercommun Hosp, Los Angeles Cty Fire Dept, Los Angeles, CA USA. [Kramer, Ian] Presbyterian Intercommun Hosp, Dept Emergency Med, Los Angeles, CA USA. [Moreau, Gary] Huntington Mem Hosp, Long Beach Mem Med Ctr, Dept Emergency Med, Los Angeles, CA USA. [Goldweber, Robert] Huntington Mem Hosp, Dept Emergency Med, Dept Emergency Med, Los Angeles, CA USA. [Stratton, Samuel J.] Los Angeles Cty Emergency Med Serv EMS Agcy, Torrance, CA USA. [Stratton, Samuel J.] Harbor UCLA Med Ctr, Dept Emergency Med, Torrance, CA 90509 USA. [Hamilton, Scott] Stanford Univ, Palo Alto, CA 94304 USA. [Conwit, Robin] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Saver, JL (reprint author), Univ Calif Los Angeles, Comprehens Stroke Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM jsaver@mednet.ucla.edu OI Saver, Jeffrey/0000-0001-9141-2251 FU National Institute of Neurological Disorders and Stroke FX Supported by the National Institute of Neurological Disorders and Stroke. NR 24 TC 65 Z9 67 U1 0 U2 14 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 FEB 5 PY 2015 VL 372 IS 6 BP 528 EP 536 DI 10.1056/NEJMoa1408827 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CA8CH UT WOS:000349143600007 PM 25651247 ER PT J AU Sandino, CM Kellman, P Arai, AE Hansen, MS Xue, H AF Sandino, Christopher M. Kellman, Peter Arai, Andrew E. Hansen, Michael S. Xue, Hui TI Myocardial T2*mapping: influence of noise on accuracy and precision SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T2*mapping; Iron overload; Mapping; Hemochromatosis; Thalassemia ID T2-ASTERISK-CARDIOVASCULAR MAGNETIC-RESONANCE; SICKLE-CELL-DISEASE; IRON OVERLOAD; WATER/FAT SEPARATION; IMAGE-RECONSTRUCTION; THALASSEMIA; HEART; DIAGNOSIS AB Background: Pixel-wise, parametric T2* mapping is emerging as a means of automatic measurement of iron content in tissues. It enables quick, intuitive interpretation and provides the potential benefit of spatial context between tissues. However, pixel-wise mapping uses much lower SNR data to estimate T2* when compared to region-based mapping thereby decreasing both its accuracy and precision. In this study, the effects that noise has on the precision and accuracy of pixel-wise T2* mapping were investigated and techniques to mitigate those effects are proposed. Methods: To study precision across T2* mapping techniques, a pipeline to estimate the pixel-wise standard deviation (SD) of the T2* based on the fit residuals is proposed. For validation, a Monte-Carlo analysis was performed in which T2* phantoms were scanned N = 64 times, the true SD was measured and compared to the estimated SD. To improve accuracy and precision, the automatic truncation method for mitigating noise bias was extended to pixel-wise fitting by using an SNR scaled image reconstruction and truncating low SNR measurements. Finally, the precision and accuracy of non-linear regression with and without automatic truncation, were investigated using Monte-Carlo simulations. Results: Measured and estimated SD's were >99.9% correlated for non-linear regression with and without truncation. Non-linear regression with automatic truncation was shown to be the best mapping technique for improving accuracy and precision in low T2* and low SNR measurements. Conclusions: A method for applying an automatic truncation method to pixel-wise T2* mapping that reduces T2* overestimation due to noise bias was proposed. A formulation for estimating pixel-wise standard deviation (SD) maps for T2* that can serve as a quality map for interpreting images and for comparison of imaging protocols was also proposed and validated. C1 [Sandino, Christopher M.; Kellman, Peter; Arai, Andrew E.; Hansen, Michael S.; Xue, Hui] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Sandino, Christopher M.] Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. RP Xue, H (reprint author), NHLBI, NIH, DHHS, 10 Ctr Dr MSC 1061, Bethesda, MD 20892 USA. EM hui.xue@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB] FX Supported by the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB). NR 25 TC 4 Z9 4 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 FEB 4 PY 2015 VL 17 AR 7 DI 10.1186/s12968-015-0115-3 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CB9IM UT WOS:000349945200001 PM 25648167 ER PT J AU Kupferschmidt, DA Cody, PA Lovinger, DM Davis, MI AF Kupferschmidt, David A. Cody, Patrick A. Lovinger, David M. Davis, Margaret I. TI Brain BLAQ: Post-hoc thick-section histochemistry for localizing optogenetic constructs in neurons and their distal terminals SO FRONTIERS IN NEUROANATOMY LA English DT Article DE histochemistry; optogenetic neuroimaging; striosome and matrix compartments; tract-tracing; viral expression; Cre transgenic mouse ID SODIUM-BOROHYDRIDE; NUCLEUS-ACCUMBENS; CATECHOL AMINES; MOUSE-BRAIN; FLUORESCENCE; AUTOFLUORESCENCE; RECONSTRUCTION; RESOLUTION; REDUCTION; SYSTEMS AB Optogenetic constructs have revolutionized modern neuroscience, but the ability to accurately and efficiently assess their expression in the brain and associate it with prior functional measures remains a challenge. High-resolution imaging of thick, fixed brain sections would make such post-hoc assessment and association possible; however, thick sections often display autofluorescence that limits their compatibility with fluorescence microscopy. We describe and evaluate a method we call "Brain BLAQ" (Block Lipids and Aldehyde Quench) to rapidly reduce autofluorescence in thick brain sections, enabling efficient axon-level imaging of neurons and their processes in conventional tissue preparations using standard epifluorescence microscopy. Following viral-mediated transduction of optogenetic constructs and fluorescent proteins in mouse cortical pyramidal and dopaminergic neurons, we used BLAQ to assess innervation patterns in the striatum, a region in which autofluorescence often obscures the imaging of fine neural processes. After BLAQ treatment of 250350 mu m-thick brain sections, axons and puncta of labeled afferents were visible throughout the striatum using a standard epifluorescence stereomicroscope. BLAQ histochemistry confirmed that motor cortex (M1) projections preferentially innervated the matrix component of lateral striatum, whereas medial prefrontal cortex projections terminated largely in dorsal striosomes and distinct nucleus accumbens subregions. Ventral tegmental area dopaminergic projections terminated in a similarly heterogeneous pattern within nucleus accumbens and ventral striatum. Using a minimal number of easily manipulated and visualized sections, and microscopes available in most neuroscience laboratories, BLAQ enables simple, high-resolution assessment of virally transduced optogenetic construct expression, and post-hoc association of this expression with molecular markers, physiology and behavior. C1 [Kupferschmidt, David A.; Cody, Patrick A.; Lovinger, David M.; Davis, Margaret I.] NIAAA, Sect Synapt Pharmacol & In Vivo Neural Funct, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Davis, MI (reprint author), NIAAA, Sect Synapt Pharmacol & In Vivo Neural Funct, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,TS 20,MSC9411, Bethesda, MD 20892 USA. EM midavis@mail.nih.gov OI Davis, Margaret/0000-0002-0489-8351 FU National Institute of Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research FX The authors thank Dr. William Shain for excellent training, years of useful discussions on thick-section imaging techniques, and comments during the preparation of this manuscript. We also thank Dr. Shain and Kristen Trett for testing the utility of BLAQ for high-resolution automated confocal imaging, and Amber Luo for assistance with mice genotyping. The Iba antibody was generously provided by Dr. Giorgi Kharebava, Laboratory of Molecular Signaling, NIAAA. This work was supported by the National Institute of Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and is subject to the NIH Public Access Policy. The authors declare no competing financial interests. NR 33 TC 1 Z9 1 U1 0 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD FEB 4 PY 2015 VL 9 AR 6 DI 10.3389/fnana.2015.00006 PG 9 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CB6QL UT WOS:000349751500001 PM 25698938 ER PT J AU Huang, Y Karuna, ST Janes, H Frahm, N Nason, M Edlefsen, PT Kublin, JG Corey, L McElrath, MJ Gilbert, PB AF Huang, Yunda Karuna, Shelly T. Janes, Holly Frahm, Nicole Nason, Martha Edlefsen, Paul T. Kublin, James G. Corey, Lawrence McElrath, M. Juliana Gilbert, Peter B. TI Use of placebos in Phase 1 preventive HIV vaccine clinical trials SO VACCINE LA English DT Article DE Randomization; Blinding; Sample sizes; Clinical trial; Vaccine safety; Vaccine tolerability; Vaccine immunogenicity ID SAFETY; PRIME AB Phase 1 preventive HIV vaccine trials are often designed as randomized, double-blind studies with the inclusion of placebo recipients. Careful consideration is needed to determine when the inclusion of placebo recipients is highly advantageous and when it is optional for achieving the study objectives of assessing vaccine safety, tolerability and immunogenicity. The inclusion of placebo recipients is generally important to form a reference group that ensures fair evaluation and interpretation of subjective study endpoints, or endpoints whose levels may change due to exposures besides vaccination. In some settings, however, placebo recipients are less important because other data sources and tools are available to achieve the study objectives. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Huang, Yunda; Karuna, Shelly T.; Janes, Holly; Frahm, Nicole; Edlefsen, Paul T.; Kublin, James G.; Corey, Lawrence; McElrath, M. Juliana; Gilbert, Peter B.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Huang, Yunda; Janes, Holly; Edlefsen, Paul T.; Gilbert, Peter B.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Janes, Holly; Edlefsen, Paul T.; Gilbert, Peter B.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Frahm, Nicole; McElrath, M. Juliana] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Nason, Martha] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Corey, Lawrence; McElrath, M. Juliana] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Corey, Lawrence; McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA USA. RP Huang, Y (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Vaccine & Infect Dis Div, 1100 Fairview Ave North,M2-C202,POB 19024, Seattle, WA 98109 USA. EM yunda@scharp.org FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI068635, 2 UM1 AIO68614, UM1AI068618] FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI068635, 2 UM1 AIO68614 and UM1AI068618]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 13 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 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 4 PY 2015 VL 33 IS 6 BP 749 EP 752 DI 10.1016/j.vaccine.2014.10.017 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CB4CP UT WOS:000349576100001 PM 25454855 ER PT J AU Mejias-Aponte, CA Ye, CQ Bonci, A Kiyatkin, EA Morales, M AF Mejias-Aponte, Carlos A. Ye, Changquan Bonci, Antonello Kiyatkin, Eugene A. Morales, Marisela TI A Subpopulation of Neurochemically-Identified Ventral Tegmental Area Dopamine Neurons Is Excited by Intravenous Cocaine SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cocaine; in-vivo electrophysiology; intravenous; juxtacellular; single unit; ventral tegmental area ID PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; IN-VIVO; GABA NEURONS; RATS; REWARD; BURST; AMPHETAMINE; ACTIVATION; RECEPTORS AB Systemic administration of cocaine is thought to decrease the firing rates of ventral tegmental area (VTA) dopamine (DA) neurons. However, this view is based on categorizations of recorded neurons as DA neurons using preselected electrophysiological characteristics lacking neurochemical confirmation. Without applying cellular preselection, we recorded the impulse activity of VTA neurons in response to cocaine administration in anesthetized adult rats. The phenotype of recorded neurons was determined by their juxtacellular labeling and immunohistochemical detection of tyrosine hydroxylase (TH), a DA marker. We found that intravenous cocaine altered firing rates in the majority of recorded VTA neurons. Within the cocaine-responsive neurons, half of the population was excited and the other half was inhibited. Both populations had similar discharge rates and firing regularities, and most neurons did not exhibit changes in burst firing. Inhibited neurons were more abundant in the posterior VTA, whereas excited neurons were distributed evenly throughout the VTA. Cocaine-excited neurons were more likely to be excited by footshock. Within the subpopulation of TH-positive neurons, 36% were excited by cocaine and 64% were inhibited. Within the subpopulation of TH-negative neurons, 44% were excited and 28% were inhibited. Contrary to the prevailing view that all DA neurons are inhibited by cocaine, we found a subset of confirmed VTA DA neurons that is excited by systemic administration of cocaine. We provide evidence indicating that DA neurons are heterogeneous in their response to cocaine and that VTA non-DA neurons play an active role in processing systemic cocaine. C1 [Mejias-Aponte, Carlos A.; Ye, Changquan; Morales, Marisela] NIDA, Integrat Neurosci Res Branch, Neuronal Networks Sect, Baltimore, MD 21224 USA. [Bonci, Antonello] NIDA, Cellular Neurobiol Res Branch, Synapt Physiol Sect, Baltimore, MD 21224 USA. [Kiyatkin, Eugene A.] NIDA, Behav Neurosci Res Branch, Behav Neurosci Sect, Vivo Electrophysiol Unit,Intramural Res Program, Baltimore, MD 21224 USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. RP Morales, M (reprint author), NIDA, Integrat Neurosci Res Branch, Neuronal Networks Sect, Intramural Res Program,Biomed Res Ctr, Suite 200,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@nih.gov FU National Institute on Drug Abuse Intramural Research Program FX This work was supported by the National Institute on Drug Abuse Intramural Research Program. We thank Robert Ator for his help in surgeries, Jean Pieper for histology processing, and Drs. Lindsay De Biase, Alexxai Kravitz, Jana Mejia-Tobier, Meriem Gaval Cruz, David Barker, and David Root for their helpful comments on this manuscript. NR 49 TC 8 Z9 8 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2015 VL 35 IS 5 BP 1965 EP 1978 DI 10.1523/JNEUROSCI.3422-13.2015 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CB5MI UT WOS:000349671100013 PM 25653355 ER PT J AU Francis, SP Krey, JF Krystofiak, ES Cui, RJ Nanda, S Xu, WH Kachar, B Barr-Gillespie, PG Shin, JB AF Francis, Shimon P. Krey, Jocelyn F. Krystofiak, Evan S. Cui, Runjia Nanda, Sonali Xu, Wenhao Kachar, Bechara Barr-Gillespie, Peter G. Shin, Jung-Bum TI A Short Splice Form of Xin-Actin Binding Repeat Containing 2 (XIRP2) Lacking the Xin Repeats Is Required for Maintenance of Stereocilia Morphology and Hearing Function SO JOURNAL OF NEUROSCIENCE LA English DT Article DE CRISPR; hair bundle; hair cell; hearing; stereocilia; XIRP2 ID HAIR-CELL STEREOCILIA; PROTEIN; MICE; CRISPR/CAS; DEAFNESS; BUNDLES; RADIXIN; ALPHA; IDENTIFICATION; PROKARYOTES AB Approximately one-third of known deafness genes encode proteins located in the hair bundle, the sensory hair cell's mechanoreceptive organelle. In previous studies, we used mass spectrometry to characterize the hair bundle's proteome, resulting in the discovery of novel bundle proteins. One such protein is Xin-actin binding repeat containing 2 (XIRP2), an actin-cross-linking protein previously reported to be specifically expressed in striated muscle. Because mutations in other actin-cross-linkers result in hearing loss, we investigated the role of XIRP2 in hearing function. In the inner ear, XIRP2 is specifically expressed in hair cells, colocalizing with actin-rich structures in bundles, the underlying cuticular plate, and the circumferential actin belt. Analysis using peptide mass spectrometry revealed that the bundle harbors a previously uncharacterized XIRP2 splice variant, suggesting XIRP2's role in the hair cell differs significantly from that reported in myocytes. To determine the role of XIRP2 in hearing, we applied clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated genome-editing technology to induce targeted mutations into the mouse Xirp2 gene, resulting in the elimination of XIRP2 protein expression in the inner ear. Functional analysis of hearing in the resulting Xirp2-null mice revealed high-frequency hearing loss, and ultrastructural scanning electron microscopy analyses of hair cells demonstrated stereocilia degeneration in these mice. We thus conclude that XIRP2 is required for long-term maintenance of hair cell stereocilia, and that its dysfunction causes hearing loss in the mouse. C1 [Francis, Shimon P.; Nanda, Sonali; Shin, Jung-Bum] Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA. [Shin, Jung-Bum] Univ Virginia, Dept Brain, Charlottesville, VA 22908 USA. [Shin, Jung-Bum] Univ Virginia, Dept Immunol, Charlottesville, VA 22908 USA. [Shin, Jung-Bum] Univ Virginia, Glia Ctr, Charlottesville, VA 22908 USA. [Xu, Wenhao] Univ Virginia, Gene Targeting & Transgen Facil, Charlottesville, VA 22908 USA. [Krey, Jocelyn F.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Krey, Jocelyn F.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Krystofiak, Evan S.; Cui, Runjia; Kachar, Bechara] NIDCD, NIH, Bethesda, MD 20892 USA. RP Shin, JB (reprint author), Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA. EM js2ee@virginia.edu FU National Institutes of Health-National Institute for Deafness and Communication Disorders [R01 DC014254, K99/R00 DC009412, R01 DC002368, R01 DC011034, P30 DC005983] FX This study was funded by National Institutes of Health-National Institute for Deafness and Communication Disorders grants R01 DC014254 and K99/R00 DC009412 to J.B.S. and R01 DC002368, R01 DC011034, and P30 DC005983 to P.G.B.-G. We thank James Pagana, Ben Thiede, and Jeff Corwin for helping with the SEM preparations. NR 56 TC 14 Z9 15 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2015 VL 35 IS 5 BP 1999 EP 2014 DI 10.1523/JNEUROSCI.3449-14.2015 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CB5MI UT WOS:000349671100016 PM 25653358 ER PT J AU Abitbol, R Lebreton, M Hollard, G Richmond, BJ Bouret, S Pessiglione, M AF Abitbol, Raphaelle Lebreton, Mael Hollard, Guillaume Richmond, Barry J. Bouret, Sebastien Pessiglione, Mathias TI Neural Mechanisms Underlying Contextual Dependency of Subjective Values: Converging Evidence from Monkeys and Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article DE decision making; electrophysiology; fMRI; neuroeconomics; reward; ventromedial prefrontal cortex ID VENTROMEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; ACTIVITY FLUCTUATIONS; BRAIN ACTIVITY; REWARD VALUE; VALUATION SYSTEM; MACAQUE MONKEY; FREE-ENERGY; VARIABILITY; CHOICE AB A major challenge for decision theory is to account for the instability of expressed preferences across time and context. Such variability could arise from specific properties of the brain system used to assign subjective values. Growing evidence has identified the ventromedial prefrontal cortex (VMPFC) as a key node of the human brain valuation system. Here, we first replicate this observation with an fMRI study in humans showing that subjective values of painting pictures, as expressed in explicit pleasantness ratings, are specifically encoded in the VMPFC. We then establish a bridge with monkey electrophysiology, by comparing single-unit activity evoked by visual cues between theVMPFCand the orbitofrontal cortex. At the neural population level, expected reward magnitude was only encoded in the VMPFC, which also reflected subjective cue values, as expressed in Pavlovian appetitive responses. In addition, we demonstrate in both species that the additive effect of prestimulus activity on evoked activity has a significant impact on subjective values. In monkeys, the factor dominating prestimulus VMPFC activity was trial number, which likely indexed variations in internal dispositions related to fatigue or satiety. In humans, prestimulus VMPF Cactivity was externally manipulated through changes in the musical context, which induced a systematic bias in subjective values. Thus, the apparent stochasticity of preferences might relate to the VMPFC automatically aggregating the values of contextual features, which would bias subsequent valuation because of temporal autocorrelation in neural activity. C1 [Abitbol, Raphaelle; Lebreton, Mael; Bouret, Sebastien; Pessiglione, Mathias] Grp Hosp Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Motivat Brain & Behav Lab, Ctr Neuroimagerie Rech, F-75013 Paris, France. [Abitbol, Raphaelle; Hollard, Guillaume] Univ Paris 01, Ctr Econ Sorbonne, F-75013 Paris, France. [Abitbol, Raphaelle; Lebreton, Mael; Bouret, Sebastien; Pessiglione, Mathias] UPMC P6, UMR S 1127, CNRS UMR 7225, INSERM U975, F-75651 Paris 13, France. [Richmond, Barry J.; Bouret, Sebastien] NIMH, Lab Neuropsychol, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Pessiglione, M (reprint author), Grp Hosp Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Brain Behav Team, F-75013 Paris, France. EM mathias.pessiglione@gmail.com RI Pessiglione, Mathias/E-2141-2017 FU European Research Council; National Institutes of Health Intra-Mural Research Program; French Direction Generale de l'Armement and Investissement d'avenir [ANR-10-IAIHU-06] FX This work was supported by European Research Council Starting Grant ERC-BioMotiv and National Institutes of Health Intra-Mural Research Program. It has also benefited from the Federation pour la Recherche Medicale. R.A. was supported by the French Direction Generale de l'Armement and Investissement d'avenir ANR-10-IAIHU-06. NR 44 TC 6 Z9 6 U1 0 U2 22 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2015 VL 35 IS 5 BP 2308 EP 2320 DI 10.1523/JNEUROSCI.1878-4.2015 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CB5MI UT WOS:000349671100042 PM 25653384 ER PT J AU Lee, JH Li, F Grishaev, A Bax, A AF Lee, Jung Ho Li, Fang Grishaev, Alexander Bax, Ad TI Quantitative Residue-Specific Protein Backbone Torsion Angle Dynamics from Concerted Measurement of (3)J Couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; DIPOLAR COUPLINGS; NMR-SPECTROSCOPY; UBIQUITIN; MOTION; RELAXATION; CONSTANTS AB Three-bond (3)J(C'C') and (3)J(HNH alpha) couplings in peptides and proteins are functions of the intervening backbone torsion angle phi. In well-ordered regions, (3)J(HNH alpha) is tightly correlated with (3)J(C'C'), but the presence of large phi angle fluctuations differentially affects the two types of couplings. Assuming the phi angles follow a Gaussian distribution, the width of this distribution can be extracted from (3)J(C'C') and (3)J(HNH alpha), as demonstrated for the folded proteins ubiquitin and GB3. In intrinsically disordered proteins, slow transverse relaxation permits measurement of (3)J(C'C')' and (3)J(HNH) couplings at very high precision, and impact of factors other than the intervening torsion angle on (3)J will be minimal, making these couplings exceptionally valuable structural reporters. Analysis of alpha-synuclein yields rather homogeneous widths of 69 +/- 6 degrees for the phi angle distributions and (3)J(C'C') values that agree well with those of a recent maximum entropy analysis of chemical shifts, J couplings, and H-1-H-1 NOEs. Data are consistent with a modest (<= 30%) population of the polyproline II region. C1 [Lee, Jung Ho; Li, Fang; Grishaev, Alexander; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Antiviral Target Program of the Office of the Director, NIH; KVSTA Fellowship; China Scholarship Council FX We thank J. Ying, J. L. Baber, and A. Mantsyzov for technical support. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and by the Intramural Antiviral Target Program of the Office of the Director, NIH. J.H.L. is the recipient of the KVSTA Fellowship, and F.L. acknowledges financial support from the China Scholarship Council. NR 31 TC 9 Z9 9 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 4 PY 2015 VL 137 IS 4 BP 1432 EP 1435 DI 10.1021/ja512593s PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CA8AJ UT WOS:000349138600013 PM 25590347 ER PT J AU Xu, BJM Levy, S Butman, J Pham, D Cohen, LG Sandrini, M AF Xu, Benjamin Levy, Sarah Butman, John Pham, Dzung Cohen, Leonardo G. Sandrini, Marco TI Effect of foreknowledge on neural activity of primary "go" responses relates to response stopping and switching SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE response inhibition; foreknowledge; fMRI stop-signal; impulse ID INHIBITORY MOTOR CONTROL; PREFRONTAL CORTEX; NEURONAL-ACTIVITY; VISUAL-ATTENTION; SIGNAL PARADIGM; MECHANISMS; BRAIN; TASK; ACTIVATIONS; STIMULATION AB Being able to stop (or inhibit) an action rapidly as in a stop-signal task (SST) is an essential human ability. Previous studies showed that when a pie stimulus cue warned of the possible need to stop a response in an upcoming trial, participants' response time (RI) increased if the subsequent trial required a "go" response (i.e., "go" RI cost) relative to a trial where this uncertainty was not present. This increase of the "go" RI correlated with more efficient response stopping. However, it remains a question whether foreknowledge of upcoming inhibition trials given prior to the task is sufficient to modulate neural activity associated with the primary "go" responses irrespective of whether stopping an overt response is required. We presented three task conditions with identical primary (i.e., "go") response trials but without pre-stimulus cues. Participants were informed that Condition 1 had only "go" trials (All go condition), Condition 2 required a "stop" response for some trials (Stop condition), and Condition 3 required a response incongruent with the primary response (i.e., Switch response) for some trials (Switch condition). Participants performed the tasks during functional magnetic resonance imaging (fMRI) scans. Results showed a significant increase in the "go" RI (cost) in the Stop and Switch conditions relative to the All-go condition. The "go" RT cost was correlated with decreased inhibition time. fMRI activation in the frontal-basal-ganglia regions during the "go" responses in the Stop and Switch conditions was also correlated with the efficiency of Stop and Switch responses. These results suggest that foreknowledge prior to the task is sufficient to influence neural activity associated with the primary response and modulate inhibition efficiency, irrespective of whether stopping an overt response is required. C1 [Xu, Benjamin; Levy, Sarah; Cohen, Leonardo G.; Sandrini, Marco] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Xu, Benjamin; Levy, Sarah; Pham, Dzung; Sandrini, Marco] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Butman, John] NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. RP Xu, BJM (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, 7D51 Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. EM benxu1@mail.nih.gov RI Butman, John/J-2780-2013; Sandrini, Marco/J-2276-2014 OI Butman, John/0000-0002-1547-9195; Sandrini, Marco/0000-0002-1664-5722 FU Department of Defense through the Center for Neuroscience and Regenerative Medicine (CNRM) [G189AN, G189BK]; Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This research was supported, in part, by the grants (G189AN and G189BK) from the Department of Defense through the Center for Neuroscience and Regenerative Medicine (CNRM) and by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. We thank Leonora Wilkinson for helpful comments. NR 46 TC 3 Z9 3 U1 3 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 4 PY 2015 VL 9 AR 34 DI 10.3389/fnhum.2015.00034 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CA5AB UT WOS:000348918100001 PM 25698959 ER PT J AU Basile, BM AF Basile, Benjamin M. TI Rats remind us what actually counts in episodic memory research SO FRONTIERS IN PSYCHOLOGY LA English DT Editorial Material DE episodic; semantic; source; context; rat ID MONKEYS MACACA-MULATTA; RHESUS-MONKEYS; RECALL; HIPPOCAMPUS; METAMEMORY; ANIMALS; BINDING; PIGEONS; EVENTS C1 NIMH, Sect Neurobiol Learning & Memory, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. RP Basile, BM (reprint author), NIMH, Sect Neurobiol Learning & Memory, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. EM benjamin.basile@nih.gov NR 29 TC 0 Z9 0 U1 2 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD FEB 4 PY 2015 VL 6 AR 75 DI 10.3389/fpsyg.2015.00075 PG 2 WC Psychology, Multidisciplinary SC Psychology GA CA4BL UT WOS:000348849100001 PM 25699000 ER PT J AU Hunsberger, JG Chibane, FL Elkahloun, AG Henderson, R Singh, R Lawson, J Cruceanu, C Nagarajan, V Turecki, G Squassina, A Medeiros, CD Del Zompo, M Rouleau, GA Alda, M Chuang, DM AF Hunsberger, J. G. Chibane, F. L. Elkahloun, A. G. Henderson, R. Singh, R. Lawson, J. Cruceanu, C. Nagarajan, V. Turecki, G. Squassina, A. Medeiros, C. D. Del Zompo, M. Rouleau, G. A. Alda, M. Chuang, D-M TI Novel integrative genomic tool for interrogating lithium response in bipolar disorder SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID MAPPING SUSCEPTIBILITY GENES; SPECTRUM DISORDER; MOOD STABILIZERS; EXPRESSION; IDENTIFICATION; LYMPHOBLASTS; PREVALENCE; BIOMARKERS; CELLS AB We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery. C1 [Hunsberger, J. G.; Chibane, F. L.; Chuang, D-M] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Elkahloun, A. G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Henderson, R.; Nagarajan, V.] NIAID, BCBB, OCICB, NIH, Bethesda, MD 20892 USA. [Singh, R.] Lockheed Martin Corp, IS&GS, Bethesda, MD USA. [Lawson, J.] KG Sci Associates LLC, San Diego, CA USA. [Cruceanu, C.; Turecki, G.; Medeiros, C. D.] McGill Univ, Douglas Mental Hlth Inst, McGill Grp Suicide Studies, Montreal, PQ, Canada. [Cruceanu, C.; Rouleau, G. A.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Squassina, A.; Del Zompo, M.] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy. [Alda, M.] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. RP Hunsberger, JG (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. EM hunsbergerjg@gmail.com; chuang@mail.nih.gov OI Squassina, Alessio/0000-0001-7415-7607 FU NIMH; Office of Cyber Infrastructure and Computational Biology of NIAID, NIH FX We would like to acknowledge the support of the Intramural Research Program of the NIMH, and the Office of Cyber Infrastructure and Computational Biology of NIAID, NIH. We would also like to acknowledge the technical support kindly provided by Weiwei Wu for array processing, and Peter Leeds for editorial suggestions. NR 34 TC 4 Z9 4 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD FEB 3 PY 2015 VL 5 AR e504 DI 10.1038/tp.2014.139 PG 8 WC Psychiatry SC Psychiatry GA DA2UF UT WOS:000367651400004 PM 25646593 ER PT J AU Chen, X Zhu, YQ Li, FH Zheng, ZY Chang, EC Ma, JW Wong, STC AF Chen, Xu Zhu, Yanqiao Li, Fuhai Zheng, Ze-Yi Chang, Eric C. Ma, Jinwen Wong, Stephen T. C. TI Accurate segmentation of touching cells in multi-channel microscopy images with geodesic distance based clustering SO NEUROCOMPUTING LA English DT Article DE Cell segmentation; Color information; Riemannian metric; Clustering analysis; Quantitative evaluation ID AUTOMATED MODEL SELECTION; PHASE IDENTIFICATION; GAUSSIAN MIXTURE; CLASSIFICATION; TRACKING; CYCLE AB Multi-channel microscopy images have been widely used for drug and target discovery in biomedical studies by investigating morphological changes of individual cells. However, it is still challenging to segment densely touching individual cells in such images accurately and automatically. Herein, we propose a geodesic distance based clustering approach to efficiently segmenting densely touching cells in multi-channel microscopy images. Specifically, an adaptive learning scheme is introduced to iteratively adjust the clustering centers which can significantly improve the segmentation accuracy of cell boundaries. Moreover, a novel seed selection procedure based on nuclei segmentation is suggested to determine the true number of cells in an image. To validate this proposed method, we applied it to segment the touching Madin-Darby Canine Kidney (MDCK) epithelial cells in multi-channel images for measuring the distinct N-Ras protein expression patterns inside individual cells. The experimental results demonstrated its advantages on accurately segmenting massive touching cells, as well as the robustness to the low signal-to-noise ratio and varying intensity contrasts in multi-channel microscopy images. Moreover, the quantitative comparison showed its superiority over the typical existing cell segmentation methods. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chen, Xu; Zhu, Yanqiao; Ma, Jinwen] Peking Univ, Dept Informat Sci, Sch Math Sci, Beijing 100871, Peoples R China. [Chen, Xu; Zhu, Yanqiao; Ma, Jinwen] Peking Univ, LMAM, Beijing 100871, Peoples R China. [Chen, Xu] PLA, Unit 91635, Beijing, Peoples R China. [Li, Fuhai; Wong, Stephen T. C.] Cornell Univ, NCI Ctr Modeling Canc Dev, Dept Syst Med & Bioengn, Methodist Hosp Res Inst,Weill Cornell Med Coll, Houston, TX 77030 USA. [Zheng, Ze-Yi; Chang, Eric C.] Baylor Coll Med, Dept Mol & Cellular Biol, Breast Ctr, Houston, TX 77030 USA. RP Ma, JW (reprint author), Peking Univ, Dept Informat Sci, Sch Math Sci, Beijing 100871, Peoples R China. EM jwma@math.pku.edu.cn FU Natural Science Foundation of China [61171138]; NIH [U54 CA149196-01, R01LM009161]; John S Dunn Research Foundation FX This work was supported by the Natural Science Foundation of China for Grants 61171138, NIH U54 CA149196-01, R01LM009161 and John S Dunn Research Foundation. NR 30 TC 2 Z9 2 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 EI 1872-8286 J9 NEUROCOMPUTING JI Neurocomputing PD FEB 3 PY 2015 VL 149 BP 39 EP 47 DI 10.1016/j.neucom.2014.01.061 PN A PG 9 WC Computer Science, Artificial Intelligence SC Computer Science GA CP6WL UT WOS:000360028800006 ER PT J AU Qian, X Brinton, LA Schairer, C Matthews, CE AF Qian, X. Brinton, L. A. Schairer, C. Matthews, C. E. TI Sleep duration and breast cancer risk in the Breast Cancer Detection Demonstration Project follow-up cohort SO BRITISH JOURNAL OF CANCER LA English DT Article DE sleep; breast cancer; hormone receptor-positive breast cancer; hormone receptor-negative breast cancer ID MELATONIN; WOMEN AB Background: Short sleep has been hypothesised to increase the risk of breast cancer. However, little is known about the association between sleep and different subtypes of breast cancer defined by hormone receptor status. Methods: Among 40013 women in the Breast Cancer Detection Demonstration Project, including 1846 incident breast cancer cases, we prospectively examined self-reported weekday and weekend sleep duration in relation to breast cancer risk. We used multivariate Cox proportional hazards regression models to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: We found no association between sleep and overall breast cancer. However, we observed a decreased risk of ER+PR+ breast cancer (RR (<6) (vs) (8-9h) (95% CI): 0.54 (0.31, 0.93), P for trend, 0.003) with shorter sleep duration. Conclusions: Our finding does not support an association between sleep duration and overall breast cancer risk. However, the effect of sleep on different subtypes of breast cancer deserves further investigation. C1 [Qian, X.; Matthews, C. E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Brinton, L. A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Schairer, C.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Qian, X (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. EM qian.xiao@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 18 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 3 PY 2015 VL 112 IS 3 BP 567 EP 571 DI 10.1038/bjc.2014.600 PG 5 WC Oncology SC Oncology GA CB1QP UT WOS:000349403200022 PM 25474248 ER PT J AU Cook, MB Freedman, ND Gamborg, M Sorensen, TIA Baker, JL AF Cook, M. B. Freedman, N. D. Gamborg, M. Sorensen, T. I. A. Baker, J. L. TI Childhood body mass index in relation to future risk of oesophageal adenocarcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE (MeSH): body height; body mass index; body weight; cohort studies; oesophageal neoplasms ID GASTROESOPHAGEAL-REFLUX DISEASE; INTERNATIONAL BEACON CONSORTIUM; GASTRIC CARDIA; UNITED-STATES; FOLLOW-UP; BARRETTS-ESOPHAGUS; METABOLIC SYNDROME; POOLED ANALYSIS; BIRTH COHORT; OBESITY AB Background: Middle-aged obese adults are at substantially elevated risk of oesophageal adenocarcinoma. It is unclear whether this risk originates earlier in life. Methods: We assessed associations between childhood body mass index (BMI) and height-measured annually between ages 7 and 13-with adult oesophageal adenocarcinoma in a cohort from the Copenhagen School Health Records Register. Analyses included 255053 children born during 1930-1971. Danish Cancer Registry linkage provided outcomes. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression. Results: During 5.4 million person-years of follow-up, 254 (216 males) incident oesophageal adenocarcinomas occurred. At each examined age, cancer risk increased linearly per unit BMI z-score, although associations were only statistically significant for ages 9-13. The HR for the age of 13 years was 1.31 (95% CI: 1.13, 1.51) per unit BMI z-score. Associations were similar in men and women and across birth cohorts. Childhood height was not related to cancer risk in men but was in women, although these analyses included just 38 female cases. HRs per unit height z-score at the age of 13 years were 1.04 (0.90, 1.19) in males and 1.77 (1.27, 2.47) in females, with similar results observed at the other examined ages. Conclusion: Individuals with higher childhood BMI were at elevated risk of oesophageal adenocarcinoma, even though these cancers occurred many decades later in life. Although the mechanisms require further investigation, our findings provide additional evidence for the long-term health risks of childhood obesity. C1 [Cook, M. B.; Freedman, N. D.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Gamborg, M.; Sorensen, T. I. A.; Baker, J. L.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Copenhagen, Denmark. [Sorensen, T. I. A.; Baker, J. L.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. RP Baker, JL (reprint author), Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Copenhagen, Denmark. EM jennifer.lyn.baker@regionh.dk RI Freedman, Neal/B-9741-2015; Cook, Michael/A-5641-2009; Baker, Jennifer/F-1917-2010 OI Freedman, Neal/0000-0003-0074-1098; Cook, Michael/0000-0002-0533-7302; Baker, Jennifer/0000-0002-9649-6615 FU Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; European Research Council-European Union's Seventh Framework Programme (FP)/ERC [281418] FX This study was funded by the Intramural Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services and by the European Research Council-European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 281418, childgrowth2cancer to JLB. NR 47 TC 8 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 3 PY 2015 VL 112 IS 3 BP 601 EP 607 DI 10.1038/bjc.2014.646 PG 7 WC Oncology SC Oncology GA CB1QP UT WOS:000349403200026 PM 25562436 ER PT J AU Eddy, MT Andreas, L Teijido, O Su, YC Clark, L Noskov, SY Wagner, G Rostovtseva, TK Griffin, RG AF Eddy, Matthew T. Andreas, Loren Teijido, Oscar Su, Yongchao Clark, Lindsay Noskov, Sergei Y. Wagner, Gerhard Rostovtseva, Tatiana K. Griffin, Robert G. TI Magic Angle Spinning Nuclear Magnetic Resonance Characterization of Voltage-Dependent Anion Channel Gating in Two-Dimensional Lipid Crystalline Bilayers SO BIOCHEMISTRY LA English DT Article ID MITOCHONDRIAL OUTER-MEMBRANE; VDAC1 N-TERMINUS; SELECTIVE CHANNEL; CROSS-POLARIZATION; ION SELECTIVITY; ALPHA-HEMOLYSIN; CELL-DEATH; DYNAMICS; PROTEIN; NMR AB The N-terminus of the voltage-dependent anion channel (VDAC) has been proposed to contain the mechanistically important gating helices that modulate channel opening and closing. In this study, we utilize magic angle spinning nuclear magnetic resonance (MAS NMR) to determine the location and structure of the N-terminus for functional channels in lipid bilayers by measuring long-range C-13-C-13 distances between residues in the N-terminus and other domains of VDAC reconstituted into DMPC lipid bilayers. Our structural studies show that the distance between A14 C-beta in the N-terminal helix and S193 C beta is similar to 4-6 angstrom. Furthermore, VDAC phosphorylation by a mitochondrial kinase at residue S193 has been claimed to delay mitochondrial cell death by causing a conformational change that closes the channel, and a VDAC-Ser193Glu mutant has been reported to show properties very similar to those of phosphorylated VDAC in a cellular context. We expressed VDAC-S193E and reconstituted it into DMPC lipid bilayers. Two-dimensional C-13-C-13 correlation experiments showed chemical shift perturbations for residues located in the N-terminus, indicating possible structural perturbations to that region. However, electrophysiological data recorded on VDAC-S193E showed that channel characteristics were identical to those of wild type samples, indicating that phosphorylation of S193 does not directly affect channel gating. The combination of NMR and electrophysiological results allows us to discuss the validity of proposed gating models. C1 [Eddy, Matthew T.; Andreas, Loren; Su, Yongchao; Clark, Lindsay; Griffin, Robert G.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Eddy, Matthew T.; Andreas, Loren; Su, Yongchao; Clark, Lindsay; Griffin, Robert G.] MIT, Francis Bitter Magnet Lab, Cambridge, MA 02139 USA. [Teijido, Oscar; Noskov, Sergei Y.; Rostovtseva, Tatiana K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Noskov, Sergei Y.] Univ Calgary, Dept Biol Sci, Ctr Mol Simulat, Calgary, AB T2N 1N4, Canada. [Wagner, Gerhard] Harvard Univ, Sch Med, Dept Mol Pharmacol & Biochem, Boston, MA 02115 USA. RP Griffin, RG (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA. EM rgg@mit.edu RI Su, Yongchao/B-6749-2009 OI Su, Yongchao/0000-0001-5063-3218 FU National Institutes of Health (NIH) [EB001960, EB002026, GM075879]; National Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-315019]; Alberta Innovates Technology Futures (AITF) Strategic Chair in BioMolecular Simulations (Centre for Molecular Simulation); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH) FX This research was supported by National Institutes of Health (NIH) Grants EB001960, EB002026 (R.G.G.), and GM075879 (G.W.). S.Y.N. was supported by the National Sciences and Engineering Research Council of Canada (NSERC) (Discovery Grant RGPIN-315019) and the Alberta Innovates Technology Futures (AITF) Strategic Chair in BioMolecular Simulations (Centre for Molecular Simulation). The Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH) supported O.T. and T.K.R. NR 56 TC 11 Z9 11 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 3 PY 2015 VL 54 IS 4 BP 994 EP 1005 DI 10.1021/bi501260r PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CA6WZ UT WOS:000349059400005 PM 25545271 ER PT J AU Bergeron, JRC Sgourakis, NG AF Bergeron, Julien R. C. Sgourakis, Nikolaos G. TI Type IV Pilus: One Architectural Problem, Many Structural Solutions SO STRUCTURE LA English DT Editorial Material AB Type IV pili are long appendages found at the surface of many bacteria, composed of an oligomerized pilin protein and involved in processes such as adherence, motility and DNA transfer. In this issue of Structure, Piepenbrink and colleagues report the first structure a major pilin from a Gram-positive bacterium, revealing an unprecedented stabilization mechanism that may have implications for pilus evolution. C1 [Bergeron, Julien R. C.] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada. [Bergeron, Julien R. C.] Univ British Columbia, Ctr Blood Res, Vancouver, BC V6T 1Z3, Canada. [Sgourakis, Nikolaos G.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Sgourakis, NG (reprint author), NIDDK, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nikolaos.sgourakis@nih.gov NR 9 TC 0 Z9 0 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 3 PY 2015 VL 23 IS 2 BP 253 EP 255 DI 10.1016/j.str.2015.01.004 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CB1QJ UT WOS:000349402500003 PM 25651057 ER PT J AU Tong, Q Cui, GF Botuyan, MV Rothbart, SB Hayashi, R Musselman, CA Singh, N Appella, E Strahl, BD Mer, G Kutateladze, TG AF Tong, Qiong Cui, Gaofeng Botuyan, Maria Victoria Rothbart, Scott B. Hayashi, Ryo Musselman, Catherine A. Singh, Namit Appella, Ettore Strahl, Brian D. Mer, Georges Kutateladze, Tatiana G. TI Structural Plasticity of Methyllysine Recognition by the Tandem Tudor Domain of 53BP1 SO STRUCTURE LA English DT Article ID LYSINE METHYLATION; DNA-REPAIR; TUMOR-SUPPRESSOR; CHEMICAL-SHIFT; P53 ACTIVITY; BINDING; PROTEIN; ACTIVATION; REPRESSION; CHROMATIN AB p53 is dynamically regulated through various post-translational modifications (PTMs), which differentially modulate its function and stability. The dimethylated marks p53K370me2 and p53K382me2 are associated with p53 activation or stabilization and both are recognized by the tandem Tudor domain (TTD) of 53BP1, a p53 cofactor. Here we detail the molecular mechanisms for the recognition of p53K370me2 and p53K382me2 by 53BP1. The solution structures of TTD in complex with the p53K370me2 and p53K382me2 peptides show a remarkable plasticity of 53BP1 in accommodating these diverse dimethyllysine-containing sequences. We demonstrate that dimeric TTDs are capable of interacting with the two PTMs on a single p53K370me2K382me2 peptide, greatly strengthening the 53BP1-p53 interaction. Analysis of binding affinities of TTD toward methylated p53 and histones reveals strong preference of 53BP1 for p53K382me2, H4K20me2, and H3K36me2 and suggests a possible role of multivalent contacts of 53BP1 in p53 targeting to and accumulation at the sites of DNA damage. C1 [Tong, Qiong; Musselman, Catherine A.; Kutateladze, Tatiana G.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [Cui, Gaofeng; Botuyan, Maria Victoria; Singh, Namit; Mer, Georges] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Rothbart, Scott B.; Strahl, Brian D.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Rothbart, Scott B.; Strahl, Brian D.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hayashi, Ryo; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mer, G (reprint author), Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. EM mer.georges@mayo.edu; tatiana.kutateladze@ucdenver.edu RI Strahl, Brian/C-7601-2012 OI Strahl, Brian/0000-0002-4947-6259 FU NIH [GM101664, CA132878, GM110058, CA181343]; Mayo Clinic SPORE NCI grants [P50CA116201, P50CA108961]; Center for Cancer Research, National Cancer Institute, NIH FX This research is supported by grants from the NIH, GM101664 (T. G. K.), CA132878 (G. M.), GM110058 (B. D. S.) and CA181343 (S. B. R.). G. M. acknowledges partial support from the Mayo Clinic SPORE NCI grants P50CA116201 and P50CA108961. This research is also supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (EA). NR 50 TC 6 Z9 6 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 3 PY 2015 VL 23 IS 2 BP 312 EP 321 DI 10.1016/j.str.2014.11.013 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CB1QJ UT WOS:000349402500010 PM 25579814 ER PT J AU Tong, Q Mazur, SJ Rincon-Arano, H Rothbart, SB Kuznetsov, DM Cui, GF Liu, WH Gete, Y Klein, BJ Jenkins, L Mer, G Kutateladze, AG Strahl, BD Groudine, M Appella, E Kutateladze, TG AF Tong, Qiong Mazur, Sharlyn J. Rincon-Arano, Hector Rothbart, Scott B. Kuznetsov, Dmitry M. Cui, Gaofeng Liu, Wallace H. Gete, Yantenew Klein, Brianna J. Jenkins, Lisa Mer, Georges Kutateladze, Andrei G. Strahl, Brian D. Groudine, Mark Appella, Ettore Kutateladze, Tatiana G. TI An Acetyl-Methyl Switch Drives a Conformational Change in p53 SO STRUCTURE LA English DT Article ID EMBRYONIC STEM-CELLS; DNA-DAMAGE; LYSINE METHYLATION; STRUCTURAL BASIS; ACTIVATES P53; IN-VIVO; 53BP1; RECOGNITION; NEDDYLATION; MECHANISM AB Individual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses; however, much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 cofactors, including 53BP1 and p300. The 1.8 angstrom resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The alpha-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and nuclear magnetic resonance analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners. C1 [Tong, Qiong; Liu, Wallace H.; Klein, Brianna J.; Kutateladze, Tatiana G.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [Mazur, Sharlyn J.; Gete, Yantenew; Jenkins, Lisa; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Rincon-Arano, Hector; Groudine, Mark] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Rothbart, Scott B.; Strahl, Brian D.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Rothbart, Scott B.; Strahl, Brian D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Kuznetsov, Dmitry M.; Kutateladze, Andrei G.] Univ Denver, Dept Chem & Biochem, Denver, CO 80210 USA. [Cui, Gaofeng; Mer, Georges] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Groudine, Mark] Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98109 USA. RP Kutateladze, TG (reprint author), Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. EM tatiana.kutateladze@ucdenver.edu RI Strahl, Brian/C-7601-2012; Kuznetsov, Dmitry/K-7694-2013 OI Strahl, Brian/0000-0002-4947-6259; Kuznetsov, Dmitry/0000-0002-7956-1833 FU NIH [GM101664, HL65440, T32CA009657, GM110058, CA181343, CA132878, GM093930]; Intramural Research Program of the National Cancer Institute, NIH FX We thank Siddhartha Roy and Catherine Musselman for help with experiments and Jay Nix at beamline 4.2.2 of the ALS in Berkeley for help with X-ray crystallographic data collection. We thank the ENCODE Consortium and the ENCODE production laboratories (Ren Lab-LICR-SCSD) that generated data sets used in this study. This research is supported by grants from the NIH, GM101664 (T.G.K.), HL65440 (M.G.), T32CA009657 (H.R-A), GM110058 (B.D.S.), CA181343 (S.B.R.), CA132878 (G.M.), and GM093930 (A.G.K.), and, in part, by the Intramural Research Program of the National Cancer Institute, NIH (E.A.). NR 36 TC 6 Z9 6 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 3 PY 2015 VL 23 IS 2 BP 322 EP 331 DI 10.1016/j.str.2014.12.010 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CB1QJ UT WOS:000349402500011 PM 25651062 ER PT J AU Lee, CT Bendriem, RM Kindberg, AA Worden, LT Williams, MP Drgon, T Mallon, BS Harvey, BK Richie, CT Hamilton, RS Chen, J Errico, SL Tsai, SYA Uhl, GR Freed, WJ AF Lee, Chun-Ting Bendriem, Raphael M. Kindberg, Abigail A. Worden, Lila T. Williams, Melanie P. Drgon, Tomas Mallon, Barbara S. Harvey, Brandon K. Richie, Christopher T. Hamilton, Rebecca S. Chen, Jia Errico, Stacie L. Tsai, Shang-Yi A. Uhl, George R. Freed, William J. TI Functional Consequences of 17q21.31/WNT3-WNT9B Amplification in hPSCs with Respect to Neural Differentiation SO CELL REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; COPY NUMBER VARIATION; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; IPS CELLS; HUMAN ES; PATHWAY; CULTURE; WNT-5A AB Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter in vitro properties as well as suitability for clinical use. We examined associations between copy-number variations (CNVs) on chromosome 17 and hPSC mesodiencephalic dopaminergic (mDA) differentiation. Among 24 hPSC lines, two karyotypically normal lines, BG03 and CT3, and BG01V2, with trisomy 17, exhibited amplification of the WNT3/WNT9B region and rapid mDA differentiation. In hPSC lines with amplified WNT3/WNT9B, basic fibroblast growth factor (bFGF) signaling through mitogen-activated protein kinase (MAPK)/ERK amplifies canonical WNT signaling by phosphorylating LRP6, resulting in enhanced undifferentiated proliferation. When bFGF is absent, noncanonical WNT signaling becomes dominant due to upregulation of SIAH2, enhancing JNK signaling and promoting loss of pluripotency. When bFGF is present during mDA differentiation, stabilization of canonical WNT signaling causes upregulation of LMX1A and mDA induction. Therefore, CNVs in 17q21.31, a "hot spot" for genetic variation, have multiple and complex effects on hPSC cellular phenotype. C1 [Lee, Chun-Ting; Bendriem, Raphael M.; Kindberg, Abigail A.; Worden, Lila T.; Williams, Melanie P.; Drgon, Tomas; Harvey, Brandon K.; Richie, Christopher T.; Chen, Jia; Errico, Stacie L.; Tsai, Shang-Yi A.; Uhl, George R.; Freed, William J.] NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. [Mallon, Barbara S.; Hamilton, Rebecca S.] NINDS, NIH Stem Cell Unit, Intramural Res Program, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Lee, CT (reprint author), NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. EM clee@mail.nih.gov FU IRP of NIDA, NIH FX This research was supported by the IRP of NIDA, NIH. We thank Teruo Hayashi, Donna Walther, and Aaron Russell for assistance. NR 27 TC 6 Z9 6 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 3 PY 2015 VL 10 IS 4 BP 616 EP 632 DI 10.1016/j.celrep.2014.12.050 PG 17 WC Cell Biology SC Cell Biology GA CB1QX UT WOS:000349404100015 PM 25640183 ER PT J AU Millum, J Sina, B Glass, R AF Millum, Joseph Sina, Barbara Glass, Roger TI International Research Ethics Education SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Millum, Joseph; Sina, Barbara; Glass, Roger] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Millum, Joseph] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Millum, J (reprint author), NIH, Clin Ctr Dept Bioeth, Fogarty Int Ctr, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM millumj@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 7 TC 2 Z9 2 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 3 PY 2015 VL 313 IS 5 BP 461 EP 462 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AV UT WOS:000349070300006 PM 25647198 ER PT J AU Holcomb, JB Tilley, BC Baraniuk, S Fox, EE Wade, CE Podbielski, JM del Junco, DJ Brasel, KJ Bulger, EM Callcut, RA Cohen, MJ Cotton, BA Fabian, TC Inaba, K Kerby, JD Muskat, P O'Keeffe, T Rizoli, S Robinson, BRH Scalea, TM Schreiber, MA Stein, DM Weinberg, JA Callum, JL Hess, JR Matijevic, N Miller, CN Pittet, JF Hoyt, DB Pearson, GD Leroux, B van Belle, G AF Holcomb, John B. Tilley, Barbara C. Baraniuk, Sarah Fox, Erin E. Wade, Charles E. Podbielski, Jeanette M. del Junco, Deborah J. Brasel, Karen J. Bulger, Eileen M. Callcut, Rachael A. Cohen, Mitchell Jay Cotton, Bryan A. Fabian, Timothy C. Inaba, Kenji Kerby, Jeffrey D. Muskat, Peter O'Keeffe, Terence Rizoli, Sandro Robinson, Bryce R. H. Scalea, Thomas M. Schreiber, Martin A. Stein, Deborah M. Weinberg, Jordan A. Callum, Jeannie L. Hess, John R. Matijevic, Nena Miller, Christopher N. Pittet, Jean-Francois Hoyt, David B. Pearson, Gail D. Leroux, Brian van Belle, Gerald CA PROPPR Study Grp TI Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma The PROPPR Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DAMAGE CONTROL RESUSCITATION; MULTIPLE-ORGAN FAILURE; RESPIRATORY-DISTRESS-SYNDROME; FRESH-FROZEN PLASMA; MASSIVE TRANSFUSION; MAJOR TRAUMA; PRODUCTS; MULTICENTER; HEMORRHAGE; SURVIVAL AB IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2%[95% CI, -9.6% to 1.1%]; P=.12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7%[95% CI, -10.2% to 2.7%]; P=.26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4%[95% CI, -10.4% to -0.5%]; P=.03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P=.006). Despite the 1:1:1 group receiving more plasma (median of 7Uvs5U, P<.001) and platelets (12 U vs 6 U, P<.001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differenceswere identified between the 2 groups. C1 [Holcomb, John B.; Fox, Erin E.; Wade, Charles E.; Podbielski, Jeanette M.; del Junco, Deborah J.; Cotton, Bryan A.; Matijevic, Nena] Univ Texas Hlth Sci Ctr Houston, Ctr Translat Injury Res, Div Acute Care Surg, Sch Med,Dept Surg, Houston, TX 77030 USA. [Tilley, Barbara C.; Baraniuk, Sarah] Univ Texas Hlth Sci Ctr Houston, Div Biostat, Sch Publ Hlth, Houston, TX 77030 USA. [Brasel, Karen J.] Med Coll Wisconsin, Div Trauma & Crit Care, Dept Surg, Milwaukee, WI 53226 USA. [Bulger, Eileen M.] Univ Washington, Sch Med, Dept Surg, Div Trauma & Crit Care, Seattle, WA 98195 USA. [Callcut, Rachael A.; Cohen, Mitchell Jay] Univ Calif San Francisco, Sch Med, Dept Surg, Div Gen Surg, San Francisco, CA 94143 USA. [Fabian, Timothy C.; Weinberg, Jordan A.] Univ Tennessee, Ctr Hlth Sci, Coll Med, Div Trauma & Surg Crit Care,Dept Surg, Memphis, TN 38163 USA. [Inaba, Kenji] Univ So Calif, Div Trauma & Crit Care, Los Angeles, CA USA. [Kerby, Jeffrey D.] Univ Alabama Birmingham, Sch Med, Dept Surg, Div Trauma Burns & Surg Crit Care, Birmingham, AL USA. [Muskat, Peter; Robinson, Bryce R. H.] Univ Cincinnati, Coll Med, Dept Surg, Div Trauma Crit Care, Cincinnati, OH USA. [O'Keeffe, Terence] Univ Arizona, Dept Surg, Div Trauma Crit Care & Emergency Surg, Tucson, AZ USA. [Rizoli, Sandro] Univ Toronto, St Michaels Hosp, Toronto, ON, Canada. [Scalea, Thomas M.; Stein, Deborah M.] Univ Maryland, Sch Med, Program Trauma, R Adams Cowley Shock Trauma Ctr, Baltimore, MD 21201 USA. [Schreiber, Martin A.] Oregon Hlth & Sci Univ, Sch Med, Div Trauma Crit Care & Acute Care Surg, Portland, OR 97201 USA. [Callum, Jeannie L.] Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Dept Clin Pathol, Toronto, ON M4N 3M5, Canada. [Hess, John R.] Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. [Miller, Christopher N.] Univ Cincinnati, Coll Med, Dept Emergency Med, Cincinnati, OH USA. [Pittet, Jean-Francois] Univ Alabama Birmingham, Sch Med, Dept Anesthesiol, Div Crit Care & Perioperat Med, Birmingham, AL USA. [Hoyt, David B.] Amer Coll Surg, Chicago, IL USA. [Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Leroux, Brian; van Belle, Gerald] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [van Belle, Gerald] Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. RP Holcomb, JB (reprint author), Univ Texas Hlth Sci Ctr Houston, Ctr Translat Injury Res, 6410 Fannin St, Houston, TX 77030 USA. EM john.holcomb@uth.tmc.edu RI Leroux, Brian/H-2254-2015 FU US National Heart, Lung, and Blood Institute [U01HL077863]; US Department of Defense; Defence Research and Development Canada; Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health [CRR-120612] FX This work was supported with grant U01HL077863 from the US National Heart, Lung, and Blood Institute and funding from the US Department of Defense, the Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR-120612). NR 60 TC 225 Z9 235 U1 3 U2 32 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 3 PY 2015 VL 313 IS 5 BP 471 EP 482 DI 10.1001/jama.2015.12 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CA7AV UT WOS:000349070300011 PM 25647203 ER PT J AU Tarasenko, TN Rosas, OR Singh, LN Kristaponis, K Vernon, H McGuire, PJ AF Tarasenko, Tatyana N. Rosas, Odrick R. Singh, Larry N. Kristaponis, Kara Vernon, Hilary McGuire, Peter J. TI A New Mouse Model of Mild Ornithine Transcarbamylase Deficiency (spf-j) Displays Cerebral Amino Acid Perturbations at Baseline and upon Systemic Immune Activation SO PLOS ONE LA English DT Article ID UREA CYCLE DISORDERS; AMMONIA METABOLISM; HYPERAMMONEMIA; MANAGEMENT; MUTANT; EXPRESSION; ADULT AB Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic: polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans. C1 [Tarasenko, Tatyana N.; Singh, Larry N.; McGuire, Peter J.] NHGRI, NIH, Bethesda, MD 20892 USA. Univ Cent Caribe, Bayamon, PR USA. [Kristaponis, Kara] Johns Hopkins Univ, Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD USA. [Vernon, Hilary] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA. RP McGuire, PJ (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU intramural research program of the National Institutes of Health; Kennedy Kreiger Institute at Johns Hopkins University FX Work performed by T.N.T., L.N.S., O.R.R., and P.J.M. was supported by the intramural research program of the National Institutes of Health. Work performed by H.V. and K.K. was supported by institutional funding from the Kennedy Kreiger Institute at Johns Hopkins University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 0 Z9 0 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 3 PY 2015 VL 10 IS 2 AR e0116594 DI 10.1371/journal.pone.0116594 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA3QZ UT WOS:000348822600029 PM 25647322 ER PT J AU Remaley, AT AF Remaley, Alan T. TI HDL Cholesterol/HDL Particle Ratio A New Measure of HDL Function? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE biomarkers; cardiovascular risk; cholesterol; HDL; NMR ID DENSITY-LIPOPROTEIN CHOLESTEROL; MAGNETIC-RESONANCE-SPECTROSCOPY; ATHEROSCLEROSIS; EVENTS; EFFLUX; TRANSPORT; NUMBER; RISK C1 NIH, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Bldg 10,Room 2C-433,10 Ctr Dr, Bethesda, MD 20892 USA. EM aremaley1@nhlbi.nih.gov NR 19 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 3 PY 2015 VL 65 IS 4 BP 364 EP 366 DI 10.1016/j.jacc.2014.11.018 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CA1IR UT WOS:000348666800008 PM 25634835 ER PT J AU Ramphul, UN Garver, LS Molina-Cruz, A Canepa, GE Barillas-Mury, C AF Ramphul, Urvashi N. Garver, Lindsey S. Molina-Cruz, Alvaro Canepa, Gaspar E. Barillas-Mury, Carolina TI Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE malaria transmission; Plasmodium; JNK apoptosis; mosquito immunity; immune evasion ID NF-KAPPA-B; ANOPHELES-GAMBIAE; SIGNALING PATHWAYS; OOKINETE INVASION; SCAFFOLD PROTEIN; FACTOR RELISH; DROSOPHILA; ACTIVATION; INHIBITOR; NITRATION AB The malaria parasite, Plasmodium, must survive and develop in the mosquito vector to be successfully transmitted to a new host. The Plasmodium falciparum Pfs47 gene is critical for malaria transmission. Parasites that express Pfs47 (NF54 WT) evade mosquito immunity and survive, whereas Pfs47 knockouts (KO) are efficiently eliminated by the complement-like system. Two alternative approaches were used to investigate the mechanism of action of Pfs47 on immune evasion. First, we examined whether Pfs47 affected signal transduction pathways mediating mosquito immune responses, and show that the Jun-N-terminal kinase (JNK) pathway is a key mediator of Anopheles gambiae antiplasmodial responses to P. falciparum infection and that Pfs47 disrupts JNK signaling. Second, we used microarrays to compare the global transcriptional responses of A. gambiae midguts to infection with WT and KO parasites. The presence of Pfs47 results in broad and profound changes in gene expression in response to infection that are already evident 12 h postfeeding, but become most prominent at 26 h postfeeding, the time when ookinetes invade the mosquito midgut. Silencing of 15 differentially expressed candidate genes identified caspase-S2 as a key effector of Plasmodium elimination in parasites lacking Pfs47. We provide experimental evidence that JNK pathway regulates activation of caspases in Plasmodium- invaded midgut cells, and that caspase activation is required to trigger midgut epithelial nitration. Pfs47 alters the cell death pathway of invaded midgut cells by disrupting JNK signaling and prevents the activation of several caspases, resulting in an ineffective nitration response that makes the parasite undetectable by the mosquito complement-like system. C1 [Ramphul, Urvashi N.; Garver, Lindsey S.; Molina-Cruz, Alvaro; Canepa, Gaspar E.; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM cbarillas@niaid.nih.gov OI Garver, Lindsey/0000-0003-2893-0130 FU Intramural Research Program of the Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX We thank Andre Laughinghouse and Kevin Lee for insectary support; Jose Luis Ramirez, Nitin Kamath, Rebecca Greene, Alejandro Padron, Ashley Haile, and Noelle Pavlovic for experimental assistance; and Timothy Myers, Qin Su, and the National Institute of Allergy and Infectious Diseases Genomic Technologies Section for microarray hybridization and scanning. This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 23 Z9 23 U1 1 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2015 VL 112 IS 5 BP 1273 EP 1280 DI 10.1073/pnas.1423586112 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7HF UT WOS:000349087700029 PM 25552553 ER PT J AU Battle, C Ott, CM Burnette, DT Lippincott-Schwartz, J Schmidt, CF AF Battle, Christopher Ott, Carolyn M. Burnette, Dylan T. Lippincott-Schwartz, Jennifer Schmidt, Christoph F. TI Intracellular and extracellular forces drive primary cilia movement SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE primary cilium; mechanosensing; ciliary motility; flexural rigidity; active fluctuations ID POLYCYSTIC KIDNEY-DISEASE; FLEXURAL RIGIDITY; EPITHELIAL-CELLS; BASAL BODIES; GROWING MICROTUBULES; THERMAL FLUCTUATIONS; SENSORY ORGANELLE; SPERM FLAGELLA; MYOSIN-II; CALCIUM AB Primary cilia are ubiquitous, microtubule-based organelles that play diverse roles in sensory transduction in many eukaryotic cells. They interrogate the cellular environment through chemosensing, osmosensing, and mechanosensing using receptors and ion channels in the ciliary membrane. Little is known about the mechanical and structural properties of the cilium and how these properties contribute to ciliary perception. We probed the mechanical responses of primary cilia from kidney epithelial cells [Madin-Darby canine kidney-II (MDCK-II)], which sense fluid flow in renal ducts. We found that, on manipulation with an optical trap, cilia deflect by bending along their length and pivoting around an effective hinge located below the basal body. The calculated bending rigidity indicates weak microtubule doublet coupling. Primary cilia of MDCK cells lack interdoublet dynein motors. Nevertheless, we found that the organelles display active motility. 3D tracking showed correlated fluctuations of the cilium and basal body. These angular movements seemed random but were dependent on ATP and cytoplasmic myosin-II in the cell cortex. We conclude that force generation by the actin cytoskeleton surrounding the basal body results in active ciliary movement. We speculate that actin-driven ciliary movement might tune and calibrate ciliary sensory functions. C1 [Battle, Christopher; Schmidt, Christoph F.] Univ Gottingen, Drittes Phys Inst, D-37077 Gottingen, Germany. [Ott, Carolyn M.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Burnette, Dylan T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hu, NIH, Bethesda, MD 20892 USA. [Burnette, Dylan T.] Vanderbilt Univ Sch Med, Dept Cell & Dev Biol, Nashville, TN 37232 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov; cfs@physik3.gwdg.de RI Schmidt, Christoph/G-3787-2011 OI Schmidt, Christoph/0000-0003-2864-6973 FU Intramural Program of the National Institutes of Health, National Institute of Child Health and Human Development; Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 803, Sonderforschungsbereich 937]; Center for Nanoscale Microscopy and Molecular Physiology of the Brain; European Research Council [PF7 ERC-2013-AdG, 340528]; Gottingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences FX We thank Hiroaki Ishikawa, Claus Heussinger, Giovanni Marelli, and Andrej Vilfan for helpful discussion and Andreas Janshoff for providing us with the Madin-Darby canine kidney-II cell line. We acknowledge discussions at the Woods Hole Marine Biology Laboratory. We also thank Monica Bettencourt-Dias, Tristan Ursell, and Kimberly Yasutis for help with early experiments monitoring cilia movement. Rafael Vilasmil from the National Eye Institute Flow Cytometry Core sorted cells for this study. This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Child Health and Human Development; the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 803 Project A7 and 937 Project A2; the Center for Nanoscale Microscopy and Molecular Physiology of the Brain; and European Research Council Grant PF7 ERC-2013-AdG, Project 340528 (to C.F.S.). Fellowship funding was provided by the Gottingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences. NR 52 TC 3 Z9 3 U1 5 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2015 VL 112 IS 5 BP 1410 EP 1415 DI 10.1073/pnas.1421845112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7HF UT WOS:000349087700052 PM 25605896 ER PT J AU Poruchynsky, MS Komlodi-Pasztor, E Trostel, S Wilkerson, J Regairaz, M Pommier, Y Zhang, X Maity, TK Robey, R Burotto, M Sackett, D Guha, U Fojo, AT AF Poruchynsky, Marianne S. Komlodi-Pasztor, Edina Trostel, Shana Wilkerson, Julia Regairaz, Marie Pommier, Yves Zhang, Xu Maity, Tapan Kumar Robey, Robert Burotto, Mauricio Sackett, Dan Guha, Udayan Fojo, Antonio Tito TI Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microtubule targeting agents; DNA-damaging agents; combination chemotherapy; targeted therapies; DNA repair protein trafficking ID METASTATIC PROSTATE-CANCER; ANDROGEN RECEPTOR; NUCLEAR ACCUMULATION; MITOTIC ARREST; INCREASED SURVIVAL; CELLS; CHEMOTHERAPY; MITOSIS; TUBULIN; INHIBITORS AB The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained gamma-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens. C1 [Poruchynsky, Marianne S.; Komlodi-Pasztor, Edina; Trostel, Shana; Wilkerson, Julia; Zhang, Xu; Maity, Tapan Kumar; Burotto, Mauricio; Guha, Udayan; Fojo, Antonio Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Regairaz, Marie; Pommier, Yves; Robey, Robert] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Sackett, Dan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Fojo, AT (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Yvona Ward, PhD, Head, Microscopy Core Facility, Center for Cancer Research, National Cancer Institute, Cancer Cell Biology Program, Bethesda, MD, for expert technical advice and assistance for the immunofluorescence and confocal microscopy imaging experiments. This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 39 TC 27 Z9 27 U1 4 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2015 VL 112 IS 5 BP 1571 EP 1576 DI 10.1073/pnas.1416418112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7HF UT WOS:000349087700079 PM 25605897 ER PT J AU Riolo, MA Rohani, P AF Riolo, Maria A. Rohani, Pejman TI Combating pertussis resurgence: One booster vaccination schedule does not fit all SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pertussis; booster schedule; immunization; genetic algorithm ID BORDETELLA-PERTUSSIS; DISEASE BURDEN; HERD-IMMUNITY; VACCINES; EPIDEMIOLOGY; IMMUNIZATION; IMPACT; TRANSMISSION; EVOLUTION; EXEMPTIONS AB Pertussis has reemerged as a major public health concern in many countries where it was once considered well controlled. Although the mechanisms responsible for continued pertussis circulation and resurgence remain elusive and contentious, many countries have nevertheless recommended booster vaccinations, the timing and number of which vary widely. Here, using a stochastic, age-stratified transmission model, we searched for cost-effective booster vaccination strategies using a genetic algorithm. We did so assuming four hypothesized mechanisms underpinning contemporary pertussis epidemiology: (I) insufficient coverage, (II) frequent primary vaccine failure, (III) waning of vaccine-derived protection, and (IV) vaccine "leakiness." For scenarios I-IV, successful booster strategies were identified and varied considerably by mechanism. Especially notable is the inability of booster schedules to alleviate resurgence when vaccines are leaky. Critically, our findings argue that the ultimate effectiveness of vaccine booster schedules will likely depend on correctly pinpointing the causes of resurgence, with misdiagnosis of the problem epidemiologically ineffective and economically costly. C1 [Riolo, Maria A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Riolo, Maria A.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Riolo, MA (reprint author), Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. EM mariolo@umich.edu FU Research and Policy in Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH; NIH [R01AI101155]; Models of Infectious Disease Agent Study, National Institute of General Medical Sciences [U54-GM111274] FX We thank Aaron King, Micaela Martinez-Bakker, Matthieu Domenech de Celles, and Felicia Magpantay for stimulating discussion. We also thank Alison Galvani, Meagan Fitzpatrick, and an anonymous reviewer for their insightful comments on this manuscript. This work was supported by the Research and Policy in Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, NIH; by a research grant from the NIH (Grant R01AI101155); and by the Models of Infectious Disease Agent Study, National Institute of General Medical Sciences (Grant U54-GM111274). NR 60 TC 9 Z9 9 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2015 VL 112 IS 5 BP E472 EP E477 DI 10.1073/pnas.1415573112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7HF UT WOS:000349087700014 PM 25605878 ER PT J AU Walmacq, C Wang, LF Chong, J Scibelli, K Lubkowska, L Gnatt, A Brooks, PJ Wang, D Kashlev, M AF Walmacq, Celine Wang, Lanfeng Chong, Jenny Scibelli, Kathleen Lubkowska, Lucyna Gnatt, Averell Brooks, Philip J. Wang, Dong Kashlev, Mikhail TI Mechanism of RNA polymerase II bypass of oxidative cyclopurine DNA lesions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNA polymerase II; translesion transcription; oxidative DNA damage; transcriptional mutagenesis; transcription factor TFIIF ID NUCLEOTIDE EXCISION-REPAIR; TRANSCRIPTIONAL MUTAGENESIS; TRANSLESION SYNTHESIS; STRUCTURAL BASIS; HUMAN-CELLS; ELONGATION COMPLEX; ATOMIC-RESOLUTION; DAMAGED DNA; A-RULE; FIDELITY AB In human cells, the oxidative DNA lesion 8,5 '-cyclo-2 '-deoxyadenosine (CydA) induces prolonged stalling of RNA polymerase II (Pol II) followed by transcriptional bypass, generating both error-free and mutant transcripts with AMP misincorporated immediately downstream from the lesion. Here, we present biochemical and crystallographic evidence for the mechanism of CydA recognition. Pol II stalling results from impaired loading of the template base (5 ') next to CydA into the active site, leading to preferential AMP misincorporation. Such predominant AMP insertion, which also occurs at an abasic site, is unaffected by the identity of the 5 '-templating base, indicating that it derives from nontemplated synthesis according to an A rule known for DNA polymerases and recently identified for Pol II bypass of pyrimidine dimers. Subsequent to AMP misincorporation, Pol II encounters a major translocation block that is slowly overcome. Thus, the translocation block combined with the poor extension of the dA.rA mispair reduce transcriptional mutagenesis. Moreover, increasing the active-site flexibility by mutation in the trigger loop, which increases the ability of Pol II to accommodate the bulky lesion, and addition of transacting factor TFIIF facilitate CydA bypass. Thus, blocking lesion entry to the active site, translesion A rule synthesis, and translocation block are common features of transcription across different bulky DNA lesions. C1 [Walmacq, Celine; Scibelli, Kathleen; Lubkowska, Lucyna; Kashlev, Mikhail] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Wang, Lanfeng; Chong, Jenny; Wang, Dong] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Gnatt, Averell] Biopolcore Inc, Baltimore, MD 21208 USA. [Brooks, Philip J.] NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIAAA, Div Metab & Hlth Effects, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Wang, D (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. EM dongwang@ucsd.edu; kashlevm@mail.nih.gov FU National Institutes of Health (NIH) Research Grant [GM102362]; Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego; Intramural Research Program of the NIH, NCI FX We thank Z. Burton and Y. Nedialkov for providing the recombinant human TFIIF. P.J.B. thanks Tsu-Fan Cheng and Jinping Jia for generating preliminary data. K.S. was a participant in the National Cancer Institute (NCI) Summer Internship Program. D.W. acknowledges National Institutes of Health (NIH) Research Grant GM102362, the Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research, and start-up funds from the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, for support of this work. M.K. acknowledges the Intramural Research Program of the NIH, NCI, for support of this work. NR 45 TC 8 Z9 8 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2015 VL 112 IS 5 BP E410 EP E419 DI 10.1073/pnas.1415186112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA7HF UT WOS:000349087700007 PM 25605892 ER PT J AU Hladik, F Burgener, A Ballweber, L Gottardo, R Vojtech, L Fourati, S Dai, JY Cameron, MJ Strobl, J Hughes, SM Hoesley, C Andrew, P Johnson, S Piper, J Friend, DR Ball, TB Cranston, RD Mayer, KH McElrath, MJ McGowan, I AF Hladik, Florian Burgener, Adam Ballweber, Lamar Gottardo, Raphael Vojtech, Lucia Fourati, Slim Dai, James Y. Cameron, Mark J. Strobl, Johanna Hughes, Sean M. Hoesley, Craig Andrew, Philip Johnson, Sherri Piper, Jeanna Friend, David R. Ball, T. Blake Cranston, Ross D. Mayer, Kenneth H. McElrath, M. Juliana McGowan, Ian TI Mucosal effects of tenofovir 1% gel SO ELIFE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; FEMALE GENITAL-TRACT; DNA COPY NUMBER; MICROARRAY DATA; ILLUMINA MICROARRAY; TGF-BETA; EXPRESSION; CELLS; GENE; BIOINFORMATICS AB Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored. C1 [Hladik, Florian; Vojtech, Lucia; Hughes, Sean M.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Hladik, Florian; McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Gottardo, Raphael; Dai, James Y.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hladik, Florian; Burgener, Adam; Ballweber, Lamar; Gottardo, Raphael; Dai, James Y.; Strobl, Johanna; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Gottardo, Raphael] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Fourati, Slim; Cameron, Mark J.] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. [Ball, T. Blake] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Burgener, Adam; Ball, T. Blake] Publ Hlth Agcy Canada, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada. [Hoesley, Craig] Univ Alabama Birmingham, Birmingham, AL USA. [Cranston, Ross D.; McGowan, Ian] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Andrew, Philip; Johnson, Sherri] FHI 360, Durham, NC USA. [Piper, Jeanna] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Friend, David R.] Eastern Virginia Med Sch, CONRAD, Arlington, VA 22209 USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Fenway Hlth, Boston, MA USA. [Mayer, Kenneth H.] Harvard Univ, Sch Med, Boston, MA USA. [Cranston, Ross D.; McGowan, Ian] Magee Womens Res Inst, Microbicide Trials Network, Pittsburgh, PA USA. RP Hladik, F (reprint author), Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. EM fhladik@fhcrc.org; imcgowan@pitt.edu OI Fourati, Slim/0000-0001-6609-7587; Hughes, Sean/0000-0002-9409-9405; Hladik, Florian/0000-0002-0375-2764; Vojtech, Lucia/0000-0003-2343-0719; Cranston, Ross/0000-0002-2687-6217 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [U01AI068633, U19AI082637, R01HD51455] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers U01AI068633 ( to Sharon Hillier), U19AI082637 (to I. M.) and R01HD51455 (to F.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CONRAD. The funders had no role in data collection and analysis, and decision to publish. Jeanna Piper, employee of the National Institute of Allergy and Infectious Diseases, participated in design of the clinical study and preparation of the manuscript. NR 54 TC 7 Z9 7 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 3 PY 2015 VL 4 AR e04525 DI 10.7554/eLife.04525 PG 48 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CA3CN UT WOS:000348783800001 ER PT J AU VieBrock, L Evans, SM Beyer, AR Larson, CL Beare, PA Ge, H Singh, S Rodino, KG Heinzen, RA Richards, AL Carlyon, JA AF VieBrock, Lauren Evans, Sean M. Beyer, Andrea R. Larson, Charles L. Beare, Paul A. Ge, Hong Singh, Smita Rodino, Kyle G. Heinzen, Robert A. Richards, Allen L. Carlyon, Jason A. TI Orientia tsutsugamushi ankyrin repeat-containing protein family members are Type 1 secretion system substrates that traffic to the host cell endoplasrnic reticulum SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE Rickettsia; intracellular bacteria; bacterial effector; scrub typhus; ankyrin repeat; bacterial secretion; ER-tropic effector; secretory pathway ID ANAPLASMA-PHAGOCYTOPHILUM ANKA; ESCHERICHIA-COLI HEMOLYSIN; LEGIONELLA-PNEUMOPHILA; COXIELLA-BURNETII; TRANSPORT SIGNAL; EFFECTOR PROTEIN; SCRUB TYPHUS; DOMAINS; IDENTIFICATION; PROLIFERATION AB Scrub typhus is an understudied, potentially fatal infection that threatens one billion persons in the Asia-Pacific region. How the causative obligate intracellular bacterium, Orientia tsutsugamushi, facilitates its intracellular survival and pathogenesis is poorly understood. Many intracellular bacterial pathogens utilize the Type 1 (T1SS) or Type 4 secretion system (T4SS) to translocate ankyrin repeat-containing proteins (Anks) that traffic to distinct subcellular locations and modulate host cell processes. The O. tsutsugamushi genome encodes one of the largest known bacterial Ank repertoires plus T1SS and T4SS components. Whether these potential virulence factors are expressed during infection, how the Anks are potentially secreted, and to where they localize in the host cell are not known. We determined that O. tsutsugamushi transcriptionally expresses 20 unique ank genes as well as genes for both T1SS and T4SS during infection of mammalian host cells. Examination of the Anks' C-termini revealed that the majority of them resemble T1SS substrates. Escherichia colt expressing a functional T1SS was able to secrete chimeric hemolysin proteins bearing the C-termini of 19 of 20 O. tsutsugamushi Anks in an HlyBD-dependent manner. Thus, O. tsutsugamushi Anks C-termini are T1SS-compatible. Conversely, Coxiella burnetii could not secrete heterologously expressed Anks in a T4SS-dependent manner. Analysis of the subcellular distribution patterns of 20 ectopically expressed Anks revealed that, while 6 remained cytosolic or trafficked to the nucleus, 14 localized to, and in some cases, altered the morphology of the endoplasmic reticulum. This study identifies O. tsutsugamushi Anks as T1SS substrates and indicates that many display a tropism for the host cell secretory pathway. C1 [VieBrock, Lauren; Evans, Sean M.; Beyer, Andrea R.; Singh, Smita; Rodino, Kyle G.; Carlyon, Jason A.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Sch Med, Richmond, VA 23298 USA. [Larson, Charles L.; Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Rocky Mt Labs, NIH, Hamilton, MT USA. [Ge, Hong; Richards, Allen L.] Naval Med Res Ctr, Viral & Rickettsial Dis Dept, Silver Spring, MD USA. RP Carlyon, JA (reprint author), Virginia Commonwealth Univ, Dept Microbiol & Immunol, Sch Med, POB 980678, Richmond, VA 23298 USA. EM jacarlyon@vcu.edu FU National Institutes of Health [R03 AI101666, R21 AI103606]; American Heart Association (AHA) [13GRNT16810009]; AHA Predoctoral Fellowship [13PRE16840032]; Military Infectious Diseases Research Program [6000.RAD1.J.A0310]; Virginia Commonwealth University (VCU) Presidential Research Quest Fund; VCU Institutional Research and Academic Career Development Award [K12 GM093857]; NIH-NINDS Center core grant [5P30NS047463] FX We gratefully acknowledge Peter Sebo (Institute of Microbiology, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic) for providing plasmid pLG575, E. coli strain A0 34/86, and many helpful discussions. We thank Rodney Welch (University of Wisconsin, Madison, WI) for providing the HlyA antibody G3, and Marci Scidmore of Cornell University (Ithaca, NY) for providing the pEGFP-C1 vector. This work was supported by National Institutes of Health grants R03 AI101666 and R21 AI103606 (to Jason A. Carlyon), American Heart Association (AHA) Grant-in-Aid 13GRNT16810009 (to Jason A. Carlyon), AHA Predoctoral Fellowship 13PRE16840032 (to Lauren VieBrock), Military Infectious Diseases Research Program 6000.RAD1.J.A0310 (to Hong Ge and Allen L. Richards), and the Virginia Commonwealth University (VCU) Presidential Research Quest Fund (to Jason A. Carlyon). Andrea R. Beyer is a fellowship recipient supported by VCU Institutional Research and Academic Career Development Award grant K12 GM093857. LSCM was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, which is supported in part by funding from NIH-NINDS Center core grant 5P30NS047463. NR 70 TC 4 Z9 4 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD FEB 3 PY 2015 VL 4 AR 186 DI 10.3389/fcimb.2014.00186 PG 20 WC Immunology; Microbiology SC Immunology; Microbiology GA CA8HQ UT WOS:000349159300001 PM 25692099 ER PT J AU Papaneri, AB Bernbaum, JG Blaney, JE Jahrling, PB Schnell, MJ Johnson, RF AF Papaneri, Amy B. Bernbaum, John G. Blaney, Joseph E. Jahrling, Peter B. Schnell, Matthias J. Johnson, Reed F. TI Controlled viral glycoprotein expression as a safety feature in a bivalent rabies-ebola vaccine SO VIRUS RESEARCH LA English DT Article DE Filovirus; Vaccine; Rabies virus; Ebola; RNA viruses; Biodefense ID VIRUS GLYCOPROTEIN; ENTRY; PATHOGENICITY; IMMUNIZATION; REPLICATION; PROTECTION; ANTIBODIES; SEQUENCE; VECTORS; PROTEIN AB Using a recombinant rabies (RABV) vaccine platform, we have developed several safe and effective vaccines. Most recently, we have developed a RABV-based ebolavirus (EBOV) vaccine that is efficacious in nonhuman primates. One safety feature of this vaccine is the utilization of a live but replication-deficient RABV construct. In this construct, the RABV glycoprotein (G) has been deleted from the genome, requiring G trans complementation in order for new infectious viruses to be released from the initial infected cell. Here we analyze this safety feature of the bivalent RABV-based EBOV vaccine comprised of the G-deleted RABV backbone expressing EBOV glycoprotein (GP). We found that, while the level of RABV genome in infected cells is equivalent regardless of G supplementation, the production of infectious virus is indeed restricted by the lack of G, and most importantly, that the presence of EBOV GP does not substitute for G. These findings further support the safety profile of this replication-deficient RABV-EBOV bivalent vaccine. Published by Elsevier B.V. C1 [Papaneri, Amy B.; Bernbaum, John G.; Blaney, Joseph E.; Jahrling, Peter B.; Schnell, Matthias J.; Johnson, Reed F.] NIAID, NIH, Ft Detrick, MD USA. RP Johnson, RF (reprint author), NIAID, NIH, Ft Detrick, MD USA. EM johnsonreed@mail.nih.gov OI Papaneri, Amy/0000-0003-2144-2441 FU NIAID Division of Intramural Research; NIAID Division of Clinical Research; Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) Division of Clinical Research [HHSN272200700016I] FX This work was supported by the NIAID Division of Intramural Research and in part by the NIAID Division of Clinical Research. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) Division of Clinical Research under Contract No. HHSN272200700016I. The subcontractor to Battelle Memorial Institute who performed this work was: J.G.B. an employee of Tunnell Government Services, Inc. We would like to thank Dr. Owen Schwartz, NIAID/DIR/RTB/BIS, for technical assistance with the Leica TCS SP5 Confocal microscope. We also thank Jiro Wada, NIAID/DCR/OCSIRFF, for his technical assistance in preparing the figures for publication. NR 31 TC 1 Z9 1 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD FEB 2 PY 2015 VL 197 BP 54 EP 58 DI 10.1016/j.virusres.2014.11.028 PG 5 WC Virology SC Virology GA CC7AI UT WOS:000350519700008 PM 25481284 ER PT J AU McMahon, GM Hwang, SJ Tanner, RM Jacques, PF Selhub, J Muntner, P Fox, CS AF McMahon, Gearoid M. Hwang, Shih-Jen Tanner, Rikki M. Jacques, Paul F. Selhub, Jacob Muntner, Paul Fox, Caroline S. TI The association between vitamin B12, albuminuria and reduced kidney function: an observational cohort study SO BMC NEPHROLOGY LA English DT Article DE Homocysteine; Albuminuria; Vitamin B12; Reduced kidney function ID RANDOMIZED CONTROLLED-TRIAL; FOLATE; DEFICIENCY; PATHOPHYSIOLOGY; HEMODIALYSIS; METABOLISM; DISEASE; BLOOD AB Background: Variants in CUBN, the gene encoding cubilin, a proximal tubular transport protein, have been associated with albuminuria and vitamin B12 (B12) deficiency. We hypothesized that low levels of B12 would be associated with albuminuria in a population-based cohort. Methods: We analyzed participants from the Framingham Heart Study (n = 2965, mean age 58 years, 53% female) who provided samples for plasma B12. Logistic regression models adjusted for covariates including homocysteine were constructed to test the association between B12 and prevalent albuminuria (UACR >= 17 mg/g [ men] and >= 25 mg/g [women]) and reduced kidney function (defined as an eGFR < 60 ml/min/1.73 m(2), RKF). Because of a significant interaction between B12 and homocysteine in the prevalent RKF model (p = 0.005), the model was stratified by the median homocysteine levels. Logistic regression models were constructed to test the association between B12 and incident albuminuria and RKF. The results were replicated in 4445 participants from NHANES 2003-2004. Results: Baseline B12 levels ranged from 50-1690 pg/ml. Elevated B12 was associated with prevalent albuminuria (OR 1.44 per 1 SD increase, 95% CI 1.10-1.87) and RKF (OR 1.83, 95% CI 1.30-2.60). However after stratifying by median homocysteine levels, this relationship remained only in the higher homocysteine stratum. There was no association between B12 and incident albuminuria (OR 1.17, 95% CI 0.79 - 1.73) or RKF (OR 1.45, 95% CI 0.97 - 1.88). In the NHANES cohort, elevated B12 was associated with RKF after full covariate adjustment (OR 3.06, 95% CI 2.30-4.08). There was no association with albuminuria. Conclusion: In participants with high baseline homocysteine levels, increased plasma B12 was associated with RKF. C1 [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA 01702 USA. [McMahon, Gearoid M.; Fox, Caroline S.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [McMahon, Gearoid M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Tanner, Rikki M.; Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Jacques, Paul F.; Selhub, Jacob] Tufts Univ, USDA, Human Nutr Ctr Aging, Boston, MA 02111 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI McMahon, Gearoid/0000-0002-7723-2198 FU USDA [58-1950-0-014]; [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195. Drs. Selhub and Jacques are supported by USDA agreement No. 58-1950-0-014. The funding bodies played no role in the study design, analysis or interpretation of data, writing the manuscript or the decision to submit for publication. NR 25 TC 0 Z9 0 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 2 PY 2015 VL 16 AR 16 DI 10.1186/1471-2369-16-7 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CC4ID UT WOS:000350316000001 ER PT J AU Gounden, V Sacks, DB Zhao, Z AF Gounden, Verena Sacks, David B. Zhao, Zhen TI Interference of cerebrospinal fluid total protein measurement by povidone-iodine contamination SO CLINICA CHIMICA ACTA LA English DT Article DE Cerebrospinal fluid; Total protein; Pre-analytical interference; Povidone; Iodine AB Background: A falsely high cerebrospinal fluid (CSF) total protein (TP) result measured by pyrogallol red (PGR) method was suspected to be caused by preparation of the collection site with povidone-iodine (PVP-iodine) solution. Methods: CSF TP was evaluated for interference in samples with different final concentrations of PVP-iodine (up to 0.25% PVP and 0.025% iodine) or iodine alone (up to 0.025% iodine) using three methods: PGR, modified biuret and benzethonium chloride (BZTC). Interference exceeding +/- 20% of the baseline value is considered clinically significant according to the criterion defined by the College of American Pathologists. Results: There were positive interference with the PGR method and negative inference for the BZTC method in CSF samples spiked with PVP-iodine. The PVP-iodine (up to 0.25% PVP and 0.025% iodine) did not cause a clinically significant interference with the modified biuret method. PVP alone without iodine caused a positive interference with the PGR method but did not interfere with the modified biuret or the BZTC method. When the samples were spiked with iodine alone, none of the three methods was affected (change <20%) by iodine concentration up to 0.025%. Conclusions: Contamination of CSF specimens with PVP-iodine can lead to interference with CSF TP measurements using PGR or BZTC methods. Published by Elsevier B.V. C1 [Gounden, Verena; Sacks, David B.; Zhao, Zhen] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Gounden, V (reprint author), NIH, Ctr Clin, Dept Lab Med, Bldg 10,Room 2C-306, Bethesda, MD 20892 USA. EM zhen.zhao@nih.gov OI Sacks, David/0000-0003-3100-0735 FU Intramural Research Program of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health. NR 2 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD FEB 2 PY 2015 VL 440 BP 3 EP 5 DI 10.1016/j.cca.2014.10.008 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CB4BT UT WOS:000349573900002 PM 25446880 ER PT J AU Folco, HD Campbell, CS May, KM Espinoza, CA Oegema, K Hardwick, KG Grewal, SIS Desai, A AF Folco, H. Diego Campbell, Christopher S. May, Karen M. Espinoza, Celso A. Oegema, Karen Hardwick, Kevin G. Grewal, Shiv I. S. Desai, Arshad TI The CENP-A N-Tail Confers Epigenetic Stability to Centromeres via the CENP-T Branch of the CCAN in Fission Yeast SO CURRENT BIOLOGY LA English DT Article ID HISTONE FOLD DOMAIN; CHROMOSOME SEGREGATION; OUTER KINETOCHORE; CHROMATIN; HETEROCHROMATIN; RECRUITMENT; DISTINCT; PROTEIN; RECOGNITION; REQUIREMENT AB In most eukaryotes, centromeres are defined epigenetically by presence of the histone H3 variant CENP-A [1-3]. CENPA-containing chromatin recruits the constitutive centromere-associated network (CCAN) of proteins, which in turn directs assembly of the outer kinetochore to form microtubule attachments and ensure chromosome segregation fidelity [4-6]. Whereas the mechanisms that load CENP-A at centromeres are being elucidated, the functions of its divergent N-terminal tail remain enigmatic [7-12]. Here, we employ the well-studied fission yeast centromere [13-16] to investigate the function of the CENP-A (Cnp1) N-tail. We show that alteration of the N-tail does not affect Cnp1 loading at centromeres, outer kinetochore formation, or spindle checkpoint signaling but nevertheless elevates chromosome loss. N-tail mutants exhibited synthetic lethality with an altered centromeric DNA sequence, with rare survivors harboring chromosomal fusions in which the altered centromere was epigenetically inactivated. Elevated centromere inactivation was also observed for N-tail mutants with unaltered centromeric DNA sequences. N-tail mutants specifically reduced localization of the CCAN proteins Cnp20/CENP-T and Mis6/CENP-I, but not Cnp3/CENP-C. Overexpression of Cnp20/CENP-T suppressed defects in an N-tail mutant, suggesting a link between reduced CENP-T recruitment and the observed centromere inactivation phenotype. Thus, the Cnp1 N-tail promotes epigenetic stability of centromeres in fission yeast, at least in part via recruitment of the CENP-T branch of the CCAN. C1 [Folco, H. Diego; Campbell, Christopher S.; Espinoza, Celso A.; Oegema, Karen; Desai, Arshad] Univ Calif San Diego, Ludwig Inst Canc Res, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [May, Karen M.; Hardwick, Kevin G.] Univ Edinburgh, Sch Biol Sci, Inst Cell Biol, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3BF, Midlothian, Scotland. [Folco, H. Diego; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Desai, A (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. EM abdesai@ucsd.edu OI Hardwick, Kevin/0000-0002-6462-1047 FU NIH [GM074215]; NIH; Wellcome Trust [083610]; Wellcome Trust Centre for Cell Biology [092076]; NIH/NCI [T32 CA009523-27S1]; Ludwig Institute for Cancer Research FX We thank Shigeaki Saitoh and Kohta Takahashi (Kurume University); Alison Pidoux, Georgina Hamilton, and Robin Allshire (University of Edinburgh); Takeshi Sakuno and Yoshinori Watanabe (University of Tokyo); Oliver Limbo and Paul Russell (Scripps Institute); and the National BioResource Project - Yeast (Japan) for their generosity in sharing strains, plasmid, and expertise. We thank Bing Ren for supporting acquisition of the ChIP-seq data sets and Peter Svensson and Karl Ekwall (Karolinska Institute) and Ben Black and colleagues (University of Pennsylvania) for communicating unpublished results. This work was supported by NIH grant GM074215 to A.D. and the Intramural Research Program of the NIH to S.I.S.G. K.G.H. and K.M.M. were supported by a Wellcome Trust Programme Grant to K.G.H. (083610) and Wellcome Trust Centre for Cell Biology core grant 092076. C.A.E. was supported by NIH/NCI training grant T32 CA009523-27S1. A.D. and K.O. receive salary and other support from the Ludwig Institute for Cancer Research. NR 38 TC 10 Z9 10 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD FEB 2 PY 2015 VL 25 IS 3 BP 348 EP 356 DI 10.1016/j.cub.2014.11.060 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CA5SB UT WOS:000348967000023 PM 25619765 ER PT J AU Castilho, JL Luz, PM Shepherd, BE Turner, M Ribeiro, SR Bebawy, SS Netto, JS McGowan, CC Veloso, VG Engels, EA Sterling, TR Grinsztejn, B AF Castilho, Jessica L. Luz, Paula M. Shepherd, Bryan E. Turner, Megan Ribeiro, Sayonara R. Bebawy, Sally S. Netto, Juliana S. McGowan, Catherine C. Veloso, Valdilea G. Engels, Eric A. Sterling, Timothy R. Grinsztejn, Beatriz TI HIV and cancer: a comparative retrospective study of Brazilian and US clinical cohorts SO INFECTIOUS AGENTS AND CANCER LA English DT Review DE HIV; Malignancy; Cancer; Brazil; Anal cancer; Kaposi sarcoma; Non-Hodgkin lymphoma; Lung cancer; Age; Sex ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS-DEFINING MALIGNANCIES; ACTIVE ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; KAPOSIS-SARCOMA; CERVICAL-CANCER; UNITED-STATES; HAART ERA; DEATH; RISK AB Background: With successful antiretroviral therapy, non-communicable diseases, including malignancies, are increasingly contributing to morbidity and mortality among HIV-infected persons. The epidemiology of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in HIV-infected populations in Brazil has not been well described. It is not known if cancer trends in HIV-infected populations in Brazil are similar to those of other countries where antiretroviral therapy is also widely available. Methods: We performed a retrospective analysis of clinical cohorts at Instituto Nacional de Infectologia Evandro Chagas (INI) in Rio de Janeiro and Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville from 1998 to 2010. We used Poisson regression and standardized incidence ratios (SIRs) to examine incidence trends. Clinical and demographic predictors of ADCs and NADCs were examined using Cox proportional hazards models. Results: This study included 2,925 patients at INI and 3,927 patients at VCCC. There were 57 ADCs at INI (65% Kaposi sarcoma), 47 at VCCC (40% Kaposi sarcoma), 45 NADCs at INI, and 82 at VCCC. From 1998 to 2004, incidence of ADCs remained statistically unchanged at both sites. From 2005 to 2010, ADC incidence decreased in both cohorts (INI incidence rate ratio per year = 0.74, p < 0.01; VCCC = 0.75, p < 0.01). Overall Kaposi sarcoma incidence was greater at INI than VCCC (3.0 vs. 1.2 cases per 1,000 person-years, p < 0.01). Incidence of NADCs remained constant throughout the study period (overall INI incidence 3.6 per 1,000 person-years and VCCC incidence 5.3 per 1,000 person-years). Compared to general populations, overall risk of NADCs was increased at both sites (INI SIR = 1.4 [95% CI 1.1-1.9] and VCCC SIR = 1.3 [ 1.0-1.7]). After non-melanoma skin cancers, the most frequent NADCs were anal cancer at INI (n = 7) and lung cancer at VCCC (n = 11). In multivariate models, risk of ADC was associated with male sex and immunosuppression. Risk of NADC was associated with increased age. Conclusions: In both cohorts, ADCs have decreased over time, though incidence of KS was higher at INI than VCCC. Rates of NADCs remained constant over time at both sites. C1 [Castilho, Jessica L.; Turner, Megan; Bebawy, Sally S.; McGowan, Catherine C.; Sterling, Timothy R.] Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37232 USA. [Luz, Paula M.; Ribeiro, Sayonara R.; Netto, Juliana S.; Veloso, Valdilea G.; Grinsztejn, Beatriz] HIV AIDS Clin Res Ctr, Inst Nacl Infectol Evandro Chagas, Fundacao Oswaldo Cruz, BR-21040360 Rio De Janeiro, RJ, Brazil. [Shepherd, Bryan E.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. [Engels, Eric A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Castilho, JL (reprint author), Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, MCN A2200,1611 21st Ave South, Nashville, TN 37232 USA. EM jessica.castilho@vanderbilt.edu FU National Institutes of Health [T32 AI007474, K24 AI65298, UO1 AI069923]; National Council of Technological and Scientific Development; Research Agency of the State of Rio de Janeiro; Intramural Research Program of the National Cancer Institute FX We are grateful to individuals at INI and VCCC who made this study possible. We thank Dan Rasbach, and Sam Stinnette at Vanderbilt for their work abstracting and validating the cancer diagnoses at VCCC. This study was the result of an INI-Vanderbilt partnership developed through the Caribbean, Central and South American network for HIV epidemiology (CCASAnet) study, a multisite HIV cohort study in which INI participates and Vanderbilt coordinates. We thank CCASAnet data manager Karu Jayathilake for his statistical assistance in this project. This project was funded by grants from the National Institutes of Health (T32 AI007474 [JLC], K24 AI65298 [TRS, SSB, MT], UO1 AI069923 [JLC, PML, BES, CCM, VGV, BG]), the National Council of Technological and Scientific Development (PML, BG), and the Research Agency of the State of Rio de Janeiro (PML, BG). Eric Engels was supported by the Intramural Research Program of the National Cancer Institute. NR 36 TC 2 Z9 2 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD FEB 2 PY 2015 VL 10 AR 4 DI 10.1186/1750-9378-10-4 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA CA8RN UT WOS:000349188700001 PM 25685180 ER PT J AU Artym, VV Swatkoski, S Matsumoto, K Campbell, CB Petrie, RJ Dimitriadis, EK Li, X Mueller, SC Bugge, TH Gucek, M Yamada, KM AF Artym, Vira V. Swatkoski, Stephen Matsumoto, Kazue Campbell, Catherine B. Petrie, Ryan J. Dimitriadis, Emilios K. Li, Xin Mueller, Susette C. Bugge, Thomas H. Gucek, Marian Yamada, Kenneth M. TI Dense fibrillar collagen is a potent inducer of invadopodia via a specific signaling network SO JOURNAL OF CELL BIOLOGY LA English DT Article ID BREAST-CARCINOMA CELLS; I COLLAGEN; EXTRACELLULAR-MATRIX; PHOSPHORYLATION SITES; ACTIN POLYMERIZATION; CANCER PROGRESSION; STATISTICAL-MODEL; BASEMENT-MEMBRANE; GENE-EXPRESSION; INTEGRIN AB Cell interactions with the extracellular matrix (ECM) can regulate multiple cellular activities and the matrix itself in dynamic, bidirectional processes. One such process is local proteolytic modification of the ECM. Invadopodia of tumor cells are actin-rich proteolytic protrusions that locally degrade matrix molecules and mediate invasion. We report that a novel high-density fibrillar collagen (HDFC) matrix is a potent inducer of invadopodia, both in carcinoma cell lines and in primary human fibroblasts. In carcinoma cells, HDFC matrix induced formation of invadopodia via a specific integrin signaling pathway that did not require growth factors or even altered gene and protein expression. In contrast, phosphoproteomics identified major changes in a complex phosphosignaling network with kindlin2 serine phosphorylation as a key regulatory element. This kindlin2-dependent signal transduction network was required for efficient induction of invadopodia on dense fibrillar collagen and for local degradation of collagen. This novel phosphosignaling mechanism regulates cell surface invadopodia via kindlin2 for local proteolytic remodeling of the ECM. C1 [Artym, Vira V.; Matsumoto, Kazue; Campbell, Catherine B.; Petrie, Ryan J.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Swatkoski, Stephen; Gucek, Marian] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] Natl Inst Biomol Imaging & Bioengn, Biomol Engn & Phys Sci Shared Resource Program, NIH, Bethesda, MD 20892 USA. [Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Artym, Vira V.; Mueller, Susette C.] Georgetown Univ, Sch Med, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. [Li, Xin] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC 20057 USA. RP Artym, VV (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM vartym@mail.nih.gov; kyamada@dir.nidcr.nih.gov FU Pathway to Independence Award from National Cancer Institute [K99CA129205]; American Recovery and Reinvestment Act of 2009 award; National Institutes of Health/National Institute of Dental and Craniofacial Research Intramural project [ZIA DE 000719] FX This work was supported by Pathway to Independence Award K99CA129205 from National Cancer Institute with American Recovery and Reinvestment Act of 2009 award to V.V. Artym and National Institutes of Health/National Institute of Dental and Craniofacial Research Intramural project ZIA DE 000719 to K.M. Yamada. NR 93 TC 15 Z9 15 U1 3 U2 12 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 2 PY 2015 VL 208 IS 3 BP 331 EP 350 DI 10.1083/jcb.201405099 PG 20 WC Cell Biology SC Cell Biology GA CA5TZ UT WOS:000348972000007 PM 25646088 ER PT J AU Chen, SL Lee, SY Chang, YH Wang, TY Chen, SH Chu, CH Chen, PS Yang, YK Hong, JS Lu, RB AF Chen, Shiou-Lan Lee, Sheng-Yu Chang, Yun-Hsuan Wang, Tzu-Yun Chen, Shih-Heng Chu, Chun-Hsien Chen, Po See Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients SO SCIENTIFIC REPORTS LA English DT Article ID ALZHEIMERS-DISEASE; SERUM CONCENTRATIONS; RAT-BRAIN; NEURONS; SCHIZOPHRENIA; METAANALYSIS; ADDICTION; RECEPTORS; PLATELETS; MEMORY AB BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency. C1 [Chen, Shiou-Lan] Kaohsiung Med Univ, Sch Med, Dept Neurol, Kaohsiung, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Inst Behav Med, Tainan 70101, Taiwan. [Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Po See; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med, Inst Allied Hlth Sci, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70101, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Tainan, Taiwan. [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Chen, Shih-Heng; Chu, Chun-Hsien; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Inst Behav Med, Tainan 70101, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3, NSC101-2314-B-006-063-MY3]; National Cheng Kung University Project to Promote Academic Excellence and Develop a World Class Research Center FX This study was supported in part by grants NSC98-2314-B-006-022-MY3 (to RBL) and NSC101-2314-B-006-063-MY3 (to RBL) from the Taiwan National Science Council, and by a grant from the National Cheng Kung University Project to Promote Academic Excellence and Develop a World Class Research Center. NR 37 TC 2 Z9 3 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 2 PY 2015 VL 5 AR 8148 DI 10.1038/srep08148 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA1JW UT WOS:000348669900001 PM 25640280 ER PT J AU Wang, Z Yu, DZ Wang, MQ Wang, QL Kouznetsova, J Yang, RZ Qian, K Wu, WJ Shuldiner, A Sztalryd, C Zou, MH Zheng, W Gong, DW AF Wang, Zhi Yu, Daozhan Wang, Mengqiao Wang, Qilong Kouznetsova, Jennifer Yang, Rongze Qian, Kun Wu, Wenjun Shuldiner, Alan Sztalryd, Carole Zou, Minghui Zheng, Wei Gong, Da-Wei TI Elabela-Apelin Receptor Signaling Pathway is Functional in Mammalian Systems SO SCIENTIFIC REPORTS LA English DT Article ID ENDOGENOUS LIGAND APELIN; NITRIC-OXIDE SYNTHASE; IN-VIVO; CARDIAC CONTRACTILITY; FLUID HOMEOSTASIS; ORPHAN RECEPTOR; BLOOD-PRESSURE; APJ RECEPTOR; KINASE; ACTIVATION AB Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development. C1 [Wang, Zhi; Yu, Daozhan; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan; Sztalryd, Carole; Gong, Da-Wei] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Wang, Zhi] Southeast Univ, Nanjing Chest Hosp, Dept Cardiol, Sch Med, Nanjing 210029, Jiangsu, Peoples R China. [Wang, Mengqiao; Kouznetsova, Jennifer; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Wang, Qilong; Zou, Minghui] Univ Oklahoma, Hlth Sci Ctr, Dept Internal Med, Oklahoma City, OK 73104 USA. RP Gong, DW (reprint author), Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. EM dgong@medicine.umaryland.edu RI Zheng, Wei/J-8889-2014; wang, qilong/O-1962-2013 OI Zheng, Wei/0000-0003-1034-0757; FU Maryland Stem Cell Research Fund; Mid-Atlantic Nutrition Obesity Research Center [DK072488]; Baltimore Diabetes Research and Training Center [P60-DK-079637] FX This work was supported in part by grants from Maryland Stem Cell Research Fund, the Mid-Atlantic Nutrition Obesity Research Center (DK072488), and the Baltimore Diabetes Research and Training Center (P60-DK-079637). NR 39 TC 11 Z9 11 U1 1 U2 19 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 FEB 2 PY 2015 VL 5 AR 8170 DI 10.1038/srep08170 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA1KB UT WOS:000348670400004 PM 25639753 ER PT J AU Repunte-Canonigo, V Shin, W Vendruscolo, LF Lefebvre, C van der Stap, L Kawamura, T Schlosburg, JE Alvarez, M Koob, GF Califano, A Sanna, PP AF Repunte-Canonigo, Vez Shin, William Vendruscolo, Leandro F. Lefebvre, Celine van der Stap, Lena Kawamura, Tomoya Schlosburg, Joel E. Alvarez, Mariano Koob, George F. Califano, Andrea Sanna, Pietro Paolo TI Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks SO GENOME BIOLOGY LA English DT Article AB Background: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. Results: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. Conclusions: Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence. C1 [Repunte-Canonigo, Vez; van der Stap, Lena; Kawamura, Tomoya; Sanna, Pietro Paolo] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Vendruscolo, Leandro F.; Schlosburg, Joel E.; Koob, George F.] Scripps Res Inst, Committee Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Shin, William] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Shin, William; Lefebvre, Celine; Alvarez, Mariano; Califano, Andrea] Columbia Univ, Dept Syst Biol, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Biomed Informat, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Inst Canc Genet, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Dept Biochem & Mol Biophys, Hammer Hlth Sci Ctr, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Canc Regulatory Network Program, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Lefebvre, Celine] INSERM, Unit U981, Inst Gustave Roussy, Villejuif, France. [Vendruscolo, Leandro F.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Koob, George F.] NIAAA, Rockville, MD 20852 USA. [Califano, Andrea] Scripps Res Inst, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. RP Sanna, PP (reprint author), Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA.; Califano, A (reprint author), Columbia Univ, Dept Syst Biol, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA.; Califano, A (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Biomed Informat, New York, NY 10032 USA.; Califano, A (reprint author), Columbia Univ, Inst Canc Genet, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA.; Califano, A (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, Hammer Hlth Sci Ctr, New York, NY 10032 USA.; Califano, A (reprint author), Columbia Univ, Canc Regulatory Network Program, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA.; Califano, A (reprint author), Scripps Res Inst, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM califano@c2b2.columbia.edu; psanna@scripps.edu RI Lefebvre, Celine/E-6290-2013; koob, george/P-8791-2016 FU NIH [AA017371, AA020960, DA013821, GM085659, AA021667, CA121852-09, CA1968426, HL111566] FX Supported by NIH grants AA017371, AA020960, DA013821, GM085659 (PPS); AA021667 (PPS/AC); CA121852-09, CA1968426, HL111566 (AC). We are grateful to Dr. Ronald A. Bush of NIH/NIDCD for the AAV expressing Psip1 and control AAV. NR 50 TC 8 Z9 8 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD FEB 2 PY 2015 VL 16 AR 68 DI 10.1186/s13059-015-0593-5 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA V45YM UT WOS:000209851900001 PM 25886852 ER PT J AU Muller, TA Grundler, R Istvanffy, R Hennighausen, L Illert, AL Duyster, J AF Mueller, T. A. Grundler, R. Istvanffy, R. Hennighausen, L. Illert, A. L. Duyster, J. TI The Role Of Stat5 in FLT3-Mediated Leukemogenesis SO ANNALS OF HEMATOLOGY LA English DT Meeting Abstract C1 [Mueller, T. A.; Illert, A. L.; Duyster, J.] Univ Hosp Freiburg, Dept Internal Med 1, Freiburg, Germany. [Grundler, R.; Istvanffy, R.] Mission Res Inc, Dept Internal Med 3, Munich, Germany. [Hennighausen, L.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 EI 1432-0584 J9 ANN HEMATOL JI Ann. Hematol. PD FEB PY 2015 VL 94 SU 1 MA 21 BP S80 EP S81 PG 2 WC Hematology SC Hematology GA DA0HS UT WOS:000367478800068 ER PT J AU Wertheimer, A AF Wertheimer, Alan TI The ethics of promulgating principles of research ethics: the problem of diversion effects SO JOURNAL OF LAW AND THE BIOSCIENCES LA English DT Article DE Research ethics; regulation; promulgations; standard of care; incentives ID CARE AB There is an important distinction between ethical standards for the conduct of research with human subjects and the ethics of promulgating principles of research ethics. Those who promulgate ethical standards for the conduct of research have an ethical responsibility to consider the consequences to which those promulgations give rise. In particular, they must consider whether their promulgations will give researchers incentives not to conduct research or not to conduct research in locales in which participants would benefit from participation. I first show how such 'diversion effects' are possible and then examine four principles of research ethics in that light. I then consider several objections to the argument that those who promulgate principles of research ethics should consider diversion effects. C1 [Wertheimer, Alan] Natl Inst Hlth, Ctr Clin, Dept Bioeth, Res Triangle Pk, NC 27709 USA. RP Wertheimer, A (reprint author), Natl Inst Hlth, Ctr Clin, Dept Bioeth, Res Triangle Pk, NC 27709 USA. EM wertheimera@cc.nih.gov NR 38 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2053-9711 J9 J LAW BIOSCI JI J. Law Biosci. PD FEB PY 2015 VL 2 IS 1 BP 2 EP 32 DI 10.1093/jlb/lsu039 PG 31 WC Law SC Government & Law GA CY6HW UT WOS:000366510800002 ER PT J AU Buck, SM Isaacs, E Baldeweg, T Polkey, CE Mishkin, M Vargha-Khadem, F AF Buck, S. M. Isaacs, E. Baldeweg, T. Polkey, C. E. Mishkin, M. Vargha-Khadem, F. TI BETTER POST-OPERATIVE VERBAL LEARNING CAPACITY IN PATIENTS WITH EARLIER ONSET OF EPILEPSY SO EPILEPSIA LA English DT Meeting Abstract CT 31st International Epilepsy Congress CY SEP 05-09, 2015 CL Istanbul, TURKEY C1 [Buck, S. M.; Baldeweg, T.; Vargha-Khadem, F.] UCL, Inst Child Hlth, Cognit Neurosci & Neuropsychiat, London, England. [Isaacs, E.] UCL, Inst Child Hlth, MRC, Childhood Nutr Res Ctr, London, England. [Polkey, C. E.] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, London WC2R 2LS, England. [Mishkin, M.] NIMH, Neuropsychol Lab, 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 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD FEB PY 2015 VL 56 SU 1 SI SI MA p0295 BP 79 EP 79 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CX5QG UT WOS:000365756500231 ER PT J AU Dehghani, A Isaacs, E Della Rocchetta, AI Pitts, G Polkey, CE Mishkin, M Vargha-Khadem, F AF Dehghani, A. Isaacs, E. Della Rocchetta, A. I. Pitts, G. Polkey, C. E. Mishkin, M. Vargha-Khadem, F. TI MEMORY & LEARNING AFTER TEMPORAL LOBE SURGERY: EFFECTS OF HEMISPHERIC SIDE AND EXTENT OF SURGICAL REMOVAL SO EPILEPSIA LA English DT Meeting Abstract CT 31st International Epilepsy Congress CY SEP 05-09, 2015 CL Istanbul, TURKEY C1 [Dehghani, A.] BIHE, Biol, Tehran, Iran. [Isaacs, E.] UCL, Inst Child Hlth, MRC, Childhood Nutr Res Ctr, London, England. [Della Rocchetta, A. I.] Wellington Hosp, Neuropsychol, London, England. [Pitts, G.; Vargha-Khadem, F.] UCL, Inst Child Hlth, Sect Cognit Neurosci & Neuropsychiat, London, England. [Pitts, G.; Vargha-Khadem, F.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Polkey, C. E.] Kings Coll London, London WC2R 2LS, England. [Polkey, C. E.] Univ London, London, England. [Polkey, C. E.] Maudsley Hosp & Inst Psychiat, London SE5 8AZ, England. [Mishkin, M.] NIMH, Neuropsychol Lab, 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 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD FEB PY 2015 VL 56 SU 1 SI SI MA p0297 BP 80 EP 80 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CX5QG UT WOS:000365756500233 ER PT J AU Cooper, HA Najafi, AH Ghafourian, K Paixao, ARM Aljaabari, M Iantorno, M Canos, D Asch, FM Paza, JA AF Cooper, Howard A. Najafi, Amir H. Ghafourian, Kambiz Paixao, Andre R. M. Aljaabari, Mohamed Iantorno, Micaela Canos, Daniel Asch, Federico M. Paza, Julio A. TI Diagnosis of cardiogenic shock without the use of a pulmonary artery catheter SO EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE LA English DT Article DE Shock; diagnosis; echocardiography ID RANDOMIZED CONTROLLED-TRIAL; RISK SURGICAL PATIENTS; VASCULAR-SURGERY; OUTCOMES; MANAGEMENT AB Background: Current diagnostic criteria for cardiogenic shock (CS) require the use of a pulmonary artery catheter (PAC), which is time-consuming and may cause complications. A set of simple yet accurate noninvasive diagnostic criteria would be of significant utility. Methods: Candidate components for the Noninvasive Parameters for Assessment of Cardiogenic Shock (N-PACS) criteria were required to be objective, readily available, and noninvasive. Variables encompassing hypotension, hypoperfusion, predisposing conditions, and elevated intracardiac filling pressures were optimized versus a PAC-based standard in a retrospective developmental cohort of 122 patients with acute myocardial infarction (AMI). The finalized criteria were validated in a prospective cohort of coronary care unit patients in whom a PAC was placed for clinical indications. Results: According to invasive criteria, CS was present in 32 of 217 consecutive patients undergoing PAC. Compared to the PAC-based standard, the N-PACS criteria had a sensitivity of 96.9% (95% confidence interval (CI) 82.0-99.8), specificity of 90.8% (95% CI 85.5-94.4), positive predictive value of 64.6% (95% CI 49.4-77.4), negative predictive value of 99.4% (95% CI 96.2-100), positive likelihood ratio of 10.5 (95% CI 6.7-16.7), negative likelihood ratio of 0.03 (95% CI 0.00-0.24), and diagnostic odds ratio of 306.4. Results were similar among patients with and without AMI. Conclusion: A simple, echocardiography-based set of noninvasive diagnostic criteria can be used to accurately diagnose CS. C1 [Cooper, Howard A.; Najafi, Amir H.; Ghafourian, Kambiz; Asch, Federico M.] Medstar Washington Hosp Ctr, MedStar Heart Inst, Washington, DC 20010 USA. [Paixao, Andre R. M.] Univ Texas, Dept Med, Houston, TX USA. [Aljaabari, Mohamed] Tufts Univ, Dept Internal Med, Medford, MA USA. [Iantorno, Micaela] NIH, Dept Crit Care Med, Bethesda, MD USA. [Canos, Daniel] US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. [Paza, Julio A.] New York Med Coll, Westchester Med Ctr, Valhalla, NY 10595 USA. RP Cooper, HA (reprint author), Medstar Washington Hosp Ctr, 110 Irving St NW,Suite NA-1103, Washington, DC 20010 USA. EM cooperh@verizon.net NR 25 TC 1 Z9 1 U1 2 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2048-8726 EI 2048-8734 J9 EUR HEART J-ACUTE CA JI Eur. Heart J.-Acute Cardiovasc. Care PD FEB PY 2015 VL 4 IS 1 BP 88 EP 95 DI 10.1177/2048872614534564 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CW6NW UT WOS:000365115300013 PM 24833639 ER PT J AU Bandara, G Beaven, MA Olivera, A Gilfillan, AM Metcalfe, DD AF Bandara, Geethani Beaven, Michael A. Olivera, Ana Gilfillan, Alasdair M. Metcalfe, Dean D. TI Activated Mast Cells Produce Soluble ST2, a Decoy Receptor for IL-33 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Bandara, Geethani; Olivera, Ana; Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 206 BP AB64 EP AB64 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600207 ER PT J AU Chiang, D Burks, AW Davidson, W Dawson, P Grishin, A Henning, A Jones, SM Leung, DYM Lindblad, RW Liu, AH Scurlock, AM Sicherer, SH Vickery, BP Wood, RA Sampson, HA Berin, C AF Chiang, David Burks, A. Wesley Davidson, Wendy Dawson, Peter Grishin, Alexander Henning, Alice Jones, Stacie M. Leung, Donald Y. M. Lindblad, Robert W. Liu, Andrew H. Scurlock, Amy M. Sicherer, Scott H. Vickery, Brian P. Wood, Robert A. Sampson, Hugh A. Berin, Cecilia TI Phenotypic Analysis of Peanut-Responsive T Cells at Baseline in Subjects Enrolled in CoFAR6, a Randomized Placebo-Controlled Epicutaneous Immunotherapy (EPIT) Trial for the Treatment of Peanut Allergy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Chiang, David; Grishin, Alexander; Sicherer, Scott H.; Berin, Cecilia] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Burks, A. Wesley] Univ N Carolina, Chapel Hill, NC USA. [Davidson, Wendy] NIH, Bethesda, MD 20892 USA. [Dawson, Peter; Henning, Alice; Lindblad, Robert W.] EMMES Corp, Rockville, MD USA. [Jones, Stacie M.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Leung, Donald Y. M.; Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Scurlock, Amy M.] UAMS AR Childrens Hosp, Little Rock, AR USA. [Vickery, Brian P.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 731 BP AB226 EP AB226 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600730 ER PT J AU Clark, A Metcalfe, DD Cantave, D Scott, LM Carter, MC AF Clark, Alicia Metcalfe, Dean D. Cantave, Daly Scott, Linda M. Carter, Melody C. TI Adverse Vaccine Reactions in Children with Pediatric Mastocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Clark, Alicia] NIH, Bethesda, MD 20892 USA. [Metcalfe, Dean D.; Scott, Linda M.; Carter, Melody C.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Cantave, Daly] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 865 BP AB266 EP AB266 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600864 ER PT J AU Cruse, G Beaven, MA Music, SC Bradding, P Metcalfe, DD AF Cruse, Glenn Beaven, Michael A. Music, Stephen C. Bradding, Peter Metcalfe, Dean D. TI The Fceri beta Homologue, MS4A4, Promotes Fc epsilon ri- Dependent Human Mast Cell Degranulation By Facilitating PLC gamma 1 Signaling SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Cruse, Glenn; Music, Stephen C.; Metcalfe, Dean D.] NHLBI, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bradding, Peter] Univ Leicester, Leicester, Leics, England. NR 0 TC 1 Z9 1 U1 1 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 775 BP AB240 EP AB240 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600774 ER PT J AU Druey, KM Balenga, N Xie, ZH Laviolette, M Klichinsky, M Panettieri, RA Chan, EC Jude, J Zhao, M AF Druey, Kirk M. Balenga, Nariman Xie, Zhihui Laviolette, Michel Klichinsky, Michael Panettieri, Reynold A., Jr. Chan, Eunice C. Jude, Joseph Zhao, Ming TI A Fungal Protease Allergen Provokes Airway Hyperresponsiveness in Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Druey, Kirk M.] NIAID, NIH, LAD, Bethesda, MD 20892 USA. [Balenga, Nariman; Xie, Zhihui; Chan, Eunice C.; Zhao, Ming] NIH, Bethesda, MD USA. [Laviolette, Michel] Ctr Pheum Laval, Ste Foy, PQ, Canada. [Klichinsky, Michael; Panettieri, Reynold A., Jr.; Jude, Joseph] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA L25 BP AB389 EP AB389 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600944 ER PT J AU Gallagher, JL Eckrich, M Cohen, J Patel, NC AF Gallagher, Joel L. Eckrich, Michael Cohen, Jeffrey Patel, Niraj C. TI Tubular Interstitial Nephritis, an Unusual Manifestation of T Cell-Associated Severe Chronic Active Epstein-Barr Virus Infection SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Gallagher, Joel L.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Eckrich, Michael] Levine Childrens Hosp, Charlotte, NC USA. [Cohen, Jeffrey] NIH, Bethesda, MD 20892 USA. [Patel, Niraj C.] Carolinas Med Ctr, Levine Childrens Hosp, Charlotte, NC 28203 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 38 BP AB12 EP AB12 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600039 ER PT J AU Gorelik, M Narisety, S Chichester, K Guerrerio, A Bieneman, AP Keet, C Hamilton, RG Wood, RA Schroeder, JT Guerrerio, PF AF Gorelik, Mark Narisety, Satya Chichester, Kristin Guerrerio, Anthony Bieneman, Anja P. Keet, Corinne Hamilton, Robert G. Wood, Robert A. Schroeder, John T. Guerrerio, Pamela Frischmeyer TI Impact of Sublingual and Oral Immunotherapy for Peanut Allergy on Blood Dendritic Cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Gorelik, Mark] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Narisety, Satya; Chichester, Kristin; Guerrerio, Anthony; Keet, Corinne; Hamilton, Robert G.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bieneman, Anja P.; Schroeder, John T.] Johns Hopkins Univ, Baltimore, MD USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Guerrerio, Pamela Frischmeyer] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 203 BP AB63 EP AB63 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600204 ER PT J AU Green, BJ Nayak, AP Croston, TL Lemons, AR Marshall, NB Goldsmith, WT Kashon, M Law, BF Wagner, LM Long, CM Germolec, DM Beezhold, DH AF Green, Brett J. Nayak, Ajay P. Croston, Tara L. Lemons, Angela R. Marshall, Nikki B. Goldsmith, W. Travis Kashon, Michael Law, Brandon F. Wagner, Lauren M. Long, Carrie M. Germolec, Dori M. Beezhold, Donald H. TI Fungal Viability Is Essential in Modulating of Adaptive Immune Responses in Mice SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Green, Brett J.; Nayak, Ajay P.; Croston, Tara L.; Lemons, Angela R.; Marshall, Nikki B.; Law, Brandon F.; Wagner, Lauren M.; Long, Carrie M.; Beezhold, Donald H.] NIOSH, CDC, ACIB, Morgantown, WV USA. [Goldsmith, W. Travis] NIOSH, CDC, PPRB, Morgantown, WV USA. [Kashon, Michael] NIOSH, CDC, BEB, Morgantown, WV USA. [Germolec, Dori M.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 56 BP AB18 EP AB18 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600057 ER PT J AU Happel, CS Stone, KD Hickstein, DD Freeman, AF Su, HC AF Happel, Corinne Savides Stone, Kelly D. Hickstein, Dennis D. Freeman, Alexandra F. Su, Helen C. TI Persisting Food Allergen Sensitization after Allogeneic Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Happel, Corinne Savides; Su, Helen C.] NIAID, NIH, Host Def Lab, Bethesda, MD 20892 USA. [Stone, Kelly D.] NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. [Hickstein, Dennis D.] NCI, NIH, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 NR 0 TC 1 Z9 1 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 FEB PY 2015 VL 135 IS 2 SU S MA 832 BP AB256 EP AB256 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600831 ER PT J AU Hillyer, P Shepard, RE Uehling, M Sheik, F Luongo, C Buchholz, UJ Collins, PL Donnelly, RP Rabin, RL AF Hillyer, Philippa Shepard, Rachel E. Uehling, Megan Sheik, Faruk Luongo, Cindy Buchholz, Ursula J. Collins, Peter L. Donnelly, Raymond P. Rabin, Ronald L. TI Respiratory Syncytial Virus-Induced Host IFN Signaling Differs Between A549 and BEAS-2B Epithelial Cell Lines SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Hillyer, Philippa; Shepard, Rachel E.; Uehling, Megan; Rabin, Ronald L.] US FDA, CBER, Silver Spring, MD USA. [Sheik, Faruk; Donnelly, Raymond P.] US FDA, CDER, Silver Spring, MD USA. [Luongo, Cindy; Buchholz, Ursula J.; Collins, Peter L.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 29 BP AB9 EP AB9 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600030 ER PT J AU Khoury, P Lee, CCR Abiodun, AO Klion, AD AF Khoury, Paneez Lee, Chyi-chia R. Abiodun, Annalise O. Klion, Amy D. TI Skin Histopathology in Patients with Dermatologic Manifestations of Hypereosinophilic Syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Khoury, Paneez; Lee, Chyi-chia R.; Abiodun, Annalise O.; Klion, Amy D.] NIH, Bethesda, MD 20892 USA. [Abiodun, Annalise O.] Univ Utah, Sch Med, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 864 BP AB266 EP AB266 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600863 ER PT J AU Kim, D Beaven, MA Cruse, G Prussin, C Komarow, H Carter, MC Metcalfe, DD Olivera, A AF Kim, Dokyun Beaven, Michael A. Cruse, Glenn Prussin, Calman Komarow, Hirsh Carter, Melody C. Metcalfe, Dean D. Olivera, Ana TI Constitutively Activated KIT in Mastocytosis Patients Is Associated with Decreased Levels of the Scavenger Protein DJ1 and Reciprocal Increases in Reactive Oxygen Species SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Kim, Dokyun; Cruse, Glenn; Prussin, Calman; Komarow, Hirsh; Carter, Melody C.; Metcalfe, Dean D.; Olivera, Ana] NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA L27 BP AB389 EP AB389 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600946 ER PT J AU Kirshenbaum, AS Bandara, G Desai, A Fischer, E Leerkes, M Metcalfe, DD Cruse, G AF Kirshenbaum, Arnold S. Bandara, Geethani Desai, Avanti Fischer, Elizabeth Leerkes, Maarten Metcalfe, Dean D. Cruse, Glenn TI Mast Cells Expressing the Germline HPS1 16-Bp Duplication (c.1470_1486dup16, Hermansky-Pudlak Syndrome-1) Defect Produce Extracellular Matrix Components SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Kirshenbaum, Arnold S.; Bandara, Geethani; Desai, Avanti; Fischer, Elizabeth; Metcalfe, Dean D.; Cruse, Glenn] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Leerkes, Maarten] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 557 BP AB172 EP AB172 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600556 ER PT J AU Knight, JM Mak, G Shaw, J McDermott, C Roberts, L You, R Yuan, XY Millien, VO Qian, YP Song, LZ Frazier, V Kim, C Kim, JJ Bond, R Luong, AU Kheradmand, F McMurray, J Mandal, PK Morlacchi, P Milner, JD Corry, DB AF Knight, John M. Mak, Garbo Shaw, Joanne McDermott, Catherine Roberts, Luz You, Ran Yuan, Xiaoyi Millien, Valentine O. Qian, Yuping Song, Li-Zhen Frazier, Vincent Kim, Choel Kim, Jeong J. Bond, Richard Luong, Amber U. Kheradmand, Farrah McMurray, John Mandal, Pijus K. Morlacchi, Pietro Milner, Joshua D. Corry, David B. TI Long-Acting Beta Agonists Enhance Allergic Airway Disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Knight, John M.; Mandal, Pijus K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Knight, John M.; Mak, Garbo; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong J.] Baylor Coll Med, Houston, TX 77030 USA. [Shaw, Joanne; Luong, Amber U.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Qian, Yuping; Kheradmand, Farrah; Corry, David B.] Baylor Coll Med, Houston, TX 77030 USA. [Bond, Richard] Univ Houston, Houston, TX USA. [McMurray, John; Morlacchi, Pietro] MD Anderson, Bethesda, MD USA. [Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA L2 BP AB381 EP AB381 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600921 ER PT J AU Laffey, KG Garnier, B Hitchinson, B Tarasova, N Gaponenko, V Ackerman, SJ AF Laffey, Kimberly G. Garnier, Boris Hitchinson, Ben Tarasova, Nadya Gaponenko, Vadim Ackerman, Steven J. TI Development of a Novel Peptide Nanoparticle Inhibitor for Human CCR3/Eotaxin-Mediated Eosinophil Migration SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Laffey, Kimberly G.; Garnier, Boris; Hitchinson, Ben; Gaponenko, Vadim; Ackerman, Steven J.] Univ Illinois, Chicago, IL USA. [Tarasova, Nadya] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 FEB PY 2015 VL 135 IS 2 SU S MA 523 BP AB160 EP AB160 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600522 ER PT J AU Legrand, F Alpaugh, A Falahati, R Makiya, M Klion, AD AF Legrand, Fanny Alpaugh, Alexandra Falahati, Rustom Makiya, Michelle Klion, Amy D. TI A Novel Therapeutic Target for the Treatment of Eosinophilic Disorders SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Legrand, Fanny; Alpaugh, Alexandra; Makiya, Michelle; Klion, Amy D.] NIH, Bethesda, MD 20892 USA. [Falahati, Rustom] Allakos Inc, San Carlos, CA USA. RI Falahati, Rustom/Q-4098-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 716 BP AB221 EP AB221 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600715 ER PT J AU Lyons, JJ Yu, XM Karpe, KA Treadwell, SM Ma, CA O'Connell, MP Sun, GP Hughes, JD Mehmet, H McElwee, J Holland, SM Freeman, AF Milner, JD AF Lyons, Jonathan J. Yu, Xiaomin Karpe, Kendal A. Treadwell, Shirin M. Ma, Chi A. O'Connell, Michael P. Sun, Guangping Hughes, Jason D. Mehmet, Huseyin McElwee, Joshua Holland, Steven M. Freeman, Alexandra F. Milner, Joshua D. TI Convergence of Clinical and Cellular Phenotypes Among Patients with STAT3 and ERBB2IP Mutations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Lyons, Jonathan J.; Yu, Xiaomin; Karpe, Kendal A.; Treadwell, Shirin M.; Ma, Chi A.; O'Connell, Michael P.; Sun, Guangping; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Hughes, Jason D.; Mehmet, Huseyin; McElwee, Joshua] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. OI Lyons, Jonathan/0000-0002-2346-8189 NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 497 BP AB152 EP AB152 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600496 ER PT J AU Moran, TP Nakano, H Nakano, K Cook, D AF Moran, Timothy P. Nakano, Hideki Nakano, Keiko Cook, Donald TI Inhalational Exposure to House Dust Conditions Pulmonary Conventional Dendritic Cells to Induce T Helper 2 Responses Against Innocuous Antigens SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Moran, Timothy P.] Univ N Carolina, Chapel Hill, NC USA. [Nakano, Hideki; Nakano, Keiko; Cook, Donald] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 FEB PY 2015 VL 135 IS 2 SU S MA 898 BP AB276 EP AB276 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600897 ER PT J AU Mueller, G Pedersen, L Glesner, J Edwards, LL Zakzuk, J London, R Arruda, LKP Chapman, MD Caraballo, L Pomes, A AF Mueller, Geoffrey Pedersen, Lars Glesner, Jill Edwards, Lori L. Zakzuk, Josefina London, Robert Arruda, Luisa Karla P. Chapman, Martin D. Caraballo, Luis Pomes, Anna TI Analysis of GST Allergen Cross-Reactivity in a North American Population for Molecular Diagnosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Mueller, Geoffrey; Pedersen, Lars; Edwards, Lori L.; London, Robert] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Glesner, Jill; Chapman, Martin D.; Pomes, Anna] Indoor Biotechnol Inc, Charlottesville, VA USA. [Zakzuk, Josefina; Caraballo, Luis] Univ Cartagena, Inst Immunol Res, Cartagena, Colombia. [Arruda, Luisa Karla P.] Univ Sao Paulo, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, Brazil. RI Arruda, L. Karla /D-5845-2013 OI Arruda, L. Karla /0000-0002-7505-210X NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 604 BP AB187 EP AB187 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600603 ER PT J AU Nayak, AP Green, BJ Croston, TL Lemons, AR Marshall, NB Goldsmith, WT Kashon, M Law, BF Wagner, LM Long, CM Germolec, DM Beezhold, DH AF Nayak, Ajay P. Green, Brett J. Croston, Tara L. Lemons, Angela R. Marshall, Nikki B. Goldsmith, W. Travis Kashon, Michael Law, Brandon F. Wagner, Lauren M. Long, Carrie M. Germolec, Dori M. Beezhold, Donald H. TI Characterization of Antigen Presenting Cells in a Murine Subchronic Fungal Exposure Model SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Nayak, Ajay P.; Green, Brett J.; Croston, Tara L.; Lemons, Angela R.; Marshall, Nikki B.; Law, Brandon F.; Wagner, Lauren M.; Long, Carrie M.; Beezhold, Donald H.] NIOSH, CDC, ACIB, Morgantown, WV USA. [Goldsmith, W. Travis] NIOSH, CDC, PPRB, Morgantown, WV USA. [Kashon, Michael] NIOSH, CDC, BEB, Morgantown, WV USA. [Germolec, Dori M.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 59 BP AB19 EP AB19 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600060 ER PT J AU O'Connell, MP Hox, V Nelson, C DiMaggio, T Jones, N Sackstein, P Freeman, AF Olivera, A Metcalfe, DD Milner, JD AF O'Connell, Michael P. Hox, Valerie Nelson, Celeste DiMaggio, Thomas Jones, Nina Sackstein, Paul Freeman, Alexandra F. Olivera, Ana Metcalfe, Dean D. Milner, Joshua D. TI Deficiencies in STAT3 Signaling Confers Resistance to Histamine/PAF Induced Vascular Permeability in Autosomal Dominant-Hyper IgE Syndrome (AD-HIES) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [O'Connell, Michael P.; Hox, Valerie; Nelson, Celeste; DiMaggio, Thomas; Sackstein, Paul; Olivera, Ana; Metcalfe, Dean D.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Jones, Nina] Frederick Natl Lab Clin Res, Frederick, MD USA. [Freeman, Alexandra F.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 648 BP AB200 EP AB200 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600647 ER PT J AU Pomes, A Glesner, J Woodfolk, JA Wright, P Kepley, CL Li, M Himly, M Gustchina, A Wlodawer, A Chapman, MD AF Pomes, Anna Glesner, Jill Woodfolk, Judith A. Wright, Paul Kepley, Christopher L. Li, Mi Himly, Martin Gustchina, Alla Wlodawer, Alexander Chapman, Martin D. TI Bla g 2 Hypoallergens Retaining the Native Fold and Capacity to Modulate T Cell Reactivity Provide Candidates for Cockroach Immunotherapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Pomes, Anna; Glesner, Jill; Chapman, Martin D.] Indoor Biotechnol Inc, Charlottesville, VA USA. [Woodfolk, Judith A.] Univ Virginia Hlth Syst, Div Asthma Allergy & Immunol, Charlottesville, VA USA. [Wright, Paul] Univ Virginia, Charlottesville, VA USA. [Kepley, Christopher L.] Univ N Carolina, Joint Sch Nanosci & Nanoengn, Greensboro, NC 27412 USA. [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Frederick, MD 21701 USA. [Himly, Martin] Salzburg Univ, A-5020 Salzburg, Austria. RI Himly, Martin/D-1568-2015 OI Himly, Martin/0000-0001-5416-085X NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 536 BP AB165 EP AB165 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600535 ER PT J AU Salo, PM Jaramillo, R Rose, KM Calatroni, A Mitchell, H Zeldin, DC AF Salo, Paivi M. Jaramillo, Renee Rose, Kathryn M. Calatroni, Agustin Mitchell, Herman Zeldin, Darryl C. TI Predictors of Bedroom Allergen Exposures in US Homes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, Environm Cardiopulm Dis Grp, Immun Inflammat & Dis Lab, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. [Jaramillo, Renee; Rose, Kathryn M.] Social & Sci Syst Inc, Durham, NC USA. [Calatroni, Agustin; Mitchell, Herman] Rho Inc, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 66 BP AB21 EP AB21 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600067 ER PT J AU Spergel, AKR Chen, CC Beegle, CA Littel, P Garofalo, M Anaya-O'Brien, S Marquesen, M Bagci, U Mollura, DJ Gallin, JI Malech, HL AF Spergel, Amanda K. Rudman Chen, Clara C. Beegle, Cheryl Ann Littel, Patricia Garofalo, Mary Anaya-O'Brien, Sandra Marquesen, Martha Bagci, Ulas Mollura, Daniel J. Gallin, John I. Malech, Harry L. TI The Use of Radiolabelled 18-F-2-Deoxy-2-Fluro-Glucose (18-FDG) in Combined Positron Emission Tomography-Computed Tomography (PET-CT) to Evaluate Infection: Lessons Learned from a Case Series of 23 Patients with Chronic Granulomatous Disease (CGD) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Spergel, Amanda K. Rudman; Littel, Patricia; Garofalo, Mary; Anaya-O'Brien, Sandra; Marquesen, Martha; Gallin, John I.; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.; Beegle, Cheryl Ann] NIH, Nucl Med Sect, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 316 BP AB98 EP AB98 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600316 ER PT J AU Wessell, KMR Holland, S Lisco, A Roifman, CM Tcheurekdjian, H Hostoffer, RW AF Wessell, Kathryn Marie Ruda Holland, Steven Lisco, Andrea Roifman, Chaim M. Tcheurekdjian, Haig Hostoffer, Robert W. TI A Young Adult Male with Chronic Mucocutaneous Candidiasis (CMC) with Signal Transduction and Activator of Transcription 1 (STAT 1) Mutation and Progressive Multifocal Leukoencephalopathy (PML) SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Wessell, Kathryn Marie Ruda] Univ Hosp Reg Hosp Cleveland, South Euclid, OH USA. [Holland, Steven] NIH, Bethesda, MD 20892 USA. [Lisco, Andrea] Univ Hosp Case Med Ctr Cleveland Ohio, Cleveland, OH USA. [Roifman, Chaim M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Tcheurekdjian, Haig; Hostoffer, Robert W.] Allergy Immunol Associates Inc, South Euclid, OH USA. NR 0 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 FEB PY 2015 VL 135 IS 2 SU S MA 601 BP AB186 EP AB186 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600600 ER PT J AU Williams, KW McGowan, K Sowerwine, KJ Davis, J Holland, SM Freeman, AF AF Williams, Kelli W. McGowan, Katherine Sowerwine, Kathryn J. Davis, Joie Holland, Steven M. Freeman, Alexandra F. TI Prompt Diagnosis of Autosomal Dominant Hyper IgE Syndrome Leads to Reduced Infection and Improved Clinical Phenotype SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Williams, Kelli W.; McGowan, Katherine; Davis, Joie; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sowerwine, Kathryn J.] Dermatol Specialists Virgnia, Reston, VA USA. [Freeman, Alexandra F.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 590 BP AB183 EP AB183 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600589 ER PT J AU Yang, I Liu, AH Pedersen, B O'Connor, GT Teach, SJ Kattan, M Misiak, RT Gruchalla, RS Steinbach, SF Szefler, SJ Gill, MA Calatroni, A David, GL Hennessy, CE Davidson, EJ Zhang, WM Gergen, PJ Togias, A Busse, WW Schwartz, DA AF Yang, Ivana Liu, Andrew H. Pedersen, Brent O'Connor, George T. Teach, Stephen J. Kattan, Meyer Misiak, Rana T. Gruchalla, Rebecca S. Steinbach, Suzanne F. Szefler, Stanley J. Gill, Michelle A. Calatroni, Agustin David, Gloria L. Hennessy, Corinne E. Davidson, Elizabeth J. Zhang, Weiming Gergen, Peter J. Togias, Alkis Busse, William W. Schwartz, David A. TI DNA Methylation and Childhood Asthma in the Inner-City SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Yang, Ivana] Univ Colorado Denver, Dept Med, Denver, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Aurora, CO USA. [Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Pedersen, Brent] Univ Colorado, Aurora, CO USA. [O'Connor, George T.; Steinbach, Suzanne F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Washington, DC USA. [Kattan, Meyer] NewYork Presbyterian Columbia, New York, NY USA. [Misiak, Rana T.] Henry Ford Hlth Syst, Northville, MI USA. [Gruchalla, Rebecca S.; Gill, Michelle A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Szefler, Stanley J.] Childrens Hosp Colorado, Breathing Inst, Aurora, CO USA. [Calatroni, Agustin; David, Gloria L.] Rho Inc, Chapel Hill, NC USA. [Hennessy, Corinne E.; Davidson, Elizabeth J.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Zhang, Weiming] Univ Colorado, Colorado Sch Publ Hlth, Boulder, CO 80309 USA. [Gergen, Peter J.] NIH, AAIB, DAIT, Bethesda, MD 20892 USA. [Togias, Alkis] NIAID, NIH, Bethesda, MD 20892 USA. [Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Schwartz, David A.] Univ Colorado Denver, Sch Med, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 530 BP AB163 EP AB163 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600529 ER PT J AU Yang, Q Ge, MQ Kubala, S Jiang, ZL Redai, IG Soni, M Chen, B Cohen, NA Bhandoola, A Haczku, A AF Yang, Qi Ge, Moyar Q. Kubala, Stephanie Jiang, Zhilong Redai, Imre G. Soni, Monica Chen, Bei Cohen, Noam A. Bhandoola, Avinash Haczku, Angela TI Epithelial IL-33 and TSLP Elicit Innate Lymphoid Cell Responses to Mediate Ozone-Induced Airway Inflammation and Hyperresponsiveness SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Yang, Qi; Ge, Moyar Q.; Kubala, Stephanie; Jiang, Zhilong; Redai, Imre G.; Soni, Monica; Chen, Bei] Univ Penn, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Dept Otorhinolaryngol Head & Neck, Philadelphia, PA USA. [Bhandoola, Avinash] NCI, NIH, Bethesda, MD 20892 USA. [Haczku, Angela] Univ Calif Davis, Davis, CA 95616 USA. RI Ge, Qing/N-5855-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2015 VL 135 IS 2 SU S MA 263 BP AB82 EP AB82 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600263 ER PT J AU Yin, YZ Prussin, C AF Yin, Yuzhi Prussin, Calman TI Rapamycin Preferentially Inhibits IL5+Th2 Cell Proliferation through the mTORC1/S6 Kinase Pathway SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) CY FEB 20-24, 2015 CL Houston, TX SP Amer Acad Allergy, Asthma & Immunol C1 [Yin, Yuzhi; Prussin, Calman] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2015 VL 135 IS 2 SU S MA 266 BP AB83 EP AB83 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA CR2BN UT WOS:000361129600266 ER PT J AU Cerbini, T Luo, YQ Rao, MS Zou, JZ AF Cerbini, Trevor Luo, Yongquan Rao, Mahendra S. Zou, Jizhong TI Transfection, Selection, and Colony-picking of Human Induced Pluripotent Stem Cells TALEN-targeted with a GFP Gene into the AAVS1 Safe Harbor SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Developmental Biology; Issue 96; induced pluripotent stem cell; gene editing; AAVS1; TALEN; GFP ID INTEGRATION; NUCLEASES; EXPRESSION; DISEASE AB Targeted transgene addition can provide persistent gene expression while circumventing the gene silencing and insertional mutagenesis caused by viral vector mediated random integration. This protocol describes a universal and efficient transgene targeted addition platform in human iPSCs based on utilization of validated open-source TALENs and a gene-trap-like donor to deliver transgenes into a safe harbor locus. Importantly, effective gene editing is rate-limited by the delivery efficiency of gene editing vectors. Therefore, this protocol first focuses on preparation of iPSCs for transfection to achieve high nuclear delivery efficiency. When iPSCs are dissociated into single cells using a gentle-cell dissociation reagent and transfected using an optimized program,>50% cells can be induced to take up the large gene editing vectors. Because the AAVS1 locus is located in the intron of an active gene (PPP1R12C), a splicing acceptor (SA)-linked puromycin resistant gene (PAC) was used to select targeted iPSCs while excluding random integration-only and untransfected cells. This strategy greatly increases the chance of obtaining targeted clones, and can be used in other active gene targeting experiments as well. Two weeks after puromycin selection at the dose adjusted for the specific iPSC line, clones are ready to be picked by manual dissection of large, isolated colonies into smaller pieces that are transferred to fresh medium in a smaller well for further expansion and genetic and functional screening. One can follow this protocol to readily obtain multiple GFP reporter iPSC lines that are useful for in vivo and in vitro imaging and cell isolation. C1 [Cerbini, Trevor; Luo, Yongquan; Zou, Jizhong] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zou, JZ (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM jizhong.zou@nih.gov FU NIH; Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases FX This research was supported by the NIH Common Fund and Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases. NR 19 TC 1 Z9 1 U1 1 U2 8 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD FEB PY 2015 IS 96 AR e52504 DI 10.3791/52504 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MH UT WOS:000361533700065 ER PT J AU House, CD Hernandez, L Annunziata, CM AF House, Carrie D. Hernandez, Lidia Annunziata, Christina M. TI In vitro Enrichment of Ovarian Cancer Tumor-initiating Cells SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 96; Ovarian cancer; tumor-initiating cells; cancer stem cell; tumorigenicity; spheroid; mouse; gynecological cancer ID STEM-CELLS; FALLOPIAN-TUBE; EPITHELIAL-CELLS; CD133; DEFINES; NANOG; POPULATION; RESISTANCE; CARCINOMA; IMPACT AB Evidence suggests that small subpopulations of tumor cells maintain a unique self-renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent 'floater' cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential. Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse. C1 [House, Carrie D.; Hernandez, Lidia; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. RP Annunziata, CM (reprint author), NCI, Womens Malignancies Branch, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU National Institute for General Medical Sciences FX We thank Dr. John Risinger and Memorial Health University Medical Center, Inc. for generously providing the ACI-23 cell line. The authors acknowledge financial support through the Postdoctoral Research Training (PRAT) Award to C. House from The National Institute for General Medical Sciences. NR 35 TC 1 Z9 2 U1 2 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD FEB PY 2015 IS 96 AR e52446 DI 10.3791/52446 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MH UT WOS:000361533700052 ER PT J AU Aufforth, R Boufraqech, M Li-Chittenden, Y Zhang, Y Shen, M Gaskins, K Zhang, L Kebebew, E AF Aufforth, R. Boufraqech, M. Li-Chittenden, Y. Zhang, Y. Shen, M. Gaskins, K. Zhang, L. Kebebew, E. TI Quantitative High Throughput Screening Identifies Carfilzomib as an Effective Anticancer Agent for Adrenocortical Carcinoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Aufforth, R.; Boufraqech, M.; Li-Chittenden, Y.; Gaskins, K.; Zhang, L.; Kebebew, E.] NCI, Endocrine Oncol, Washington, DC USA. [Zhang, Y.; Shen, M.] Natl Ctr Adv Translat Sci, Bethesda, MD USA. RI Boufraqech, Myriem/E-4823-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA 68 BP S29 EP S29 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500068 ER PT J AU Beane, JD Chen, I Steinberg, S Rudloff, U AF Beane, J. D. Chen, I. Steinberg, S. Rudloff, U. TI Novel Genotype-phenotype Correlations in Patients with Hereditary Diffuse Gastric Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Chen, I.; Rudloff, U.] NIH, Ctr Canc Res, GI & Thorac Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, S.] NCI, Ctr Canc Res, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Beane, J. D.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2015 VL 22 SU 1 MA P403 BP S177 EP S177 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500494 ER PT J AU Hiroshima, Y Maawy, A Zhang, Y Murakami, T De Magalhaes, N Garcia-Guzman, M Heim, R Makings, L Luiken, G Kobayashi, H Hoffman, R Bouvet, M AF Hiroshima, Y. Maawy, A. Zhang, Y. Murakami, T. De Magalhaes, N. Garcia-Guzman, M. Heim, R. Makings, L. Luiken, G. Kobayashi, H. Hoffman, R. Bouvet, M. TI Efficacy of Photoimmunotherapy after Surgical Resection on a Pancreatic Cancer Patient Derived Orthotopic Xenograft (PDOX) Nude Mouse Model SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Maawy, A.; De Magalhaes, N.; Bouvet, M.] Univ Calif San Diego, Surg, La Jolla, CA 92093 USA. [Hiroshima, Y.; Zhang, Y.; Murakami, T.; Hoffman, R.] AntiCancer Inc, San Diego, CA USA. [Garcia-Guzman, M.; Heim, R.; Makings, L.] Aspyrian Therapeut Inc, San Diego, CA USA. [Luiken, G.] OncoFluor, San Diego, CA USA. [Kobayashi, H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P393 BP S173 EP S174 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500485 ER PT J AU Schaub, N Bapiro, T Pflicke, H Chen, I Avital, I Schrump, D Jodrell, D Rudloff, U AF Schaub, N. Bapiro, T. Pflicke, H. Chen, I. Avital, I. Schrump, D. Jodrell, D. Rudloff, U. TI Gemcitabine Cooperates with TGF beta Inhibition to Effectively Suppress Tumor Growth in Genetically Engineered Mouse Models of Pancreas Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Schaub, N.; Pflicke, H.; Chen, I.; Schrump, D.; Rudloff, U.] NCI, Thorac & GI Oncol Branch, Surg Branch, NIH, Bethesda, MD 20892 USA. [Bapiro, T.; Jodrell, D.] Cambridge Res Inst, Canc Res UK, Cambridge, England. [Avital, I.] Bon Secours Canc Inst, Richmond, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2015 VL 22 SU 1 MA P411 BP S178 EP S179 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500501 ER PT J AU Schaub, N Sorber, R Janes, J Lopez, H Martin, G Rudloff, U AF Schaub, N. Sorber, R. Janes, J. Lopez, H. Martin, G. Rudloff, U. TI An Immunomodulating Peptide that Enhances Gemcitabine Inhibition of Pancreatic Growth in the KRAS/p16 Mouse Model of Pancreatic Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 68th Annual Cancer Symposium of the Society-of-Surgical-Oncology (SSO) CY MAR 25-28, 2015 CL Houston, TX SP Soc Surg Oncol C1 [Schaub, N.; Rudloff, U.] NCI, Thorac & GI Oncol Branch, Surg Branch, NIH, Bethesda, MD 20892 USA. [Sorber, R.] Indiana Univ, Dept Surg, Indianapolis, IN 46204 USA. [Janes, J.] Tuskegee Univ, Tuskegee, AL 36088 USA. [Lopez, H.] Murigenics Inc, Vallejo, CA USA. [Martin, G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2015 VL 22 SU 1 MA P407 BP S178 EP S178 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA CQ9MZ UT WOS:000360940500498 ER PT J AU Janes, K Wahlman, C Little, JW Doyle, T Tosh, DK Jacobson, KA Salvemini, D AF Janes, Kali Wahlman, Carrie Little, Joshua W. Doyle, Timothy Tosh, Dillip K. Jacobson, Kenneth A. Salvemini, Daniela TI Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A(3) adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Adenosine; A3 adenosine receptor; Neuroinflammation; Chemotherapy-induced peripheral neuropathy; Neuropathic pain; Oxaliplatin; Astrocytes; Spinal cord ID DORSAL-ROOT GANGLIA; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; HEPATOCELLULAR-CARCINOMA; INTERNATIONAL UNION; CANCER-THERAPY; UP-REGULATION; CHRONIC PAIN; TNF-ALPHA; PACLITAXEL AB Many commonly used chemotherapeutics including oxaliplatin are associated with the development of a painful chemotherapy-induced peripheral neuropathy (CIPN). This dose-limiting complication can appear long after the completion of therapy causing a significant reduction in quality-of-life and impeding cancer treatment. We recently reported that activation of the G(i)/G(q)-coupled A(3) adenosine receptor (A(3)Ag) with selective A(3)AR agonists (i.e.. IB-MECA) blocked the development of chemotherapy induced-neuropathic pain in models evoked by distinct agents including oxaliplatin without interfering with their anticancer activities. The mechanism(s) of action underlying these beneficial effects has yet to be explored. Our results herein demonstrate that the development of oxaliplatin-induced mechano-hypersensitivity (allodynia and hyperalgesia) in rats is associated with the hyperactivation of astrocytes, but not microglial cells, increased production of pro-inflammatory and neuroexcitatory cytokines (TNF, IL-1 beta), and reductions in the levels of anti-inflammatory/neuroprotective cytokines (IL-10, IL-4) in the dorsal horn of the spinal cord. These events did not require lymphocytic mobilization since oxaliplatin did not induce CD45(+)/CD3(+) T-cell infiltration into the spinal cord. A(3)AR agonists blocked the development of neuropathic pain with beneficial effects strongly associated with the modulation of spinal neuroinflammatory processes: attenuation of astrocytic hyperactivation, inhibition of TNF and IL-1 beta production, and an increase in IL-10 and IL-4. These results suggest that inhibition of an astrocyte-associated neuroinflammatory response contributes to the protective actions of A(3)AR signaling and continues to support the pharmacological basis for selective A(3)AR agonists as adjuncts to chemotherapeutic agents for the management of chronic pain. (C) 2014 Elsevier Inc. All rights reserved. C1 [Janes, Kali; Wahlman, Carrie; Little, Joshua W.; Doyle, Timothy; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Tosh, Dillip K.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Salvemini, D (reprint author), St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, 1402 South Grand Blvd, St Louis, MO 63104 USA. EM salvemd@slu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Cancer Institute [RO1CA169519]; Saint Louis Cancer Center; NIDDK Intramural Research Program FX We would like to thank Leesa Bryant for her technical assistance in performing some of the animal experiments. This study was funded by grants from the National Cancer Institute (RO1CA169519) with additional support from the Saint Louis Cancer Center, and the NIDDK Intramural Research Program. NR 72 TC 17 Z9 18 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD FEB PY 2015 VL 44 BP 91 EP 99 DI 10.1016/j.bbi.2014.08.010 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CQ4RS UT WOS:000360592900012 PM 25220279 ER PT J AU Lewis, SS Hutchinson, MR Frick, MM Zhang, YN Maier, SF Sammakia, T Rice, KC Watkins, LR AF Lewis, Susannah S. Hutchinson, Mark R. Frick, Morin M. Zhang, Yingning Maier, Steven F. Sammakia, Tarek Rice, Kenner C. Watkins, Linda R. TI Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Corticosterone; Corticosterone-21-glucuronide; Estradiol; Estradiol-17-glucuronide; Estradiol-3-glucuronide; TLR4; (+)-Naloxone ID MENSTRUAL-CYCLE; LIPOPOLYSACCHARIDE; STRESS; HYPERALGESIA; RECOGNITION; PREVALENCE; MECHANISMS; ALLODYNIA; ESTROGENS; MIGRAINE AB We have recently shown that several classes of glucuronide metabolites, including the morphine metabolite morphine-3-glucuronide and the ethanol metabolite ethyl glucuronide, cause toll like receptor 4 (TLR4)-dependent signaling in vitro and enhanced pain in vivo. Steroid hormones, including estrogens and corticosterone, are also metabolized through glucuronidation. Here we demonstrate that in silico docking predicts that corticosterone, corticosterone-21-glucuronide, estradiol, estradiol-3-glucuronide and estradiol-17-glucuronide all dock with the MD-2 component of the TLR4 receptor complex. In addition to each docking with MD-2, the docking of each was altered by pre-docking with (+)-naloxone, a TLR4 signaling inhibitor. As agonist versus antagonist activity cannot be determined from these in silico interactions, an in vitro study was undertaken to clarify which of these compounds can act in an agonist fashion. Studies using a cell line transfected with TLR4, necessary co-signaling molecules, and a reporter gene revealed that only estradiol-3-glucuronide and estradiol-17-glucuronide increased reporter gene product, indicative of TLR4 agonism. Finally, in in vivo studies, each of the 5 drugs was injected intrathecally at equimolar doses. In keeping with the in vitro results, only estradiol-3-glucuronide and estradiol-17-glucuronide caused enhanced pain. For both compounds, pain enhancement was blocked by the TLR4 antagonist lipopolysaccharide from Rhodobacter sphaeroides, evidence for the involvement in TLR4 in the resultant pain enhancement. These findings have implications for several chronic pain conditions, including migraine and temporomandibular joint disorder, in which pain episodes are more likely in cycling females when estradiol is decreasing and estradiol metabolites are at their highest. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lewis, Susannah S.; Zhang, Yingning; Maier, Steven F.; Watkins, Linda R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Frick, Morin M.; Sammakia, Tarek] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Hutchinson, Mark R.] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA, Australia. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, NIH, Rockville, MD USA. [Rice, Kenner C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Lewis, SS (reprint author), Univ Colorado, Dept Psychol, Campus Box 345, Boulder, CO 80309 USA. EM susannah.lewis@colorado.edu OI Hutchinson, Mark/0000-0003-2154-5950 FU NIH [DA023132, DA024044, DE017782]; NIH of NIDA; NIH of National Institute on Alcohol Abuse and Alcoholism; Colorado Bioscience Discovery Evaluation Grant Program FX This work was supported in part by NIH Grants DA023132, DA024044, and DE017782. This work was also supported in part by the NIH Intramural Research Programs of NIDA and National Institute on Alcohol Abuse and Alcoholism and the Colorado Bioscience Discovery Evaluation Grant Program. Mark R. Hutchinson is a NHMRC CJ Martin Fellow (ID 465423; 2007-2010) and an Australian Research Council Research Fellow (DP110100297). We thank Dr. Kirk Johnson from Avigen for the gift of the HEK-TLR4 cell line. NR 42 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 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD FEB PY 2015 VL 44 BP 128 EP 136 DI 10.1016/j.bbi.2014.09.004 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CQ4RS UT WOS:000360592900016 PM 25218902 ER PT J AU Kobayashi, H AF Kobayashi, H. TI Near infrared photoimmunotherapy: basis, applications, and beyond SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Kobayashi, H.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 34 BP 11 EP 12 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300035 ER PT J AU Nguyen, V Panyutin, IV Neumann, RD Panyutin, IG AF Nguyen, V. Panyutin, I. V. Neumann, R. D. Panyutin, I. G. TI A genomic study of alteration events caused by ionizing radiation in human embryonic stem cells via next-generation sequencing. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Nguyen, V.; Panyutin, I. V.; Neumann, R. D.; Panyutin, I. G.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 42 BP 14 EP 14 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300043 ER PT J AU Schnermann, MJ Nani, RR Gorka, AP AF Schnermann, M. J. Nani, R. R. Gorka, A. P. TI Near-IR uncaging chemistry: discovery and applications. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Schnermann, M. J.; Nani, R. R.; Gorka, A. P.] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 53 BP 17 EP 17 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300054 ER PT J AU Swenson, R Bhattacharyya, F Blackman, B Coble, V Lane, K Li, C Opina, A Sail, D Shi, ZD Vasalatiy, O Wu, H Xu, B Zhang, X Krishna, M Mitchell, J AF Swenson, R. Bhattacharyya, F. Blackman, B. Coble, V. Lane, K. Li, C. Opina, A. Sail, D. Shi, Z. -D. Vasalatiy, O. Wu, H. Xu, B. Zhang, X. Krishna, M. Mitchell, J. TI The Imaging Probe Development Center makes all types of diagnostic imaging agents. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT AACR/SNMMI Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy CY FEB 11-14, 2015 CL San Diego, CA SP Amer Assoc Canc Res, Soc Nucl Med & Mol Imaging C1 [Swenson, R.; Bhattacharyya, F.; Blackman, B.; Coble, V.; Lane, K.; Li, C.; Opina, A.; Sail, D.; Shi, Z. -D.; Vasalatiy, O.; Wu, H.; Xu, B.; Zhang, X.; Krishna, M.; Mitchell, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD FEB 1 PY 2015 VL 56 IS 2 SU 1 MA 57 BP 19 EP 19 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CP5PH UT WOS:000359935300058 ER PT J AU Broker, J Schindeldecker, B Guzmann, R Weissgerber, P Schwarz, Y Dietrich, A Birnbaumer, L Flockerzi, V Mathar, I Bruns, D Freichel, M AF Broeker, J. Schindeldecker, B. Guzmann, R. Weissgerber, P. Schwarz, Y. Dietrich, A. Birnbaumer, L. Flockerzi, V. Mathar, I. Bruns, D. Freichel, M. TI Functional analysis of TRPC1/TRPC4/TRPC5 channel proteins in the hippocampus SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 81st Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und -Toxikologie-e-V CY MAR 10-12, 2015 CL Kiel, GERMANY SP Deutsch Gesell Experimentelle & Klinische Pharmakologie & Pharmakologie e V C1 [Broeker, J.; Mathar, I.; Freichel, M.] Heidelberg Univ, Inst Pharmakol, D-69115 Heidelberg, Germany. [Schindeldecker, B.; Guzmann, R.; Schwarz, Y.; Bruns, D.] Univ Saarland, Mol Neurophysiol, Homburg, Germany. [Weissgerber, P.; Flockerzi, V.] Univ Saarland, Expt & Klin Pharmakol & Toxikol, Homburg, Germany. [Dietrich, A.] Univ Munich, Walther Straub Inst Pharmakol & Toxikol, D-80539 Munich, Germany. [Birnbaumer, L.] NIH, Neurobiol Lab, Transmembrane Signaling Grp, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 EI 1432-1912 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD FEB PY 2015 VL 388 SU 1 MA 058 BP S16 EP S16 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP0AV UT WOS:000359539100059 ER PT J AU Londono, JEC Tian, Q Hammer, K Londono, JC Reil, J Oberhofer, M Mannebach, S Mathar, I Philipp, S Tabellion, W Schwede, F Dietrich, A Kastner, L Laufs, U Birnbaumer, L Flockerzi, V Lipp, P Freichel, M AF Londono, Camacho J. E. Tian, Q. Hammer, K. Londono, Camacho J. Reil, J. Oberhofer, M. Mannebach, S. Mathar, I Philipp, S. Tabellion, W. Schwede, F. Dietrich, A. Kaestner, L. Laufs, U. Birnbaumer, L. Flockerzi, V Lipp, P. Freichel, M. TI The development of cardiac hypertrophy is critically regulated by a Background Ca2+ Entry (BGCE) pathway mediated by TRPC1/TRPC4 SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 81st Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und -Toxikologie-e-V CY MAR 10-12, 2015 CL Kiel, GERMANY SP Deutsch Gesell Experimentelle & Klinische Pharmakologie & Pharmakologie e V C1 [Londono, Camacho J. E.; Mathar, I; Freichel, M.] Heidelberg Univ, Pharmakol Inst, D-69115 Heidelberg, Germany. [Londono, Camacho J. E.; Freichel, M.] DZHK German Ctr Cardiovasc Res, Berlin, Germany. [Tian, Q.; Hammer, K.; Oberhofer, M.; Tabellion, W.; Kaestner, L.; Lipp, P.] Univ Saarland, Inst Mol Zellbiol, Homburg, Germany. [Londono, Camacho J.; Mannebach, S.; Philipp, S.; Flockerzi, V] Univ Saarland, Expt & Klin Pharmakol & Toxikol, Homburg, Germany. [Reil, J.; Laufs, U.] Univ Saarland, Innere Med 3, Homburg, Germany. [Schwede, F.] Univ Regensburg, Inst Physiol, D-93053 Regensburg, Germany. [Dietrich, A.] Univ Munich, Walther Straub Inst Pharmakol & Toxikol, D-80539 Munich, Germany. [Birnbaumer, L.] NIEHS, Transmembrane Signaling Grp, Res Triangle Pk, NC 27709 USA. RI Kaestner, Lars/P-6988-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 EI 1432-1912 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD FEB PY 2015 VL 388 SU 1 MA 132 BP S33 EP S33 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CP0AV UT WOS:000359539100133 ER PT J AU Hong, B Le Gallo, M Bell, DW AF Hong, Bo Le Gallo, Matthieu Bell, Daphne W. TI The mutational landscape of endometrial cancer SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID UTERINE SEROUS CARCINOMA; GERMLINE PTEN MUTATIONS; TUMOR TYPES; MICROSATELLITE INSTABILITY; GENES; IDENTIFICATION; SIGNATURES; POLE AB Globally, endometrial carcinoma causes about 74000 deaths annually. Endometrial carcinomas can be classified into several histological subtypes including endometrioid and serous histologies. Over the course of the past two years, a number of studies have decoded the exomes of endometrioid and serous endometrial carcinomas revealing novel somatically mutated genes that are likely to drive their development. Moreover, an integrated genomic analysis of these two histological subtypes by The Cancer Genome Atlas has led to their molecular reclassification into four discrete molecular subgroups. Collectively, these genomic advances set the stage for future biological and clinical studies to determine their relevance for patient care. C1 [Hong, Bo; Le Gallo, Matthieu; Bell, Daphne W.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. RP Bell, DW (reprint author), NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute at NIH FX All authors are funded by the Intramural Research Program of the National Human Genome Research Institute at NIH. NR 36 TC 11 Z9 11 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD FEB PY 2015 VL 30 BP 25 EP 31 DI 10.1016/j.gde.2014.12.004 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA CM1KL UT WOS:000357439700004 PM 25622247 ER PT J AU Musci, RJ Masyn, KE Uhl, G Maher, B Kellam, SG Ialongo, NS AF Musci, Rashelle J. Masyn, Katherine E. Uhl, George Maher, Brion Kellam, Sheppard G. Ialongo, Nicholas S. TI Polygenic Score x Intervention Moderation: An application of discrete-time survival analysis to modeling the timing of first tobacco use among urban youth SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID ANTISOCIAL PERSONALITY-DISORDER; RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; DIFFERENTIAL SUSCEPTIBILITY; NICOTINE DEPENDENCE; SMOKING-CESSATION; ELEMENTARY-SCHOOL; MARIJUANA USE; PREVENTIVE INTERVENTIONS; ENVIRONMENTAL-INFLUENCES AB The present study examines the interaction between a polygenic score and an elementary school-based universal preventive intervention trial. The polygenic score reflects the contribution of multiple genes and has been shown in prior research to be predictive of smoking cessation and tobacco use (Uhl et al., 2014). Using data from a longitudinal preventive intervention study, we examined age of first tobacco use from sixth grade to age 18. Genetic data were collected during emerging adulthood and were genotyped using the Affymetrix 6.0 microarray. The polygenic score was computed using these data. Discrete-time survival analysis was employed to test for intervention main and interaction effects with the polygenic score. We found a main effect of the intervention, with the intervention participants reporting their first cigarette smoked at an age significantly later than controls. We also found an Intervention x Polygenic Score interaction, with participants at the higher end of the polygenic score benefitting the most from the intervention in terms of delayed age of first use. These results are consistent with Belsky and colleagues' (e.g., Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2007; Belsky & Pleuss, 2009, 2013; Ellis, Boyce, Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2011) differential susceptibility hypothesis and the concept of for better or worse, wherein the expression of genetic variants are optimally realized in the context of an enriched environment, such as provided by a preventive intervention. C1 [Musci, Rashelle J.; Maher, Brion; Kellam, Sheppard G.; Ialongo, Nicholas S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Masyn, Katherine E.] Harvard Univ, Grad Sch Educ, Cambridge, MA 02138 USA. [Uhl, George] NIDA, NIH, IRP, Mol Neurobiol Branch, Bethesda, MD 20892 USA. RP Musci, RJ (reprint author), Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, 624 North 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] FX This research was supported by Grants MH57005 and T32 MH18834 from the National Institute of Mental Health (to N.S.I.) and Grant NIDA R37 DA11796 from the National Institute on Drug Abuse (to N.S.I.). NR 88 TC 2 Z9 3 U1 5 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FEB PY 2015 VL 27 IS 1 SI SI BP 111 EP 122 DI 10.1017/S0954579414001333 PG 12 WC Psychology, Developmental SC Psychology GA CH5WL UT WOS:000354106300009 PM 25640834 ER PT J AU Nussinov, R Tsai, CJ AF Nussinov, Ruth Tsai, Chung-Jung TI Allostery without a conformational change? Revisiting the paradigm SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID CATABOLITE ACTIVATOR PROTEIN; CAP-DNA COMPLEX; ENERGY LANDSCAPES; COUPLED RECEPTOR; BINDING CASCADES; STRUCTURAL BASIS; PLAUSIBLE MODEL; HEMOGLOBIN; MECHANISM; DYNAMICS AB Classically, allostery induces a functional switch through a conformational change. However, lately an increasing number of studies concluded that the allostery they observe takes place through sheer dynamics. Here we explain that even if a structural comparison between the active and inactive states does not detect a conformational change, it does not mean that there is no conformational change. We list likely reasons for this lack of observation, including crystallization conditions and crystal effects; one of the states is disordered; the structural comparisons disregard the quaternary protein structure; overlooking synergy effects among allosteric effectors and graded incremental switches and too short molecular dynamics simulations. Specific functions are performed by distinct conformations; they emerge through specific interactions between conformationally selected states. C1 [Nussinov, Ruth; Tsai, Chung-Jung] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM NussinoR@helix.nih.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 65 TC 38 Z9 39 U1 6 U2 34 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2015 VL 30 BP 17 EP 24 DI 10.1016/j.sbi.2014.11.005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CI2PF UT WOS:000354588800005 PM 25500675 ER PT J AU Fang, XY Stagno, JR Bhandari, YR Zuo, XB Wang, YX AF Fang, Xianyang Stagno, Jason R. Bhandari, Yuba R. Zuo, Xiaobing Wang, Yun-Xing TI Small-angle X-ray scattering: a bridge between RNA secondary structures and three-dimensional topological structures SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID REV-RESPONSE ELEMENT; TIME-RESOLVED SAXS; BIOLOGICAL MACROMOLECULES; MOLECULAR-STRUCTURE; SHAPE DETERMINATION; RESOLUTION; PROTEIN; COMPLEX; BINDING; HIV-1 AB Whereas the structures of small to medium-sized well folded RNA molecules often can be determined by either X-ray crystallography or NMR spectroscopy, obtaining structural information for large RNAs using experimental, computational, or combined approaches remains a major interest and challenge. RNA is very sensitive to small-angle X-ray scattering (SAXS) due to high electron density along phosphate-sugar backbones, whose scattering contribution dominates SAXS intensity. For this reason, SAXS is particularly useful in obtaining global RNA structural information that outlines backbone topologies and, therefore, molecular envelopes. Such information is extremely valuable in bridging the gap between the secondary structures and three-dimensional topological structures of RNA molecules, particularly those that have proven difficult to study using other structure-determination methods. Here we review published results of RNA topological structures derived from SAXS data or in combination with other experimental data, as well as details on RNA sample preparation for SAXS experiments. C1 [Fang, Xianyang; Wang, Yun-Xing] Natl Canc Inst, NCI Small Angle Xray Scattering Core Facil, Struct Biophys Lab, NIH, Rockville, MD 20850 USA. [Stagno, Jason R.; Bhandari, Yuba R.; Wang, Yun-Xing] Natl Canc Inst, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Rockville, MD USA. [Zuo, Xiaobing] Argonne Natl Lab, Adv Photon Source, Argonne, IL 60439 USA. RP Wang, YX (reprint author), Natl Canc Inst, NCI Small Angle Xray Scattering Core Facil, Struct Biophys Lab, NIH, Rockville, MD 20850 USA. EM wangyunx@mail.nih.gov OI Zuo, Xiaobing/0000-0002-0134-4804 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research; U.S. DOE [DE-AC02-06CH11357]; NCI [PUP-77]; Argonne National Laboratory [PUP-77] FX We sincerely thank David Lilley, Samuel Butcher, Marc Jamin, Norman Pace, Alexei Kazanstev, Ajaykumar Gopal and William Gelbart for providing materials for figures. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357 and by NCI under the PUP-77 Agreement between NCI and Argonne National Laboratory. NR 94 TC 7 Z9 7 U1 1 U2 21 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2015 VL 30 BP 147 EP 160 DI 10.1016/j.sbi.2015.02.010 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CI2PF UT WOS:000354588800019 PM 25765781 ER PT J AU Bolnick, AD Bolnick, JM Singh, M Fritz, R Kilburn, BA Simmerman, N Drewlo, S Diamond, MP Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Singh, Manvinder Fritz, Rani Kilburn, Brian A. Simmerman, Neil Drewlo, Sascha Diamond, Michael P. Armant, D. Randall TI Trophoblast Retrieval and Isolation from the Cervix (TRIC) for Non-Invasive First Trimester Fetal Gender Determination in a Carrier of Congenital Adrenal Hyperplasia SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 63rd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) on Building Connections, Achieving Excellence CY MAR 11-15, 2015 CL Rancho Mirage, CA SP Pacific Coast Reprod Soc C1 [Bolnick, Alan D.; Bolnick, Jay M.; Singh, Manvinder; Fritz, Rani; Kilburn, Brian A.; Simmerman, Neil; Drewlo, Sascha; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2015 VL 103 IS 2 SU S MA P-10 BP E13 EP E13 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CH2GJ UT WOS:000353843400019 ER PT J AU Bolnick, AD Bolnick, JM Kilburn, BA Barrak, C Jain, C Singhi, P Diamond, MP Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Kilburn, Brian A. Barrak, Charbel Jain, Chandni Singhi, Pooja Diamond, Michael P. Armant, D. Randall TI Clarifying the Role of MAP Kinases in the Molecular Pathway That Regulates HBEGF Mobilization for Trophoblast Survival at Low O-2 during the First Trimester of Pregnancy SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 63rd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) on Building Connections, Achieving Excellence CY MAR 11-15, 2015 CL Rancho Mirage, CA SP Pacific Coast Reprod Soc C1 [Bolnick, Alan D.; Bolnick, Jay M.; Kilburn, Brian A.; Barrak, Charbel; Jain, Chandni; Singhi, Pooja; Armant, D. Randall] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Armant, D. Randall] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2015 VL 103 IS 2 SU S MA P-11 BP E13 EP E13 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CH2GJ UT WOS:000353843400020 ER PT J AU Lim, JA Li, LS Kakhlon, O Myerowitz, R Raben, N AF Lim, Jeong-A Li, Lishu Kakhlon, Or Myerowitz, Rachel Raben, Nina TI Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease SO AUTOPHAGY LA English DT Article DE autophagy; calcium; lysosome; mitochondria; mitophagy; Pompe disease ID LYSOSOMAL STORAGE DISEASE; APOPTOSIS-INDUCING FACTOR; ACID MALTASE DEFICIENCY; KINASE KINASE-BETA; SKELETAL-MUSCLE; MOUSE MODEL; AUTOPHAGOSOME FORMATION; DAMAGED MITOCHONDRIA; OXIDATIVE STRESS; CLINICAL-TRIALS AB Mitochondria-induced oxidative stress and flawed autophagy are common features of neurodegenerative and lysosomal storage diseases (LSDs). Although defective autophagy is particularly prominent in Pompe disease, mitochondrial function has escaped examination in this typical LSD. We have found multiple mitochondrial defects in mouse and human models of Pompe disease, a life-threatening cardiac and skeletal muscle myopathy: a profound dysregulation of Ca2+ homeostasis, mitochondrial Ca2+ overload, an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, an increase in caspase-independent apoptosis, as well as a decreased oxygen consumption and ATP production of mitochondria. In addition, gene expression studies revealed a striking upregulation of the beta 1 subunit of L-type Ca2+ channel in Pompe muscle cells. This study provides strong evidence that disturbance of Ca2+ homeostasis and mitochondrial abnormalities in Pompe disease represent early changes in a complex pathogenetic cascade leading from a deficiency of a single lysosomal enzyme to severe and hard-to-treat autophagic myopathy. Remarkably, L-type Ca2+ channel blockers, commonly used to treat other maladies, reversed these defects, indicating that a similar approach can be beneficial to the plethora of lysosomal and neurodegenerative disorders. C1 [Lim, Jeong-A; Li, Lishu; Myerowitz, Rachel; Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Kakhlon, Or] Hadassah Hebrew Univ, Med Ctr, Dept Neurol, Jerusalem, Israel. [Myerowitz, Rachel] St Marys Coll Maryland, St Marys City, MD 20686 USA. RP Raben, N (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. EM rabenn@mail.nih.gov RI Li, Lishu /J-3191-2015 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health; CRADA; Acid Maltase Deficiency Association FX This research 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. Dr. Lim and Dr. Li are supported in part by a CRADA between NIH and Genzyme Corporation and from the Acid Maltase Deficiency Association. NR 95 TC 8 Z9 8 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD FEB PY 2015 VL 11 IS 2 BP 385 EP 402 DI 10.1080/15548627.2015.1009779 PG 18 WC Cell Biology SC Cell Biology GA CF8AX UT WOS:000352778700016 PM 25758767 ER PT J AU Federoff, M Schottlaender, LV Houlden, H Singleton, A AF Federoff, Monica Schottlaender, Lucia V. Houlden, Henry Singleton, Andrew TI Multiple system atrophy: the application of genetics in understanding etiology SO CLINICAL AUTONOMIC RESEARCH LA English DT Review DE Genome-wide association; Linkage analysis; Genetic risk; Mutation ID PROGRESSIVE SUPRANUCLEAR PALSY; MYOTONIC-DYSTROPHY TYPE-2; COPY-NUMBER-VARIATION; ALPHA-SYNUCLEIN GENE; AMYOTROPHIC-LATERAL-SCLEROSIS; GLIAL CYTOPLASMIC INCLUSIONS; FAMILIAL PARKINSONS-DISEASE; TRANSGENIC MOUSE MODEL; REVEALS NO ASSOCIATION; MICROGLIAL ACTIVATION AB Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies. C1 [Federoff, Monica; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Federoff, Monica; Schottlaender, Lucia V.; Houlden, Henry] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. RP Singleton, A (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM h.houlden@ion.ucl.ac.uk; singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000958] FX The authors work is supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000958. NR 150 TC 0 Z9 1 U1 1 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0959-9851 EI 1619-1560 J9 CLIN AUTON RES JI Clin. Auton. Res. PD FEB PY 2015 VL 25 IS 1 SI SI BP 19 EP 36 DI 10.1007/s10286-014-0267-5 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CG4VW UT WOS:000353286500004 PM 25687905 ER PT J AU Goldstein, DS Kopin, IJ Sharabi, Y Holmes, C AF Goldstein, David S. Kopin, Irwin J. Sharabi, Yehonatan Holmes, Courtney TI Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the parkinsonian form of multiple system atrophy SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE Parkinson disease; Biomarker; Multiple system atrophy; Orthostatic hypotension; Autonomic; Sympathetic; Fluorodopamine ID CARDIAC SYMPATHETIC INNERVATION; CATECHOLS; HUMANS AB Parkinson disease with orthostatic hypotension (PD + OH) and the parkinsonian form of multiple system atrophy (MSA-P) can be difficult to distinguish clinically. Recent studies indicate that PD entails a vesicular storage defect in catecholaminergic neurons. Although cardiac sympathetic neuroimaging by F-18-dopamine positron emission tomography can identify decreased vesicular storage, this testing is not generally available. We assessed whether plasma biomarkers of a vesicular storage defect can separate PD + OH from MSA-P. We conceptualized that after F-dopamine injection, augmented production of F-dihydroxyphenylacetic acid (F-DOPAC) indicates decreased vesicular storage, and we therefore predicted that arterial plasma F-DOPAC would be elevated in PD + OH but not in MSA-P. We measured arterial plasma F-DOPAC after F-18-dopamine administration (infused i.v. over 3 min) in patients with PD + OH (N = 12) or MSA-P (N = 21) and in healthy control subjects (N = 26). Peak F-DOPAC:dihydroxyphenylglycol (DHPG) was also calculated to adjust for effects of denervation on F-DOPAC production. Plasma F-DOPAC accumulated rapidly after initiation of F-18-dopamine infusion. Peak F-DOPAC (5-10 min) in PD + OH averaged three times that in MSA-P (P < 0.0001). Among MSA-P patients, none had peak F-DOPAC > 300 nCi-kg/cc-mCi, in contrast with 7 of 12 PD + OH patients (chi (2) = 16.6, P < 0.0001). DHPG was lower in PD + OH (3.83 +/- A 0.36 nmol/L) than in MSA-P (5.20 +/- A 0.29 nmol/L, P = 0.007). All MSA-P patients had peak F-DOPAC:DHPG < 60, in contrast with 9 of 12 PD + OH patients (chi (2) = 17.5, P < 0.0001). Adjustment of peak F-DOPAC for DHPG increased test sensitivity from 58 to 81 % at similar high specificity. After F-dopamine injection, plasma F-DOPAC and F-DOPAC:DHPG distinguish PD + OH from MSA-P. C1 [Goldstein, David S.; Kopin, Irwin J.; Holmes, Courtney] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Tel Aviv Univ, Chaim Sheba Med Ctr, Tel Hashomer, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, 10 Ctr Dr MSC-1620,Bldg 10 Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU NIH, National Institute of Neurological Disorders and Stroke FX Authors acknowledge the support of the intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. NR 14 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0959-9851 EI 1619-1560 J9 CLIN AUTON RES JI Clin. Auton. Res. PD FEB PY 2015 VL 25 IS 1 SI SI BP 61 EP 67 DI 10.1007/s10286-015-0268-z PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CG4VW UT WOS:000353286500008 PM 25638582 ER PT J AU Wen, L Shi, YB AF Wen, Luan Shi, Yun-Bo TI Unliganded Thyroid Hormone Receptor alpha Controls Developmental Timing in Xenopus tropicalis SO ENDOCRINOLOGY LA English DT Article ID EFFECTOR NUCLEASES TALENS; RETINOIC ACID RECEPTORS; INTESTINAL STEM-CELLS; IN-VIVO ANALYSIS; AMPHIBIAN METAMORPHOSIS; BETA GENE; POSTEMBRYONIC DEVELOPMENT; MEDIATED TRANSCRIPTION; LAEVIS METAMORPHOSIS; HISTONE ACETYLATION AB Thyroid hormone (T-3) affects adult metabolism and postembryonic development in vertebrates. T-3 functions mainly via binding to its receptors (TRs) to regulate gene expression. There are 2 TR genes, TR alpha and TR beta, with TR alpha more ubiquitously expressed. During development, TR alpha expression appears earlier than T-3 synthesis and secretion into the plasma. This and the ability of TRs to regulate gene expression both in the presence and absence of T-3 have indicated a role for unliganded TR during vertebrate development. On the other hand, it has been difficult to study the role of unliganded TR during development in mammals because of the difficulty to manipulate the uterus-enclosed, late-stage embryos. Here we use amphibian development as a model to address this question. We have designed transcriptional activator-like effector nucleases (TALENs) to mutate the TR alpha gene in Xenopus tropicalis. We show that knockdown of TR alpha enhances tadpole growth in premetamorphic tadpoles, in part because of increased growth hormone gene expression. More importantly, the knockdown also accelerates animal development, with the knockdown animals initiating metamorphosis at a younger age and with a smaller body size. On the other hand, such tadpoles are resistant to exogenous T3 treatment and have delayed natural metamorphosis. Thus, our studies not only have directly demonstrated a critical role of endogenous TR alpha in mediating the metamorphic effect of T-3 but also revealed novel functions of unliganded TR alpha during postembryonic development, that is, regulating both tadpole growth rate and the timing of metamorphosis. C1 [Wen, Luan; Shi, Yun-Bo] NICHHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 86 TC 15 Z9 15 U1 2 U2 8 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 FEB PY 2015 VL 156 IS 2 BP 721 EP 734 DI 10.1210/en.2014-1439 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG2UV UT WOS:000353131800030 PM 25456066 ER PT J AU Burotto, M Tageja, N Rosenberg, A Mahalingam, S Quezado, M Velarde, M Edgerly, M Fojo, T AF Burotto, Mauricio Tageja, Nishant Rosenberg, Avi Mahalingam, Sowmya Quezado, Martha Velarde, Margarita Edgerly, Maureen Fojo, Tito TI Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CANCER-PATIENTS; MANAGEMENT; RECURRENT; SURVIVAL; UPDATE; CHILD AB Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. C1 [Burotto, Mauricio; Tageja, Nishant; Velarde, Margarita; Edgerly, Maureen; Fojo, Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rosenberg, Avi; Quezado, Martha] NCI, Natl Lab Pathol, NIH, Bethesda, MD 20892 USA. [Mahalingam, Sowmya] George Washington Univ, Rockville, MD 20852 USA. RP Burotto, M (reprint author), NCI, Ctr Canc Res, 10 Ctr Dr 12N226, Bethesda, MD 20892 USA. EM mauricio.burottopichun@nih.gov OI Rosenberg, Avi/0000-0003-2356-950X NR 22 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP 331 EP 336 DI 10.1210/jc.2014-2650 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900032 PM 25412413 ER PT J AU Raff, H Auchus, RJ Findling, JW Nieman, LK AF Raff, Hershel Auchus, Richard J. Findling, James W. Nieman, Lynnette K. TI Urine Free Cortisol in the Diagnosis of Cushing's Syndrome: Is It Worth Doing and, If So, How? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID TANDEM MASS-SPECTROMETRY; NIGHT SALIVARY CORTISOL; DISCOVERY C1 [Raff, Hershel] Med Coll Wisconsin, Dept Med, Dept Surg, Milwaukee, WI 53226 USA. [Raff, Hershel] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Raff, Hershel] Aurora St Lukes Med Ctr, Endocrine Res Lab, Milwaukee, WI 53215 USA. [Auchus, Richard J.] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Findling, James W.] Med Coll Wisconsin, Endocrinol Ctr & Clin, Milwaukee, WI 53226 USA. [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Raff, H (reprint author), Aurora St Lukes Med Ctr, Endocrinol, 2801 West Kinnickinnic River Pkwy,Suite 245, Milwaukee, WI 53215 USA. EM hraff@mcw.edu FU Intramural NIH HHS; NIDDK NIH HHS [P30 DK020572] NR 14 TC 15 Z9 15 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP 395 EP 397 DI 10.1210/jc.2014-3766 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900039 PM 25423573 ER PT J AU Rao, JU Engelke, UFH Sweep, FCGJ Pacak, K Kusters, B Goudswaard, AG Hermus, ARMM Mensenkamp, AR Eisenhofer, G Qin, N Richter, S Kunst, HPM Timmers, HJLM Wevers, RA AF Rao, J. U. Engelke, U. F. H. Sweep, F. C. G. J. Pacak, K. Kusters, B. Goudswaard, A. G. Hermus, A. R. M. M. Mensenkamp, A. R. Eisenhofer, G. Qin, N. Richter, S. Kunst, H. P. M. Timmers, H. J. L. M. Wevers, R. A. TI Genotype-Specific Differences in the Tumor Metabolite Profile of Pheochromocytoma and Paraganglioma Using Untargeted and Targeted Metabolomics SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PURINE METABOLISM; IN-VIVO; H-1-NMR AB Context and Objective: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs. Design: Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton (H-1) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling. Results: 1H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes. Conclusions: The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs. C1 [Rao, J. U.; Engelke, U. F. H.; Sweep, F. C. G. J.; Goudswaard, A. G.; Wevers, R. A.] Radboud Univ Nijmegen, Lab Genet Endocrine & Metab Dis, Dept Lab Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Rao, J. U.; Hermus, A. R. M. M.; Timmers, H. J. L. M.] Radboud Univ Nijmegen, Endocrinol Sect, Dept Internal Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Kusters, B.] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands. [Mensenkamp, A. R.] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6525 ED Nijmegen, Netherlands. [Eisenhofer, G.; Qin, N.; Richter, S.] Univ Hosp Carl Gustav Carus, Dept Med, Dresden, Germany. [Eisenhofer, G.; Qin, N.; Richter, S.] Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany. [Kunst, H. P. M.] Radboud Univ Nijmegen, Dept Otolaryngol, NL-6525 ED Nijmegen, Netherlands. [Kusters, B.] Maastricht Univ, Med Ctr, Dept Pathol, NL-6200 MD Maastricht, Netherlands. RP Wevers, RA (reprint author), Radboud Univ Med, Lab Genet Endocrine & Metab Dis, Dept Lab Med, Route 830,Ctr Geert Grootepl 10, NL-6525 GA Nijmegen, Netherlands. EM ron.wevers@radboudumc.nl RI Kunst, Henricus/J-6456-2012; Wevers, Ron/H-8116-2014; Hermus, A.R.M.M./H-8043-2014; Engelke, U.F.H./L-4293-2015; Mensenkamp, A.R./L-4520-2015; Sweep, C.G.J./H-8096-2014; Kusters, B./L-4465-2015 OI Wevers, Ron/0000-0003-2278-9746; FU European Union Seventh Framework Programme (FP7) (ENSAT CANCER) [259735] FX The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant No. 259735 (ENSAT CANCER). NR 19 TC 9 Z9 9 U1 0 U2 7 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP E214 EP E222 DI 10.1210/jc.2014-2138 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900011 PM 25459911 ER PT J AU Reich, A Bae, AS Barnes, AM Cabral, WA Hinek, A Stimec, J Hill, SC Chitayat, D Marini, JC AF Reich, Adi Bae, Alison S. Barnes, Aileen M. Cabral, Wayne A. Hinek, Aleksander Stimec, Jennifer Hill, Suvimol C. Chitayat, David Marini, Joan C. TI Type V OI Primary Osteoblasts Display Increased Mineralization Despite Decreased COL1A1 Expression SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IMPERFECTA TYPE-V; OSTEOGENESIS-IMPERFECTA; PHENOTYPIC VARIABILITY; HYPERPLASTIC CALLUS; IFITM5 MUTATION; I COLLAGEN; DEFICIENCY; DEPOSITION; SERPINF1; 5'-UTR AB Context: Patients with type V osteogenesis imperfecta (OI) are heterozygous for a dominant IFITM5c.-14C>T mutation, which adds five residues to the N terminus of bone-restricted inter-feron-induced transmembrane-like protein (BRIL), a transmembrane protein expressed in osteoblasts. Type VOI skeletal findings include hyperplastic callus formation, ossification of the forearm interosseous membrane, and dense metaphyseal bands. Objective: The objective of this study was to examine the role of osteoblasts in the active mineralization traits of type V OI and the effect of the IFITM5 mutation on type I collagen. Methods: We identified eight patients with the IFITM5c.-14C>T mutation. Cultured osteoblasts from type V OI patients were used to study osteoblast differentiation and mineralization. Results: We verified the expression and stability of mutant IFITM5 transcripts. In differentiated type V OI primary osteoblasts in culture, the IFITM5 expression and BRIL level is comparable with control. Both early and late markers of osteoblast differentiation are increased in type V OI osteoblasts. Mineralization, assayed by alizarin red staining, was increased in type V OI osteoblasts compared with control. However, type V OI osteoblasts have significantly decreased COL1A1 transcripts in mid-to late differentiation. Type I collagen protein is concomitantly decreased, with decreased cross-linked collagen in matrix and altered appearance of fibrils deposited in culture. Conclusions: This study demonstrates that type V OI mineralization has a gain-of-function mechanism at the osteoblast level, which likely underlies the overactive tissue mineralization seen in patients. Decreased type I collagen expression, secretion, and matrix incorporation establish type V OI as a collagen-related defect. C1 [Reich, Adi; Bae, Alison S.; Barnes, Aileen M.; Cabral, Wayne A.; Marini, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bone & Extracellular Matrix Branch, Bethesda, MD 20892 USA. [Hill, Suvimol C.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Hinek, Aleksander] Univ Toronto, Hosp Sick Children, Ctr Heart, Expt Med Program, Toronto, ON M5S 3OA4, Canada. [Stimec, Jennifer] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Diagnost Imaging, Toronto, ON M5G 1X8, Canada. [Chitayat, David] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Chitayat, David] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1Z5, Canada. RP Marini, JC (reprint author), Bone & Extracellular Matrix Branch, Bldg 10,Room 10D39,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding (to J.C.M.). NR 35 TC 5 Z9 5 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP E325 EP E332 DI 10.1210/jc.2014-3082 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900026 PM 25387264 ER PT J AU Sklavos, MM Stratton, P Giri, N Alter, BP Savage, SA Pinto, LA AF Sklavos, Martha M. Stratton, Pamela Giri, Neelam Alter, Blanche P. Savage, Sharon A. Pinto, Ligia A. TI Reduced Serum Levels of Anti-Mullerian Hormone in Females With Inherited Bone Marrow Failure Syndromes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; PRIMARY OVARIAN INSUFFICIENCY; ANTIMULLERIAN HORMONE; DYSKERATOSIS-CONGENITA; MENSTRUAL-CYCLE; FANCONI-ANEMIA; RESERVE; TRANSPLANTATION; CANCER; CHEMOTHERAPY AB Context: Previously, reduced levels of anti-Mullerian hormone (AMH), a circulating marker of ovarian reserve, were found in females with Fanconi anemia (FA). FA, dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) associated with high risks of bone marrow failure, leukemia, and solid tumors. Objective: The objective of the study was to assess AMH levels in females with DC or DBA. Design and Setting: This observational study used the National Cancer Institute's inherited bone marrow failure syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included females with DC, unaffected female relatives of patients with DC, females with DBA, unaffected female relatives of patients with DBA, and unrelated healthy female volunteers younger than 41 years of age. Main Outcome measure: Serum AMH levels were measured. Results: Females with DC had significantly lower levels of AMH(median 0.55 ng/mL) compared with unaffected relatives (median 2.28 ng/mL, P = .004) or unrelated healthy volunteers (median 2.69 ng/mL, P = .005). Females with DBA showed a nonsignificant trend for lower levels of AMH(median 0.89 ng/mL) compared with unaffected relatives (median 1.71 ng/mL, P = .21) or unrelated healthy volunteers (P = .11). Patients with DC and DBA had significantly higher levels of AMH (P = .013, P = .003) compared with FA (median 0.05 ng/mL). Conclusions: Our findings suggest that women with IBMFS have lower levels of AMH than unaffected women. This AMH deficiency could be a primary ovarian defect or a consequence of the pathophysiology of the syndromes. Additional studies of AMH and ovarian function in women with IBMFS are warranted to better understand the underlying biology. C1 [Sklavos, Martha M.; Pinto, Ligia A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Human Papillomavirus Immunol Lab, Frederick, MD 21702 USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Pinto, LA (reprint author), Leidos Biomed Res Inc, Human Papillomavirus Immunol Lab, Bldg 469,Room 111,1050 Boyles St, Frederick, MD 21702 USA. EM pintol@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Fanconi Anemia Research Fund; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute of the National Institutes of Health; National Institutes of Health Clinical Center; Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Westat, Inc. [N02-CP-91026, N02-CP-11019, HHSN261200655001C]; National Cancer Institute of the National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the Fanconi Anemia Research Fund (fanconi.org) (to N.G.); in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute of the National Institutes of Health (to B.P.A. and N.G.), the National Institutes of Health Clinical Center, and the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study was also supported by Contracts N02-CP-91026, N02-CP-11019, and HHSN261200655001C from Westat, Inc. This project also has been funded in whole or in part with federal funds from the National Cancer Institute of the National Institutes of Health under Contract HHSN261200800001E. NR 36 TC 1 Z9 1 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP E197 EP E203 DI 10.1210/jc.2014-2838 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900009 PM 25405500 ER PT J AU Marx, SJ AF Marx, Stephen J. TI Letter to the Editor: Distinguishing Typical Primary Hyperparathyroidism From Familial Hypocalciuric Hypercalcemia by Using an Index of Urinary Calcium SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Letter ID 4TH INTERNATIONAL WORKSHOP C1 NIDDK, Genet & Endocrinol Sect, NIH, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIDDK, Genet & Endocrinol Sect, NIH, Bethesda, MD 20892 USA. EM marxs@mail.nih.gov FU Intramural NIH HHS NR 9 TC 2 Z9 2 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2015 VL 100 IS 2 BP L29 EP U90 DI 10.1210/jc.2014-4221 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG5RF UT WOS:000353350900008 PM 25658165 ER PT J AU Modali, SD Parekh, VI Kebebew, E Agarwal, SK AF Modali, Sita D. Parekh, Vaishali I. Kebebew, Electron Agarwal, Sunita K. TI Epigenetic Regulation of the lncRNA MEG3 and Its Target c-MET in Pancreatic Neuroendocrine Tumors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; DIFFERENTIALLY METHYLATED REGION; TRANSCRIPTION REPRESSOR DAXX; LONG NONCODING RNAS; INSULIN-SECRETION; MEN1 GENE; CELL-PROLIFERATION; PITUITARY-TUMORS; DNA METHYLATION; PROMOTER REGION AB Biallelic inactivation of MEN1 encoding menin in pancreatic neuroendocrine tumors (PNETs) associated with the multiple endocrine neoplasia type 1 (MEN1) syndrome is well established, but how menin loss/inactivation initiates tumorigenesis is not well understood. We show that menin activates the long noncoding RNA maternally expressed gene 3 (Meg3) by histone-H3 lysine-4 trimethylation and CpG hypomethylation at the Meg3 promoter CRE site, to allow binding of the transcription factor cAMP response element-binding protein. We found that Meg3 has tumorsuppressor activity in PNET cells because the overexpression of Meg3 in MIN6 cells (insulin-secreting mouse PNET cell line) blocked cell proliferation and delayed cell cycle progression. Gene expression microarray analysis showed that Meg3 overexpression in MIN6 mouse insulinoma cells down-regulated the expression of the protooncogene c-Met (hepatocyte growth factor receptor), and these cells showed significantly reduced cell migration/invasion. Compared with normal islets, mouse or human MEN1-associated PNETs expressed less MEG3 and more c-MET. Therefore, a tumor-suppressor long noncoding RNA (MEG3) and suppressed protooncogene (c-MET) combination could elicit menin's tumor-suppressor activity. Interestingly, MEG3 and c-MET expression was also altered in human sporadic insulinomas (insulin secreting PNETs) with hypermethylation at the MEG3 promoter CRE-site coinciding with reduced MEG3 expression. These data provide insights into the beta-cell proliferation mechanisms that could retain their functional status. Furthermore, in MIN6 mouse insulinoma cells, DNA-demethylating drugs blocked cell proliferation and activated Meg3 expression. Our data suggest that the epigenetic activation of lncRNA MEG3 and/or inactivation of c-MET could be therapeutic for treating PNETs and insulinomas. C1 [Modali, Sita D.; Parekh, Vaishali I.; Agarwal, Sunita K.] NCI, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, NIDDK, NIH, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIH, Bldg 10,Room 8C-101, Bethesda, MD 20892 USA. EM sunitaa@mail.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases [1ZIADK07503503]; National Cancer Institute [1ZIABC01127503] FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (Project 1ZIADK07503503, to SK.A.) and the National Cancer Institute (Project 1ZIABC01127503, to E.K.). NR 47 TC 26 Z9 27 U1 3 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2015 VL 29 IS 2 BP 224 EP 237 DI 10.1210/me.2014-1304 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CG4XD UT WOS:000353291200007 PM 25565142 ER PT J AU Moody, TW Mantey, SA Moreno, P Nakamura, T Lacivita, E Leopoldo, M Jensen, RT AF Moody, Terry W. Mantey, Samuel A. Moreno, Paola Nakamura, Taichi Lacivita, Enza Leopoldo, Marcello Jensen, Robert T. TI ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth SO PEPTIDES LA English DT Article DE Bombesin receptor subtype 3; Nonpeptide antagonist; Lung cancer; Proliferation ID GASTRIN-RELEASING-PEPTIDE; HUMAN ORPHAN RECEPTOR; HIGH-AFFINITY; TYROSINE PHOSPHORYLATION; CARCINOMA CELLS; EXPRESSION; AGONISTS; PHARMACOLOGY; CLONING; IDENTIFICATION AB Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-family of peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specific agonists and antagonists. PD168368 is a nonpeptide antagonist for the neuromedin B (NMB) receptor (R) whereas PD176252 is a nonpeptide antagonist for the gastrin releasing peptide (GRP) R and NMBR but not BRS-3. Here nonpeptide analogs of PD176252 e.g. the S-enantiomer ML-18, and the R-enantiomer, EMY-98, were investigated as BRS-3 antagonists using lung cancer cells. ML-18 and EMY-98 inhibited specific I-125-BA1 (DTyr-Gln-Trp-Ala-Val-beta Ala-His-Phe-Nle-NH2)BB6-14 binding to NCI-H1299 lung cancer cells stably transfected with BRS-3 with IC50 values of 4.8 and >100 mu M, respectively. In contrast, ML-18 bound with lower affinity to the GRPR and NMBR with IC50 values of 16 and >100 mu M, respectively. ML-18 (16 mu M), but not its enantiomer EMY-98, inhibited the ability of 10 nM BA1 to elevate cytosolic Ca2+ in a reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16 mu M), but not EMY-98, inhibited the ability of 100 nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancer cells. ML-18 but not EMY-98 inhibited the proliferation of lung cancer cells. The results indicate that ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity. Published by Elsevier Inc. C1 [Moody, Terry W.] NCI, Dept Hlth & Human Serv, Ctr Canc Res, Off Director, Bethesda, MD 20892 USA. [Mantey, Samuel A.; Moreno, Paola; Nakamura, Taichi; Jensen, Robert T.] Natl Inst Diabet Digest & Kidney Dis, Digest Dis Branch, Bethesda, MD 20892 USA. [Lacivita, Enza; Leopoldo, Marcello] Univ Bari A Moro, Dipartimento Farm, Sci Farmaco, Bari, Italy. RP Moody, TW (reprint author), NCI, Off Director, CCR, 9609 Med Ctr Dr,Room 2W-130, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov OI Leopoldo, Marcello/0000-0001-8401-2815; Lacivita, Enza/0000-0003-2443-1174 FU intramural program of NCI; intramural program of NIDDK of the NIH FX The authors thank Dr. D. Coy (Tulane Univ.) for the BA1 and Drs. M. Nicklaus and M. Peach NCI for helpful discussions. This research is supported by the intramural programs of NCI and NIDDK of the NIH. NR 41 TC 5 Z9 5 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD FEB PY 2015 VL 64 BP 55 EP 61 DI 10.1016/j.peptides.2014.12.005 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA CF8KM UT WOS:000352808100009 PM 25554218 ER PT J AU Heissler, SM Sellers, JR AF Heissler, Sarah M. Sellers, James R. TI Four Things to Know about Myosin Light Chains as Reporters for Non-muscle Myosin-2 Dynamics in Live Cells SO CYTOSKELETON LA English DT Editorial Material DE regulatory light chain; myosin; GFP; cell motility; phosphomimetics ID MOLECULAR MOTOR; MIGRATING CELLS; POINT MUTATION; IN-VIVO; II-C; PHOSPHORYLATION; PROTEIN; CYTOKINESIS; BINDING; TRAFFICKING AB The interplay between non-muscle myosins-2 and filamentous actin results in cytoplasmic contractility which is essential for eukaryotic life. Concomitantly, there is tremendous interest in elucidating the physiological function and temporal localization of non-muscle myosin-2 in cells. A commonly used method to study the function and localization of non-muscle myosin-2 is to overexpress a fluorescent protein (FP)-tagged version of the regulatory light chain (RLC) which binds to the myosin-2 heavy chain by mass action. Caveats about this approach include findings from recent studies indicating that the RLC does not bind exclusively to the non-muscle myosin-2 heavy chain. Rather, it can also associate with the myosin heavy chains of several other classes as well as other targets than myosin. In addition, the presence of the FP moiety may compromise myosin's enzymatic and mechanical performance. This and other factors to be discussed in this commentary raise questions about the possible complications in using FP-RLC as a marker for the dynamic localization and regulatory aspects of non-muscle myosin-2 motor functions in cell biological experiments. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Heissler, Sarah M.; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL001786-29]; NHLBI NIH HHS [Z01 HL001786] NR 48 TC 3 Z9 3 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1949-3584 EI 1949-3592 J9 CYTOSKELETON JI Cytoskeleton PD FEB PY 2015 VL 72 IS 2 BP 65 EP 70 DI 10.1002/cm.21212 PG 6 WC Cell Biology SC Cell Biology GA CG1PW UT WOS:000353046500001 PM 25712372 ER PT J AU Pollack, AZ Louis, GMB Chen, Z Sun, L Trabert, B Guo, Y Kannan, K AF Pollack, A. Z. Louis, G. M. Buck Chen, Z. Sun, L. Trabert, B. Guo, Y. Kannan, K. TI Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma SO ENVIRONMENTAL RESEARCH LA English DT Article DE Benzophenone; Bisphenol A; Fibroid; Phthalate; Ultraviolet filter ID HIGH PLASMA-CONCENTRATIONS; TANDEM MASS-SPECTROMETRY; PERSONAL CARE PRODUCTS; HUMAN EXPOSURE; ESTROGENIC ACTIVITY; FEMALE RATS; UV-FILTERS; IN-VITRO; DI-(2-ETHYLHEXYL) PHTHALATE; POLYCHLORINATED-BIPHENYLS AB Bisphenol A, benzophenone-type UV filters, and phthalates are chemicals in high production and use including in a range of personal care products. Exposure of humans to these chemicals has been shown to affect endocrine function. Although short-lived, widespread exposure may lead to continual opportunity for these chemicals to elicit health effects in humans. The association of these chemicals with incident uterine leiomyoma, an estrogen sensitive disease, is not known. Urinary concentrations of bisphenol A (BPA), five benzophenone-type UV filters (2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4'OH-BP), 2,2'-dihydroxybenzophenone (2,2'OH-4MeO-BP), 2,2'4,4'-tetrahydroxybenzophenone (2,2'4,4'OH-BP), and 4-hydroxybenzophenone (4OH-BP), and 14 phthalate monoesters were quantified in 495 women who later underwent laparoscopy/laparotomy at 14 clinical sites for the diagnosis of fibroids. Significantly higher geometric mean creatinine-corrected concentrations of BPA, 2,4OH-BP, and 2OH-4MeO-BP were observed in women with than without fibroids [BPA: 2.09 mu g/g vs. 1.46 mu g/g p=0.004; 2,4OH-BP:11.10 mu g/g vs. 6.71 mu g/g p=0.01; 2OH-4MeO-BP: 11.31 mu g/g vs. 6.10 mu g/p=0.01]. Mono-methyl phthalate levels were significantly lower in women with than without fibroids (1.78 mu g/g vs. 2.40 mu g/g). However, none of the exposures were associated with a significant odds ratio even when adjusting for relevant covariates. There was a lack of an association between select nonpersistent chemicals and the odds of a fibroid diagnosis. (C) 2014 Elsevier Inc. All rights reserved. C1 [Pollack, A. Z.; Louis, G. M. Buck; Chen, Z.; Sun, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Trabert, B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Guo, Y.; Kannan, K.] SUNY Albany, Div Environm Hlth Sci, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12201 USA. [Guo, Y.; Kannan, K.] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Pollack, AZ (reprint author), George Mason Univ, Coll Hlth & Human Serv, Global & Community Hlth, 4400 Univ Dr MS5B7, Fairfax, VA 22030 USA. EM apollac2@gmu.edu; louisg@mail.nih.gov; chenzhe@mail.nih.gov; sunl3@mail.nih.gov; britton.trabert@nih.gov; yxg03@notes.health.state.ny.us; kkannan@wadsworth.edu RI Trabert, Britton/F-8051-2015; OI Pollack, Anna/0000-0002-4313-3298; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). NR 78 TC 11 Z9 11 U1 5 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2015 VL 137 BP 101 EP 107 DI 10.1016/j.envres.2014.06.028 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CF1TO UT WOS:000352331000013 PM 25531814 ER PT J AU Espejo-Herrera, N Cantor, KP Malats, N Silverman, DT Tardon, A Garcia-Closas, R Serra, C Kogevinas, M Villanueva, CM AF Espejo-Herrera, Nadia Cantor, Kenneth P. Malats, Nuria Silverman, Debra T. Tardon, Adonina Garcia-Closas, Reina Serra, Consol Kogevinas, Manolis Villanueva, Cristina M. TI Nitrate in drinking water and bladder cancer risk in Spain SO ENVIRONMENTAL RESEARCH LA English DT Article DE Nitrate; Drinking water; Water contaminants; Bladder cancer; Case-control study ID N-NITROSO COMPOUNDS; GASTROINTESTINAL-TRACT; ENDOGENOUS FORMATION; NETHERLANDS COHORT; ADULT GLIOMA; LOS-ANGELES; RED MEAT; HEALTH; MUNICIPAL; HEME AB Background: Nitrate is a widespread contaminant in drinking water and ingested nitrate under conditions resulting in endogenous nitrosation is suspected to be carcinogenic. However, the suggested association between nitrate in drinking water and bladder cancer remains inconsistent. We evaluated the long-term exposure to drinking water nitrate as a risk factor for bladder cancer, considering endogenous nitrosation modifiers and other covariables. Methods: We conducted a hospital-based case-control study of bladder cancer in Spain (1998-2001). Residential histories and water consumption information were ascertained through personal interviews. Historical nitrate levels (1940-2000) were estimated in study municipalities based on monitoring records and water source. Residential histories of study subjects were linked with nitrate estimates by year and municipality to calculate individual exposure from age 18 to recruitment. We calculated odds ratios (OR) and 95% confidence intervals (CI) for bladder cancer among 531 cases and 556 controls with reliable interviews and nitrate exposure information covering at least 70% of years from age 18 to interview. Results: Average residential levels ranged from 2.1 mg/L to 12.0 mg/L among regions. Adjusted OR (95% CI) for average residential levels relative to <= 5 mg/L were 1.2 (0.7-2.0) for > 5-10 mg/L and 1.1 (0.6-1.9) for > 10 mg/L. The OR for subjects with longest exposure duration (> 20 years) to highest levels (> 9.5 mg/L) was 1.4 (0.9-2.3). Stratification by intake of vitamin C, vitamin E, meat, and gastric ulcer diagnosis did not modify these results. A non-significant negative association was found with waterborne ingested nitrate with an OR of 0.7 (0.4-1.0) for > 8 vs. <= 4 mg/day. Adjustment for several covariables showed similar results to crude analyses. Conclusion: Bladder cancer risk was inconsistently associated with chronic exposure to drinking water nitrate at levels below the current regulatory limit. Elevated risk is suggested only among subjects with longest exposure duration to the highest levels. No evidence of interaction with endogenous nitrosation modifiers was observed. (C) 2014 Elsevier Inc. All rights reserved. C1 [Espejo-Herrera, Nadia; Kogevinas, Manolis; Villanueva, Cristina M.] Ctr Recerca Epidemiol Ambiental CREAL, Barcelona 08003, Spain. [Espejo-Herrera, Nadia; Serra, Consol; Kogevinas, Manolis; Villanueva, Cristina M.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Espejo-Herrera, Nadia; Kogevinas, Manolis; Villanueva, Cristina M.] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Cantor, Kenneth P.; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, San Cristobal la Laguna, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Kogevinas, Manolis; Villanueva, Cristina M.] Hosp del Mar, Med Res Inst, IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. RP Villanueva, CM (reprint author), Ctr Recerca Epidemiol Ambiental CREAL, Doctor Aiguader 88, Barcelona 08003, Spain. EM cvillanueva@creal.cat RI Malats, Nuria/H-7041-2015; Villanueva, Cristina/N-1942-2014; Kogevinas, Manolis/C-3918-2017 OI Malats, Nuria/0000-0003-2538-3784; Villanueva, Cristina/0000-0002-0783-1259; FU Intramural Research Program of the National Institute of Health, National Cancer Institute, United States, Division of Cancer Epidemiology and Genetics [NCI NO2-CP-11015]; Spanish Health Ministry [FIS/Spain 00/0745, ISIII-G03/174, FIS PI11/00226]; European Union [BMH4-98-3243]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR FI-DGR) Generalitat de Cataluna, Spain FX This study was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, United States, Division of Cancer Epidemiology and Genetics (Contract NCI NO2-CP-11015). The project also received funding from the Spanish Health Ministry (FIS/Spain 00/0745, ISIII-G03/174, FIS PI11/00226), and the European Union (BMH4-98-3243). N. Espejo-Herrera receives financial support for the Ph.D. program from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR FI-DGR 2013) Generalitat de Cataluna, Spain. NR 41 TC 6 Z9 6 U1 0 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2015 VL 137 BP 299 EP 307 DI 10.1016/j.envres.2014.10.034 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CF1TO UT WOS:000352331000036 PM 25601732 ER PT J AU Robledo, CA Mendola, P Yeung, E Mannisto, T Sundaram, R Liu, DP Ying, Q Sherman, S Grantz, KL AF Robledo, Candace A. Mendola, Pauline Yeung, Edwina Maennistoe, Tuija Sundaram, Rajeshwari Liu, Danping Ying, Qi Sherman, Seth Grantz, Katherine L. TI Preconception and early pregnancy air pollution exposures and risk of gestational diabetes mellitus SO ENVIRONMENTAL RESEARCH LA English DT Article DE Preconception; Pregnancy; Air pollution; Gestational diabetes ID LONG-TERM EXPOSURE; C-REACTIVE PROTEIN; INSULIN-RESISTANCE; PARTICULATE MATTER; LOS-ANGELES; INFLAMMATION; ASSOCIATION; COHORT; WOMEN; MODEL AB Background: Air pollution has been linked to gestational diabetes mellitus (GDM) but no studies have evaluated impact of preconception and early pregnancy air pollution exposures on GDM risk. Methods: Electronic medical records provided data on 219,952 singleton deliveries to mothers with (n=11,334) and without GDM (n=208,618). Average maternal exposures to particulate matter (PM) <= 2.5 mu m (PM2.5) and PM2.5 constituents, PM <= 10 mu m (PM10), nitrogen oxides (NOx), carbon monoxide, sulfur dioxide (SO2) and ozone (O-3) were estimated for the 3-month preconception window, first trimester, and gestational weeks 1-24 based on modified Community Multiscale Air Quality models for delivery hospital referral regions. Binary regression models with robust standard errors estimated relative risks (RR) for GDM per interquartile range (IQR) increase in pollutant concentrations adjusted for study site, maternal age and race/ethnicity. Results: Preconception maternal exposure to NOX (RR=1.09, 95% CI: 1.04, 1.13) and SO2 (RR=1.05, 1.01, 1.09) were associated with increased risk of subsequent GDM and risk estimates remained elevated for first trimester exposure. Preconception O-3 was associated with lower risk of subsequent GDM (RR=0.93, 0.90, 0.96) but risks increased later in pregnancy. Conclusion: Maternal exposures to NOx and SO2 preconception and during the first few weeks of pregnancy were associated with increased GDM risk. O-3 appeared to increase GDM risk in association with mid-pregnancy exposure but not in earlier time windows. These common exposures merit further investigation. Published by Elsevier Inc. C1 [Robledo, Candace A.; Mendola, Pauline; Yeung, Edwina; Maennistoe, Tuija; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD 20852 USA. [Sundaram, Rajeshwari; Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Ying, Qi] Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX 77845 USA. [Sherman, Seth] EMMES Corp, Rockville, MD 20852 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B13E, Rockville, MD 20852 USA. EM pauline.mendola@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Sherman, Seth/0000-0003-3667-9898; Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health [HHSN257200603425C, HHSN275200800002I, HHSN27500008] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health through Contract no. HHSN257200603425C for the Consortium on Safe Labor, and through Contract no. HHSN275200800002I, Task no. HHSN27500008 for the Air Quality and Reproductive Health Study. NR 39 TC 14 Z9 15 U1 4 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2015 VL 137 BP 316 EP 322 DI 10.1016/j.envres.2014.12.020 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CF1TO UT WOS:000352331000038 PM 25601734 ER PT J AU Bae, J Kim, S Kannan, K Louis, GMB AF Bae, Jisuk Kim, Sungduk Kannan, Kurunthachalam Louis, Germaine M. Buck TI Couples' urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio SO ENVIRONMENTAL RESEARCH LA English DT Article DE Bisphenol A; Endocrine disruptors; Fertility; Phthalates; Sex ratio ID ENDOCRINE-DISRUPTING CHEMICALS; BUTYL BENZYL PHTHALATE; HUMAN EXPOSURE; REPRODUCTIVE FUNCTION; DEVELOPMENTAL TOXICITY; PERINATAL EXPOSURE; DIETARY EXPOSURE; UNITED-STATES; SEMEN QUALITY; NTP CENTER AB With limited research focusing on non-persistent chemicals as exogenous factors affecting human sex selection, this study aimed to evaluate the association of urinary bisphenol A (BPA) and phthalate metabolite concentrations with the secondary sex ratio (SSR), defined as the ratio of male to female live births. The current analysis is limited to singleton live births (n=220, 43.9%) from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, in which couples discontinuing contraception with the intention of becoming pregnant were enrolled and followed while trying for pregnancy and through delivery for those achieving pregnancy. Using modified Poisson regression models accounting for potential confounders, we estimated the relative risks (RRs) of a male birth per standard deviation change in the log-transformed maternal, paternal, and couple urinary BPA and 14 phthalate metabolite concentrations (ng/mL) measured upon enrollment When maternal and paternal chemical concentrations were modeled jointly, paternal BPA (RR, 0.77; 95% confidence interval [CI], 0.62-0.95) and mono-isobutyl phthalate (RR, 0.82; 95% Cl, 0.67-1.00) were significantly associated with a female excess. Contrarily, maternal BPA (RR, 1.16; 95% Cl, 1.03-131), mono-isobutyl phthalate (RR, 1.28; 95% CI, 1.06-1.54), mono-benzyl phthalate (RR, 131; 95% Cl, 1.08-1.58), and mono-n-butyl phthalate (RR, 124; 95% CI, 1.01-1.51) were significantly associated with a male excess. These findings underscore varying patterns for the SSR in relation to parental exposures. Given the absence of previous investigation, these partner-specific associations of non-persistent chemicals with the SSR need future corroboration. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bae, Jisuk; Kim, Sungduk; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Bae, Jisuk] Catholic Univ, Sch Med, Dept Prevent Med, Daegu 705718, South Korea. [Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12201 USA. [Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Bae, J (reprint author), Catholic Univ, Sch Med, Dept Prevent Med, 33 Duryugongwon Ro 17 Gil, Daegu 705718, South Korea. EM jisuk.bae@nih.gov; kims2@mail.nih.gov; kkannan@wadsworth.org; louisg@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health [VFTB057303] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358). Dr. Bae was supported by the Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health (award #VFTB057303). NR 77 TC 6 Z9 6 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2015 VL 137 BP 450 EP 457 DI 10.1016/j.envres.2014.11.011 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CF1TO UT WOS:000352331000054 PM 25677702 ER PT J AU Kemp, TJ Matsui, K Shelton, G Safaeian, M Pinto, LA AF Kemp, Troy J. Matsui, Ken Shelton, Gloriana Safaeian, Mahboobeh Pinto, Ligia A. TI A comparative study of two different assay kits for the detection of secreted alkaline phosphatase in HPV antibody neutralization assays SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE Cervarix (R); Gardasil (R); human papillomavirus; SEAP; vaccine; ZiVa ID HUMAN-PAPILLOMAVIRUS TYPE-16; RICA VACCINE TRIAL; IN-VITRO; CERVICAL-CANCER; PSEUDOVIRIONS; RESPONSES; L2; GENERATION; INFECTION; INHIBITION AB To assess immunogenicity and development of antibodies in the context of vaccination, it is critical to quantify titers of neutralizing antibodies. We have been employing the 293TT cell-based neutralization assay system to quantify anti-HPV neutralizing antibodies. In this system, human papillomavirus (HPV) pseudovirion (PsV) particles encapsidating secreted alkaline phosphatase (SEAP) gene are used to measure infection of 293TT cells in 72-hr cell-culture supernatants. SEAP has traditionally been measured by Great EscAPe (TM) SEAP Chemiluminescence Kit 2.0 (GE). To reduce the cost, and to potentially increase efficiency, we sought a cheaper kit with better detection capability. Performance characteristics of the newer chemiluminescence kit, ZiVa (R) Ultra SEAP Plus Assay (Ziva) and GE were compared using the 293TT system. Dose titration of HPV PsV 16 or 18 showed that signal-to-noise ratios at 48 and 72 hr post-infection were higher for ZiVa at nearly all doses. ZiVa was superior to GE as it was able to detect SEAP at 48 hr, as well as when lower numbers of 293TT cells were used. The ability of ZiVa to quantitate HPV-16 and -18 neutralizing antibody titers was tested using sera from Cervarix (R) immunized individuals. Spearman rank correlational analyses showed excellent correlations between the titers obtained with ZiVa and GE for anti-HPV16 (r = 0.9822, p < 0.0001) and anti-HPV18 (r = 0.9832, p < 0.0001) antibodies. We concluded that ZiVa is superior to GE in detecting SEAP, and the antibody titers in sera of vaccinated individuals were similar to those obtained with GE. Thus, Ziva is a suitable alternative to GE. C1 [Kemp, Troy J.; Matsui, Ken; Shelton, Gloriana; Pinto, Ligia A.] Leidos Biomed Res Inc, Human Papillomavirus HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Safaeian, Mahboobeh] NCI, Bethesda, MD 20892 USA. RP Pinto, LA (reprint author), Leidos Biomed Res Inc, Human Papillomavirus HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM pintol@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US. Government. NR 40 TC 0 Z9 0 U1 2 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD FEB PY 2015 VL 11 IS 2 BP 337 EP 346 DI 10.4161/21645515.2014.990851 PG 10 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA CF5RR UT WOS:000352615200017 PM 25695397 ER PT J AU Gregory, S Blair, RJ Ffytche, D Simmons, A Kumari, V Hodgins, S Blackwood, N AF Gregory, Sarah Blair, R. James Ffytche, Dominic Simmons, Andrew Kumari, Veena Hodgins, Sheilagh Blackwood, Nigel TI Punishment and psychopathy: a case-control functional MRI investigation of reinforcement learning in violent antisocial personality disordered men SO LANCET PSYCHIATRY LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; DECISION-MAKING; RESPONSE REVERSAL; GRAY-MATTER; INDIVIDUALS; OFFENDERS; DEFICITS; ACQUISITION; CHILDREN; TRAITS AB Background Men with antisocial personality disorder show lifelong abnormalities in adaptive decision making guided by the weighing up of reward and punishment information. Among men with antisocial personality disorder, modification of the behaviour of those with additional diagnoses of psychopathy seems particularly resistant to punishment. Methods We did a case-control functional MRI (fMRI) study in 50 men, of whom 12 were violent off enders with antisocial personality disorder and psychopathy, 20 were violent off enders with antisocial personality disorder but not psychopathy, and 18 were healthy non-off enders. We used fMRI to measure brain activation associated with the representation of punishment or reward information during an event-related probabilistic response-reversal task, assessed with standard general linear-model-based analysis. Findings Off enders with antisocial personality disorder and psychopathy displayed discrete regions of increased activation in the posterior cingulate cortex and anterior insula in response to punished errors during the task reversal phase, and decreased activation to all correct rewarded responses in the superior temporal cortex. This finding was in contrast to results for off enders without psychopathy and healthy non-off enders. Interpretation Punishment prediction error signalling in off enders with antisocial personality disorder and psychopathy was highly atypical. This finding challenges the widely held view that such men are simply characterised by diminished neural sensitivity to punishment. Instead, this finding indicates altered organisation of the information-processing system responsible for reinforcement learning and appropriate decision making. This difference between violent off enders with antisocial personality disorder with and without psychopathy has implications for the causes of these disorders and for treatment approaches. C1 [Gregory, Sarah; Blackwood, Nigel] Kings Coll London, Inst Psychiat, Dept Forens & Neurodev Sci, London SE5 8AF, England. [Blair, R. James] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Ffytche, Dominic] Kings Coll London, Inst Psychiat, Dept Old Age Psychiat, London SE5 8AF, England. [Simmons, Andrew; Kumari, Veena] Kings Coll London, NIHR Biomed Res Ctr Mental Hlth South London, London SE5 8AF, England. [Simmons, Andrew; Kumari, Veena] Kings Coll London, Maudsley NHS Fdn Trust, London SE5 8AF, England. [Simmons, Andrew; Kumari, Veena] Kings Coll London, Inst Psychiat, London SE5 8AF, England. [Hodgins, Sheilagh] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. RP Blackwood, N (reprint author), Kings Coll London, Inst Psychiat, Dept Forens & Neurodev Sci, POB 23,De Crespigny Pk, London SE5 8AF, England. EM nigel.blackwood@kcl.ac.uk RI Simmons, Andrew/B-8848-2008; OI Simmons, Andrew/0000-0003-2306-5811; ffytche, Dominic/0000-0002-4214-9642 FU National Forensic Mental Health Research and Development Programme; UK Ministry of Justice; Psychiatry Research Trust; NIHR Biomedical Research Centre FX National Forensic Mental Health Research and Development Programme, UK Ministry of Justice, Psychiatry Research Trust, NIHR Biomedical Research Centre. NR 38 TC 2 Z9 2 U1 5 U2 38 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD FEB PY 2015 VL 2 IS 2 BP 153 EP 160 PG 8 WC Psychiatry SC Psychiatry GA CF6ZP UT WOS:000352705900020 PM 26359751 ER PT J AU Pacheco, J Goh, JO Kraut, MA Ferrucci, L Resnick, SM AF Pacheco, Jennifer Goh, Joshua O. Kraut, Michael A. Ferrucci, Luigi Resnick, Susan M. TI Greater cortical thinning in normal older adults predicts later cognitive impairment SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Cortical thinning; Early detection; Longitudinal; Mild cognitive impairment ID HUMAN CEREBRAL-CORTEX; ALZHEIMERS ASSOCIATION WORKGROUPS; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; MILD AD DEMENTIA; GEOMETRICALLY ACCURATE; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; COORDINATE SYSTEM; DISEASE AB Cross-sectional studies have shown regional differences in cortical thickness between healthy older adults and patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). We now demonstrate that participants who subsequently develop cognitive impairment leading to a diagnosis of MCI or AD (n = 25) experience greater cortical thinning in specific neuroanatomic regions compared with control participants who remained cognitively normal (n = 96). Based on 8 years of annual magnetic resonance imaging scans beginning an average of 11 years before onset of cognitive impairment, participants who developed cognitive impairment subsequent to the scanning period had greater longitudinal cortical thinning in the temporal poles and left medial temporal lobe compared with controls. No significant regional cortical thickness differences were found at baseline between the 2 study groups indicating that we are capturing a critical time when brain changes occur before behavioral manifestations of impairment are detectable. Our findings suggest that early events of the pathway that leads to cognitive impairment may involve the temporal lobe and that this increased atrophy could be considered an early biomarker of neurodegeneration predictive of cognitive impairment years later. Published by Elsevier Inc. C1 [Pacheco, Jennifer; Goh, Joshua O.; Ferrucci, Luigi; Resnick, Susan M.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Goh, Joshua O.] Natl Taiwan Univ, Coll Med, Grad Inst Brain & Mind Sci, Taipei 10764, Taiwan. [Kraut, Michael A.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. RP Pacheco, J (reprint author), NIA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jenni.pacheco@nih.gov OI GOH, JOSHUA/0000-0001-7808-5452 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Research and Development Contract [N01-AG-3-2124] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and by Research and Development Contract N01-AG-3-2124. We are grateful to the BLSA participants and staff for their dedication to these studies and the staff of the Johns Hopkins MRI facility for their assistance. NR 47 TC 8 Z9 8 U1 0 U2 2 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 FEB PY 2015 VL 36 IS 2 BP 903 EP 908 DI 10.1016/j.neurobiolaging.2014.08.031 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400034 PM 25311277 ER PT J AU Bettcher, BM Yaffe, K Boudreau, RM Neuhaus, J Aizenstein, H Ding, J Kritchevsky, SB Launer, LJ Liu, Y Satterfield, S Rosano, C AF Bettcher, Brianne Magouirk Yaffe, Kristine Boudreau, Robert M. Neuhaus, John Aizenstein, Howard Ding, Jingzhong Kritchevsky, Stephen B. Launer, Lenore J. Liu, Yongmei Satterfield, Suzanne Rosano, Caterina CA Health ABC Study TI Declines in inflammation predict greater white matter microstructure in older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE CRP; Pro-inflammatory; Diffusion tensor imaging; Longitudinal ID C-REACTIVE PROTEIN; MILD COGNITIVE IMPAIRMENT; NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASE; CARDIOVASCULAR-DISEASE; VASCULAR DYSFUNCTION; DIFFUSION TENSOR; HEALTH ABC; TNF-ALPHA AB Protracted systemic inflammation has been associated with adverse effects on cognition and brain structure and may accelerate neurodegenerative disease processes; however, it is less clear whether changes in inflammation are associated with brain structure. We studied 276 black and white older adults (mean age = 83 years at time of imaging) enrolled in a prospective study of aging. Inflammation (measured with c-reactive protein, CRP) was assessed repeatedly over 6 years (i.e., year 2, 4, 6, and 8). Brain magnetic resonance imaging (MRIs) were obtained at years 10-11 with diffusion tensor imaging; regions of interest included late-myelinating areas vulnerable to aging, including frontal-parietal (superior longitudinal fasciculus [SLF]-dorsal) and temporal (SLF-temporal; uncinate) white matter tracts. Mean CRP values significantly declined (t = -5.54, p < 0.0001) over 6 years, and subject-specific slopes (best linear unbiased predictors of slopes) all showed a decline (mean = -0.57, standard deviation = 0.53) for our participant sample. More than 50% of study participants were still in the moderate to high cardiovascular risk range based on CRP values at year 8. After controlling for demographics, vascular risk factors and MRI white matter hyperintensities, larger decreases in CRP values over time were significantly associated with higher fractional anisotropy in the SLF-dorsal (beta = -0.0052, standard error [SE] = 0.003; 95% confidence interval [CI] = -0.0103 to -0.0025, p = 0.04), SLF-temporal (beta = -0.0109, SE = 0.004; 95% CI = -0.0189 to -0.0029, p = 0.008), and uncinate (beta = -0.0067, SE = 0.003; 95% CI = -0.0132 to -0.0001, p = 0.05) fasciculi. Results suggest that in a prospective cohort of older individuals, faster declines in inflammation over time are related to indicators of white matter health, even after accounting for vascular risk factors. (C) 2015 Elsevier Inc. All rights reserved. C1 [Bettcher, Brianne Magouirk; Neuhaus, John] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Boudreau, Robert M.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Aizenstein, Howard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Ding, Jingzhong; Kritchevsky, Stephen B.; Liu, Yongmei] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Bettcher, BM (reprint author), Memory & Aging Ctr, Dept Neurol, 675 Nelson Rising Ln,Suite 190,MC 1207, San Francisco, CA 94158 USA. EM bbettcher@memory.ucsf.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, K23 AG042492-01, RO1-AG028288]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; Alzheimer's Association [NIRP-12-259223] FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, K23 AG042492-01 (Brianne Magouirk Bettcher), RO1-AG028288 (Yongmei Liu), and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as an Alzheimer's Association New Investigator Grant (NIRP-12-259223; Brianne Magouirk Bettcher). NR 56 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2015 VL 36 IS 2 BP 948 EP 954 DI 10.1016/j.neurobiolaging.2014.11.004 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400040 PM 25554492 ER PT J AU Canugovi, C Misiak, M Scheibye-Knudsen, M Croteau, DL Mattson, MP Bohr, VA AF Canugovi, Chandrika Misiak, Magdalena Scheibye-Knudsen, Morten Croteau, Deborah L. Mattson, Mark P. Bohr, Vilhelm A. TI Loss of NEIL1 causes defects in olfactory function in mice SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging, smell; Olfactory sense; DNA repair; Base excision repair; Glycosylase; NEIL1; Oxidative stress; Oxidative DNA damage ID BASE EXCISION-REPAIR; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; DNA-REPAIR; NEURODEGENERATIVE DISEASES; BRAIN; DYSFUNCTION; SYSTEM; RAT AB Oxidative DNA damage accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The base excision repair pathway is a primary responder to oxidative DNA damage. Effects of loss of base excision repair on normal brain function is a relatively nascent area of research that needs further exploration for better understanding of related brain diseases. Recently, we found that loss of a versatile DNA glycosylase endonuclease 8-like 1 (NEIL1) causes deficits in spatial memory retention using the Morris water maze test. Furthermore, we found that there is a significant loss of NEIL1 enzyme levels and its activity in postmortem Alzheimer's disease brains. Based on the Allen Brain Atlas in situ hybridization data, the expression levels of Neil1 messenger RNA are higher in the olfactory bulb compared with other areas of the brain. Olfaction in mice is a central brain function that involves many central nervous system pathways. Here, we studied the effect of complete loss of Neil1 gene on olfactory function. We explored olfactory function in mice with 3 different behavioral tests namely, olfactory sensitivity, performance, and buried food tests. Neil1(-/-) mice performed poorly compared with wild-type mice in all 3 tests. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair. Published by Elsevier Inc. C1 [Canugovi, Chandrika; Misiak, Magdalena; Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Misiak, Magdalena; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU National Institute on Aging [AG000723-07] FX Funding for this work is entirely provided by National Institute on Aging, grant number AG000723-07. The authors thank Dr R. Stephen Lloyd for the gift of NEIL1 knockout mice. They greatly appreciate Christopher Morrell, NIA, for his help and advice with the statistical analysis of our data. They thank Dr Baptiste Beverly and Dr Somnath Ghosh for reading and revising the manuscript before submission. NR 31 TC 1 Z9 1 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 FEB PY 2015 VL 36 IS 2 BP 1007 EP 1012 DI 10.1016/j.neurobiolaging.2014.09.026 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400045 PM 25448603 ER PT J AU Scholz, SW Majounie, E Revesz, T Holton, JL Okun, MS Houlden, H Singleton, AB AF Scholz, Sonja W. Majounie, Elisa Revesz, Tamas Holton, Janice L. Okun, Michael S. Houlden, Henry Singleton, Andrew B. TI Multiple system atrophy is not caused by C9orf72 hexanucleotide repeat expansions SO NEUROBIOLOGY OF AGING LA English DT Article DE Multiple system atrophy; C9orf72; Neurodegeneration; Amyotrophic lateral sclerosis; Fronto-temporal dementia AB Multiple system atrophy (MSA) is a fatal neurodegenerative disorder of unknown etiology that presents with variable combinations of progressive ataxia, parkinsonism, and autonomic instability. Pathologic expansion of a hexanucleotide repeat in the C9orf72 gene has been demonstrated to cause neuro-degeneration with diverse neurologic presentations. To test the hypothesis whether pathologic expansions in C9orf72 are a cause of MSA, we undertook genetic screening in 100 neuropathologically confirmed cases. No pathologic repeat expansions were detected suggesting that MSA is not a C9orf72-related neurodegenerative disease. Published by Elsevier Inc. C1 [Scholz, Sonja W.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 20201 USA. [Scholz, Sonja W.; Majounie, Elisa; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Revesz, Tamas; Holton, Janice L.; Houlden, Henry] UCL, Inst Neurol, Reta Lila Weston Labs, Dept Mol Neurosci, London, England. [Okun, Michael S.] McKnight Brain Inst, UF Ctr Movement Disorders & Neurorestorat, Dept Neurol, Gainesville, FL USA. RP Scholz, SW (reprint author), Johns Hopkins Univ Hosp, Dept Neurol, 1800 Orleans St, Baltimore, MD 20201 USA. EM sscholz5@jhmi.edu RI Houlden, Henry/C-1532-2008; Revesz, Tamas/A-8732-2010; OI Houlden, Henry/0000-0002-2866-7777; Revesz, Tamas/0000-0003-2501-0259; Okun, Michael/0000-0002-6247-9358; Scholz, Sonja/0000-0002-6623-0429 NR 0 TC 2 Z9 2 U1 0 U2 1 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 FEB PY 2015 VL 36 IS 2 DI 10.1016/j.neurobiolaging.2014.08.033 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400072 ER PT J AU Schottlaender, LV Polke, JM Ling, H MacDoanld, ND Tucci, A Nanji, T Pittman, A de Silva, R Holton, JL Revesz, T Sweeney, MG Singleton, AB Lees, AJ Bhatia, KP Houlden, H AF Schottlaender, Lucia V. Polke, James M. Ling, Helen MacDoanld, Nicola D. Tucci, Arianna Nanji, Tina Pittman, Alan de Silva, Rohan Holton, Janice L. Revesz, Tamas Sweeney, Mary G. Singleton, Andy B. Lees, Andrew J. Bhatia, Kailash P. Houlden, Henry TI The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism SO NEUROBIOLOGY OF AGING LA English DT Article DE C9orf72; Parkinsonism; Multiple system atrophy (MSA); Progressive supranuclear palsy (PSP); Corticobasal degeneration (CBD) and corticobasal syndrome (CBS) ID MULTIPLE-SYSTEM ATROPHY; PROGRESSIVE SUPRANUCLEAR PALSY; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT; CORTICOBASAL DEGENERATION; PROGRANULIN MUTATION; INCREASED RISK; SNCA VARIANTS; DISEASE AB A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuro-pathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases. (C) 2015 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Schottlaender, Lucia V.; Polke, James M.; Ling, Helen; Tucci, Arianna; Nanji, Tina; Pittman, Alan; de Silva, Rohan; Holton, Janice L.; Revesz, Tamas; Sweeney, Mary G.; Lees, Andrew J.; Houlden, Henry] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Polke, James M.; Nanji, Tina; Sweeney, Mary G.; Houlden, Henry] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Neurogenet Lab, London WC1N 3BG, England. [Ling, Helen; Pittman, Alan; de Silva, Rohan; Holton, Janice L.; Revesz, Tamas; Lees, Andrew J.] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Queen Sq Brain Bank, Reta Lila Weston Inst Neurol Studies, London WC1N 3BG, England. [MacDoanld, Nicola D.; Houlden, Henry] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Singleton, Andy B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Bhatia, Kailash P.] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Sobell Dept Movement Disorders, London WC1N 3BG, England. RP Houlden, H (reprint author), Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM h.houlden@ucl.ac.uk RI Pittman, Alan/D-6231-2012; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 FU Medical Research Council [G0802760]; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; Brain Research Trust; National Organization for Rare Disorders; MSA Trust; National Institutes of Health (NIH) dystonia Coalition from ORDR in National Center for Advancing Translational Sciences (NCATS) [NS065701]; National Institutes of Neurological disorders and stroke (NINDS) as part of the NIH Rare Diseases Clinical Research Network (RDCRN); Dystonia medical research foundation (DMRF); National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC); Reta Lila Weston Trust for Medical Research FX The authors thank the patients and their families for their help and sample and brain donation. This study was supported by the Medical Research Council (G0802760) and the Wellcome Trust/MRC Joint Call (WT089698) in Neurodegeneration award (WT089698) as well as the Brain Research Trust, National Organization for Rare Disorders, the MSA Trust, the National Institutes of Health (NIH) dystonia Coalition funded by NS065701 from ORDR in National Center for Advancing Translational Sciences (NCATS) and National Institutes of Neurological disorders and stroke (NINDS) as part of the NIH Rare Diseases Clinical Research Network (RDCRN) and the Dystonia medical research foundation (DMRF). The authors are grateful to the Queen Square Brain Bank, the Harvard Brain Tissue Resource Centre, the Manchester Brain Bank, the The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders, and the Netherlands brain bank for provision of human tissue. This study was also supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), and the Reta Lila Weston Trust for Medical Research. NR 51 TC 6 Z9 6 U1 0 U2 1 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 FEB PY 2015 VL 36 IS 2 DI 10.1016/j.neurobiolaging.2014.08.024 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CF3MZ UT WOS:000352454400067 ER PT J AU Simoncic, U Zanotti-Fregonara, P AF Simoncic, Urban Zanotti-Fregonara, Paolo TI Image-derived input function with factor analysis and a-priori information SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE [C-11](R)-rolipram; factor analysis; image-derived input function; positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; BRAIN PET; QUANTIFICATION; PHOSPHODIESTERASE-4; RADIOLIGAND; METHODOLOGY; VALIDATION; RECEPTORS; ALGORITHM AB Background Quantitative PET studies often require the cumbersome and invasive procedure of arterial cannulation to measure the input function. This study sought to minimize the number of necessary blood samples by developing a factor-analysis-based image-derived input function (IDIF) methodology for dynamic PET brain studies. Materials and methods IDIF estimation was performed as follows: (a) carotid and background regions were segmented manually on an early PET time frame; (b) blood-weighted and tissue-weighted time-activity curves (TACs) were extracted with factor analysis; (c) factor analysis results were denoised and scaled using the voxels with the highest blood signal; (d) using population data and one blood sample at 40 min, whole-blood TAC was estimated from postprocessed factor analysis results; and (e) the parent concentration was finally estimated by correcting the whole-blood curve with measured radiometabolite concentrations. The methodology was tested using data from 10 healthy individuals imaged with [C-11](R)-rolipram. The accuracy of IDIFs was assessed against full arterial sampling by comparing the area under the curve of the input functions and by calculating the total distribution volume (V-T). Results The shape of the image-derived whole-blood TAC matched the reference arterial curves well, and the whole-blood area under the curves were accurately estimated (mean error 1.0 +/- 4.3%). The relative Logan-V-T error was -4.1 +/- 6.4%. Compartmental modeling and spectral analysis gave less accurate V-T results compared with Logan. Conclusion A factor-analysis-based IDIF for [C-11](R)-rolipram brain PET studies that relies on a single blood sample and population data can be used for accurate quantification of Logan-V-T values. Nucl Med Commun 36: 187-193 (C) 2015 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Simoncic, Urban] Jozef Stefan Inst, SI-1000 Ljubljana, Slovenia. [Simoncic, Urban] Ctr Excellence Biosensors Instrumentat & Proc Con, Ajdovscina, Slovenia. [Zanotti-Fregonara, Paolo] Univ Bordeaux, CNRS, INCIA, UMR 5287, Talence, France. [Zanotti-Fregonara, Paolo] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Simoncic, U (reprint author), Jozef Stefan Inst, Jamova 39, SI-1000 Ljubljana, Slovenia. EM urban.simoncic@gmail.com OI Simoncic, Urban/0000-0002-5835-072X FU Slovenian Research Agency (ARRS); Centre of Excellence for Biosensors, Instrumentation, and Process Control; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This work was supported by the Slovenian Research Agency (ARRS); the Centre of Excellence for Biosensors, Instrumentation, and Process Control and the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). NR 29 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 0143-3636 EI 1473-5628 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD FEB PY 2015 VL 36 IS 2 BP 187 EP 193 DI 10.1097/MNM.0000000000000231 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CF7IV UT WOS:000352730600013 PM 25321159 ER PT J AU Gonzalez, AR Fee, E AF Gonzalez, Ana Rita Fee, Elizabeth TI Anemia in Puerto Rico at the Turn of the Twentieth Century SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Gonzalez, Ana Rita] Policy Wisdom LLC, Miami, FL USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Gonzalez, AR (reprint author), 9981 SW 143rd St, Miami, FL 33176 USA. EM argonzalez@policywisdom.com; feee@mail.nlm.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2015 VL 105 IS 2 BP 272 EP 273 DI 10.2105/AJPH.2014.302225 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE6CD UT WOS:000351922500027 PM 25521874 ER PT J AU Garofalo, MF Fee, E AF Garofalo, Mary F. Fee, Elizabeth TI Lavinia Dock (1858-1956): Picketing, Parading, and Protesting SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Garofalo, Mary F.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), Natl Lib Med, 8600 Rockville Pike,MSC 3819,Bldg 38,Room 1E21, Bethesda, MD 20894 USA. EM feee@mail.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2015 VL 105 IS 2 BP 276 EP 277 DI 10.2105/AJPH.2014.302021 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE6CD UT WOS:000351922500029 PM 25521903 ER PT J AU Chawla, N Breen, N Liu, BM Lee, R Kagawa-Singer, M AF Chawla, Neetu Breen, Nancy Liu, Benmei Lee, Richard Kagawa-Singer, Marjorie TI Asian American Women in California: A Pooled Analysis of Predictors for Breast and Cervical Cancer Screening SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PAP TEST USE; UNITED-STATES; VIETNAMESE-AMERICANS; PACIFIC ISLANDERS; INCIDENCE TRENDS; CONTROLLED-TRIAL; HEALTH; CHINESE; DISPARITIES; IMMIGRANTS AB Objectives. We examined patterns of cervical and breast cancer screening among Asian American women in California and assessed their screening trends over time. Methods. We pooled weighted data from 5 cycles of the California Health Interview Survey (2001, 2003, 2005, 2007, 2009) to examine breast and cervical cancer screening trends and predictors among 6 Asian nationalities. We calculated descriptive statistics, bivariate associations, multivariate logistic regressions, predictive margins, and 95% confidence intervals. Results. Multivariate analyses indicated that Papanicolaou test rates did not significantly change over time (77.9% in 2001 vs 81.2% in 2007), but mammography receipt increased among Asian American women overall (75.6% in 2001 vs 81.8% in 2009). Length of time in the United States was associated with increased breast and cervical cancer screening among all nationalities. Socio-demographic and health care access factors had varied effects, with education and insurance coverage significantly predicting screening for certain groups. Overall, we observed striking variation by nationality. Conclusions. Our results underscore the need for intervention and policy efforts that are targeted to specific Asian nationalities, recent immigrants, and individuals without health care access to increase screening rates among Asian women in California. C1 [Chawla, Neetu] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Breen, Nancy] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Liu, Benmei] NCI, Stat Methodol & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Lee, Richard] Informat Management Serv Inc, Calverton, MD USA. [Kagawa-Singer, Marjorie] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Kagawa-Singer, Marjorie] Asian Amer Studies Dept, Los Angeles, CA USA. RP Chawla, N (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM neetu.chawla@nih.gov FU Cancer Prevention Fellowship Program FX The authors would like to acknowledge the support of the Cancer Prevention Fellowship Program for this research. NR 64 TC 6 Z9 6 U1 3 U2 10 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2015 VL 105 IS 2 BP E98 EP E109 DI 10.2105/AJPH.2014.302250 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CE6CD UT WOS:000351922500019 PM 25521898 ER PT J AU Kishi, S Magalhaes, TA George, RT Dewey, M Laham, RJ Niinuma, H Friedman, LA Cox, C Tanami, Y Schuijf, JD Vavere, AL Kitagawa, K Chen, MY Nomura, CH Brinker, JA Rybicki, FJ Di Carli, MF Arbab-Zadeh, A Lima, JAC AF Kishi, Satoru Magalhaes, Tiago A. George, Richard T. Dewey, Marc Laham, Roger J. Niinuma, Hiroyuki Friedman, Lisa Aronson Cox, Christopher Tanami, Yutaka Schuijf, Joanne D. Vavere, Andrea L. Kitagawa, Kakuya Chen, Marcus Y. Nomura, Cesar H. Brinker, Jeffrey A. Rybicki, Frank J. Di Carli, Marcelo F. Arbab-Zadeh, Armin Lima, Joao A. C. TI Relationship of left ventricular mass to coronary atherosclerosis and myocardial ischaemia: the CORE320 multicenter study SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE Coronary atherosclerosis; Left ventricular mass; Myocardial ischaemia; Atheroma volume ID ROW COMPUTED-TOMOGRAPHY; ARTERY-DISEASE; DIAGNOSTIC PERFORMANCE; HYPERTENSIVE PATIENTS; MAGNETIC-RESONANCE; FLOW RESERVE; HYPERTROPHY; ANGIOGRAPHY; PERFUSION; ECHOCARDIOGRAPHY AB Aims The aim of this study was to investigate the association of left ventricular mass (LVM) with coronary atherosclerosis and myocardial infarction (MI). Methods and results Patients (n = 338) underwent 320 x 0.5 mm detector row coronary computed tomography (CT) angiography, invasive coronary angiography (ICA), and single-photon emission CT (SPECT) myocardial perfusion imaging. Quantitative coronary atheroma volume was obtained from the CT images for the entire coronary tree (19-segment model) with an arterial contour detection algorithm. Normalized total atheroma volume (NormTAV) was analysed to reflect quantitative total atheroma volume. LVM was measured on myocardial CT images and indexed to height to the power of 2.7 (LVMi). Patients with obstructive coronary artery disease (CAD) were defined as those with >= 50% diameter stenosis by quantitative ICA. Abnormal perfusion defect was defined as = 1 abnormal myocardial segment by SPECT. The association of LVMi with coronary atherosclerosis and myocardial perfusion defect on SPECT at the patient level was determined with uni-and multivariable linear and logistic regression analyses. Obstructive CAD was present in 60.0% of enrolled patients. LVMi was independently associated with abnormal summed rest score [SRS; odds ratio (OR), 1.07; 95% confidence interval (CI), 1.03-1.09] and summed stress score (OR, 1.04; 95% CI, 1.01-1.07). An increase in LVMi was also independently associated with that in NormTAV (coefficient, 10.44; 95% CI, 1.50-19.39) and SRS = 1 (OR, 1.05; 95% CI, 1.01-1.10), even after adjusting for cardiovascular risk factors in patients without previous MI. Conclusions LVM was independently associated with the presence of coronary artery atherosclerosis and MI. C1 [Kishi, Satoru; Magalhaes, Tiago A.; George, Richard T.; Vavere, Andrea L.; Brinker, Jeffrey A.; Arbab-Zadeh, Armin; Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Dewey, Marc] Humboldt Univ, Charite Med Sch, Dept Radiol, D-10099 Berlin, Germany. [Dewey, Marc] Free Univ Berlin, Berlin, Germany. [Laham, Roger J.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Niinuma, Hiroyuki] St Lukes Int Hosp, Div Cardiol, Tokyo, Japan. [Friedman, Lisa Aronson; Cox, Christopher] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tanami, Yutaka] Keio Univ, Dept Radiol, Tokyo, Japan. [Schuijf, Joanne D.] Toshiba Med Syst Europe BV, Zoetermeer, Netherlands. [Kitagawa, Kakuya] Mie Univ Hosp, Dept Radiol, Tsu, Mie, Japan. [Chen, Marcus Y.] NHLBI, Adv Cardiovasc Imaging Grp, NIH, Bethesda, MD 20892 USA. [Nomura, Cesar H.] Hosp Israelita Albert Einstein, Radiol Sect, Sao Paulo, Brazil. [Rybicki, Frank J.; Di Carli, Marcelo F.] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Div Cardiol, Dept Med, Sch Med, Blalock 524,600 N Wolfe St, Baltimore, MD 21287 USA. EM jlima@jhmi.edu OI Dewey, Marc/0000-0002-4402-2733 FU CORE320 study, Toshiba Medical Systems Corporation FX The sponsor of the CORE320 study, Toshiba Medical Systems Corporation, was not involved during any stage of the planning, design, data acquisition, data analysis, or manuscript preparation of this study. NR 33 TC 1 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD FEB PY 2015 VL 16 IS 2 BP 166 EP 176 DI 10.1093/ehjci/jeu217 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CE8GP UT WOS:000352080200006 PM 25368207 ER PT J AU Warren, JL Butler, EN Stevens, J Lathan, CS Noone, AM Ward, KC Harlan, LC AF Warren, Joan L. Butler, Ebonee N. Stevens, Jennifer Lathan, Christopher S. Noone, Anne-Michelle Ward, Kevin C. Harlan, Linda C. TI Receipt of Chemotherapy Among Medicare Patients With Cancer by Type of Supplemental Insurance SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; BENEFICIARIES; THERAPY; CARE; POPULATION; HOSPITALS; TRENDS AB Purpose Medicare beneficiaries with cancer bear a greater portion of their health care costs, because cancer treatment costs have increased. Beneficiaries have supplemental insurance to reduce out-of-pocket costs; those without supplemental insurance may face barriers to care. This study examines the association between type of supplemental insurance coverage and receipt of chemotherapy among Medicare patients with cancer who, per National Comprehensive Cancer Network treatment guidelines, should generally receive chemotherapy. Patients and Methods This retrospective, observational study included 1,200 Medicare patients diagnosed with incident cancer of the breast (stage IIB to III), colon (stage III), rectum (stage II to III), lung (stage II to IV), or ovary (stage II to IV) from 2000 to 2005. Using the National Cancer Institute Patterns of Care Studies and linked SEER-Medicare data, we determined each Medicare patient's supplemental insurance status (private insurance, dual eligible [ie, Medicare with Medicaid], or no supplemental insurance), consultation with an oncologist, and receipt of chemotherapy. Using adjusted logistic regression, we evaluated the association of type of supplemental insurance with oncologist consultation and receipt of chemotherapy. Results Dual-eligible patients were significantly less likely to receive chemotherapy than were Medicare patients with private insurance. Patients with Medicare only who saw an oncologist had comparable rates of chemotherapy compared with Medicare patients with private insurance. Conclusion Dual-eligible Medicare beneficiaries received recommended cancer chemotherapy less frequently than other Medicare beneficiaries. With the increasing number of Medicaid patients under the Affordable Care Act, there will be a need for patient navigators and sufficient physician reimbursement so that low-income patients with cancer will have access to oncologists and needed treatment. (C) 2014 by American Society of Clinical Oncology C1 [Warren, Joan L.; Noone, Anne-Michelle; Harlan, Linda C.] NCI, Bethesda, MD 20892 USA. [Stevens, Jennifer] Informat Management Serv Inc, Beltsville, MD USA. [Butler, Ebonee N.] Univ N Carolina, Chapel Hill, NC USA. [Lathan, Christopher S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ward, Kevin C.] Emory Univ, Atlanta, GA 30322 USA. RP Warren, JL (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. EM joan_warren@nih.gov FU NCI NIH HHS [P50 CA058223] NR 23 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2015 VL 33 IS 4 BP 312 EP U191 DI 10.1200/JCO.2014.55.3107 PG 8 WC Oncology SC Oncology GA CF3BP UT WOS:000352422900008 PM 25534387 ER PT J AU Bourne, PE AF Bourne, Philip E. TI Confronting the Ethical Challenges of Big Data in Public Health SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 NIH, Off Director, Bethesda, MD 20892 USA. RP Bourne, PE (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM philip.bourne@nih.gov NR 4 TC 2 Z9 2 U1 4 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR e1004073 DI 10.1371/journal.pcbi.1004073 PG 2 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000030 PM 25664660 ER PT J AU Edlefsen, PT Rolland, M Hertz, T Tovanabutra, S Gartland, AJ Decamp, AC Magaret, CA Ahmed, H Gottardo, R Juraska, M Mccoy, C Larsen, BB Sanders-Buell, E Carrico, C Menis, S Bose, M Arroyo, MA O'Connell, RJ Nitayaphan, S Pitisuttithum, P Kaewkungwal, J Rerks-Ngarm, S Robb, ML Kirys, T Georgiev, IS Kwong, PD Scheffler, K Pond, SLK Carlson, JM Michael, NL Schief, WR Mullins, JI Kim, JH Gilbert, PB AF Edlefsen, Paul T. Rolland, Morgane Hertz, Tomer Tovanabutra, Sodsai Gartland, Andrew J. decamp, Allan C. Magaret, Craig A. Ahmed, Hasan Gottardo, Raphael Juraska, Michal McCoy, Connor Larsen, Brendan B. Sanders-Buell, Eric Carrico, Chris Menis, Sergey Bose, Meera Arroyo, Miguel A. O'Connell, Robert J. Nitayaphan, Sorachai Pitisuttithum, Punnee Kaewkungwal, Jaranit Rerks-Ngarm, Supachai Robb, Merlin L. Kirys, Tatsiana Georgiev, Ivelin S. Kwong, Peter D. Scheffler, Konrad Pond, Sergei L. Kosakovsky Carlson, Jonathan M. Michael, Nelson L. Schief, William R. Mullins, James I. Kim, Jerome H. Gilbert, Peter B. CA RV144 Sequencing Team TI Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID COMPETING RISKS; PEPTIDE BINDING; CELL RESPONSES; SUBTYPE-B; PROTEIN; ENVELOPE; NEUTRALIZATION; EPITOPES; ESCAPE; GP120 AB The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or "signatures" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens. C1 [Edlefsen, Paul T.; Hertz, Tomer; Gartland, Andrew J.; decamp, Allan C.; Magaret, Craig A.; Ahmed, Hasan; Gottardo, Raphael; Juraska, Michal; McCoy, Connor; Gilbert, Peter B.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Rolland, Morgane; Tovanabutra, Sodsai; Sanders-Buell, Eric; Bose, Meera; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.] US Mil HIV Res Program, Silver Spring, MD USA. [Hertz, Tomer] Ben Gurion Univ Negev, Fac Hlth Sci, Shraga Segal Dept Microbiol Immunol & Genet, IL-84105 Beer Sheva, Israel. [Hertz, Tomer] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel. [Larsen, Brendan B.; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Carrico, Chris; Menis, Sergey; Schief, William R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Arroyo, Miguel A.; Nitayaphan, Sorachai; Kaewkungwal, Jaranit] AFRIMS, Royal Thai Army Component, Bangkok, Thailand. [O'Connell, Robert J.] AFRIMS, US Army Component, Bangkok, Thailand. [Pitisuttithum, Punnee] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Rerks-Ngarm, Supachai] Thai Minist Publ Hlth, CDC Dept, Nonthaburi, Thailand. [Kirys, Tatsiana; Georgiev, Ivelin S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheffler, Konrad; Pond, Sergei L. Kosakovsky] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Carlson, Jonathan M.] Microsoft Res, eSience Res Grp, Redmond, WA USA. [Schief, William R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. RP Edlefsen, PT (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM pedlefse@fredhutch.org RI Hertz, Tomer/S-5744-2016 OI Hertz, Tomer/0000-0002-0561-1578 FU U.S. Army Medical Research and Material Command (USAMRMC) [Y1-AI-2642-12]; National Institutes of Allergy and Infectious Diseases; Department of Veterans Affairs, Veterans Health Administration, Office of Research and development; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense (DOD) [W81XWH-07-2-0067]; Vaccine Research Center, NIAID/NIH; NIH [2R37AI05465-11] FX This study was supported in part by an Interagency Agreement Y1-AI-2642-12 between U.S. Army Medical Research and Material Command (USAMRMC), the National Institutes of Allergy and Infectious Diseases, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and development. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). Additional support was provided by Intramural funding of the Vaccine Research Center, NIAID/NIH and to PBG through the NIH grant 2R37AI05465-11. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Department of Health and Human Services, National Institute for Allergy and Infectious Diseases, the Department of the Army, the Department of Defense, or the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 12 Z9 12 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR UNSP e1003973 DI 10.1371/journal.pcbi.1003973 PG 37 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000005 PM 25646817 ER PT J AU Erren, TC Slanger, TE Gross, JV Bourne, PE Cullen, P AF Erren, Thomas C. Slanger, Tracy E. Gross, J. Valerie Bourne, Philip E. Cullen, Paul TI Ten Simple Rules for Lifelong Learning, According to Hamming SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Erren, Thomas C.; Slanger, Tracy E.; Gross, J. Valerie] Univ Hosp Cologne, Inst & Policlin Occupat Med Environm Med & Preven, Cologne, Germany. [Bourne, Philip E.] NIH, Off Director, Bethesda, MD 20892 USA. [Cullen, Paul] Med Labor Munster, Munster, Germany. RP Erren, TC (reprint author), Univ Hosp Cologne, Inst & Policlin Occupat Med Environm Med & Preven, Cologne, Germany. EM tim.erren@uni-koeln.de NR 16 TC 0 Z9 0 U1 12 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR e1004020 DI 10.1371/journal.pcbi.1004020 PG 5 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000010 PM 25719205 ER PT J AU Lengauer, T Nussinov, R AF Lengauer, Thomas Nussinov, Ruth TI How to Write a Presubmission Inquiry SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Lengauer, Thomas] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, D-66123 Saarbrucken, Germany. [Nussinov, Ruth] NCI, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Lengauer, T (reprint author), Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, D-66123 Saarbrucken, Germany. EM lengauer@mpi-inf.mpg.de NR 0 TC 0 Z9 0 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR e1004098 DI 10.1371/journal.pcbi.1004098 PG 3 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000039 PM 25719491 ER PT J AU Meisel, C Klaus, A Kuehn, C Plenz, D AF Meisel, Christian Klaus, Andreas Kuehn, Christian Plenz, Dietmar TI Critical Slowing Down Governs the Transition to Neuron Spiking SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID EARLY-WARNING SIGNALS; RAT SOMATOSENSORY CORTEX; PHASE RESETTING CURVES; PYRAMIDAL NEURONS; CORTICAL-NEURONS; TIPPING POINT; IN-VIVO; DYNAMICS; MODEL; EXCITABILITY AB Many complex systems have been found to exhibit critical transitions, or so-called tipping points, which are sudden changes to a qualitatively different system state. These changes can profoundly impact the functioning of a system ranging from controlled state switching to a catastrophic break-down; signals that predict critical transitions are therefore highly desirable. To this end, research efforts have focused on utilizing qualitative changes in markers related to a system's tendency to recover more slowly from a perturbation the closer it gets to the transition-a phenomenon called critical slowing down. The recently studied scaling of critical slowing down offers a refined path to understand critical transitions: to identify the transition mechanism and improve transition prediction using scaling laws. Here, we outline and apply this strategy for the first time in a real-world system by studying the transition to spiking in neurons of the mammalian cortex. The dynamical system approach has identified two robust mechanisms for the transition from subthreshold activity to spiking, saddle-node and Hopf bifurcation. Although theory provides precise predictions on signatures of critical slowing down near the bifurcation to spiking, quantitative experimental evidence has been lacking. Using whole-cell patch-clamp recordings from pyramidal neurons and fast-spiking interneurons, we show that 1) the transition to spiking dynamically corresponds to a critical transition exhibiting slowing down, 2) the scaling laws suggest a saddle-node bifurcation governing slowing down, and 3) these precise scaling laws can be used to predict the bifurcation point from a limited window of observation. To our knowledge this is the first report of scaling laws of critical slowing down in an experiment. They present a missing link for a broad class of neuroscience modeling and suggest improved estimation of tipping points by incorporating scaling laws of critical slowing down as a strategy applicable to other complex systems. C1 [Meisel, Christian; Klaus, Andreas; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [Meisel, Christian] Univ Clin Carl Gustav Carus, Dept Neurol, Dresden, Germany. [Kuehn, Christian] Vienna Univ Technol, Inst Anal & Sci Comp, A-1040 Vienna, Austria. RP Meisel, C (reprint author), NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. EM christian@meisel.de RI Kuehn, Christian/H-3950-2014; OI Kuehn, Christian/0000-0002-7063-6173; Klaus, Andreas/0000-0002-4133-351X FU Intramural Research Program of the National Institute of Mental Health; Austrian Academy of Sciences (OAW) via an APART fellowship; European Commission (EC/REA) FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. CK would like to thank the Austrian Academy of Sciences (OAW) for support via an APART fellowship. CK also acknowledges the European Commission (EC/REA) for support by a Marie-Curie International Reintegration Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 8 Z9 8 U1 3 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2015 VL 11 IS 2 AR e1004097 DI 10.1371/journal.pcbi.1004097 PG 20 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CE8GX UT WOS:000352081000038 PM 25706912 ER PT J AU Che, J Smith, S Kim, YJ Shim, EY Myung, K Lee, SE AF Che, Jun Smith, Stephanie Kim, Yoo Jung Shim, Eun Yong Myung, Kyungjae Lee, Sang Eun TI Hyper-Acetylation of Histone H3K56 Limits Break-Induced Replication by Inhibiting Extensive Repair Synthesis SO PLOS GENETICS LA English DT Article ID S-PHASE CHECKPOINT; DOUBLE-STRAND BREAKS; CONSERVATIVE DNA-SYNTHESIS; CHROMATIN-ASSEMBLY FACTORS; H3 LYSINE-56 ACETYLATION; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; CHROMOSOMAL REARRANGEMENTS; HOMOLOGOUS RECOMBINATION; DAMAGE CHECKPOINT AB Break-induced replication (BIR) has been implicated in restoring eroded telomeres and collapsed replication forks via single-ended invasion and extensive DNA synthesis on the recipient chromosome. Unlike other recombination subtypes, DNA synthesis in BIR likely relies heavily on mechanisms enabling efficient fork progression such as chromatin modification. Herein we report that deletion of HST3 and HST4, two redundant de-acetylases of histone H3 Lysine 56 (H3K56), inhibits BIR, sensitizes checkpoint deficient cells to deoxyribonucleotide triphosphate pool depletion, and elevates translocation-type gross chromosomal rearrangements (GCR). The basis for deficiency in BIR and gene conversion with long gap synthesis in hst3. hst4. cells can be traced to a defect in extensive DNA synthesis. Distinct from other cellular defects associated with deletion of HST3 and HST4 including thermo-sensitivity and elevated spontaneous mutagenesis, the BIR defect in hst3. hst4. cannot be offset by the deletion of RAD17 or MMS22, but rather by the loss of RTT109 or ASF1, or in combination with the H3K56R mutation, which also restores tolerance to replication stress in mrc1 mutants. Our studies suggest that acetylation of H3K56 limits extensive repair synthesis and interferes with efficient fork progression in BIR. C1 [Che, Jun] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Che, Jun; Shim, Eun Yong; Lee, Sang Eun] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiat Oncol, Program Radiat Biol, San Antonio, TX 78229 USA. [Smith, Stephanie; Kim, Yoo Jung; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Shim, Eun Yong; Lee, Sang Eun] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78229 USA. RP Che, J (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. EM lees4@uthscsa.edu FU National Institute of Health [GM71011]; Cancer Prevention & Research Institute of Texas [RP101491]; National Human Genome Research Institute FX This work is supported by National Institute of Health research grant GM71011 to SEL, Cancer Prevention & Research Institute of Texas Training Grant RP101491 to JC, and the intramural Research Programs of the National Human Genome Research Institute to KM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 5 Z9 5 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004990 DI 10.1371/journal.pgen.1004990 PG 24 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800044 PM 25705897 ER PT J AU Didion, JP Morgan, AP Clayshulte, AMF Mcmullan, RC Yadgary, L Petkov, PM Bell, TA Gatti, DM Crowley, JJ Hua, KJ Aylor, DL Bai, L Calaway, M Chesler, EJ French, JE Geiger, TR Gooch, TJ Garland, T Harrill, AH Hunter, K McMillan, L Holt, M Miller, DR O'Brien, DA Paigen, K Pan, WQ Rowe, LB Shaw, GD Simecek, P Sullivan, PF Svenson, KL Weinstock, GM Threadgill, DW Pomp, D Churchill, GA de Villena, FPM AF Didion, John P. Morgan, Andrew P. Clayshulte, Amelia M. -F. Mcmullan, Rachel C. Yadgary, Liran Petkov, Petko M. Bell, Timothy A. Gatti, Daniel M. Crowley, James J. Hua, Kunjie Aylor, David L. Bai, Ling Calaway, Mark Chesler, Elissa J. French, John E. Geiger, Thomas R. Gooch, Terry J. Garland, Theodore, Jr. Harrill, Alison H. Hunter, Kent McMillan, Leonard Holt, Matt Miller, Darla R. O'Brien, Deborah A. Paigen, Kenneth Pan, Wenqi Rowe, Lucy B. Shaw, Ginger D. Simecek, Petr Sullivan, Patrick F. Svenson, Karen L. Weinstock, George M. Threadgill, David W. Pomp, Daniel Churchill, Gary A. de Villena, Fernando Pardo-Manuel TI A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2 SO PLOS GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; MEIOTIC DRIVE; MUS-SPRETUS; HOUSE MOUSE; CORRELATED RESPONSES; COLLABORATIVE CROSS; NATURAL-POPULATIONS; LABORATORY MOUSE; GENETIC-CONTROL; MICE AB Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2(WSBdel1)) that eliminates the majority of the R2d2(WSB) copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2(WSBdel1), the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2(WSBdel1), thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2(WSB) heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2(WSB) transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system. C1 [Didion, John P.; Morgan, Andrew P.; Clayshulte, Amelia M. -F.; Mcmullan, Rachel C.; Yadgary, Liran; Bell, Timothy A.; Crowley, James J.; Hua, Kunjie; Calaway, Mark; Gooch, Terry J.; Miller, Darla R.; Shaw, Ginger D.; Sullivan, Patrick F.; Pomp, Daniel; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Didion, John P.; Morgan, Andrew P.; Clayshulte, Amelia M. -F.; Mcmullan, Rachel C.; Bell, Timothy A.; Hua, Kunjie; Calaway, Mark; Gooch, Terry J.; Miller, Darla R.; O'Brien, Deborah A.; Pan, Wenqi; Shaw, Ginger D.; Pomp, Daniel; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Didion, John P.; Morgan, Andrew P.; Clayshulte, Amelia M. -F.; Mcmullan, Rachel C.; Bell, Timothy A.; Hua, Kunjie; Calaway, Mark; Gooch, Terry J.; Miller, Darla R.; Shaw, Ginger D.; Pomp, Daniel; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Petkov, Petko M.; Gatti, Daniel M.; Chesler, Elissa J.; Paigen, Kenneth; Rowe, Lucy B.; Simecek, Petr; Svenson, Karen L.; Churchill, Gary A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Hua, Kunjie; O'Brien, Deborah A.; Pan, Wenqi; Pomp, Daniel] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC USA. [Aylor, David L.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Bai, Ling; Geiger, Thomas R.; Hunter, Kent] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [French, John E.] Natl Inst Environm Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Garland, Theodore, Jr.] Univ Calif Riverside, Dept Biol, Riverside, CA 92521 USA. [Harrill, Alison H.] Univ Arkansas Med Sci, Dept Environm & Occupat Hlth, Little Rock, AR 72205 USA. [McMillan, Leonard; Holt, Matt] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA. [Weinstock, George M.] Jackson Lab Genom Med, Farmington, CT USA. [Threadgill, David W.] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX USA. [Threadgill, David W.] Texas A&M Univ, Dept Mol & Cellular Med, College Stn, TX USA. RP Didion, JP (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. EM fernando@med.unc.edu OI Crowley, James/0000-0001-9051-1557; Petkov, Petko/0000-0002-6694-9150; Didion, John/0000-0002-8111-6261; McMullan, Rachel/0000-0003-0297-4549; Morgan, Andrew Parker/0000-0003-1942-4543 FU National Institute of General Medical Sciences/National Institutes of Health [GM076468, GM078452, 2P50GM076468-06]; National Institute of Mental Health/National Institutes of Health [K01MH094406, 1R21 MH096261-01, 1F30 MH103925]; National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health [RC1DK087510, DK056350]; National Cancer Institute/National Institutes of Health [ZIA BC011255, U01CA105417, R01CA079869, RC1 CA145504-02]; National Institute of Child Health and Human Development/National Institutes of Health [R01HD065024]; NHGRI/National Institutes of Health [R01 HG00941]; National Human Genome Research Institute/National Institutes of Health [1U54 HG004968]; National Human Genome Research Institute/National Institutes of Health - JAX interspecific backcross panels; National Science Foundation [IOS-1121273]; Vaadia-BARD Postdoctoral Fellowship Award from BARD, The United States - Israel Binational Agricultural Research and Development Fund [FI-478-13] FX We acknowledge grants National Institute of General Medical Sciences/National Institutes of Health GM076468 and GM078452 (PMP); National Institute of General Medical Sciences/National Institutes of Health 2P50GM076468-06 (EJC, GAC); National Institute of Mental Health/National Institutes of Health K01MH094406 (JJC); The National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health RC1DK087510 (DWT, AHH); National Cancer Institute/National Institutes of Health ZIA BC011255 (KHun); National Institute of Child Health and Human Development/National Institutes of Health R01HD065024 (DAO, FPMdV); NHGRI/National Institutes of Health R01 HG00941 (LBR); National Cancer Institute/National Institutes of Health U01CA105417 (DWT, DP); National Cancer Institute/National Institutes of Health R01CA079869 (DWT); National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health DK056350 (DP); National Cancer Institute/National Institutes of Health RC1 CA145504-02 (GAC); National Institute of Mental Health/National Institutes of Health 1R21 MH096261-01 (FPMdV); National Institute of Mental Health/National Institutes of Health 1F30 MH103925 (APM); National Human Genome Research Institute/National Institutes of Health 1U54 HG004968 (GMW); National Human Genome Research Institute/National Institutes of Health (funded the JAX interspecific backcross panels); the National Science Foundation IOS-1121273 (TG). This research was supported also by Vaadia-BARD Postdoctoral Fellowship Award No. FI-478-13 from BARD, The United States - Israel Binational Agricultural Research and Development Fund (LY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 8 Z9 8 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004850 DI 10.1371/journal.pgen.1004850 PG 29 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800002 PM 25679959 ER PT J AU Kim, YJ Igiesuorobo, O Ramos, CI Bao, H Zhang, B Serpe, M AF Kim, Young-Jun Igiesuorobo, Oghomwen Ramos, Cathy I. Bao, Hong Zhang, Bing Serpe, Mihaela TI Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Drosophila Neuromuscular Junction SO PLOS GENETICS LA English DT Article ID PROCESSING PROTEASE PC2; SYNAPTIC DEVELOPMENT; PROPROTEIN CONVERTASES; RETROGRADE SIGNAL; KAINATE RECEPTORS; SUBUNIT; PLASTICITY; EMBRYOGENESIS; MELANOGASTER; SYNAPSES AB Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromuscular junction (NMJ). Here we show that optimal levels of Neto are crucial for stabilization of iGluRs at synaptic sites and proper NMJ development. Genetic manipulations of Neto levels shifted iGluRs distribution to extrajunctional locations. Perturbations in Neto levels also produced small NMJs with reduced synaptic transmission, but only Neto-depleted NMJs showed diminished postsynaptic components. Drosophila Neto contains an inhibitory prodomain that is processed by Furin1-mediated limited proteolysis. neto null mutants rescued with a Neto variant that cannot be processed have severely impaired NMJs and reduced iGluRs synaptic clusters. Unprocessed Neto retains the ability to engage iGluRs in vivo and to form complexes with normal synaptic transmission. However, Neto prodomain must be removed to enable iGluRs synaptic stabilization and proper postsynaptic differentiation. C1 [Kim, Young-Jun; Igiesuorobo, Oghomwen; Ramos, Cathy I.; Serpe, Mihaela] NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Bao, Hong; Zhang, Bing] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. RP Kim, YJ (reprint author), NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM mihaela.serpe@nih.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development [ZIA-HD008869, ZIA-HD008914]; National Institutes of Health, National Institute of Neurological Disorders and Stroke [RO1-NS060878] FX The work performed in Serpe laboratory was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development (projects ZIA-HD008869 and ZIA-HD008914, awarded to MS) (https://www.nichd.nih.gov/about/org/dir/Pages/index.aspx). The work performed in Zhang laboratory was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (grant # RO1-NS060878, awarded to BZ) (http://www.ninds.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 3 Z9 3 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004988 DI 10.1371/journal.pgen.1004988 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800042 PM 25723514 ER PT J AU Lageix, S Zhang, JW Rothenburg, S Hinnebusch, AG AF Lageix, Sebastien Zhang, Jinwei Rothenburg, Stefan Hinnebusch, Alan G. TI Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo SO PLOS GENETICS LA English DT Article ID UNCHARGED TRANSFER-RNA; ACID-STARVED CELLS; PROTEIN-KINASE; AMINO-ACID; TRANSLATION INITIATION; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURES; ACTIVATION; SYNTHETASE; ASSOCIATION AB The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2 alpha. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. We used a genetic approach to identify a key regulatory surface in Gcn2 that is proximal to the predicted active site of the HisRS domain and likely remodeled by tRNA binding. Mutations leading to amino acid substitutions on this surface were identified that activate Gcn2 at low levels of tRNA binding (Gcd(-) phenotype), while other substitutions block kinase activation (Gcn(-) phenotype), in some cases without altering tRNA binding by Gcn2 in vitro. Remarkably, the Gcn(-) substitutions increase affinity of the HisRS domain for the C-terminal domain (CTD), previously implicated as a kinase autoinhibitory segment, in a manner dampened by HisRS domain Gcd(-) substitutions and by amino acid starvation in vivo. Moreover, tRNA specifically antagonizes HisRS/CTD association in vitro. These findings support a model wherein HisRS-CTD interaction facilitates the autoinhibitory function of the CTD in nonstarvation conditions, with tRNA binding eliciting kinase activation by weakening HisRS-CTD association with attendant disruption of the autoinhibitory KD-CTD interaction. C1 [Lageix, Sebastien; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Zhang, Jinwei] NHLBI, NIH, Bethesda, MD 20892 USA. [Rothenburg, Stefan] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. RP Lageix, S (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU National Institutes of Health FX This research was supported by the Intramural Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004991 DI 10.1371/journal.pgen.1004991 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800045 PM 25695491 ER PT J AU Schneider, A Henegar, C Day, K Absher, D Napolitano, C Silveira, L David, VA O'Brien, SJ Menotti-Raymond, M Barsh, GS Eizirik, E AF Schneider, Alexsandra Henegar, Corneliu Day, Kenneth Absher, Devin Napolitano, Constanza Silveira, Leandro David, Victor A. O'Brien, Stephen J. Menotti-Raymond, Marilyn Barsh, Gregory S. Eizirik, Eduardo TI Recurrent Evolution of Melanism in South American Felids SO PLOS GENETICS LA English DT Article ID HAPLOTYPE STRUCTURE; POSITIVE SELECTION; ONCIFELIS-GUIGNA; COAT COLOR; GENOME; GENETICS; HISTORY; CAT; HYBRIDIZATION; PIGMENTATION AB Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy's cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13-21 per species), achieving enrichment of similar to 500-2500-fold and similar to 150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism-specific haplotype in the Geoffroy's cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations. C1 [Schneider, Alexsandra; Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande Sul PUCRS, Fac Biociencias, Lab Biol Genom & Mol, Porto Alegre, RS, Brazil. [Henegar, Corneliu; Day, Kenneth; Absher, Devin; Barsh, Gregory S.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Napolitano, Constanza] Univ Chile, Lab Ecol Mol, Santiago, Chile. [Napolitano, Constanza] Univ Chile, Fac Ciencias, Dept Ciencias Ecol, Inst Ecol & Biodiversidad, Santiago, Chile. [Silveira, Leandro] Inst Onca Pintada, Jaguar Conservat Fund, Mineiros, Go, Brazil. [David, Victor A.; Menotti-Raymond, Marilyn] NCI, Basic Res Lab, Frederick Natl Lab, Ctr Canc Res, Frederick, MD 21701 USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Informat, St Petersburg 199034, Russia. [Eizirik, Eduardo] Inst Procarnivoros, Sao Paulo, Brazil. RP Schneider, A (reprint author), Pontificia Univ Catolica Rio Grande Sul PUCRS, Fac Biociencias, Lab Biol Genom & Mol, Porto Alegre, RS, Brazil. EM gbarsh@hudsonalpha.org; eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012 OI Eizirik, Eduardo/0000-0002-9658-0999 FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil; Intramural Research Program of the NIH; Frederick National Laboratory; Center for Cancer Research; National Cancer Institute; HudsonAlpha Institute for Biotechnology FX This study was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil, the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, National Cancer Institute, and the HudsonAlpha Institute for Biotechnology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 4 Z9 4 U1 4 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2015 VL 11 IS 2 AR e1004892 DI 10.1371/journal.pgen.1004892 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA CE8HF UT WOS:000352081800006 PM 25695801 ER PT J AU Radtke, AJ Kastenmuller, W Espinosa, DA Gerner, MY Tse, SW Sinnis, P Germain, RN Zavala, FP Cockburn, IA AF Radtke, Andrea J. Kastenmueller, Wolfgang Espinosa, Diego A. Gerner, Michael Y. Tse, Sze-Wah Sinnis, Photini Germain, Ronald N. Zavala, Fidel P. Cockburn, Ian A. TI Lymph-Node Resident CD8 alpha(+) Dendritic Cells Capture Antigens from Migratory Malaria Sporozoites and Induce CD8(+) T Cell Responses SO PLOS PATHOGENS LA English DT Article ID PLASMODIUM-BERGHEI; IN-VIVO; CIRCUMSPOROZOITE PROTEIN; LIVER-STAGES; LANGERHANS CELLS; IMMUNE-RESPONSE; IRRADIATED SPOROZOITES; PROTECTIVE ANTIGEN; PRESENTING CELLS; DC SUBSETS AB Malaria infection begins when a female Anopheles mosquito injects Plasmodium sporozoites into the skin of its host during blood feeding. Skin-deposited sporozoites may enter the bloodstream and infect the liver, reside and develop in the skin, or migrate to the draining lymph nodes (DLNs). Importantly, the DLN is where protective CD8(+) T cell responses against malaria liver stages are induced after a dermal route of infection. However, the significance of parasites in the skin and DLN to CD8(+) T cell activation is largely unknown. In this study, we used genetically modified parasites, as well as antibody-mediated immobilization of sporozoites, to determine that active sporozoite migration to the DLNs is required for robust CD8(+) T cell responses. Through dynamic in vivo and static imaging, we show the direct uptake of parasites by lymph-node resident DCs followed by CD8(+) T cell-DC cluster formation, a surrogate for antigen presentation, in the DLNs. A few hours after sporozoite arrival to the DLNs, CD8(+) T cells are primed by resident CD8 alpha(+) DCs with no apparent role for skin-derived DCs. Together, these results establish a critical role for lymph node resident CD8 alpha(+) DCs in CD8(+) T cell priming to sporozoite antigens while emphasizing a requirement for motile sporozoites in the induction of CD8(+) T cell-mediated immunity. C1 [Radtke, Andrea J.; Espinosa, Diego A.; Tse, Sze-Wah; Sinnis, Photini; Zavala, Fidel P.; Cockburn, Ian A.] Johns Hopkins Malaria Res Inst, Baltimore, MD USA. [Radtke, Andrea J.; Espinosa, Diego A.; Tse, Sze-Wah; Sinnis, Photini; Zavala, Fidel P.; Cockburn, Ian A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Kastenmueller, Wolfgang; Gerner, Michael Y.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Radtke, AJ (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fzavala@jhsph.edu; ian.cockburn@anu.edu.au FU NIH [AI44375, AI056840]; Johns Hopkins Malaria Research Institute; Bloomberg Family; NIAID, NIH FX FPZ is supported by NIH grant AI44375. AJR was supported by a pre-doctoral fellowship from the Johns Hopkins Malaria Research Institute. PS is supported by NIH grant AI056840. The authors are grateful for the support of the Bloomberg Family. This work was supported in part by the Intramural Research Program of NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 19 Z9 19 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2015 VL 11 IS 2 AR e1004637 DI 10.1371/journal.ppat.1004637 PG 23 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE8HU UT WOS:000352083400024 PM 25658939 ER PT J AU Wickner, RB Edskes, HK Bateman, DA Gorkovskiy, A Dayani, Y Bezsonov, EE Mukhamedova, M AF Wickner, Reed B. Edskes, Herman K. Bateman, David A. Gorkovskiy, Anton Dayani, Yaron Bezsonov, Evgeny E. Mukhamedova, Maryam TI Yeast Prions: Proteins Templating Conformation and an Anti-prion System SO PLOS PATHOGENS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; URE3 PRION; STRAINS; MECHANISM; DISEASES; PSI+ C1 [Wickner, Reed B.; Edskes, Herman K.; Bateman, David A.; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E.; Mukhamedova, Maryam] Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Gorkovskiy, Anton/J-8930-2016 OI Gorkovskiy, Anton/0000-0003-4811-2282 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 0 Z9 0 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2015 VL 11 IS 2 AR e1004584 DI 10.1371/journal.ppat.1004584 PG 5 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CE8HU UT WOS:000352083400005 PM 25654539 ER PT J AU McKinstry-Wu, AR Bu, WM Rai, G Lea, WA Weiser, BP Liang, DF Simeonov, A Jadhav, A Maloney, DJ Eckenhoff, RG AF McKinstry-Wu, Andrew R. Bu, Weiming Rai, Ganesha Lea, Wendy A. Weiser, Brian P. Liang, David F. Simeonov, Anton Jadhav, Ajit Maloney, David J. Eckenhoff, Roderic G. TI Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening SO ANESTHESIOLOGY LA English DT Article ID GABA(A) RECEPTOR; TRANSMEMBRANE DOMAIN; BINDING-SITES; IDENTIFICATION; AGONISTS AB Background: The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Methods: Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-aminoanthracene-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for.-aminobutyric acid type A receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. Results: From an initial chemical library of more than 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-aminoanthracene binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based on a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. Conclusion: The authors demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype. C1 [McKinstry-Wu, Andrew R.; Bu, Weiming; Eckenhoff, Roderic G.] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Weiser, Brian P.] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. [Rai, Ganesha; Lea, Wendy A.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Liang, David F.] Univ Penn, Coll Arts & Sci, Philadelphia, PA 19104 USA. RP Eckenhoff, RG (reprint author), Univ Penn, Dept Anesthesiol & Crit Care, 311A John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM roderic.eckenhoff@uphs.upenn.edu FU National Institutes of Health (Bethesda, Maryland) through the Small Grant Program [R03 MH 084836]; Program Project Grant [P01 GM 55876]; intramural research program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, National Institutes of Health, Bethesda, Maryland [U54MH084681] FX Drs. McKinstry-Wu, Bu, Weiser, and Eckenhoff were supported by the National Institutes of Health (Bethesda, Maryland) through the Small Grant Program (R03 MH 084836) and a Program Project Grant (P01 GM 55876). Drs. Rai, Lea, Simenov, Jadhav, and Maloney were supported by the intramural research program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (U54MH084681, National Institutes of Health, Bethesda, Maryland). The remaining authors or their institutions have no intellectual property rights regarding the compounds generated by this reported research. NR 28 TC 3 Z9 4 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD FEB PY 2015 VL 122 IS 2 BP 325 EP 333 DI 10.1097/ALN.0000000000000505 PG 9 WC Anesthesiology SC Anesthesiology GA CE3NZ UT WOS:000351734900012 PM 25603205 ER PT J AU Zheng, CY Chang, K Suh, YH Roche, KW AF Zheng, Chan-Ying Chang, Kai Suh, Young Ho Roche, Katherine W. TI TARP gamma-8 glycosylation regulates the surface expression of AMPA receptors SO BIOCHEMICAL JOURNAL LA English DT Article DE AMPA receptor; CNIH-2; N-linked glycosylation; TARP gamma-2; TARP gamma-8; trafficking ID AUXILIARY SUBUNITS; SYNAPTIC PLASTICITY; GLUTAMATE RECEPTORS; CORNICHON PROTEINS; MUTANT MOUSE; HIPPOCAMPAL; TRAFFICKING; STARGAZIN; NEURONS; SPINES AB TARP [transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein] gamma-8 is an auxiliary subunit of AMPA receptors that is widely distributed in the hippocampus. It has been shown that TARP gamma-8 promotes surface expression of AMPA receptors; however, how TARP gamma-8 regulates the expression of AMPA receptors remains unclear. In the present study, we examined the effect of TARP glycosylation on AMPA receptor trafficking. We first showed that TARP gamma-8 is an N-glycosylated protein, which contains two glycosylation sites, Asn(53) and Asn(56), and compared this with the glycosylation of TARP gamma-2 and the AMPA receptor auxiliary protein CNIH-2 (cornichon homologue 2). We next examine the effect of TARP glycosylation on TARP trafficking and also on AMPA receptor surface expression. We find that TARP gamma-8 glycosylation is critical for surface expression of both TARP gamma-8 and GluA1 in heterologous cells and neurons. Specifically, knockdown of TARP gamma-8 causes a decrease in both total and surface AMPA receptors. We find that the expression of unglycosylated TARP gamma-8 in cultured neurons is unable to restore GluA1 expression fully. Furthermore, when the maturation of TARP gamma-8 is impaired, a large pool of immature GluA1 is retained intracellularly. Taken together, our data reveal an important role for the maturation of TARP gamma-8 in the trafficking and function of the AMPA receptor complex. C1 [Zheng, Chan-Ying; Chang, Kai; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Suh, Young Ho] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea. RP Suh, YH (reprint author), Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea. EM suhyho@snu.ac.kr; rochek@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program; Basic Science Research Program through the National Research Foundation of Korea [NRF-2011-0011694] FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. Y.H.S. was supported by the Basic Science Research Program [grant number NRF-2011-0011694] through the National Research Foundation of Korea. NR 37 TC 3 Z9 3 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD FEB 1 PY 2015 VL 465 BP 471 EP 477 DI 10.1042/BJ20140806 PN 3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CE2XV UT WOS:000351686200011 PM 25495042 ER PT J AU Okoli, TC Peer, CJ Dunleavy, K Figg, WD AF Okoli, Tracy C. Peer, Cody J. Dunleavy, Kieron Figg, William D. TI Targeted PI3K delta inhibition by the small molecule idelalisib as a novel therapy in indolent non-Hodgkin lymphoma SO CANCER BIOLOGY & THERAPY LA English DT Article DE B-cell chronic lymphocytic leukemia; follicular lymphoma; Furman etal; Gopal etal; indolent Non-Hogkin Lymphoma; idelalisb; PI3K Inhibition; rituximab; small lymphocytic lymphoma; targeted therapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; RITUXIMAB; CLL AB Indolent Non-Hodgkin Lymphomas (iNHL) are typically B-cell malignancies and are incurable with current standard approaches. Thus, there is a demand for novel agents specific for this group of disorders. In a phase II study published by Gopal etal. in the New England Journal of Medicine, idelalisib, a small molecule inhibitor of PI3K that was FDA approved in July of 2014, was shown to be effective when combined with rituximab in patients who cannot tolerate chemotherapy and as last line therapy in patients with iNHL refractory to 2 prior systemic therapies. Idelalisib demonstrated tolerable diarrhea, fatigue, nausea, pyrexia, and cough. While this novel agent is a clinically significant addition to the iNHL arsenal, further research is needed to determine its most appropriate place in iNHL therapy. C1 [Okoli, Tracy C.; Peer, Cody J.; Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Dunleavy, Kieron] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM wf13e@nih.gov RI Figg Sr, William/M-2411-2016 NR 14 TC 2 Z9 2 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD FEB PY 2015 VL 16 IS 2 BP 204 EP 206 DI 10.1080/15384047.2014.1002369 PG 3 WC Oncology SC Oncology GA CE2FZ UT WOS:000351631200005 PM 25756507 ER PT J AU Chao, CC Karabanov, AN Paine, R de Campos, AC Kukke, SN Wu, TX Wang, H Hallett, M AF Chao, Chi-Chao Karabanov, Anke Ninija Paine, Rainer de Campos, Ana Carolina Kukke, Sahana N. Wu, Tianxia Wang, Han Hallett, Mark TI Induction of Motor Associative Plasticity in the Posterior Parietal Cortex-Primary Motor Network SO CEREBRAL CORTEX LA English DT Article DE associative plasticity; corticocortical paired-associative stimulation; motor cortex; parietal motor connectivity; posterior parietal cortex ID TRANSCRANIAL MAGNETIC STIMULATION; TIMING-DEPENDENT PLASTICITY; THETA-BURST STIMULATION; EVENT-RELATED FMRI; CORTICOCORTICAL CONNECTIONS; SOMATOSENSORY CORTEX; HIPPOCAMPAL-NEURONS; PARKINSONS-DISEASE; DECISION-MAKING; HUMAN BRAIN AB There is anatomical and functional connectivity between the primary motor cortex (M1) and posterior parietal cortex (PPC) that plays a role in sensorimotor integration. In this study, we applied corticocortical paired-associative stimuli to ipsilateral PPC and M1 (parietal ccPAS) in healthy right-handed subjects to test if this procedure could modulate M1 excitability and PPC-M1 connectivity. One hundred and eighty paired transcranial magnetic stimuli to the PPC and M1 at an interstimulus interval (ISI) of 8 ms were delivered at 0.2 Hz. We found that parietal ccPAS in the left hemisphere increased the excitability of conditioned left M1 assessed by motor evoked potentials (MEPs) and the input-output curve. Motor behavior assessed by the Purdue pegboard task was unchanged compared with controls. At baseline, conditioning stimuli over the left PPC potentiated MEPs from left M1 when ISI was 8 ms. This interaction significantly attenuated at 60 min after left parietal ccPAS. Additional experiments showed that parietal ccPAS induced plasticity was timing-dependent, was absent if ISI was 100 ms, and could also be seen in the right hemisphere. Our results suggest that parietal ccPAS can modulate M1 excitability and PPC-M1 connectivity and is a new approach to modify motor excitability and sensorimotor interaction. C1 [Chao, Chi-Chao; Karabanov, Anke Ninija; Paine, Rainer; de Campos, Ana Carolina; Kukke, Sahana N.; Wang, Han; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Chao, Chi-Chao] Natl Taiwan Univ Hosp, Dept Neurol, Taipei 100, Taiwan. [Karabanov, Anke Ninija] Hvidovre Univ Hosp, Danish Res Ctr Magnet Resonance, DK-2650 Hvidovre, Denmark. [Karabanov, Anke Ninija] Univ Copenhagen, Dept Exercise & Sport Sci, DK-2200 Copenhagen, Denmark. [Wang, Han] Beijing Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Rm 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Karabanov, Anke Ninija/0000-0003-1874-393X FU National Institute of Neurological Disorder and Stroke, National Institutes of Health FX This work was supported by (in part) by the Intramural Research Program of the National Institute of Neurological Disorder and Stroke, National Institutes of Health. NR 71 TC 9 Z9 9 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD FEB PY 2015 VL 25 IS 2 BP 365 EP 373 DI 10.1093/cercor/bht230 PG 9 WC Neurosciences SC Neurosciences & Neurology GA CE6GR UT WOS:000351935300008 PM 23968834 ER PT J AU Faucz, FR Horvath, AD Azevedo, MF Levy, I Bak, B Wang, Y Xekouki, P Szarek, E Gourgari, E Manning, AD de Alexandre, RB Saloustros, E Trivellin, G Lodish, M Hofman, P Anderson, YC Holdaway, I Oldfield, E Chittiboina, P Nesterova, M Biermasz, NR Wit, JM Bernard, DJ Stratakis, CA AF Faucz, Fabio R. Horvath, Anelia D. Azevedo, Monalisa F. Levy, Isaac Bak, Beata Wang, Ying Xekouki, Paraskevi Szarek, Eva Gourgari, Evgenia Manning, Allison D. de Alexandre, Rodrigo Bertollo Saloustros, Emmanouil Trivellin, Giampaolo Lodish, Maya Hofman, Paul Anderson, Yvonne C. Holdaway, Ian Oldfield, Edward Chittiboina, Prashant Nesterova, Maria Biermasz, Nienke R. Wit, Jan M. Bernard, Daniel J. Stratakis, Constantine A. TI Is IGSF1 involved in human pituitary tumor formation? SO ENDOCRINE-RELATED CANCER LA English DT Article DE pituitary tumor; IGSF1; growth hormone; overgrowth; acromegaly; gigantism ID CONGENITAL CENTRAL HYPOTHYROIDISM; MUTATIONS; GIGANTISM; ADENOMAS AB IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p. N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation. C1 [Faucz, Fabio R.; Horvath, Anelia D.; Azevedo, Monalisa F.; Levy, Isaac; Xekouki, Paraskevi; Szarek, Eva; Gourgari, Evgenia; Manning, Allison D.; de Alexandre, Rodrigo Bertollo; Saloustros, Emmanouil; Trivellin, Giampaolo; Lodish, Maya; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Faucz, Fabio R.; de Alexandre, Rodrigo Bertollo] Pontificia Univ Catolica Parana, Sch Med, Grp Adv Mol Invest, Grad Program Hlth Sci, BR-80215 Curitiba, Parana, Brazil. [Bak, Beata; Wang, Ying; Bernard, Daniel J.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. [Gourgari, Evgenia; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Hofman, Paul; Anderson, Yvonne C.] Univ Auckland, Liggins Inst, Auckland 1023, New Zealand. [Anderson, Yvonne C.] Taranaki Base Hosp, New Plymouth 4310, New Zealand. [Holdaway, Ian] Auckland City Hosp, Auckland 1142, New Zealand. [Holdaway, Ian] Greenlane Clin Ctr, Auckland 1142, New Zealand. [Oldfield, Edward] Univ Virginia, Hlth Sci Ctr, Dept Neurosurg, Charlottesville, VA 22904 USA. [Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Biermasz, Nienke R.] Leiden Univ, Med Ctr, Dept Endocrinol & Metab Disorders, NL-2333 Leiden, Netherlands. [Wit, Jan M.] Leiden Univ, Med Ctr, Dept Pediat, NL-2333 Leiden, Netherlands. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH,Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI de Alexandre, Rodrigo/H-9489-2013; Trivellin, Giampaolo/J-6583-2016; OI de Alexandre, Rodrigo/0000-0002-1253-7716; Trivellin, Giampaolo/0000-0003-2384-4153; Saloustros, Emmanouil /0000-0002-0485-0120 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH); CNPq; University of Brasilia, Brazil; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [Process: 311166/2011-3 - PQ-2]; Government of Canada-Canadian Institutes of Health Research [CIHR MOP-133557] FX This study was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) (to C A Stratakis). Additional support was provided from a post-doctoral fellowship grant from CNPq and from the University of Brasilia, Brazil (to MF Azevedo; mentor: Dr CA Stratakis), in part, by a grant from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Process: 311166/2011-3 - PQ-2 (to Fabio Rueda Faucz), and in part by a grant from Government of Canada-Canadian Institutes of Health Research, grant number CIHR MOP-133557 (to D J Bernard). NR 15 TC 5 Z9 5 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2015 VL 22 IS 1 BP 47 EP 54 DI 10.1530/ERC-14-0465 PG 8 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA CE7FD UT WOS:000352002500013 PM 25527509 ER PT J AU Toledo, RA Hatakana, R Lourenco, DM Lindsey, SC Camacho, CP Almeida, M Lima, JV Sekiya, T Garralda, E Naslavsky, MS Yamamoto, GL Lazar, M Meirelles, O Sobreira, TJP Lebrao, ML Duarte, YAO Blangero, J Zatz, M Cerutti, JM Maciel, RMB Toledo, SPA AF Toledo, Rodrigo A. Hatakana, Roxanne Lourenco, Delmar M., Jr. Lindsey, Susan C. Camacho, Cleber P. Almeida, Marcio Lima, Jose V., Jr. Sekiya, Tomoko Garralda, Elena Naslavsky, Michel S. Yamamoto, Guilherme L. Lazar, Monize Meirelles, Osorio Sobreira, Tiago J. P. Lebrao, Maria Lucia Duarte, Yeda A. O. Blangero, John Zatz, Mayana Cerutti, Janete M. Maciel, Rui M. B. Toledo, Sergio P. A. TI Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility SO ENDOCRINE-RELATED CANCER LA English DT Article DE multiple endocrine neoplasias; RET oncogene; MEN2; medullary thyroid carcinoma; genetics ID ENDOCRINE NEOPLASIA TYPE-2; GENOTYPE-PHENOTYPE CORRELATION; HIRSCHSPRUNG-DISEASE; PROTOONCOGENE MUTATIONS; GERMLINE MUTATIONS; CANCER; SEQUENCE; FAMILIES; CODON-790/791; PENETRANCE AB Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility. C1 [Toledo, Rodrigo A.; Hatakana, Roxanne; Lourenco, Delmar M., Jr.; Sekiya, Tomoko; Toledo, Sergio P. A.] Univ Sao Paulo, Sch Med, Hosp Clin, Endocrine Genet Unit,Lab Invest Med,LIM 25, BR-05403010 Sao Paulo, Brazil. [Duarte, Yeda A. O.] Univ Sao Paulo, Sch Nursing, BR-05403010 Sao Paulo, Brazil. [Lebrao, Maria Lucia] Univ Sao Paulo, Sch Publ Hlth, BR-05403010 Sao Paulo, Brazil. [Naslavsky, Michel S.; Yamamoto, Guilherme L.; Lazar, Monize; Zatz, Mayana] Univ Sao Paulo, Human Genome Res Ctr, BR-05403010 Sao Paulo, Brazil. [Cerutti, Janete M.] Univ Fed Sao Paulo, Dept Morphol & Genet, Div Genet, Genet Bases Thyroid Tumors Lab, Sao Paulo, Brazil. [Lindsey, Susan C.; Camacho, Cleber P.; Maciel, Rui M. B.; Toledo, Sergio P. A.] Univ Fed Sao Paulo, Dept Med, Div Endocrinol, Lab Mol & Translat Endocrinol, Sao Paulo, Brazil. [Sobreira, Tiago J. P.] Brazilian Natl Lab Biosci, Sao Paulo, Brazil. [Garralda, Elena] Hosp Univ Sanchinarro, Ctr Integral Oncol Clara Campal, Madrid, Spain. [Almeida, Marcio; Blangero, John] AT&T Genom Comp Ctr, Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Lima, Jose V., Jr.] Santa Casa Hosp, Div Endocrinol, Sao Paulo, Brazil. [Meirelles, Osorio] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. RP Toledo, RA (reprint author), Univ Sao Paulo, Sch Med, Hosp Clin, Endocrine Genet Unit,Lab Invest Med,LIM 25, BR-05403010 Sao Paulo, Brazil. EM toledorodrigo@usp.br RI Lourenco , Delmar/B-8832-2012; Zatz, Mayana/M-5338-2015; Naslavsky, Michel/L-1772-2015; Sobreira, Tiago/C-1276-2008; Lindsey, Susan/N-2716-2014 OI Zatz, Mayana/0000-0003-3970-8025; Naslavsky, Michel/0000-0002-9068-1713; Sobreira, Tiago/0000-0002-0217-0084; FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [401.990/2010-9]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/01476-9, 2006/60402-1, 2010/51547-1]; Ciencias Sem Fronteiras CNPq postdoctoral fellowship; FAPESP; Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil [028/2013] FX This study was supported by funds from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), grant number 401.990/2010-9 and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) grants number 2013/01476-9 (to S P A Toledo) and 2006/60402-1 and 2010/51547-1 (to R M B Maciel). S P A Toledo, J M Cerutti and R M B Maciel are investigators with the CNPq. R A Toledo has received a Ciencias Sem Fronteiras CNPq postdoctoral fellowship and is currently working at the Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid. R Hatakana, T Sekiya, S C Lindsey, D M Lourenco Jr, and R A Toledo received research fellowships from FAPESP. S P A Toledo is a Senior Professor in the Division of Endocrinology, Department of Medicine, Federal University of Sao Paulo, SP, Brazil, with a grant from the Programa de Visitante Nacional Senior - Edital 028/2013 - from the Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil. NR 42 TC 11 Z9 12 U1 1 U2 6 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2015 VL 22 IS 1 BP 65 EP 76 DI 10.1530/ERC-14-0491 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA CE7FD UT WOS:000352002500015 PM 25425582 ER PT J AU Hoffman, K Garantziotis, S Birnbaum, LS Stapleton, HM AF Hoffman, Kate Garantziotis, Stavros Birnbaum, Linda S. Stapleton, Heather M. TI Monitoring Indoor Exposure to Organophosphate Flame Retardants: Hand Wipes and House Dust SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TRIS(1,3-DICHLORO-2-PROPYL) PHOSPHATE; URINARY METABOLITES; PHASE-OUT; VARIABILITY; ZEBRAFISH; HANDWIPES; TDCPP; TRANSCRIPTIONS; ASSOCIATIONS; DISPOSITION AB BACKGROUND: Organophosphate flame retardants (PFRs) are becoming popular replacements for the phased-out polybrominated diphenyl ether (PBDE) mixtures, and they are now commonly detected in indoor environments. However, little is known about human exposure to PFRs because they cannot be easily measured in blood or serum. OBJECTIVES: To investigate relationships between the home environment and internal exposure, we assessed associations between two PFRs, tris(1,3-dichloropropyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP), in paired hand wipe and dust samples and concentrations of their metabolites in urine samples (n = 53). We also assessed short-term variation in urinary metabolite concentrations (n = 11 participants; n = 49 samples). METHODS: Adult volunteers in North Carolina, USA, completed questionnaires and provided urine, hand wipe, and household dust samples. PFRs and PBDEs were measured in hand wipes and dust, and bis(1,3-dichloropropyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), metabolites of TDCIPP and TPHP, were measured in urine. RESULTS: TDCIPP and TPHP were detected frequently in hand wipes and dust (> 86.8%), with geometric mean concentrations exceeding those of PBDEs. Unlike PBDEs, dust TDCIPP and TPHP levels were not associated with hand wipes. However, hand wipe levels were associated with urinary metabolites. Participants with the highest hand wipe TPHP mass, for instance, had DPHP levels 2.42 times those of participants with the lowest levels (95% CI: 1.23, 4.77). Women had higher levels of DPHP, but not BDCIPP. BDCIPP and DPHP concentrations were moderately to strongly reliable over 5 consecutive days (intra-class correlation coefficients of 0.81 and 0.51, respectively). CONCLUSIONS: PFR exposures are widespread, and hand-to-mouth contact or dermal absorption may be important pathways of exposure. C1 [Hoffman, Kate; Stapleton, Heather M.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Garantziotis, Stavros] NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NCI, NIH, DHHS, Res Triangle Pk, NC USA. RP Stapleton, HM (reprint author), Duke Univ, Nicholas Sch Environm, A220 LSRC Box 90328, Durham, NC 27708 USA. EM heather.stapleton@duke.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU National Institute of Environmental Health Sciences (NIEHS) [R01 ES016099]; intramural programs of the NIEHS; National Institutes of Health; National Cancer Institute FX This study was supported by a research grant to H.M.S. from the National Institute of Environmental Health Sciences (NIEHS; R01 ES016099) and by the intramural programs of the NIEHS, the National Institutes of Health, and the National Cancer Institute. K.H. was supported through a donation provided by Fred and Alice Stanback. NR 37 TC 24 Z9 24 U1 16 U2 156 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2015 VL 123 IS 2 BP 160 EP 165 DI 10.1289/ehp.1408669 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE8GI UT WOS:000352079400016 PM 25343780 ER PT J AU Rogalsky, DK Mendola, P Metts, TA Martin, WJ AF Rogalsky, Derek K. Mendola, Pauline Metts, Tricia A. Martin, William J., II TI Estimating the Number of Vulnerable People in the United States Exposed to Residential Wood Smoke: Rogalsky et al. Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 [Rogalsky, Derek K.] Georgetown Univ, Sch Med, Washington, DC 20057 USA. [Mendola, Pauline; Martin, William J., II] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Metts, Tricia A.] E Tennessee State Univ, Dept Environm Hlth, Johnson City, TN 37614 USA. RP Rogalsky, DK (reprint author), Georgetown Univ, Sch Med, Washington, DC 20057 USA. EM dkr24@georgetown.edu OI Mendola, Pauline/0000-0001-5330-2844 NR 4 TC 0 Z9 0 U1 1 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2015 VL 123 IS 2 BP A30 EP A31 DI 10.1289/ehp.1409136R PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA CE8GI UT WOS:000352079400002 PM 25642727 ER PT J AU Krzak, JJ Corcos, DM Damiano, DL Graf, A Hedeker, D Smith, PA Harris, GF AF Krzak, Joseph J. Corcos, Daniel M. Damiano, Diane L. Graf, Adam Hedeker, Donald Smith, Peter A. Harris, Gerald F. TI Kinematic foot types in youth with equinovarus secondary to hemiplegia SO GAIT & POSTURE LA English DT Article DE Cerebral palsy; Equinovarus; Gait; Multi-segmental foot modeling ID POSTERIOR TIBIAL TENDON; CEREBRAL-PALSY; GAIT PATTERNS; SPASTIC HEMIPLEGIA; CHILDREN; DEFORMITY; ANTERIOR; SURGERY AB Background: Elevated kinematic variability of the foot and ankle segments exists during gait among individuals with equinovarus secondary to hemiplegic cerebral palsy (CP). Clinicians have previously addressed such variability by developing classification schemes to identify subgroups of individuals based on their kinematics. Objective: To identify kinematic subgroups among youth with equinovarus secondary to CP using 3-dimensional multi-segment foot and ankle kinematics during locomotion as inputs for principal component analysis (PCA), and K-means cluster analysis. Methods: In a single assessment session, multi-segment foot and ankle kinematics using the Milwaukee Foot Model (MFM) were collected in 24 children/adolescents with equinovarus and 20 typically developing children/adolescents. Results: PCA was used as a data reduction technique on 40 variables. K-means cluster analysis was performed on the first six principal components (PCs) which accounted for 92% of the variance of the dataset. The PCs described the location and plane of involvement in the foot and ankle. Five distinct kinematic subgroups were identified using K-means clustering. Participants with equinovarus presented with variable involvement ranging from primary hindfoot or forefoot deviations to deformtiy that included both segments in multiple planes. Conclusion: This study provides further evidence of the variability in foot characteristics associated with equinovarus secondary to hemiplegic CP. These findings would not have been detected using a single segment foot model. The identification of multiple kinematic subgroups with unique foot and ankle characteristics has the potential to improve treatment since similar patients within a subgroup are likely to benefit from the same intervention(s). (C) 2014 Elsevier B.V. All rights reserved. C1 [Krzak, Joseph J.] Midwestern Univ, Coll Hlth Sci, Phys Therapy Program, Downers Grove, IL 60515 USA. [Krzak, Joseph J.; Graf, Adam; Smith, Peter A.; Harris, Gerald F.] Shriners Hosp Children Chicago, Chicago, IL USA. [Corcos, Daniel M.] Northwestern Univ, Dept Phys Therapy & Human Movement Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Hedeker, Donald] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Smith, Peter A.] Rush Univ, Med Ctr, Dept Orthopaed Surg, Coll Med, Chicago, IL 60612 USA. [Harris, Gerald F.] Marquette Univ, Med Coll Wisconsin, Orthopaed & Rehabil Engn Ctr, Milwaukee, WI 53233 USA. RP Krzak, JJ (reprint author), Midwestern Univ, Coll Hlth Sci, Phys Therapy Program, 555 31st St, Downers Grove, IL 60515 USA. EM joekrzak@sbcglobal.net RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program of the NIH Clinical Center FX The authors would like to thank Ms. Kathryn Reiners for her assistance with data collection, as well as, the children and familes who gave their time to participate in this project. This work was supported in part by the Intramural Research Program of the NIH Clinical Center. NR 33 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 EI 1879-2219 J9 GAIT POSTURE JI Gait Posture PD FEB PY 2015 VL 41 IS 2 BP 402 EP 408 DI 10.1016/j.gaitpost.2014.10.027 PG 7 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA CE6GC UT WOS:000351933700009 PM 25467429 ER PT J AU Besharat, S Poustchi, H Mohamadkhani, A Katoonizadeh, A Moradi, A Roshandel, G Freedman, ND Malekzadeh, R AF Besharat, Sima Poustchi, Hossein Mohamadkhani, Ashraf Katoonizadeh, Aezam Moradi, Abdolvahab Roshandel, Gholamreza Freedman, Neal David Malekzadeh, Reza TI Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran SO HEPATITIS MONTHLY LA English DT Article DE Hepatitis B; Chronic; Mutation; Genome; Viral ID HEPATOCELLULAR-CARCINOMA; SURFACE-ANTIGEN; ESOPHAGEAL CANCER; VIRUS INFECTION; GENOTYPE; MUTANTS; REPLICATION; FREQUENCY; PROVINCE; THERAPY AB Background: Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear. Objectives: We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran. Materials and Methods: Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided. Results: Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 +/- 1.66 IU/mL vs. 1.76 +/- 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection. Conclusions: In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease. C1 [Besharat, Sima; Poustchi, Hossein; Mohamadkhani, Ashraf; Katoonizadeh, Aezam; Roshandel, Gholamreza; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Liver & Pancreatobiliary Dis Res Ctr, Tehran, Iran. [Besharat, Sima; Moradi, Abdolvahab; Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroentrol & Hepatol, Gorgan, Iran. [Freedman, Neal David] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. RP Poustchi, H (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Liver & Pancreatobiliary Dis Res Ctr, Shariati Hosp, North Kargar Ave,POB 14117-13135, Tehran, Iran. EM h.poustchi@gmail.com RI Freedman, Neal/B-9741-2015; Besharat, Sima/L-7351-2016; Roshandel, gholamreza/N-2260-2016; Moradi, Abdolvahab/C-1680-2017 OI Freedman, Neal/0000-0003-0074-1098; Besharat, Sima/0000-0002-0540-6056; Roshandel, gholamreza/0000-0002-5494-0722; Moradi, Abdolvahab/0000-0003-2877-4190 FU Tehran University of Medical Sciences (TUMS), Research Deputy FX This paper is in partial fulfillment of a doctoral thesis in cellular and molecular research. Authors give thanks for the financial support of Tehran University of Medical Sciences (TUMS), Research Deputy. Special thanks are given to the staff of Digestive Diseases Research Institute (DDRI), laboratory division. NR 31 TC 2 Z9 2 U1 3 U2 5 PU KOWSAR PUBL PI HOENSBROEK PA PATERSWEG 22,, HOENSBROEK, LIMBURG 6431 GC, NETHERLANDS SN 1735-143X EI 1735-3408 J9 HEPAT MON JI Hepat. Mon. PD FEB PY 2015 VL 15 IS 2 AR e23875 DI 10.5812/hepatmon.23875 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CE3IG UT WOS:000351719300004 PM 25788956 ER PT J AU Roukos, V Pegoraro, G Voss, TC Misteli, T AF Roukos, Vassilis Pegoraro, Gianluca Voss, Ty C. Misteli, Tom TI Cell cycle staging of individual cells by fluorescence microscopy SO NATURE PROTOCOLS LA English DT Article ID LASER-SCANNING CYTOMETRY; DNA-REPLICATION; LIVING CELLS; FLOW-CYTOMETRY; DYNAMICS; CANCER; PROLIFERATION; CHROMATIN; ANTIBODY; MITOSIS AB Progression through the cell cycle is one of the most fundamental features of cells. Studies of the cell cycle have traditionally relied on the analysis of populations, and they often require specific markers or the use of genetically modified systems, making it difficult to determine the cell cycle stage of individual, unperturbed cells. We describe a protocol, suitable for use in high-resolution imaging approaches, for determining cell cycle staging of individual cells by measuring their DNA content by fluorescence microscopy. The approach is based on the accurate quantification by image analysis of the integrated nuclear intensity of cells stained with a DNA dye, and it can be used in combination with several histochemical methods. We describe and provide the algorithms for two automated image analysis pipelines and the derivation of cell cycle profiles with both commercial and open-source software. This 1-2-d protocol is applicable to adherent cells, and it is adaptable for use with several DNA dyes. C1 [Roukos, Vassilis; Pegoraro, Gianluca; Voss, Ty C.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Pegoraro, Gianluca] NCI, High Throughput Imaging Facil, NIH, Bethesda, MD 20892 USA. [Voss, Ty C.] PerkinElmer Hlth Sci Inc, Waltham, MD USA. RP Roukos, V (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM roukosv@mail.nih.gov; mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Intramural Research Program of the US National Institutes of Health (NIH); Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research FX Work in the Misteli laboratory and in the High-Throughput Imaging Facility is supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research. We thank S. Burke for modeling the cell cycle data, K. MacKinnon for help with flow cytometry and T. Karpova (NCI Fluorescence Imaging Facility) for help with microscopy. NR 51 TC 12 Z9 12 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD FEB PY 2015 VL 10 IS 2 BP 334 EP 348 DI 10.1038/nprot.2015.016 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CE6ET UT WOS:000351930100008 PM 25633629 ER PT J AU Alewine, C Hassan, R Pastan, I AF Alewine, Christine Hassan, Raffit Pastan, Ira TI Advances in Anticancer Immunotoxin Therapy SO ONCOLOGIST LA English DT Article DE Antibody conjugate; Recombinant immunotoxin; Vascular leak syndrome; Antidrug antibody ID VASCULAR LEAK SYNDROME; NON-HODGKINS-LYMPHOMA; T-CELL LYMPHOMA; PHASE-I TRIAL; TRIPLE-NEGATIVE BREAST; MALIGNANT BRAIN-TUMORS; RECOMBINANT IMMUNOTOXIN; ANTIBODY-RICIN; CHAIN IMMUNOCONJUGATE; DENILEUKIN DIFTITOX AB Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cellsbyinhibiting protein synthesis, aunique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading torenewedinterest in these therapeutics. C1 [Alewine, Christine; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Hassan, Raffit] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@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 82 TC 36 Z9 37 U1 2 U2 8 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD FEB PY 2015 VL 20 IS 2 BP 176 EP 185 DI 10.1634/theoncologist.2014-0358 PG 10 WC Oncology SC Oncology GA CE5ZR UT WOS:000351915500014 PM 25561510 ER PT J AU Nass, SJ Beaupin, LK Demark-Wahnefried, W Fasciano, K Ganz, PA Hayes-Lattin, B Hudson, MM Nevidjon, B Oeffinger, KC Rechis, R Richardson, LC Seibel, NL Smith, AW AF Nass, Sharyl J. Beaupin, Lynda K. Demark-Wahnefried, Wendy Fasciano, Karen Ganz, Patricia A. Hayes-Lattin, Brandon Hudson, Melissa M. Nevidjon, Brenda Oeffinger, Kevin C. Rechis, Ruth Richardson, Lisa C. Seibel, Nita L. Smith, Ashley W. TI Identifying and Addressing theNeeds of Adolescents and Young Adults With Cancer: Summary of an Institute of Medicine Workshop SO ONCOLOGIST LA English DT Article DE Adolescent; Young adult; Cancer survivorship; Psychosocial aspects; Fertility preservation; Adverse effects ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; HEALTH-INSURANCE COVERAGE; CAUSE-SPECIFIC MORTALITY; CHILDHOOD-CANCER; BREAST-CANCER; FERTILITY PRESERVATION; HODGKIN LYMPHOMA; PALLIATIVE CARE; PHYSICAL-ACTIVITY AB Cancer is the leading disease-related cause of death in adolescents and young adults (AYAs). This population faces many short-and long-term health and psychosocial consequences of cancer diagnosis and treatment, but many programs for cancer treatment, survivorship care, and psychosocial support do not focus on the specific needs of AYA cancer patients. Recognizing this health care disparity, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop to examine the needs of AYA patients with cancer. Workshop participants identified many gaps and challenges in the care of AYA cancer patients and discussed potential strategies to address these needs. Suggestions included ways to improve access to care for AYAs, to deliver cancer care that better meets the medical and psychosocial needs of AYAs, to develop educational programs for providers who care for AYA cancer survivors, and to enhance the evidence base for AYAs with cancer by facilitating participation in research. C1 [Nass, Sharyl J.] Inst Med, Washington, DC 20001 USA. [Beaupin, Lynda K.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham Comprehens Canc Ctr, Birmingham, AL USA. [Fasciano, Karen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med & Publ Hlth, Los Angeles, CA USA. [Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Hudson, Melissa M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Nevidjon, Brenda] Oncol Nursing Soc, Pittsburgh, PA USA. [Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rechis, Ruth] LIVESTRONG Fdn, Austin, TX USA. [Richardson, Lisa C.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Seibel, Nita L.; Smith, Ashley W.] Natl Canc Inst, Bethesda, MD USA. RP Nass, SJ (reprint author), Inst Med, Natl Canc Policy Forum, 500 Fifth St, Washington, DC 20001 USA. EM snass@nas.edu FU LIVESTRONG Foundation; Young Adult Cancer Alliance; IOM's National Cancer Policy Forum FX The responsibility for the content of this article rests with the authors and does not necessarily represent the views of the Institute of Medicine, its committees, its sponsors, or its convening activities and does not represent the official position of the Centers for Disease Control and Prevention or that of the National Cancer Institute. We thank the LIVESTRONG Foundation for generously cosponsoring the IOM workshop and Critical Mass: The Young Adult Cancer Alliance for supporting the workshop. The activities of the IOM's National Cancer Policy Forum are supported by its sponsoring members, which currently include the Centers for Disease Control and Prevention, the National Cancer Institute, the Association of American Cancer Institutes, the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, the American Society of Hematology, the American Society for Radiation Oncology, AstraZeneca, Bristol-Myers Squibb, C-Change, the Cancer Support Community, the CEO Roundtable on Cancer, EMD Serono, Helsinn Group, the LIVESTRONG Foundation, the National Comprehensive Cancer Network, Novartis Oncology, the Oncology Nursing Society, and Sanofi Oncology. We thank the speakers and participants for their contributions to the workshop. We also thank Sarah Bender and Sara Tharakan for assistance with manuscript preparation. NR 89 TC 22 Z9 22 U1 2 U2 10 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD FEB PY 2015 VL 20 IS 2 BP 186 EP 195 DI 10.1634/theoncologist.2014-0265 PG 10 WC Oncology SC Oncology GA CE5ZR UT WOS:000351915500015 PM 25568146 ER PT J AU Zheng, M Zhang, HL Dill, DL Clark, JD Tu, SS Yablonovitch, AL Tan, MH Zhang, R Rujescu, D Wu, MH Tessarollo, L Vieira, W Gottesman, MM Deng, SH Eberlin, LS Zare, RN Billard, JM Gillet, JP Li, JB Peltz, G AF Zheng, Ming Zhang, Haili Dill, David L. Clark, J. David Tu, Susan Yablonovitch, Arielle L. Tan, Meng How Zhang, Rui Rujescu, Dan Wu, Manhong Tessarollo, Lino Vieira, Wilfred Gottesman, Michael M. Deng, Suhua Eberlin, Livia S. Zare, Richard N. Billard, Jean-Martin Gillet, Jean-Pierre Li, Jin Billy Peltz, Gary TI The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans SO PLOS MEDICINE LA English DT Article ID BLOOD-BRAIN-BARRIER; PYRIDINIUM METABOLITE; TARDIVE-DYSKINESIA; NEUROTOXIN; PARKINSONISM; MITOCHONDRIA; ASSOCIATION; DISCOVERY; TRANSPORT; PHARMACOGENOMICS AB Background We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study. Methods and Findings A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered. Conclusions ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity. C1 [Zheng, Ming; Zhang, Haili; Wu, Manhong; Peltz, Gary] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. [Dill, David L.; Tu, Susan] Stanford Univ, Comp Sci, Stanford, CA 94305 USA. [Clark, J. David] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Yablonovitch, Arielle L.; Tan, Meng How; Zhang, Rui; Li, Jin Billy] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Tessarollo, Lino] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Vieira, Wilfred; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Deng, Suhua] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Eberlin, Livia S.; Zare, Richard N.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Billard, Jean-Martin; Gillet, Jean-Pierre] Univ Namur, Lab Mol Canc Biol, Mol Physiol Res Unit URPhyM, Namur Res Inst Life Sci NARILIS, Namur, Belgium. RP Zheng, M (reprint author), Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. EM jin.billy.li@stanford.edu; gpeltz@stanford.edu RI Tan, Meng How/M-8605-2015 FU King Abdullah University of Science and Technology (KAUST) under KAUST Stanford Academic Excellence Alliance program [1R01DK090992-01]; Stanford's CURIS program; Center for Molecular Analysis and Design (CMAD) FX GP and MZ were partially supported by funding from a transformative RO1 award (1R01DK090992-01) DLD was supported by a King Abdullah University of Science and Technology (KAUST) research grant under the KAUST Stanford Academic Excellence Alliance program. ST was supported by Stanford's CURIS program for summer research interns. LSE was supported by a postdoctoral fellowship from the Center for Molecular Analysis and Design (CMAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD FEB PY 2015 VL 12 IS 2 AR UNSP e1001782 DI 10.1371/journal.pmed.1001782 PG 29 WC Medicine, General & Internal SC General & Internal Medicine GA CE3GY UT WOS:000351715900001 PM 25647612 ER PT J AU Sullivan, DC Bresolin, L Seto, B Obuchowski, NA Raunig, DL Kessler, LG AF Sullivan, Daniel C. Bresolin, Linda Seto, Belinda Obuchowski, Nancy A. Raunig, David L. Kessler, Larry G. TI Introduction to metrology series SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Editorial Material C1 [Sullivan, Daniel C.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Bresolin, Linda] RSNA, Oak Brook, IL USA. [Seto, Belinda] NEI, NIH, Bethesda, MD 20892 USA. [Obuchowski, Nancy A.] Cleveland Clin, Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Raunig, David L.] ICON Med Imaging, Warrington, Cheshire, England. [Kessler, Larry G.] Univ Washington, Dept Hlth Serv, Sch Publ Hlth, Seattle, WA 98195 USA. RP Sullivan, DC (reprint author), Duke Univ, Med Ctr, Dept Radiol, Box 3302, Durham, NC 27710 USA. EM daniel.sullivan@duke.edu NR 5 TC 3 Z9 3 U1 1 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 3 EP 8 DI 10.1177/0962280214537332 PG 6 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700001 PM 25804285 ER PT J AU Raunig, DL McShane, LM Pennello, G Gatsonis, C Carson, PL Voyvodic, JT Wahl, RL Kurland, BF Schwarz, AJ Gonen, M Zahlmann, G Kondratovich, MV O'Donnell, K Petrick, N Cole, PE Garra, B Sullivan, DC AF Raunig, David L. McShane, Lisa M. Pennello, Gene Gatsonis, Constantine Carson, Paul L. Voyvodic, James T. Wahl, Richard L. Kurland, Brenda F. Schwarz, Adam J. Goenen, Mithat Zahlmann, Gudrun Kondratovich, Marina V. O'Donnell, Kevin Petrick, Nicholas Cole, Patricia E. Garra, Brian Sullivan, Daniel C. CA QIBA Tech Performance Working Grp TI Quantitative imaging biomarkers: A review of statistical methods for technical performance assessment SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; reliability; linearity; bias; precision; repeatability; reproducibility; agreement ID CONFIDENCE-INTERVALS; ASSESSING AGREEMENT; RELIABILITY; DEFINITIONS; COEFFICIENT; MEDICINE; POINTS AB Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined. C1 [Raunig, David L.] ICON Med Imaging, Warrington, PA 18976 USA. [McShane, Lisa M.] NCI, Bethesda, MD 20892 USA. [Pennello, Gene; Kondratovich, Marina V.; Petrick, Nicholas; Garra, Brian] US FDA, CDRH, Silver Spring, MD USA. [Gatsonis, Constantine] Brown Univ, Providence, RI 02912 USA. [Carson, Paul L.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Voyvodic, James T.] Duke Univ BIAC, Durham, NC USA. [Wahl, Richard L.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Kurland, Brenda F.] Univ Pittsburgh, Pittsburgh, PA USA. [Schwarz, Adam J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zahlmann, Gudrun] Hoffman La Roche Ltd, Basel, Switzerland. [O'Donnell, Kevin] Toshiba Med Res Inst, Vernon Hills, IL USA. [Cole, Patricia E.] Takaeda, Deerfield, IL USA. [Sullivan, Daniel C.] Duke Univ, Sch Med, Durham, NC 27706 USA. RP Raunig, DL (reprint author), ICON Med Imaging, 2800 Kelly Rd, Warrington, PA 18976 USA. EM David.Raunig@iconplc.com OI Kurland, Brenda/0000-0002-5669-0595 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract #HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. NR 55 TC 20 Z9 20 U1 4 U2 12 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 27 EP 67 DI 10.1177/0962280214537344 PG 41 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700003 PM 24919831 ER PT J AU Obuchowski, NA Reeves, AP Huang, EP Wang, XF Buckler, AJ Kim, HJ Barnhart, HX Jackson, EF Giger, ML Pennello, G Toledano, AY Kalpathy-Cramer, J Apanasovich, TV Kinahan, PE Myers, KJ Goldgof, DB Barboriak, DP Gillies, RJ Schwartz, LH Sullivan, DC AF Obuchowski, Nancy A. Reeves, Anthony P. Huang, Erich P. Wang, Xiao-Feng Buckler, Andrew J. Kim, Hyun J. (Grace) Barnhart, Huiman X. Jackson, Edward F. Giger, Maryellen L. Pennello, Gene Toledano, Alicia Y. Kalpathy-Cramer, Jayashree Apanasovich, Tatiyana V. Kinahan, Paul E. Myers, Kyle J. Goldgof, Dmitry B. Barboriak, Daniel P. Gillies, Robert J. Schwartz, Lawrence H. Sullivan, Daniel C. CA Algorithm Comparison Working Grp TI Quantitative imaging biomarkers: A review of statistical methods for computer algorithm comparisons SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; image metrics; bias; precision; repeatability; reproducibility; agreement ID ASSESSING AGREEMENT; GOLD STANDARD; LUNG-CANCER; EVALUATE REPRODUCIBILITY; CONCORDANCE CORRELATION; REGRESSION PROCEDURES; INDIVIDUAL AGREEMENT; MALIGNANT-TUMORS; EM ALGORITHM; FDG-PET AB Quantitative biomarkers from medical images are becoming important tools for clinical diagnosis, staging, monitoring, treatment planning, and development of new therapies. While there is a rich history of the development of quantitative imaging biomarker (QIB) techniques, little attention has been paid to the validation and comparison of the computer algorithms that implement the QIB measurements. In this paper we provide a framework for QIB algorithm comparisons. We first review and compare various study designs, including designs with the true value (e.g. phantoms, digital reference images, and zero-change studies), designs with a reference standard (e.g. studies testing equivalence with a reference standard), and designs without a reference standard (e.g. agreement studies and studies of algorithm precision). The statistical methods for comparing QIB algorithms are then presented for various study types using both aggregate and disaggregate approaches. We propose a series of steps for establishing the performance of a QIB algorithm, identify limitations in the current statistical literature, and suggest future directions for research. C1 [Obuchowski, Nancy A.; Wang, Xiao-Feng] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Reeves, Anthony P.] Cornell Univ, Ithaca, NY USA. [Huang, Erich P.] NIH, Rockville, MD USA. [Buckler, Andrew J.] Elucid Bioimaging Inc, Wenham, MA USA. [Kim, Hyun J. (Grace)] Univ Calif Los Angeles, Los Angeles, CA USA. [Barnhart, Huiman X.; Barboriak, Daniel P.; Sullivan, Daniel C.] Duke Univ, Durham, NC USA. [Jackson, Edward F.] Univ Wisconsin, Madison, WI USA. [Giger, Maryellen L.] Univ Chicago, Chicago, IL 60637 USA. [Pennello, Gene; Myers, Kyle J.] US FDA, CDRH, Silver Spring, MD USA. [Toledano, Alicia Y.] Biostat Consulting LLC, Kensington, MD USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, MGH, Boston, MA USA. [Apanasovich, Tatiyana V.] George Washington Univ, Washington, DC USA. [Kinahan, Paul E.] Univ Washington, Seattle, WA 98195 USA. [Goldgof, Dmitry B.] Univ S Florida, Tampa, FL USA. [Gillies, Robert J.] H Moffitt Canc Ctr, Tampa, FL USA. [Schwartz, Lawrence H.] Columbia Univ, New York, NY USA. RP Obuchowski, NA (reprint author), Cleveland Clin Fdn, Quantitat Hlth Sci JJN 3, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM obuchon@ccf.org OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Jackson, Edward/0000-0002-5958-0076; Gillies, Robert/0000-0002-8888-7747; Buckler, Andrew/0000-0002-0786-4835; Giger, Maryellen/0000-0001-5482-9728 FU Radiologic Society of North America (RSNA); NIH/NIBIB [HHSN268201000050C] FX The Radiologic Society of North America (RSNA) and NIH/NIBIB contract # HHSN268201000050C supported two workshops and numerous conference calls for the authors' Working Group. NR 75 TC 16 Z9 16 U1 1 U2 14 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 68 EP 106 DI 10.1177/0962280214537390 PG 39 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700004 PM 24919829 ER PT J AU Huang, EP Wang, XF Choudhury, KR McShane, LM Gonen, M Ye, JJ Buckler, AJ Kinahan, PE Reeves, AP Jackson, EF Guimaraes, AR Zahlmann, G AF Huang, Erich P. Wang, Xiao-Feng Choudhury, Kingshuk Roy McShane, Lisa M. Goenen, Mithat Ye, Jingjing Buckler, Andrew J. Kinahan, Paul E. Reeves, Anthony P. Jackson, Edward F. Guimaraes, Alexander R. Zahlmann, Gudrun CA Meta-Anal Working Grp TI Meta-analysis of the technical performance of an imaging procedure: Guidelines and statistical methodology SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE quantitative imaging; imaging biomarkers; technical performance; repeatability; reproducibility; meta-analysis; meta-regression; systematic review ID SEMIAUTOMATED VOLUME MEASUREMENTS; INDIVIDUAL PATIENT DATA; META-REGRESSION; SYSTEMATIC REVIEWS; ASSESSING AGREEMENT; LUNG-CANCER; FDG-PET; PULMONARY NODULES; MALIGNANT-TUMORS; PRISMA STATEMENT AB Medical imaging serves many roles in patient care and the drug approval process, including assessing treatment response and guiding treatment decisions. These roles often involve a quantitative imaging biomarker, an objectively measured characteristic of the underlying anatomic structure or biochemical process derived from medical images. Before a quantitative imaging biomarker is accepted for use in such roles, the imaging procedure to acquire it must undergo evaluation of its technical performance, which entails assessment of performance metrics such as repeatability and reproducibility of the quantitative imaging biomarker. Ideally, this evaluation will involve quantitative summaries of results from multiple studies to overcome limitations due to the typically small sample sizes of technical performance studies and/or to include a broader range of clinical settings and patient populations. This paper is a review of meta-analysis procedures for such an evaluation, including identification of suitable studies, statistical methodology to evaluate and summarize the performance metrics, and complete and transparent reporting of the results. This review addresses challenges typical of meta-analyses of technical performance, particularly small study sizes, which often causes violations of assumptions underlying standard meta-analysis techniques. Alternative approaches to address these difficulties are also presented; simulation studies indicate that they outperform standard techniques when some studies are small. The meta-analysis procedures presented are also applied to actual [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) test-retest repeatability data for illustrative purposes. C1 [Huang, Erich P.; McShane, Lisa M.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wang, Xiao-Feng] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Choudhury, Kingshuk Roy] Duke Univ, Dept Radiol, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Ye, Jingjing] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Buckler, Andrew J.] Elucid Biomed Imaging Inc, Wenham, MA USA. [Kinahan, Paul E.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Reeves, Anthony P.] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY USA. [Jackson, Edward F.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Guimaraes, Alexander R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zahlmann, Gudrun] F Hoffmann La Roche Ltd, Basel, Switzerland. RP Huang, EP (reprint author), NCI, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr,MSC 9735, Bethesda, MD 20892 USA. EM erich.huang@nih.gov OI Jackson, Edward/0000-0002-5958-0076; Buckler, Andrew/0000-0002-0786-4835 FU Radiological Society of North America; NIH/NIBIB [HHSN268201000050C] FX The authors acknowledge and appreciate the Radiological Society of North America and NIH/NIBIB contract # HHSN268201000050C for supporting two workshops and numerous conference calls for the authors' Working Group. The authors would also like to thank Huiman Barnhart and Daniel Sullivan from Duke University and Gene Pennello, Norberto Pantoja-Galicia, Robert Ochs, Shing Chun Benny Lam, and Mary Pastel from the FDA for their expert advice and comments on this manuscript. NR 77 TC 5 Z9 5 U1 1 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2015 VL 24 IS 1 SI SI BP 141 EP 174 DI 10.1177/0962280214537394 PG 34 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA CE4ZZ UT WOS:000351840700006 PM 24872353 ER PT J AU Breitner, J Baker, L Drye, L Evans, D Lyketsos, C Ryan, L Zandi, P Saucedo, HH Anau, J Cholerton, B Kramer, K Casper, AS Meinert, C Martin, B Jenkins, G McCaffrey, L Meinert, J Vaidya, V Abuja, A May, P Ashe, K Steinberg, M Brandt, J Pedroso, JJ Bergey, A Gogel, C Smith, L Kraus, J Stern, RA Green, RC Gavett, B Mwicigi, J Baldwin, L McGowan, T Johnson, P Qiu, W Frederick, J Raghavan, S Rossi, C Mandell, A Dinizo, D Roth, MT Porsteinsson, A Ismail, MS Weber, M Brand, C Richard, J Stear, K Schepp, S Cosman, K Martin, K Craft, S Dahl, D Garrett, G Tidwell, J Thielke, S Smith, L Arbuckle, M Strong, W Ladenberg, J Callaghan, M Watson, S Skinner, J Bowton, K Sabbagh, M Belden, C Liebsack, C Davis, K Arnieri, L Malek-Ahmadi, M Nicholson, L Jacobson, S Schwartz, E Mullan, M Luis, C Parrish, J Faircloth, M Ervin, T Girard, J Burke, D Keegan, A AF Breitner, John Baker, Laura Drye, Lea Evans, Denis Lyketsos, Constantine Ryan, Laurie Zandi, Peter Saucedo, Hector Hernandez Anau, Jane Cholerton, Brenna Kramer, Kirise Casper, Anne Shanldin Meinert, Curtis Martin, Barbara Jenkins, Gabrielle McCaffrey, Lee Meinert, Jill Vaidya, Vijay Abuja, Alka May, Pat Ashe, Karen Steinberg, Martin Brandt, Jason Pedroso, Julia J. Bergey, Alyssa Gogel, Carol Smith, Lynn Kraus, Jennifer Stern, Robert A. Green, Robert C. Gavett, Brandon Mwicigi, Jane Baldwin, Lorraine McGowan, Theresa Johnson, Patricia Qiu, Wendy Frederick, Jamie Raghavan, Sumati Rossi, Carol Mandell, Alan Dinizo, Daniella Roth, Mary Tara Porsteinsson, Anton Ismail, M. Saleem Weber, Miriam Brand, Connie Richard, Jennifer Stear, Kelly Schepp, Sue Cosman, Kelly Martin, Kimberly Craft, Suzanne Dahl, Deborah Garrett, Grace Tidwell, Jamie Thielke, Stephen Smith, Lauren Arbuckle, Matthew Strong, William Ladenberg, Juliet Callaghan, Maureen Watson, Stennis Skinner, Jeannine Bowton, Kaysha Sabbagh, Marwan Belden, Christine Liebsack, Carolyn Davis, Kathryn Arnieri, Lauren Malek-Ahmadi, Michael Nicholson, Lisa Jacobson, Sandra Schwartz, Elliot Mullan, Michael Luis, Cheryl Parrish, Julia Faircloth, Marlee Ervin, Terry Girard, Janette Burke, Deborah Keegan, Andrew CA ADAPT-FS Res Grp TI Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study SO ALZHEIMERS & DEMENTIA LA English DT Article DE Prevention; Clinical trial; Alzheimer's disease; Cognitive function; Nonsteroidal anti-inflammatory drug; Naproxen; Celecoxib ID NSAID USE; DECLINE; DRUGS; CELECOXIB; NAPROXEN; ASSOCIATION; POPULATION; VALIDATION; ASPIRIN; SCALE AB Objective: The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) and Follow-up Study (ADAPT-FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. Methods: A total of 2356 participants completed baseline and at least one follow-up cognitive evaluation between 2001 and 2004. Study treatments were discontinued in 2004, but participants were followed until 2007. A total of 1537 participants were reevaluated in 2010 to 2011. Outcomes include seven cognitive evaluations administered yearly in person in ADAPT and three of these evaluations that were administered by telephone near the end of ADAPT and again in ADAPT-FS. Results: There were no important differences over time by treatment group on any ADAPT cognitive measure, a global composite, or the three cognitive measures reassessed in ADAPT-FS by telephone. Conclusions: Treatment for 1 to 3 years with naproxen or celecoxib did not protect against cognitive decline in older adults with a family history of AD. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Breitner, John] Douglas Mental Hlth Univ Inst, Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada. [Breitner, John] McGill Univ, Montreal, PQ, Canada. [Baker, Laura] Veteran Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Baker, Laura] Univ Washington, Sch Med, Seattle, WA USA. [Drye, Lea; Zandi, Peter; Casper, Anne Shanldin; Meinert, Curtis; Martin, Barbara; Jenkins, Gabrielle; McCaffrey, Lee; Meinert, Jill; Vaidya, Vijay; Abuja, Alka; May, Pat] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Evans, Denis] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Lyketsos, Constantine; Steinberg, Martin; Brandt, Jason; Pedroso, Julia J.; Bergey, Alyssa; Gogel, Carol; Smith, Lynn; Kraus, Jennifer] Johns Hopkins Sch Med, Baltimore, MD USA. [Ryan, Laurie] NIA, Bethesda, MD 20892 USA. [Ashe, Karen] N Bud Grossman Ctr Memory Res & Care, Minneapolis, MN USA. [Stern, Robert A.; Green, Robert C.; Gavett, Brandon; Mwicigi, Jane; Baldwin, Lorraine; McGowan, Theresa; Johnson, Patricia; Qiu, Wendy; Frederick, Jamie; Raghavan, Sumati; Rossi, Carol; Mandell, Alan; Dinizo, Daniella; Roth, Mary Tara] Boston Univ, Sch Med, Boston, MA 02118 USA. [Porsteinsson, Anton; Ismail, M. Saleem; Weber, Miriam; Brand, Connie; Richard, Jennifer; Stear, Kelly; Schepp, Sue; Cosman, Kelly; Martin, Kimberly] Univ Rochester, Sch Med, Rochester, NY 14627 USA. [Sabbagh, Marwan; Belden, Christine; Liebsack, Carolyn; Davis, Kathryn; Arnieri, Lauren; Malek-Ahmadi, Michael; Nicholson, Lisa; Jacobson, Sandra; Schwartz, Elliot] Sun Hlth Res Inst, Sun City, AZ USA. [Mullan, Michael; Luis, Cheryl; Parrish, Julia; Faircloth, Marlee; Ervin, Terry; Girard, Janette; Burke, Deborah; Keegan, Andrew] Roskamp Inst Memory Clin, Tampa, FL USA. [Evans, Denis] Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. RP Breitner, J (reprint author), Douglas Mental Hlth Univ Inst, Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada. FU National Institute on Aging (NIA) [U01 AG15477, 2U01 AG015477-06A2]; N. Bud Grossman Center for Memory Research and Care; Minnesota Medical Foundation FX This study was supported by National Institute on Aging (NIA) U01 AG15477, 2U01 AG015477-06A2; N. Bud Grossman Center for Memory Research and Care, and Minnesota Medical Foundation. NR 29 TC 5 Z9 5 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD FEB PY 2015 VL 11 IS 2 BP 216 EP 225 DI 10.1016/j.jalz.2014.03.009 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CD7FB UT WOS:000351255100011 ER PT J AU Reynolds, MR Sweeney, KJ Crilly, SM Farrell, M Jaffe, ES Javadpour, M AF Reynolds, Matthew R. Sweeney, Kieron J. Crilly, Shane M. Farrell, Michael Jaffe, Elaine S. Javadpour, Mohsen TI Rapid, de novo development of isolated intracranial rosai-dorfman disease: A case report SO BRITISH JOURNAL OF NEUROSURGERY LA English DT Article DE de novo development; isolated; intracranial; rosai-dorfman disease; sinus histiocytosis with massive lymphadenopathy AB Isolated intracranial Rosai-Dorfman Disease is rare. Here, we describe a patient who developed an asymptomatic, right parietal RDD lesion over 18 months while being followed radiographically for another brain lesion. To our knowledge, rapid, de novo radiographic formation of isolated intracranial RDD has never been reported in an asymptomatic patient. C1 [Reynolds, Matthew R.] Washington Univ, Dept Neurol Surg, St Louis, MO USA. [Reynolds, Matthew R.; Sweeney, Kieron J.; Crilly, Shane M.; Javadpour, Mohsen] Beaumont Hosp, Natl Ctr Neurosurg, Dept Neurol Surg, Dublin 9, Ireland. [Farrell, Michael] Beaumont Hosp, Natl Ctr Neurosurg, Dept Neuropathol, Dublin 9, Ireland. [Jaffe, Elaine S.] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Reynolds, MR (reprint author), Barnes Jewish Hosp, Dept Neurol Surg, Campus Box 8057,660 South Euclid Ave, St Louis, MO 63110 USA. EM ReynoldsM@wudosis.wustl.edu RI Jaffe, Elaine/G-8984-2014; OI Jaffe, Elaine/0000-0003-4632-0301; Javadpour, Mohsen/0000-0001-9836-1741 NR 3 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0268-8697 EI 1360-046X J9 BRIT J NEUROSURG JI Br. J. Neurosurg. PD FEB PY 2015 VL 29 IS 1 BP 82 EP 84 DI 10.3109/02688697.2014.950634 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA CE2KQ UT WOS:000351644900018 ER PT J AU Cruz, MC Ruano, G Wolf, M Hecker, D Vidaurre, EC Schmittgens, R Rajal, VB AF Cecilia Cruz, Mercedes Ruano, Gustavo Wolf, Marcus Hecker, Dominic Castro Vidaurre, Elza Schmittgens, Ralph Beatriz Rajal, Veronica TI Plasma deposition of silver nanoparticles on ultrafiltration membranes: Antibacterial and anti-biofouling properties SO CHEMICAL ENGINEERING RESEARCH & DESIGN LA English DT Article DE Ultrafiltration; Biofouling; Silver nanoparticles; Plasma; Gas flow sputtering; XPS ID SURFACE MODIFICATION; POLYPROPYLENE MEMBRANE; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; WASTE-WATER; POLYETHERSULFONE; NANOFILTRATION; NANOMATERIALS; PERFORMANCE; POLYMERIZATION AB A novel and versatile plasma reactor was used to modify polyethersulphone commercial membranes. The equipment was applied to: (i) functionalize the membranes with low-temperature plasmas, (ii) deposit a film of poly(methyl methacrylate) (PMMA) by Plasma Enhanced Chemical Vapor Deposition (PECVD) and, (iii) deposit silver nanoparticles (SNP) by gas flow sputtering. Each modification process was performed in the same reactor consecutively, without exposure of the membranes to atmospheric air. Scanning electron microscopy and transmission electron microscopy were used to characterize the particles and modified membranes. SNP are evenly distributed on the membrane surface. Particle fixation and transport inside membranes were assessed before- and after-washing assays by X-ray photoelectron spectroscopy depth profiling analysis. PMMA addition improved SNP fixation. Plasma-treated membranes showed higher hydrophilicity. Anti-biofouling activity was successfully achieved against Gram-positive (Enterococcus faecalis) and -negative (Salmonella) Typhimurium bacteria. Therefore, disinfection by ultrafiltration showed substantial resistance to biofouling. The post-synthesis functionalization process developed provides a more efficient fabrication route for anti-biofouling and anti-bacterial membranes used in the water treatment field. To the best of our knowledge, this is the first report of a gas phase condensation process combined with a PECVD procedure in order to deposit SNP on commercial membranes to inhibit biofouling formation. (C) 2014 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved. C1 [Cecilia Cruz, Mercedes; Castro Vidaurre, Elza; Beatriz Rajal, Veronica] Univ Nacl Salta, Inst Invest Ind Quim, Consejo Nacl Invest Cient & Tecn, Salta Capital, Argentina. [Cecilia Cruz, Mercedes; Castro Vidaurre, Elza; Beatriz Rajal, Veronica] Univ Nacl Salta, Fac Ingn, Salta Capital, Argentina. [Ruano, Gustavo] CNEA, Ctr Atom Bariloche, RA-8400 San Carlos De Bariloche, Rio Negro, Argentina. [Wolf, Marcus; Hecker, Dominic; Schmittgens, Ralph] Tech Univ Dresden, Inst Festkorperelekt, D-01062 Dresden, Germany. [Hecker, Dominic] Fraunhofer Inst Elektronenstrahl & Plasmatech, D-01277 Dresden, Germany. [Beatriz Rajal, Veronica] Univ Calif Davis, Fogarty Int Ctr, Davis, CA 95616 USA. RP Rajal, VB (reprint author), Consejo Nacl Invest Cient & Tecn, INIQUI, A4402FDC, RA-177 Buenos Aires, Salta Capital, Argentina. EM vbrajal@gmail.com FU Secretaria de Ciencia, Tecnologia e Innovacion Productiva (SECyT, Argentina) [DA0704]; German Academic Exchange Service (DAAD, Germany) [DA0704]; NIH - Fogarty International Center [D43 TW005718]; National Institute of Environmental Health Sciences (USA); CONICET FX This project was supported by the Scientific and Technological Cooperation Program between the Secretaria de Ciencia, Tecnologia e Innovacion Productiva (SECyT, Argentina) and the German Academic Exchange Service (DAAD, Germany) project code DA0704. It was also partially supported by NIH Grant D43 TW005718 funded by the Fogarty International Center and the National Institute of Environmental Health Sciences (USA). Mercedes Cecilia Cruz and Gustavo Ruano were supported by CONICET fellowships. The SEM micrographs were taken in the Laboratorio de Microscopia Electronica de Barrido (LASEM) - ANPCyT UNSa CONICET - Salta. NR 46 TC 7 Z9 7 U1 8 U2 43 PU INST CHEMICAL ENGINEERS PI RUGBY PA 165-189 RAILWAY TERRACE, DAVIS BLDG, RUGBY CV21 3HQ, ENGLAND SN 0263-8762 EI 1744-3563 J9 CHEM ENG RES DES JI Chem. Eng. Res. Des. PD FEB PY 2015 VL 94 BP 524 EP 537 DI 10.1016/j.cherd.2014.09.014 PG 14 WC Engineering, Chemical SC Engineering GA CC2SI UT WOS:000350194500050 PM 26166926 ER PT J AU Kouprina, N Larionov, V AF Kouprina, Natalay Larionov, Vladimir TI Recent advances in chromosome engineering SO CHROMOSOME RESEARCH LA English DT Article DE Artificial chromosome; CRISPR; Gene therapy; Kinetochore; Stem cell; Synthetic biology; TALEN; Transgenic; ZFN ID CELLS C1 [Kouprina, Natalay; Larionov, Vladimir] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. RP Kouprina, N (reprint author), NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov; larionov@mail.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0967-3849 EI 1573-6849 J9 CHROMOSOME RES JI Chromosome Res. PD FEB PY 2015 VL 23 IS 1 SI SI BP 1 EP 5 DI 10.1007/s10577-015-9469-5 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CE0YU UT WOS:000351538300001 PM 25682170 ER PT J AU Ohzeki, J Larionov, V Earnshaw, WC Masumoto, H AF Ohzeki, Jun-ichirou Larionov, Vladimir Earnshaw, William C. Masumoto, Hiroshi TI Genetic and epigenetic regulation of centromeres: a look at HAC formation SO CHROMOSOME RESEARCH LA English DT Review DE Centromere; CENP-A; HAC; Kinetochore; Heterochromatin; CENP-B; HAT ID ALPHA-SATELLITE DNA; HUMAN ARTIFICIAL CHROMOSOME; CENP-A CHROMATIN; FUNCTIONAL HUMAN CENTROMERE; FISSION YEAST CENTROMERE; B NULL MICE; BUDDING YEAST; HUMAN-CELLS; KINETOCHORE; HETEROCHROMATIN AB The centromere is a specialized chromosomal locus required for accurate chromosome segregation. A specific histone H3 variant, CENP-A, assembles at centromeres. CENP-A is required for kinetochore protein assembly and is an epigenetic marker for the maintenance of a functional centromere. Human CENP-A chromatin normally assembles on alpha-satellite DNA (alphoid DNA), a centromeric repetitive sequence. Using alphoid DNA arrays, human artificial chromosomes (HACs) have been constructed in human HT1080 cells and used to dissect the requirements for CENP-A assembly on DNA sequence. However, centromere formation is not a simple genetic event. In other commonly used human cell lines, such as HeLa and U2OS cells, no functional de novo centromere formation occurs efficiently with the same centromeric alphoid DNA sequences. Recent studies using protein tethering combined with the HAC system and/or genetic manipulation have revealed that epigenetic chromatin regulation mechanisms are also involved in the CENP-A chromatin assembly pathway and subsequent centromere/kinetochore formation. We summarize the DNA sequence requirements for CENP-A assembly and discuss the epigenetic regulation of human centromeres. C1 [Ohzeki, Jun-ichirou; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Larionov, Vladimir] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh, Midlothian, Scotland. RP Masumoto, H (reprint author), Kazusa DNA Res Inst, Dept Frontier Res, Lab Cell Engn, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 2920818, Japan. EM masumoto@kazusa.or.jp FU Intramural NIH HHS; Wellcome Trust [073915] NR 133 TC 6 Z9 6 U1 4 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0967-3849 EI 1573-6849 J9 CHROMOSOME RES JI Chromosome Res. PD FEB PY 2015 VL 23 IS 1 SI SI BP 87 EP 103 DI 10.1007/s10577-015-9470-z PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CE0YU UT WOS:000351538300009 PM 25682171 ER PT J AU Nsoesie, EO Kluberg, SA Mekaru, SR Majumder, MS Khan, K Hay, SI Brownstein, JS AF Nsoesie, E. O. Kluberg, S. A. Mekaru, S. R. Majumder, M. S. Khan, K. Hay, S. I. Brownstein, J. S. TI New digital technologies for the surveillance of infectious diseases at mass gathering events SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Review DE Communicable diseases; Internet; mass gatherings; novel technologies; wireless sensor networks ID PUBLIC-HEALTH SURVEILLANCE; FIFA WORLD CUP; SYNDROMIC SURVEILLANCE; GEOSENTINEL EXPERIENCE; HAJJ PILGRIMAGE; LARGE OUTBREAK; AUSTRALIA; RISKS; PREVENTION; TRAVELERS AB Outbreaks of infectious diseases at mass gatherings can strain the health system of the host region and pose a threat to local and global health. In addition to strengthening existing surveillance systems, most host nations also use novel technologies to assess disease risk and augment traditional surveillance approaches. We review novel approaches to disease surveillance using the Internet, mobile phone applications, and wireless sensor networks. These novel approaches to disease surveillance can result in prompt detection. (C) 2015 Clinical Microbiology and Infection published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. C1 [Nsoesie, E. O.; Kluberg, S. A.; Mekaru, S. R.; Majumder, M. S.; Brownstein, J. S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Nsoesie, E. O.; Brownstein, J. S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Majumder, M. S.] MIT, Engn Syst Div, Cambridge, MA 02139 USA. [Brownstein, J. S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Khan, K.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Hay, S. I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Hay, S. I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Nsoesie, EO (reprint author), HealthMap BCH3409, 300 Longwood Ave, Boston, MA 02115 USA. EM onelaine@vt.edu RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Nsoesie, Elaine/0000-0001-9170-8714 FU NLM NIH HHS [R01 LM010812]; Wellcome Trust [095066] NR 54 TC 5 Z9 6 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1198-743X EI 1469-0691 J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD FEB PY 2015 VL 21 IS 2 BP 134 EP 140 DI 10.1016/j.cmi.2014.12.017 PG 7 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA CE2MB UT WOS:000351648600005 PM 25636385 ER PT J AU Sugui, JA Kwon-Chung, KJ Juvvadi, PR Latge, JP Steinbach, WJ AF Sugui, Janyce A. Kwon-Chung, Kyung J. Juvvadi, Praveen R. Latge, Jean-Paul Steinbach, William J. TI Aspergillus fumigatus and Related Species SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; CHRONIC GRANULOMATOUS-DISEASE; LINKED-IMMUNOSORBENT-ASSAY; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; NONRIBOSOMAL PEPTIDE SYNTHETASE; EPIDEMIOLOGIC CUTOFF VALUES; HOST-CELL INTERACTIONS; METHOD M38-A2 DOCUMENT; PROTEIN-KINASE-A; PULMONARY ASPERGILLOSIS AB The genus Aspergillus contains etiologic agents of aspergillosis. The clinical manifestations of the disease range from allergic reaction to invasive pulmonary infection. Among the pathogenic aspergilli, Aspergillus fumigatus is most ubiquitous in the environment and is the major cause of the disease, followed by Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, and several species in the section Fumigati that morphologically resemble A. fumigatus. Patients that are at risk for acquiring aspergillosis are those with an altered immune system. Early diagnosis, species identification, and adequate antifungal therapy are key elements for treatment of the disease, especially in cases of pulmonary invasive aspergillosis that often advance very rapidly. Incorporating knowledge of the basic biology of Aspergillus species to that of the diseases that they cause is fundamental for further progress in the field. C1 [Sugui, Janyce A.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Juvvadi, Praveen R.; Steinbach, William J.] Duke Univ, Dept Pediat, Div Pediat Infect Dis, Durham, NC 27715 USA. [Latge, Jean-Paul] Inst Pasteur, Unite Aspergillus, F-75724 Paris, France. [Steinbach, William J.] Duke Univ, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP Steinbach, WJ (reprint author), Duke Univ, Dept Pediat, Div Pediat Infect Dis, Durham, NC 27715 USA. EM bill.steinbach@duke.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD FX J.A.S. and K.J.K.-C. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. NR 151 TC 5 Z9 5 U1 2 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD FEB PY 2015 VL 5 IS 2 AR a019786 DI 10.1101/cshperspect.a019786 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CD6YP UT WOS:000351237300006 ER PT J AU AlGhatrif, M Lakatta, EG AF AlGhatrif, Majd Lakatta, Edward G. TI The Conundrum of Arterial Stiffness, Elevated Blood Pressure, and Aging SO CURRENT HYPERTENSION REPORTS LA English DT Article DE Aging; Hypertension; Pulse wave velocity; Aortic diameter; Aortic remodeling ID ISOLATED SYSTOLIC HYPERTENSION; NUTRITION EXAMINATION SURVEY; PULSE-WAVE VELOCITY; AORTIC STIFFNESS; INCIDENT HYPERTENSION; NATIONAL-HEALTH; PROGRESSION; DISEASE; HEART; AGE AB Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naive. The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short-and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level. Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits-all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves. C1 [AlGhatrif, Majd; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [AlGhatrif, Majd] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP AlGhatrif, M (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM Majd.alghatrif@nih.gov; LakattaE@grc.nia.nih.gov FU Intramural NIH HHS [ZIA AG000856-13] NR 34 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1522-6417 EI 1534-3111 J9 CURR HYPERTENS REP JI Curr. Hypertens. Rep. PD FEB PY 2015 VL 17 IS 2 AR 12 DI 10.1007/s11906-014-0523-z PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CE1HW UT WOS:000351563700010 PM 25687599 ER PT J AU Pagani, JH Avram, SKW Cui, Z Song, J Mezey, E Senerth, JM Baumann, MH Young, WS AF Pagani, J. H. Avram, S. K. Williams Cui, Z. Song, J. Mezey, E. Senerth, J. M. Baumann, M. H. Young, W. S. TI Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Conditional knockout; maternal aggression; oxytocin; serotonin ID MATERNAL AGGRESSION; POSTTRAUMATIC-STRESS; VASOPRESSIN 1A; RATS; DISORDER; DOPAMINE; NUCLEUS; ATTACHMENT; DEFICIENT; PROFILES AB Serotonin and oxytocin influence aggressive and anxiety-like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically mediated anxiety-like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open-field, olfactory habituation/dishabituation or, surprisingly, anxiety-like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to 8 of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident-intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety-like behaviors or maternal care. C1 [Pagani, J. H.; Avram, S. K. Williams; Song, J.; Senerth, J. M.; Young, W. S.] NIMH, Sect Neural Gene Regulat, NIH, DHHS, Bethesda, MD 20892 USA. [Cui, Z.] NIDDK, Mol Signaling Sect, NIH, DHHS, Bethesda, MD 20892 USA. [Mezey, E.] Natl Inst Dent & Craniofacial Res, Adult Stem Cell Sect, NIH, DHHS, Bethesda, MD USA. [Baumann, M. H.] NIDA, Med Chem Sect, NIH, DHHS, Baltimore, MD USA. RP Young, WS (reprint author), 9000 Rockville Pike,Bldg 49,Room 5A56, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU NIMH [Z01-MH-002498] FX We greatly appreciate the technical assistance of Emily Shepard and Raquel Collier and the animal care provided by the building 49 Animal Research Facility. This research was supported by the NIMH (Z01-MH-002498). NR 58 TC 7 Z9 7 U1 4 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD FEB PY 2015 VL 14 IS 2 BP 167 EP 176 DI 10.1111/gbb.12202 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CE2FF UT WOS:000351629000004 PM 25677455 ER PT J AU Mayeur, C Kolodziej, SA Wang, A Xu, X Lee, A Yu, PB Shen, J Bloch, KD Bloch, DB AF Mayeur, Claire Kolodziej, Starsha A. Wang, Amy Xu, Xin Lee, Arthur Yu, Paul B. Shen, John Bloch, Kenneth D. Bloch, Donald B. TI Oral administration of a bone morphogenetic protein type I receptor inhibitor prevents the development of anemia of inflammation SO HAEMATOLOGICA LA English DT Letter DE anemia of inflammation; BMP inhibitor; hepcidin ID HEPCIDIN EXPRESSION; CHRONIC DISEASE; IRON; RATS C1 [Mayeur, Claire; Kolodziej, Starsha A.; Bloch, Kenneth D.; Bloch, Donald B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Mayeur, Claire; Kolodziej, Starsha A.; Yu, Paul B.; Bloch, Kenneth D.; Bloch, Donald B.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Amy; Xu, Xin; Lee, Arthur; Shen, John] NCATS, Therapeut Rare & Neglected Dis TRND Program, NIH, Rockville, MD USA. [Yu, Paul B.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Mayeur, C (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. EM cmayeur@mgh.harvard.edu OI Yu, Paul/0000-0003-2145-4944 FU NIAMS NIH HHS [R01 AR057374]; NIDDK NIH HHS [R01 DK082971, R01DK082971]; NINDS NIH HHS [1X01NS070702] NR 15 TC 10 Z9 11 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2015 VL 100 IS 2 BP E68 EP E71 DI 10.3324/haematol.2014.111484 PG 4 WC Hematology SC Hematology GA CD7OB UT WOS:000351278900008 PM 25326432 ER PT J AU Saxena, V Johnson, CG Negussie, AH Sharma, KV Dreher, MR Wood, BJ AF Saxena, Vishal Johnson, Carmen Gacchina Negussie, Ayele H. Sharma, Karun V. Dreher, Matthew R. Wood, Bradford J. TI Temperature-sensitive liposome-mediated delivery of thrombolytic agents SO INTERNATIONAL JOURNAL OF HYPERTHERMIA LA English DT Article DE Staphylokinase; temperature sensitive liposomes; thrombolysis; tissue plasminogen activator ID TISSUE-PLASMINOGEN ACTIVATOR; RECOMBINANT STAPHYLOKINASE VARIANTS; ACUTE MYOCARDIAL-INFARCTION; LOADED ECHOGENIC LIPOSOMES; ACUTE ISCHEMIC-STROKE; THERMOSENSITIVE LIPOSOMES; IN-VIVO; ALTERED IMMUNOREACTIVITY; DRUG-RELEASE; ACCELERATED THROMBOLYSIS AB Background: Clinical efficacy of thrombolytic drugs is limited by lack of specific delivery and requires large therapeutic doses which increase toxicity. Encapsulating these drugs in temperature-sensitive liposomes and applying hyperthermia to deliver thrombolytic agents locally to thrombus might theoretically favourably alter the therapeutic window. The objectives of this study were to formulate liposomes encapsulating thrombolytics and assess thrombolytic activity following hyperthermia. Methods: Three liposome formulations were investigated: temperature-sensitive liposome (TSL, DPPC: DSPE-PEG2000 (mol% 95:5)), low temperature-sensitive liposome (LTSL, DPPC: MSPC:DSPE-PEG2000(mol% 85.3:9.7:5)), and traditional temperature-sensitive liposome (TTSL, DPPC: HSPC: Chol: DSPE-PEG2000 (mol% 55: 25: 15: 5)). To characterise temperature-dependent release of high molecular weight cargo from each formulation, fluorescein-conjugated dextrans (70 kDa) were loaded and release was quantified via spectrophotometry. Staphylokinase (SAK), urokinase, and tissue-type plasminogen activator were also loaded individually into each liposome formulation. Leakage at 37 degrees C and release at 38-44 degrees C were quantified via chromogenic enzymatic activity assay. Clot lysis was evaluated by measuring mass of blood clots before and after thrombolytic liposome treatment. Results: The LTSL formulation had optimal release characteristics with maximum release at 41.3 degrees C. Release of dextrans from LTSLs was observed to be 11.5 +/- 1.5%, 79.7 +/- 1.6%, and 93.6 +/- 3.7% after 15 min in plasma at 37 degrees, 39 degrees, and 41.3 degrees C, respectively. The SAK LTSL had the highest release/leakage ratio and demonstrated greater clot lysis. Conclusions: The SAK LTSL achieves significant clot lysis in vitro. When combined with local hyperthermia, the SAK LTSL potentially produces sufficient thrombolysis while minimising systemic side effects. C1 [Saxena, Vishal; Johnson, Carmen Gacchina; Negussie, Ayele H.; Sharma, Karun V.; Dreher, Matthew R.; Wood, Bradford J.] NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Saxena, Vishal] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Sharma, Karun V.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Wood, BJ (reprint author), NIH, Radiol & Imaging Sci, 10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM bwood@mail.nih.gov FU Center for Interventional Oncology, the Intramural Research Program of the National Institutes of Health (NIH); Howard Hughes Medical Institute NIH Research Scholars Program; NIH Imaging Sciences Training Program FX This research was supported by the Center for Interventional Oncology, the Intramural Research Program of the National Institutes of Health (NIH), the Howard Hughes Medical Institute NIH Research Scholars Program (V.S.), and the NIH Imaging Sciences Training Program (C.G.J.). NIH and Biocompatibles BTG have a cooperative research and development agreement. None of the authors have any forms of conflicts of interest and the mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the National Institutes of Health. The authors alone are responsible for the content and writing of the paper. NR 52 TC 5 Z9 5 U1 4 U2 28 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0265-6736 EI 1464-5157 J9 INT J HYPERTHER JI Int. J. Hyperthermia PD FEB PY 2015 VL 31 IS 1 BP 67 EP 73 DI 10.3109/02656736.2014.991428 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CE1LW UT WOS:000351574200010 PM 25766387 ER PT J AU Aoude, LG Pritchard, AL Robles-Espinoza, CD Wadt, K Harland, M Choi, J Gartside, M Quesada, V Johansson, P Palmer, JM Ramsay, AJ Zhang, XJ Jones, K Symmons, J Holland, EA Schmid, H Bonazzi, V Woods, S Dutton-Regester, K Stark, MS Snowden, H van Doom, R Montgomery, GW Martin, NG Keane, TM Lopez-Otin, C Gerdes, AM Olsson, H Ingvar, C Borg, A Gruis, NA Trent, JM Jonsson, G Bishop, DT Mann, GJ Newton-Bishop, JA Brown, KM Adams, DJ Hayward, NK AF Aoude, Lauren G. Pritchard, Antonia L. Robles-Espinoza, Carla Daniela Wadt, Karin Harland, Mark Choi, Jiyeon Gartside, Michael Quesada, Victor Johansson, Peter Palmer, Jane M. Ramsay, Andrew J. Zhang, Xijun Jones, Kristine Symmons, Judith Holland, Elizabeth A. Schmid, Helen Bonazzi, Vanessa Woods, Susan Dutton-Regester, Ken Stark, Mitchell S. Snowden, Helen van Doom, Remco Montgomery, Grant W. Martin, Nicholas G. Keane, Thomas M. Lopez-Otin, Carlos Gerdes, Anne-Marie Olsson, Hakan Ingvar, Christian Borg, Ake Gruis, Nelleke A. Trent, Jeffrey M. Jonsson, Goran Bishop, D. Timothy Mann, Graham J. Newton-Bishop, Julia A. Brown, Kevin M. Adams, David J. Hayward, Nicholas K. TI Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID TELOMERE LENGTH CONTROL; POT1; VARIANTS; PREDISPOSE; QUEENSLAND; SAMPLE; PHENOTYPE; INTERACTS; DESIGN; TUMORS AB Background: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Methods: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with chi(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). Results: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. Conclusions: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility. C1 [Aoude, Lauren G.; Pritchard, Antonia L.; Gartside, Michael; Johansson, Peter; Palmer, Jane M.; Symmons, Judith; Bonazzi, Vanessa; Woods, Susan; Dutton-Regester, Ken; Stark, Mitchell S.; Montgomery, Grant W.; Martin, Nicholas G.; Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Robles-Espinoza, Carla Daniela; Keane, Thomas M.; Adams, David J.] Wellcome Trust Sanger Inst, Cambridge, England. [Wadt, Karin; Gerdes, Anne-Marie] Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Harland, Mark; Snowden, Helen; Bishop, D. Timothy; Newton-Bishop, Julia A.] Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. [Choi, Jiyeon; Brown, Kevin M.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Quesada, Victor; Ramsay, Andrew J.; Lopez-Otin, Carlos] Univ Oviedo, IUOPA, Dept Bioquim & Biol Mol, Oviedo, Spain. [Zhang, Xijun; Jones, Kristine] SAIC Frederick Inc, Canc Genom Res Lab, NCI Frederick, Frederick, MD USA. [van Doom, Remco; Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Olsson, Hakan; Ingvar, Christian; Borg, Ake; Jonsson, Goran] Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden. [Trent, Jeffrey M.] Translat Genom Inst, Phoenix, AZ USA. [Holland, Elizabeth A.; Schmid, Helen; Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Holland, Elizabeth A.; Schmid, Helen; Mann, Graham J.] Melanoma Inst Australia, Sydney, NSW, Australia. RP Aoude, LG (reprint author), QIMR Berghofer Med Res Inst, 300 Herston Rd, Brisbane, Qld 4006, Australia. EM Lauren.Aoude@qimrberghofer.edu.au RI Pritchard, Antonia/F-4288-2010; Stark, Mitchell/E-3542-2010; Montgomery, Grant/B-7148-2008; Johansson, Peter/K-1053-2014; hayward, nicholas/C-1367-2015; Quesada, Victor/B-6557-2014; Lopez-Otin, Carlos/C-6657-2013 OI Bonazzi, Vanessa/0000-0002-2574-0334; Bishop, Tim/0000-0002-8752-8785; Newton Bishop, Julia/0000-0001-9147-6802; Keane, Thomas/0000-0001-7532-6898; Pritchard, Antonia/0000-0001-5336-0454; Gruis, Nelleke/0000-0002-5210-9150; Woods, Susan/0000-0002-8955-2017; Robles Espinoza, Carla Daniela/0000-0003-3277-7466; Stark, Mitchell/0000-0002-4510-2161; Montgomery, Grant/0000-0002-4140-8139; Johansson, Peter/0000-0001-7015-5452; hayward, nicholas/0000-0003-4760-1033; Quesada, Victor/0000-0002-8398-3457; Lopez-Otin, Carlos/0000-0001-6964-1904 FU Australia and New Zealand Banking Group Limited Trustees and Rigshospitalet, University Hospital of Copenhagen; Cure Cancer Australia; National Health and Medical Research Council of Australia (NHMRC); Cancer Research UK; Wellcome Trust; Consejo Nacional de Ciencia y Tecnologia of Mexico; Dutch Cancer Society [UL 2012-5489]; Swedish Research Council; Swedish Cancer Society; Nordic Cancer Union; European Research Council; Division of Cancer Epidemiology and Genetics, National Cancer Institute; Spanish Ministry of Economy and Competitiveness; Red Tematica de Investigacion del Cancer (RTICC); Consolider-Ingenio RNAREG Consortium; NHMRC; Cancer Institute NSW; Cancer Council Queensland; Melanoma Research Alliance; Aase and Ejnar Danielsens fund FX LGA and KW are supported by PhD scholarships from the Australia and New Zealand Banking Group Limited Trustees and Rigshospitalet, University Hospital of Copenhagen, respectively. ALP is supported by Cure Cancer Australia. NKH and GWM are supported by fellowships from the National Health and Medical Research Council of Australia (NHMRC). DJA, CDRE, and TMK were supported by Cancer Research UK and the Wellcome Trust. CDRE was also supported by Consejo Nacional de Ciencia y Tecnologia of Mexico. MH, JANB, and DTB were supported by Cancer Research UK. NAG and RvD were supported by a grant from the Dutch Cancer Society (UL 2012-5489). GJ, AB, HO, and CI were supported by the Swedish Research Council, the Swedish Cancer Society and the Nordic Cancer Union. HO was also supported by European Research Council. KMB and JC are supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute. CLO is an Investigator of the Botin Foundation, and work at his laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness and Red Tematica de Investigacion del Cancer (RTICC). VQ is a Ramon y Cajal fellow supported by the Consolider-Ingenio RNAREG Consortium. The work was funded in part by the NHMRC, Cancer Institute NSW, Cancer Council Queensland, the Melanoma Research Alliance, and the Aase and Ejnar Danielsens fund. NR 26 TC 24 Z9 24 U1 3 U2 8 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 FEB PY 2015 VL 107 IS 2 AR dju408 DI 10.1093/jnci/dju408 PG 7 WC Oncology SC Oncology GA CD7TN UT WOS:000351295700006 ER PT J AU Baker, SG AF Baker, Stuart G. TI A Cancer Theory Kerfuffle Can Lead to New Lines of Research SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID IDENTIFYING DRIVER MUTATIONS; SOMATIC MUTATION; IN-VIVO; INTRATESTICULAR GRAFTS; TISSUE MORPHOGENESIS; TUMOR-SUPPRESSOR; PROGENITOR CELLS; FOREIGN-BODIES; MAMMARY-GLAND; COLON-CANCER AB The standard viewpoint that cancer is a genetic disease is often stated as a fact rather than a theory. By not acknowledging that it is a theory, namely the Somatic Mutation Theory (SMT), researchers are limiting their progress. An attractive alternative to SMT is the tissue organization field theory (TOFT), which is summarized as "development gone awry." To initiate a kerfuffle, I discuss the interpretation of various results under both TOFT and SMT, including recurrent mutations, hereditary cancers, induction of tumors in transgenic experiments, remission of tumors following the inhibition of enzymes activated by mutated genes, nongenotoxic carcinogens, denervation experiments, foreign-body carcinogenesis, transplantation experiments, and tumors with zero mutations. Thinking in terms of TOFT can spur new lines of research; examples are given related to the early detection of cancer. C1 NCI, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 131 TC 6 Z9 6 U1 1 U2 6 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 FEB PY 2015 VL 107 IS 2 AR dju405 DI 10.1093/jnci/dju405 PG 8 WC Oncology SC Oncology GA CD7TN UT WOS:000351295700004 ER PT J AU Clarke, CA Robbins, HA Tatalovich, Z Lynch, CF Pawlish, KS Finch, JL Hernandez, BY Fraumeni, JF Madeleine, MM Engels, EA AF Clarke, Christina A. Robbins, Hilary A. Tatalovich, Zaria Lynch, Charles F. Pawlish, Karen S. Finch, Jack L. Hernandez, Brenda Y. Fraumeni, Joseph F., Jr. Madeleine, Margaret M. Engels, Eric A. TI Risk of Merkel Cell Carcinoma After Solid Organ Transplantation SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SKIN-CANCER; HIV-INFECTION; DNA-REPAIR; CYCLOSPORINE-A; RECIPIENTS; IMMUNOSUPPRESSION; AZATHIOPRINE; MELANOMA; KIDNEY; DAMAGE AB Background: Solid organ transplant recipients have elevated risks of virus-related cancers, in part because of long-term immunosuppression. Merkel cell carcinoma (MCC) is an aggressive skin cancer recently found to have a viral origin, but little is known regarding the occurrence of MCC after transplant. Methods: We linked the US Scientific Registry of Transplant Recipients with data from 15 population-based cancer registries to ascertain MCC occurrence among 189 498 solid organ transplant recipients from 1987 to 2009. Risks for MCC following transplantation were compared with the general population using standardized incidence ratios, and Poisson regression was used to compare incidence rates according to key patient and transplant characteristics. All statistical tests were two-sided. Results: After solid organ transplantation, overall risk of MCC was increased 23.8-fold (95% confidence interval = 19.6 to 28.7, n = 110). Adjusted risks were highest among older recipients, increased with time since transplantation, and varied by organ type (all P <=.007). Azathioprine, cyclosporine, and mTOR inhibitors given for maintenance immunosuppression increased risk, and non-Hispanic white recipients on cyclosporine and azathioprine experienced increasing MCC risk with lower latitude of residence (ie, higher ultraviolet radiation exposure, P = .012). Conclusions: MCC risk is sharply elevated after solid organ transplant, likely resulting from long-term immunosuppression. Immunosuppressive medications may act synergistically with ultraviolet radiation to increase risk. C1 [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Clarke, Christina A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Clarke, Christina A.] Stanford Canc Inst, Palo Alto, CA USA. [Robbins, Hilary A.; Tatalovich, Zaria; Fraumeni, Joseph F., Jr.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Pawlish, Karen S.] New Jersey Dept Hlth, New Jersey State Canc Registry, Trenton, NJ USA. [Finch, Jack L.] Colorado Dept Publ Hlth & Environm, Colorado Cent Canc Registry, Denver, CO USA. [Hernandez, Brenda Y.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Madeleine, Margaret M.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Madeleine, Margaret M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Clarke, CA (reprint author), Canc Prevent Inst Calif, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. EM tina@cpic.org FU Stanford Cancer Institute; National Cancer Institute of the National Institutes of Health FX This work was supported in part by the Stanford Cancer Institute and the National Cancer Institute of the National Institutes of Health. NR 30 TC 6 Z9 6 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD FEB PY 2015 VL 107 IS 2 AR dju382 DI 10.1093/jnci/dju382 PG 9 WC Oncology SC Oncology GA CD7TN UT WOS:000351295700001 ER PT J AU Loftfield, E Freedman, ND Graubard, BI Hollenbeck, AR Shebl, FM Mayne, ST Sinha, R AF Loftfield, Erikka Freedman, Neal D. Graubard, Barry I. Hollenbeck, Albert R. Shebl, Fatma M. Mayne, Susan T. Sinha, Rashmi TI Coffee Drinking and Cutaneous Melanoma Risk in the NIH-AARP Diet and Health Study SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BASAL-CELL CARCINOMA; MALIGNANT-MELANOMA; SOCIOECONOMIC-STATUS; COX-2 EXPRESSION; CANCER INCIDENCE; NORWEGIAN MEN; UNITED-STATES; CAFFEIC ACID; SKIN-CANCER; DNA-DAMAGE AB Background: Cutaneous melanoma is the fifth most common cancer in the United States. Modifiable risk factors, with the exception of exposure to ultraviolet radiation (UVR), are poorly understood. Coffee contains numerous bioactive compounds and may be associated inversely with melanoma. However, previous epidemiological evidence is limited. Methods: Coffee intake was assessed at baseline with a food frequency questionnaire in the National Institutes of Health-AARP prospective cohort study. Among 447 357 non-Hispanic whites who were cancer-free at baseline, 2904 incident cases of malignant melanoma were identified during 4 329 044 person-years of follow-up, with a median of 10.5 years of followup. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee intake and subsequent melanoma risk with non-coffee drinkers as the reference group. Statistical tests were two-sided, and P values less than .05 were interpreted as statistically significant. Results: The highest category of coffee intake was inversely associated with malignant melanoma (>= 4 cups/day: HR = 0.80, 95% CI = 0.68 to 0.93, P-trend =.01). This association was statistically significant for caffeinated (>= 4 cups/day: HR = 0.75, 95% CI = 0.64 to 0.89, P-trend =.01) but not for decaffeinated coffee (P-trend =.55). Conclusions: Higher coffee intake was associated with a modest decrease in risk of melanoma in this large US cohort study. Additional investigations of coffee intake and its constituents, particularly caffeine, with melanoma are warranted. C1 [Loftfield, Erikka; Shebl, Fatma M.; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Loftfield, Erikka; Freedman, Neal D.; Graubard, Barry I.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Shebl, Fatma M.; Mayne, Susan T.] Yale Canc Ctr, New Haven, CT USA. RP Loftfield, E (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr 6E332, Rockville, MD 20850 USA. EM erikka.loftfield@nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU Yale-National Cancer Institute (NCI) predoctoral training grant [T32 CA105666]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported in part by the Yale-National Cancer Institute (NCI) predoctoral training grant T32 CA105666 to STM and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 39 TC 8 Z9 8 U1 8 U2 39 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 FEB PY 2015 VL 107 IS 2 AR dju421 DI 10.1093/jnci/dju421 PG 9 WC Oncology SC Oncology GA CD7TN UT WOS:000351295700011 ER PT J AU Ying, TL Li, HY Lu, L Dimitrov, DS Jiang, SB AF Ying, Tianlei Li, Haoyang Lu, Lu Dimitrov, Dimiter S. Jiang, Shibo TI Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections SO MICROBES AND INFECTION LA English DT Article DE Coronavirus; MERS-CoV; mAbs; Receptor binding domain (RBD) ID EAST RESPIRATORY SYNDROME; SYNDROME CORONAVIRUS INFECTION; RECEPTOR-BINDING DOMAIN; MONOMERIC IGG1 FC; POTENT NEUTRALIZATION; SARS CORONAVIRUS; SPIKE PROTEIN; SAUDI-ARABIA; BAT CORONAVIRUS; ORGAN CULTURES AB The recent Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak poses a serious threat to public health. Here, we summarize recent advances in identifying human neutralizing monoclonal antibodies (mAbs) against MERS-CoV, describe their mechanisms of action, and analyze their potential for treatment of MERS-CoV infections. (C) 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Ying, Tianlei; Li, Haoyang; Lu, Lu; Jiang, Shibo] Fudan Univ, Shanghai Med Coll, Key Lab Med Mol Virol MOE MOH, Shanghai 200032, Peoples R China. [Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Jiang, Shibo] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10065 USA. RP Ying, TL (reprint author), Bldg 13,Room 606,130 Dong An Rd, Shanghai 200032, Peoples R China. EM tlying@fudan.edu.cn RI Lu, Lu/K-7070-2014; OI Lu, Lu/0000-0002-2255-0391 FU National Natural Science Foundation of China; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the National Natural Science Foundation of China and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 67 TC 8 Z9 11 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2015 VL 17 IS 2 BP 142 EP 148 DI 10.1016/j.micinf.2014.11.008 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CD5CQ UT WOS:000351105900008 PM 25456101 ER PT J AU Chio, A Traynor, BJ AF Chio, Adriano Traynor, Bryan J. TI Biomarkers for ALS-in search of the Promised Land SO NATURE REVIEWS NEUROLOGY LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; TRIAL AB The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014. C1 [Chio, Adriano] Univ Turin, Rita Levi Montalcini Dept Neurosci, I-10126 Turin, Italy. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Chio, A (reprint author), Univ Turin, Rita Levi Montalcini Dept Neurosci, Via Cherasco 15, I-10126 Turin, Italy. EM achio@usa.net OI Chio, Adriano/0000-0001-9579-5341 FU Italian Health Ministry [RF-2010-2309849]; European Community [259867, 278611]; Joint Programme-Neurodegenerative Disease Research - Italian Ministry of Health (Sophia Project); Joint Programme-Neurodegenerative Disease Research - Italian Ministry of University and Research (ALS-CARE Project); Joint Programme-Neurodegenerative Disease Research - Italian Ministry of University and Research (Strength Project); intramural Research Programs of the US National Institutes of Health (NIH), National Institute on Aging [Z01-AG000949-02]; NINDS FX A.C. is currently funded by Italian Health Ministry grant RF-2010-2309849, European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreements 259867 and 278611, and the Joint Programme-Neurodegenerative Disease Research granted by Italian Ministry of Health (Sophia Project) and by Italian Ministry of University and Research (ALS-CARE and Strength Projects). B.J.T. is currently funded by intramural Research Programs of the US National Institutes of Health (NIH), National Institute on Aging (Z01-AG000949-02) and NINDS. NR 10 TC 6 Z9 6 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD FEB PY 2015 VL 11 IS 2 DI 10.1038/nrneurol.2014.250 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CE0SC UT WOS:000351514800003 PM 25534912 ER PT J AU Henrich, CJ Brooks, AD Erickson, KL Thomas, CL Bokesch, HR Tewary, P Thompson, CR Pompei, RJ Gustafson, KR McMahon, JB Sayers, TJ AF Henrich, C. J. Brooks, A. D. Erickson, K. L. Thomas, C. L. Bokesch, H. R. Tewary, P. Thompson, C. R. Pompei, R. J. Gustafson, K. R. McMahon, J. B. Sayers, T. J. TI Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation SO CELL DEATH & DISEASE LA English DT Article ID HUMAN-MELANOMA CELLS; CANCER-CELLS; C-FLIP; DOWN-REGULATION; MEDIATED APOPTOSIS; INHIBITOR PS-341; UP-REGULATION; WITHAFERIN-A; LIGAND TRAIL; TUMOR-CELLS AB Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects. C1 [Henrich, C. J.; Erickson, K. L.; Thomas, C. L.; Bokesch, H. R.; Gustafson, K. R.; McMahon, J. B.] NCI, Mol Targets Lab, Frederick, MD 21702 USA. [Henrich, C. J.; Brooks, A. D.; Bokesch, H. R.; Tewary, P.; Sayers, T. J.] Leidos Biomed Res Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Brooks, A. D.; Tewary, P.; Thompson, C. R.; Pompei, R. J.; Sayers, T. J.] NCI, Lab Expt Immunol, Frederick, MD 21702 USA. [Brooks, A. D.; Tewary, P.; Thompson, C. R.; Pompei, R. J.; Sayers, T. J.] NCI, Canc Inflammat Program, Frederick, MD 21702 USA. [Erickson, K. L.] Clark Univ, Dept Chem, Worcester, MA 01610 USA. RP Henrich, CJ (reprint author), NCI, Basic Res Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Bldg 538,Room 167, Frederick, MD 21702 USA. EM henrichcj@mail.nih.gov RI Sayers, Thomas/G-4859-2015 FU Federal funds from the Frederick; Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the Frederick. Laboratory for Cancer Research, 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. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. NCI-Frederick is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the 'Guide for Care and Use of Laboratory Animals' (National Research Council; 1996; National Academy Press; Washington, DC). We thank Dr. Avi Ashkenazi (Genentech) for advice on the administration of drozitumab for in vivo studies. NR 58 TC 13 Z9 13 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD FEB PY 2015 VL 6 AR e1666 DI 10.1038/cddis.2015.38 PG 10 WC Cell Biology SC Cell Biology GA CC7VF UT WOS:000350575800038 PM 25719250 ER PT J AU Love, CB Arnesen, SJ Phillips, SJ AF Love, Cynthia B. Arnesen, Stacey J. Phillips, Steven J. TI Ebola Outbreak Response: The Role of Information Resources and the National Library of Medicine SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE disease outbreaks; crowdsourcing; social media; mass media; Internet AB The US National Library of Medicine (NLM) offers Internet-based, no-cost resources useful for responding to the 2014 West Africa Ebola outbreak. Resources for health professionals, planners, responders, and researchers include PubMed, Disaster Lit, the Web page Ebola Outbreak 2014: Information Resources, and the Virus Variation database of sequences for Ebolavirus. In cooperation with participating publishers, NLM offers free access to full-text articles from over 650 biomedical journals and 4000 online reference books through the Emergency Access Initiative. At the start of a prolonged disaster event or disease outbreak, the documents and information of most immediate use may not be in the peer-reviewed biomedical journal literature. To maintain current awareness may require using any of the following: news outlets; social media; preliminary online data, maps, and situation reports; and documents published by nongovernmental organizations, international associations, and government agencies. Similar to the pattern of interest shown in the news and social media, use of NLM Ebola-related resources is also increasing since the start of the outbreak was first reported in March 2014 (Disaster Med Public Health Preparedness. 2014;0:1-4) C1 [Love, Cynthia B.; Arnesen, Stacey J.] Natl Lib Med, Disaster Informat Management Res Ctr, Specialized Informat Serv Div, Bethesda, MD USA. [Phillips, Steven J.] Natl Lib Med, Specialized Informat Serv, Bethesda, MD USA. RP Love, CB (reprint author), NIH, Disaster Informat Management Res Ctr, Specialized Informat Serv, Natl Lib Med,US Dept HHS, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM cindy_love@nlm.nih.gov FU American Academy of Pediatrics; American Association for the Advancement of Science; American Chemical Society; American College of Physicians; American Medical Association; American Society of Health-Systems Pharmacists; American Society for Microbiology; B.C. Decker; BMJ; EBSCOHost; Elsevier; FA Davis; Mary Ann Liebert; Massachusetts Medical Society; McGraw-Hill; Merck Publishing; Oxford University Press; People's Medical Publishing House; Springer; University of Chicago Press; Wiley; Wolters Kluwer FX The NLM thanks the numerous participating publishers for their generous support of the EAI initiative: American Academy of Pediatrics, American Association for the Advancement of Science, American Chemical Society, American College of Physicians, American Medical Association, American Society of Health-Systems Pharmacists, American Society for Microbiology, B.C. Decker, BMJ, EBSCOHost, Elsevier, FA Davis, Mary Ann Liebert, Massachusetts Medical Society, McGraw-Hill, Merck Publishing, Oxford University Press, People's Medical Publishing House, Springer, University of Chicago Press, Wiley, and Wolters Kluwer. NR 6 TC 2 Z9 2 U1 5 U2 31 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD FEB PY 2015 VL 9 IS 1 BP 82 EP 85 DI 10.1017/dmp.2014.108 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CC9DR UT WOS:000350668600018 PM 25325189 ER PT J AU Horton, JK Gassman, NR Dunigan, BD Stefanick, DF Wilson, SH AF Horton, Julie K. Gassman, Natalie R. Dunigan, Brittany D. Stefanick, Donna F. Wilson, Samuel H. TI DNA polymerase beta-dependent cell survival independent of XRCC1 expression SO DNA REPAIR LA English DT Article DE DNA polymerase beta; XRCC1; Methyl methanesulfonate; PARP inhibitor; Camptothecin ID BASE-EXCISION-REPAIR; STRAND-BREAK REPAIR; PARP INHIBITION; DAMAGE; HYPERSENSITIVITY; REQUIREMENT; INVOLVEMENT; DEFICIENCY; PROTEIN; LESIONS AB Base excision repair (BER) is a primary mechanism for repair of base lesions in DNA such as those formed by exposure to the DNA methylating agent methyl methanesulfonate (MMS). Both DNA polymerase 13 (pol beta)- and XRCC1 -deficient mouse fibroblasts are hypersensitive to MMS. This is linked to a repair deficiency as measured by accumulation of strand breaks and poly(ADP-ribose) (PAR). The interaction between pol 13 and XRCC1 is important for recruitment of pol beta to sites of DNA damage. Endogenous DNA damage can substitute for MMS-induced damage such that BER deficiency as a result of either pol beta- or XRCC1 -deletion is associated with sensitivity to PARP inhibitors. Pol beta shRNA was used to knock down pol beta in Xrcc1(+/+) and Xrcc1(-/-) mouse fibroblasts. We determined whether pol beta-mediated cellular resistance to MMS and PARP inhibitors resulted entirely from coordination with XRCC1 within the same BER sub-pathway. We find evidence for pol beta-dependent cell survival independent of XRCC1 expression for both types of agents. The results suggest a role for pol beta-dependent, XRCC1-independent repair. PAR immunofluorescence data are consistent with the hypothesis of a decrease in repair in both pol beta knock down cell variants. Published by Elsevier B.V. C1 [Horton, Julie K.; Gassman, Natalie R.; Dunigan, Brittany D.; Stefanick, Donna F.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES050158, ES050159] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project numbers Z01 ES050158 and ES050159). NR 28 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD FEB PY 2015 VL 26 BP 23 EP 29 DI 10.1016/j.dnarep.2014.11.008 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CD2PS UT WOS:000350922100003 PM 25541391 ER PT J AU Bogaerts, J Sydes, MR Keat, N McConnell, A Benson, A Ho, A Rotha, A Fortpied, C Eng, C Peckitt, C Coens, C Pettaway, C Arnold, D Hall, E Marshall, E Sclafani, F Hatcher, H Earl, H Ray-Coquard, I Paul, J Blay, JY Whelan, J Panageas, K Wheatley, K Harrington, K Licitra, L Billingham, L Hensley, M McCabe, M Patel, PM Carvajal, R Wilson, R Glynne-Jones, R McWilliams, R Leyvraz, S Rao, S Nicholson, S Filiaci, V Negrouk, A Lacombe, D Dupont, E Pauporte, I Welch, JJ Law, K Trimble, T Seymour, M AF Bogaerts, Jan Sydes, Matthew R. Keat, Nicola McConnell, Andrea Benson, Al Ho, Alan Rotha, Arnaud Fortpied, Catherine Eng, Cathy Peckitt, Clare Coens, Corneel Pettaway, Curtis Arnold, Dirk Hall, Emma Marshall, Ernie Sclafani, Francesco Hatcher, Helen Earl, Helena Ray-Coquard, Isabelle Paul, James Blay, Jean-Yves Whelan, Jeremy Panageas, Kathy Wheatley, Keith Harrington, Kevin Licitra, Lisa Billingham, Lucinda Hensley, Martee McCabe, Martin Patel, Poulam M. Carvajal, Richard Wilson, Richard Glynne-Jones, Rob McWilliams, Rob Leyvraz, Serge Rao, Sheela Nicholson, Steve Filiaci, Virginia Negrouk, Anastassia Lacombe, Denis Dupont, Elisabeth Pauporte, Iris Welch, John J. Law, Kate Trimble, Ted Seymour, Matthew TI Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative SO EUROPEAN JOURNAL OF CANCER LA English DT Review DE Rare cancers; Clinical trials; Randomised controlled trials; Methodology; Frequentist; Bayesian; Multi-arm ID RANDOMIZED CONTROLLED-TRIAL; UTERINE LEIOMYOSARCOMA; CHOROIDAL MELANOMA; ADJUVANT THERAPY; UVEAL MELANOMA; SURVIVAL; CARCINOMA; EPIDEMIOLOGY; STATISTICS; STAMPEDE AB Background: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional usually randomised clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider :these for use in future trials and understand the choices made for each design. Interpretation: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Bogaerts, Jan; Fortpied, Catherine; Coens, Corneel; Negrouk, Anastassia; Lacombe, Denis] EORTC, Brussels, Belgium. [Sydes, Matthew R.] UCL, Med Res Council Clin Trial Unit, London WC1E 6BT, England. [Keat, Nicola; McConnell, Andrea; Law, Kate] Canc Res UK, London, England. [Ho, Alan; Panageas, Kathy; Hensley, Martee; Carvajal, Richard] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Eng, Cathy; Pettaway, Curtis] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Peckitt, Clare; Sclafani, Francesco; Rao, Sheela] Royal Marsden, London, England. [Arnold, Dirk] Univ Canc Ctr Hamburg, Hubertus Wald Tumorzentrum, Hamburg, Germany. [Hall, Emma; Harrington, Kevin] Inst Canc Res, London SW3 6JB, England. [Marshall, Ernie] Univ Liverpool, Liverpool L69 3BX, Merseyside, England. [Hatcher, Helen; Earl, Helena] Univ Cambridge, Dept Oncol, Cambridge CB2 1TN, England. [Hatcher, Helen; Earl, Helena] NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Ray-Coquard, Isabelle; Blay, Jean-Yves] Leon Berard Canc Ctr, Lyon, France. [Paul, James] Univ Glasgow, Inst Canc Sci, Canc Res UK Clin Trials Unit, Glasgow G12 8QQ, Lanark, Scotland. [Whelan, Jeremy] Univ Coll London Hosp, Biomed Res Ctr, NIHR, London, England. [Wheatley, Keith] Univ Birmingham, Birmingham B15 2TT, W Midlands, England. [Licitra, Lisa] Ist Nazl Tumori, I-20133 Milan, Italy. [Billingham, Lucinda] Univ Birmingham, Canc Res UK Clin Trials Unit, Birmingham B15 2TT, W Midlands, England. [Billingham, Lucinda] Univ Birmingham, MRC Midland Hub Trials Methodol Res, Birmingham B15 2TT, W Midlands, England. [Billingham, Lucinda] Univ Manchester, Manchester M13 9PL, Lancs, England. [Wilson, Richard] Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland. [McWilliams, Rob] Mayo Clin, Rochester, MN USA. [Leyvraz, Serge] CHU Vaudois, Lausanne, Switzerland. [Nicholson, Steve] Locum Consultant Med Oncol, London, England. [Filiaci, Virginia] NRG Oncol, Gynecol Oncol Grp, Orange, CA USA. [Dupont, Elisabeth; Welch, John J.; Trimble, Ted] US Natl Canc Inst, Ctr Global Hlth, Bethesda, MD USA. [Pauporte, Iris] Natl Canc Inst, Boulogne, France. [Benson, Al] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Rotha, Arnaud] Univ Hosp Geneva, Med Oncol, Geneva, Switzerland. [Patel, Poulam M.] Univ Nottingham, Nottingham NG7 2RD, England. [Glynne-Jones, Rob] Mt Vernon Canc Ctr, Northwood, Middx, England. RP Bogaerts, J (reprint author), EORTC, Brussels, Belgium. RI McCabe, Martin/P-5896-2015; Blay, Jean-Yves/N-3966-2016; Licitra, Lisa/C-6271-2017; OI McCabe, Martin/0000-0002-5138-0707; Blay, Jean-Yves/0000-0001-7190-120X; Licitra, Lisa/0000-0003-0623-4118; Hall, Emma/0000-0001-5999-5020; Earl, Helena/0000-0003-1549-8094; Sydes, Matthew/0000-0002-9323-1371 FU Medical Research Council; NCI NIH HHS [U10 CA027469, U10 CA037517, U10 CA180822, P30 CA016672, U10 CA180868, UG1 CA189867] NR 44 TC 22 Z9 22 U1 0 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 FEB PY 2015 VL 51 IS 3 BP 271 EP 281 DI 10.1016/j.ejca.2014.10.027 PG 11 WC Oncology SC Oncology GA CD1KP UT WOS:000350834100001 PM 25542058 ER PT J AU Espey, MG AF Espey, Michael Graham TI Redox physical oncology: intersections between redox and the physical environment in cancer SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Editorial Material C1 NCI, Div Canc Biol, Rockville, MD 20850 USA. RP Espey, MG (reprint author), NCI, Div Canc Biol, Rockville, MD 20850 USA. EM sp@nih.gov NR 10 TC 0 Z9 0 U1 2 U2 7 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 FEB PY 2015 VL 79 BP 251 EP 252 DI 10.1016/j.freeradbiomed.2014.11.023 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA CC5IS UT WOS:000350392900023 PM 25496800 ER PT J AU Huh, WK Ault, KA Chelmow, D Davey, DD Goulart, RA Garcia, FAR Kinney, WK Massad, LS Mayeaux, EJ Saslow, D Schiffman, M Wentzensen, N Lawson, HW Einstein, MH AF Huh, Warner K. Ault, Kevin A. Chelmow, David Davey, Diane D. Goulart, Robert A. Garcia, Francisco A. R. Kinney, Walter K. Massad, L. Stewart Mayeaux, Edward J. Saslow, Debbie Schiffman, Mark Wentzensen, Nicolas Lawson, Herschel W. Einstein, Mark H. TI Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID LIQUID-BASED CYTOLOGY; FOLLOW-UP; WOMEN; TRIAL; COLPOSCOPY; PREVENTION; SERVICES; FINLAND AB In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology and cotesting (cytology in combination with hrHPV testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for healthcare providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation. (C) 2014 the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology. Published by Elsevier Inc. All rights reserved. C1 [Huh, Warner K.] Univ Alabama Birmingham, Birmingham, AL USA. [Ault, Kevin A.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Chelmow, David] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Davey, Diane D.] Univ Cent Florida, Orlando, FL 32816 USA. [Goulart, Robert A.] New England Pathol Associates, Springfield, MA USA. [Garcia, Francisco A. R.] Pima Cty Hlth Dept, Tucson, AZ USA. [Kinney, Walter K.] Kaiser Permanente, Sacramento, CA USA. [Massad, L. Stewart] Washington Univ, Sch Med, St Louis, MO USA. [Mayeaux, Edward J.] Univ S Carolina, Sch Med, Columbia, SC USA. [Saslow, Debbie] Amer Canc Soc, Atlanta, GA 30329 USA. [Schiffman, Mark; Wentzensen, Nicolas] NCI, Bethesda, MD 20892 USA. [Lawson, Herschel W.] Amer Soc Colposcopy & Cerv Pathol, Frederick, MD USA. [Einstein, Mark H.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Huh, WK (reprint author), Div Gynecol Oncol, 1700 6th Ave South,WIC Room 10250, Birmingham, AL 35233 USA. EM whuh@uabmc.edu RI Schiffman, Mark/B-9766-2015 NR 23 TC 63 Z9 74 U1 4 U2 10 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 FEB PY 2015 VL 136 IS 2 BP 178 EP 182 DI 10.1016/j.ygyno.2014.12.022 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CC7DI UT WOS:000350527500002 PM 25579107 ER PT J AU Toporcov, TN Znaor, A Zhang, ZF Yu, GP Winn, DM Wei, Q Vilensky, M Vaughan, T Thomson, P Talamini, R Szeszenia-Dabrowska, N Sturgis, EM Smith, E Shangina, O Schwartz, SM Schantz, S Rudnai, P Richiardi, L Ramroth, H Purdue, MP Olshan, AF Eluf-Neto, J Muscat, J Moyses, RA Morgenstern, H Menezes, A McClean, M Matsuo, K Mates, D Macfarlane, TV Lissowska, J Levi, F Lazarus, P La Vecchia, C Lagiou, P Koifman, S Kjaerheim, K Kelsey, K Holcatova, I Herrero, R Healy, C Hayes, RB Franceschi, S Fernandez, L Fabianova, E Daudt, AW Curioni, OA Dal Maso, L Curado, MP Conway, DI Chen, C Castellsague, X Canova, C Cadoni, G Brennan, P Boccia, S Antunes, JLF Ahrens, W Agudo, A Boffetta, P Hashibe, M Lee, YCA Wuensch, V AF Toporcov, Tatiana Natasha Znaor, Ariana Zhang, Zuo-Feng Yu, Guo-Pei Winn, Deborah M. Wei, Qingyi Vilensky, Marta Vaughan, Thomas Thomson, Peter Talamini, Renato Szeszenia-Dabrowska, Neonila Sturgis, Erich M. Smith, Elaine Shangina, Oxana Schwartz, Stephen M. Schantz, Stimson Rudnai, Peter Richiardi, Lorenzo Ramroth, Heribert Purdue, Mark P. Olshan, Andrew F. Eluf-Neto, Jose Muscat, Joshua Moyses, Raquel Ajub Morgenstern, Hal Menezes, Ana McClean, Michael Matsuo, Keitaro Mates, Dana Macfarlane, Tatiana V. Lissowska, Jolanta Levi, Fabio Lazarus, Philip La Vecchia, Carlo Lagiou, Pagona Koifman, Sergio Kjaerheim, Kristina Kelsey, Karl Holcatova, Ivana Herrero, Rolando Healy, Claire Hayes, Richard B. Franceschi, Silvia Fernandez, Leticia Fabianova, Eleonora Daudt, Alexander W. Curioni, Otavio Alberto Dal Maso, Luigino Curado, Maria Paula Conway, David I. Chen, Chu Castellsague, Xavier Canova, Cristina Cadoni, Gabriella Brennan, Paul Boccia, Stefania Antunes, Jose Leopoldo Ferreira Ahrens, Wolfgang Agudo, Antonio Boffetta, Paolo Hashibe, Mia Lee, Yuan-Chin Amy Wuensch Filho, Victor TI Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Head and neck neoplasms; adult; smoking; alcohol drinking; diet ID SQUAMOUS-CELL CARCINOMA; UPPER AERODIGESTIVE TRACT; AGED 45 YEARS; ORAL-CANCER; PHARYNGEAL CANCER; TOBACCO USE; EPIDEMIOLOGY CONSORTIUM; GENETIC SUSCEPTIBILITY; HUMAN-PAPILLOMAVIRUS; INTERNATIONAL HEAD AB Background: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients. Methods: We pooled data from 25 case-control studies and conducted separate analyses for adults <= 45 years old ('young adults', 2010 cases and 4042 controls) and > 45 years old ('older adults', 17 700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, =19.9% (95% CI = 9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking = 5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR = 2.27 (95% CI = 1.26, 4.10)], but not in the older adults [OR = 1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2 .41%, 5.80%) in older adults. Conclusions: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults. C1 [Toporcov, Tatiana Natasha; Antunes, Jose Leopoldo Ferreira; Wuensch Filho, Victor] Univ Sao Paulo, Fac Saude Publ, BR-01246904 Sao Paulo, SP, Brazil. [Znaor, Ariana] Croatian Natl Canc Registry, Zagreb, Croatia. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Yu, Guo-Pei] Peking Univ, Med Informat Ctr, Beijing 100871, Peoples R China. [Yu, Guo-Pei] New York Med Coll, Valhalla, NY 10595 USA. [Winn, Deborah M.; Purdue, Mark P.] NCI, Bethesda, MD 20892 USA. [Wei, Qingyi; Sturgis, Erich M.] UT MD Anderson Canc Ctr, Houston, TX USA. [Vilensky, Marta] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Vaughan, Thomas; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Thomson, Peter] Univ Newcastle, Sch Dent Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Talamini, Renato; Dal Maso, Luigino] Aviano Canc Ctr, I-33081 Aviano, Italy. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Lodz, Poland. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Shangina, Oxana] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Vaughan, Thomas; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schantz, Stimson] New York Eye & Ear Infirm, New York, NY 10003 USA. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Richiardi, Lorenzo] Univ Turin, Canc Epidemiol Unit, Dept Med Sci, Turin, Italy. [Ramroth, Heribert] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Eluf-Neto, Jose] Univ Sao Paulo, Fac Med, Sao Paulo, Brazil. [Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Moyses, Raquel Ajub] Univ Sao Paulo, Fac Med, Cirurgia Cabeca & Pescoco LIM 28, Sao Paulo, Brazil. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Nagoya, Aichi 464, Japan. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Macfarlane, Tatiana V.] Univ Aberdeen, Sch Dent, Aberdeen, Scotland. [Lissowska, Jolanta] M Skasodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Levi, Fabio] CHU Vaudois, IUMSP, CH-1011 Lausanne, Switzerland. [Levi, Fabio] Univ Lausanne, Lausanne, Switzerland. [Lazarus, Philip] Washington State Univ, Coll Pharm, Spokane, WA USA. [La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, IRCCS, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Lagiou, Pagona] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Koifman, Sergio] Fundacao Osvvaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Kjaerheim, Kristina] Canc Registry Norway, Oslo, Norway. [Kelsey, Karl] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Holcatova, Ivana] Charles Univ Prague, Fac Med 1, Prague, Czech Republic. [Herrero, Rolando] WHO, Int Agcy Res Canc, Prevent & Implementat Grp, Lyon, France. [Healy, Claire] Trinity Coll Sch Dent Sci, Dublin, Ireland. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY USA. [Franceschi, Silvia] Int Agcy Res Canc, F-69372 Lyon, France. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Fabianova, Eleonora] Reg Author Publ Hlth Banska Bystrica, Banska Bystrica, Slovakia. [Daudt, Alexander W.; Brennan, Paul] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Curioni, Otavio Alberto] Secretaria Estado Saude Sao Paulo, Hosp Heliopolis, Sao Paulo, Brazil. [Curado, Maria Paula] Int Prevent Res Inst, Lyon, France. [Conway, David I.] Univ Glasgow, Sch Dent, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland. [Castellsague, Xavier] CIBER ESP, IDIBELL, ICO, Barcelona, Spain. [Canova, Cristina] Univ Padua, Padua, Italy. [Cadoni, Gabriella] Univ Cattolica Sacro Cuore, Inst Otorhinolaryngol, Rome, Italy. [Boccia, Stefania] Univ Cattolica Sacro Cuore, Inst Publ Hlth, Rome, Italy. [Ahrens, Wolfgang] BIPS, Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, Fac Math & Comp Sci, D-28359 Bremen, Germany. [Agudo, Antonio] IDIBELL, ICO, Barcelona, Spain. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Hashibe, Mia] Univ Utah, Sch Med, Huntsnnan Canc Inst, Salt Lake City, UT USA. [Lee, Yuan-Chin Amy] Univ Utah, Sch Med, Dept Family & Prevent Med, Div Publ Hlth, Salt Lake City, UT 84112 USA. RP Toporcov, TN (reprint author), Univ Sao Paulo, Fac Saude Publ, Dept Epidemiol, Av Dr Arnaldo 715, BR-01246904 Sao Paulo, SP, Brazil. EM tati_toporcov@yahoo.com.br RI Thomson, Peter/L-7719-2016; Antunes, Jose/F-6969-2010; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Moyses, Raquel/N-4376-2015; Purdue, Mark/C-9228-2016; Eluf-Neto, Jose/B-2522-2009; Agudo, Antonio/J-1805-2016; Toporcov, Tatiana /M-7729-2015; Menezes, Ana/G-7266-2012; Curado, Maria Paula/M-6200-2013 OI Matsuo, Keitaro/0000-0003-1761-6314; Ahrens, Wolfgang/0000-0003-3777-570X; mates, dana/0000-0002-6219-9807; dal maso, luigino/0000-0001-6163-200X; Thomson, Peter/0000-0002-2007-7975; Macfarlane, Tatiana/0000-0002-9392-0812; richiardi, lorenzo/0000-0003-0316-9402; La Vecchia, Carlo/0000-0003-1441-897X; Kjaerheim, Kristina/0000-0003-0691-3735; Hayes, Richard/0000-0002-0918-661X; Healy, Claire M/0000-0001-7940-4611; Antunes, Jose/0000-0003-3972-9723; Castellsague Pique, Xavier/0000-0002-0802-3595; Purdue, Mark/0000-0003-1177-3108; Eluf-Neto, Jose/0000-0001-7504-2115; Curado, Maria Paula/0000-0001-8172-2483 FU US National Institutes of Health; National Cancer Institute [R03CA113157]; National Institute of Dental and Craniofacial Health [R03DE016611]; Italian Association for Research on Cancer (AIRC); Italian League Against Cancer; Italian Ministry of Research; Swiss League against Cancer [KFS1069-09-2000]; Fribourg League against Cancer [FOR381.88]; Swiss Cancer Research [AKT 617]; Gustave-Roussy Institute [88D28]; Swiss League against Cancer; Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; World Cancer Research Fund; European Commission INCO-COPERNICUS Program [IC15-CT98-0332]; National Institutes of Health (NIH) US [P01CA068384 K07CA104231, R01CA078609, R01CA100679]; NIH [R01CA048996, R01DE012609, NIDCR R01DE11979, NIDCR R01DE13110, NIH FIRCA TW01500, R01CA61188, P01CA068384, K07CA104231, R01DE13158, P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667, R01ES11740, R01CA100264, R01CA51845, R01CA30022]; Veterans Affairs Merit Review Funds; National Institute of Environmental Health Sciences [P30ES010126]; Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; National Institutes of Health (NCI) US; NIDCR intramural programmes; Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina; IMIM (Barcelona); Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP) [01/01768-2]; European Commission [IC18-CT97-0222]; IARC multicentre study: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer (UICC); Yamagiwa-Yoshida Memorial International Cancer Study Grant; AIRC (Italian Agency for Research on Cancer) [10068]; US multicentre study: the Intramural Program of the NCI, NIH, United States; Sao Paulo study: Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP) [04/12054-9, 10/51168-0]; European Community [QLK1-CT-2001-00182]; German Ministry of Education and Research [01GB9702/3]; Ministry of Education, Science, Sports, Culture and Technology of Japan [17015052]; Ministry of Health, Labour and Welfare of Japan [H20-002] FX This work was supported by the US National Institutes of Health, the National Cancer Institute [R03CA113157] and the National Institute of Dental and Craniofacial Health [R03DE016611]. The individual studies were funded by the following grants: Milan study: Italian Association for Research on Cancer (AIRC); Aviano study: Italian Association for Research on Cancer (AIRC), Italian League Against Cancer and Italian Ministry of Research; France study: Swiss League against Cancer [KFS1069-09-2000], Fribourg League against Cancer [FOR381.88], Swiss Cancer Research [AKT 617] and Gustave-Roussy Institute [88D28]; Italy multicentre study: Italian Association for Research on Cancer (AIRC), Italian League against Cancer and Italian Ministry of Research; Swiss study: Swiss League against Cancer and the Swiss Research against Cancer/Oncosuisse [KFS-700, OCS-1633]; Central Europe study: World Cancer Research Fund and the European Commission INCO-COPERNICUS Program [Contract No. IC15-CT98-0332]; New York study: National Institutes of Health (NIH) US [P01CA068384 K07CA104231]; Seattle study: NIH [R01CA048996, R01DE012609]; Iowa study: NIH [NIDCR R01DE11979, NIDCR R01DE13110, NIH FIRCA TW01500] and Veterans Affairs Merit Review Funds; North Carolina study: NIH [R01CA61188] and in part by a grant from the National Institute of Environmental Health Sciences [P30ES010126]; Tampa study: NIH [P01CA068384, K07CA104231, R01DE13158]; Los Angeles study: NIH [P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667] and the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center; Houston study: NIH [R01ES11740, R01CA100264]; Puerto Rico study: jointly funded by National Institutes of Health (NCI) US and NIDCR intramural programmes; Latin America study: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP) [No 01/01768-2] and European Commission [IC18-CT97-0222]; IARC multicentre study: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013], International Union Against Cancer (UICC) and Yamagiwa-Yoshida Memorial International Cancer Study Grant; Boston study: National Institutes of Health (NIH) US [R01CA078609, R01CA100679]; Rome study: AIRC (Italian Agency for Research on Cancer) [10068]; US multicentre study: the Intramural Program of the NCI, NIH, United States; Sao Paulo study: Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP) [04/12054-9, 10/51168-0]; MSKCC study: NIH [R01CA51845]; Seattle study: NIH [R01CA30022]; European study: European Community (5th Framework Programme) [QLK1-CT-2001-00182]; Germany-Heidelberg study: German Ministry of Education and Research [01GB9702/3]; Japan study: Scientific Research grant from the Ministry of Education, Science, Sports, Culture and Technology of Japan [17015052] and a grant for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan [H20-002]. NR 75 TC 21 Z9 21 U1 5 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2015 VL 44 IS 1 BP 169 EP 185 DI 10.1093/ije/dyu255 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD1WC UT WOS:000350864200024 PM 25613428 ER PT J AU Geng, EH Neilands, TB Thiebaut, R Bwana, MB Nash, D Moore, RD Wood, R Zannou, DM Althoff, KN Lim, PL Nachega, JB Easterbrook, PJ Kambugu, A Little, F Nakigozi, G Nakanjako, D Kiggundu, V Li, PCK Bangsberg, DR Fox, MP Prozesky, HW Hunt, PW Davies, MA Reynolds, SJ Egger, M Yiannoutsos, CT Vittinghoff, EV Deeks, SG Martin, JN AF Geng, Elvin H. Neilands, Torsten B. Thiebaut, Rodolphe Bwana, Mwebesa Bosco Nash, Denis Moore, Richard D. Wood, Robin Zannou, Djimon Marcel Althoff, Keri N. Lim, Poh Lian Nachega, Jean B. Easterbrook, Philippa J. Kambugu, Andrew Little, Francesca Nakigozi, Gertrude Nakanjako, Damalie Kiggundu, Valerian Li, Patrick Chung Ki Bangsberg, David R. Fox, Matthew P. Prozesky, Hans W. Hunt, Peter W. Davies, Mary-Ann Reynolds, Steven J. Egger, Matthias Yiannoutsos, Constantin T. Vittinghoff, Eric V. Deeks, Steven G. Martin, Jeffrey N. TI CD4+T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HIV; Africa; antiretroviral therapy; CD4+T cell counts; immunological activation ID SUBTYPE-D; INFECTED INDIVIDUALS; VIRAL SUPPRESSION; GENETIC SUBTYPES; COUNT RECOVERY; UGANDA; REDISTRIBUTION; RECOMBINANTS; ACTIVATION; INITIATION AB Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally. Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/mu l in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years. Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150 mu l was 529/mu l [95% confidence interval (Cl): 517-541] in North America, 494/mu l (95% Cl: 429-559) in West Africa, 5150 (95% Cl: 508-522) in Southern Africa, 503/mu l (95% Cl: 478-528) in Asia and 437/mu l (95% Cl: 425-449) in East Africa. Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level. C1 [Geng, Elvin H.; Neilands, Torsten B.; Hunt, Peter W.; Vittinghoff, Eric V.; Deeks, Steven G.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94110 USA. [Thiebaut, Rodolphe] Bordeaux Univ, INSERM, U897, Bordeaux, France. [Bwana, Mwebesa Bosco] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Nash, Denis] CUNY, New York, NY 10021 USA. [Moore, Richard D.; Althoff, Keri N.; Reynolds, Steven J.] Johns Hopkins Univ, Baltimore, MD USA. [Wood, Robin; Little, Francesca; Davies, Mary-Ann] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Zannou, Djimon Marcel] Ctr Natl Hosp Univ, Cotonou, Benin. [Lim, Poh Lian] Tan Tock Seng Hosp, Inst Infect Dis, Singapore, Singapore. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Program Infect Dis, Pittsburgh, PA USA. [Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Nachega, Jean B.] Univ Stellenbosch, Dept Med, Cape Town, South Africa. [Nachega, Jean B.] Univ Stellenbosch, Ctr Infect Dis, Cape Town, South Africa. [Easterbrook, Philippa J.; Kambugu, Andrew; Nakanjako, Damalie] Infect Dis Inst, Kampala, Uganda. [Nakigozi, Gertrude; Kiggundu, Valerian; Reynolds, Steven J.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Li, Patrick Chung Ki] Queen Elizabeth Hosp, Hong Kong, Hong Kong, Peoples R China. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02115 USA. [Fox, Matthew P.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02215 USA. [Fox, Matthew P.] Univ Witwatersrand, Fac Hlth Sci, Sch Clin Med, Hlth Econ & Epidemiol Res Off,Dept Internal Med, Johannesburg, South Africa. [Prozesky, Hans W.] Univ Stellenbosch, Dept Med, Div Infect Dis, Cape Town, South Africa. [Prozesky, Hans W.] Tygerberg Acad Hosp, Cape Town, South Africa. [Reynolds, Steven J.] NIAID, Washington, DC USA. [Egger, Matthias] Univ Bern, Bern, Switzerland. [Yiannoutsos, Constantin T.] Indiana Univ, Indianapolis, IN 46204 USA. RP Geng, EH (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, 995 Potrero Ave,Bldg 80,Box 0874, San Francisco, CA 94110 USA. EM genge@php.ucsf.edu OI Prozesky, Hans/0000-0001-9715-3449 FU National Institutes of Health [K23 AI084544, U01 AI069918, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, R01 MH054907, P30 AI027763]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Funding has been provided by the National Institutes of Health [K23 AI084544, U01 AI069918, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, R01 MH054907 and P30 AI027763] and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 38 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 EI 1464-3685 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2015 VL 44 IS 1 BP 251 EP 263 DI 10.1093/ije/dyu271 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CD1WC UT WOS:000350864200033 PM 25859596 ER PT J AU Maeda, S Zempo-Miyaki, A Sasai, H Tsujimoto, T So, R Tanaka, K AF Maeda, Seiji Zempo-Miyaki, Asako Sasai, Hiroyuki Tsujimoto, Takehiko So, Rina Tanaka, Kiyoji TI Lifestyle Modification Decreases Arterial Stiffness in Overweight and Obese Men: Dietary Modification vs. Exercise Training SO INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM LA English DT Article DE diet; exercise; obesity; endothelin-1; nitric oxide ID PULSE-WAVE VELOCITY; NITRIC-OXIDE; POSTMENOPAUSAL WOMEN; ENDOTHELIAL FUNCTION; AEROBIC EXERCISE; ADIPOSE-TISSUE; IN-VIVO; REGULAR EXERCISE; BODY-WEIGHT; ADIPONECTIN AB Obesity and increased arterial stiffness are independent risk factors for cardiovascular disease. Arterial stiffness is increased in obese individuals than in age-matched nonobese individuals. We demonstrated that dietary modification and exercise training are effective in reducing arterial stiffness in obese persons. However, the differences in the effect on arterial stiffness between dietary modification and exercise training are unknown. The purpose of the current study was to compare the effect of dietary modification and aerobic exercise training on arterial stiffness and endothelial function in overweight and obese persons. Forty-five overweight and obese men (48 +/- 1 year) completed either a dietary modification (well-balanced nutrient, 1680 kcal/day) or an exercise-training program (walking, 40-60 min/day, 3 days/week) for 12 weeks. Before and after the intervention, all participants underwent anthropometric measurements. Arterial stiffness was measured based on carotid arterial compliance, brachial-ankle pulse wave velocity (baPWV), and endothelial function was determined by circulating level of endothelin-1 (ET-1) and nitric oxide metabolite (nitrites/nitrate as metabolite: NOx). Body mass and waist circumference significantly decreased after both intervention programs. Weight loss was greater after dietary modification than after exercise training (-10.1 +/- 0.6 kg vs. -3.6 +/- 0.5 kg, p < .01). Although arterial stiffness and the plasma levels of ET-1 and NOx were improved after dietary modification or exercise training, there were no differences in those improvements between the 2 types of interventions. Exercise training improves arterial function in obese men without as much weight loss as after dietary modification. C1 [Maeda, Seiji; Tsujimoto, Takehiko; So, Rina; Tanaka, Kiyoji] Univ Tsukuba, Fac Hlth & Sport Sci, Tsukuba, Ibaraki, Japan. [Zempo-Miyaki, Asako] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan. [Sasai, Hiroyuki] NIH, Bethesda, MD 20892 USA. RP Maeda, S (reprint author), Univ Tsukuba, Fac Hlth & Sport Sci, Tsukuba, Ibaraki, Japan. EM maeda@taiiku.tsukuba.ac.jp OI Sasai, Hiroyuki/0000-0001-8120-6163 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [18300215] FX This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (18300215). NR 41 TC 3 Z9 3 U1 0 U2 6 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1526-484X EI 1543-2742 J9 INT J SPORT NUTR EXE JI Int. J. Sport Nutr. Exerc. Metab. PD FEB PY 2015 VL 25 IS 1 BP 69 EP 77 DI 10.1123/ijsnem.2013-0107 PG 9 WC Nutrition & Dietetics; Sport Sciences SC Nutrition & Dietetics; Sport Sciences GA CD0PS UT WOS:000350777000009 PM 25029200 ER PT J AU Logan, JG Engler, MB Kim, H AF Logan, Jeongok G. Engler, Mary B. Kim, Hyungsuk TI Genetic Determinants of Arterial Stiffness SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Article DE Arterial stiffness; Arteriosclerosis; Atherosclerosis; Genotype; Hypertension ID PULSE-WAVE VELOCITY; II TYPE-1 RECEPTOR; ANGIOTENSIN-CONVERTING ENZYME; SMOOTH-MUSCLE-CELLS; LAMIN A/C GENE; AORTIC STIFFNESS; HYPERTENSIVE PATIENTS; BLOOD-PRESSURE; NITRIC-OXIDE; CARDIOVASCULAR-DISEASE AB Stiffness of large arteries (called arteriosclerosis) is an independent predictor of cardiovascular morbidity and mortality. Although previous studies have shown that arterial stiffness is moderately heritable, genetic factors contributing to arterial stiffness are largely unknown. In this paper, we reviewed the available literature on genetic variants that are potentially related to arterial stiffness. Most variants have shown mixed depictions of their association with arterial stiffness across multiple studies. Various methods to measure arterial stiffness at different arterial sites can contribute to these inconsistent results. In addition, studies in patient populations with hypertension or atherosclerosis may overestimate the impact of genetic variants on arterial stiffness. Future studies are recommended to standardize current measures of arterial stiffness in different age groups. Studies conducted in normal healthy subjects may also provide better opportunities to find novel genetic variants of arterial stiffness. C1 [Logan, Jeongok G.] Univ Virginia, Sch Nursing, Charlottesville, VA 22903 USA. [Engler, Mary B.; Kim, Hyungsuk] NINR, NIH, Div Intramural Res, Bethesda, MD 20892 USA. RP Logan, JG (reprint author), Univ Virginia, Sch Nursing, 225 Jeanette Lancaster Way, Charlottesville, VA 22903 USA. EM jl3zj@virginia.edu; englermb@mail.nih.gov; kimhy@mail.nih.gov NR 149 TC 0 Z9 0 U1 4 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD FEB PY 2015 VL 8 IS 1 BP 23 EP 43 DI 10.1007/s12265-014-9597-x PG 21 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA CD1AJ UT WOS:000350805700003 PM 25472935 ER PT J AU Dhalla, F Murray, S Sadler, R Chaigne-Delalande, B Sadaoka, T Soilleux, E Uzel, G Miller, J Collins, GP Hatton, CSR Bhole, M Ferry, B Chapel, HM Cohen, JI Patel, SY AF Dhalla, Fatima Murray, Sarah Sadler, Ross Chaigne-Delalande, Benjamin Sadaoka, Tomohiko Soilleux, Elizabeth Uzel, Gulbu Miller, Joanne Collins, Graham Peter Hatton, Christian Simon Ross Bhole, Malini Ferry, Berne Chapel, Helen M. Cohen, Jeffrey I. Patel, Smita Y. TI Identification of a Novel Mutation in MAGT1 and Progressive Multifocal Leucoencephalopathy in a 58-Year-Old Man with XMEN Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE XMEN Disease; MAGT1; Epstein-Barr virus (EBV); progressive multifocal leucoencephalopathy (PML) ID CD4(+) T-LYMPHOCYTOPENIA; JC VIRUS; BONE-MARROW; CELLS; PATHOGENESIS; INFECTION; PATIENT AB XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years. C1 [Dhalla, Fatima; Miller, Joanne; Chapel, Helen M.; Patel, Smita Y.] Univ Oxford, Nuffield Dept Med, Oxford, England. [Dhalla, Fatima; Murray, Sarah; Miller, Joanne; Chapel, Helen M.; Patel, Smita Y.] John Radcliffe Hosp, Dept Clin Immunol, Oxford OX3 9DU, England. [Sadler, Ross; Ferry, Berne] Churchill Hosp, Dept Clin Lab Immunol, Oxford OX3 7LJ, England. [Chaigne-Delalande, Benjamin] NIAID, Mol Dev Sect, Lymphocyte Mol Genet Unit, Lab Immunol,NIH, Bethesda, MD 20892 USA. [Sadaoka, Tomohiko; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Soilleux, Elizabeth] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford, England. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Collins, Graham Peter; Hatton, Christian Simon Ross] Churchill Hosp, Dept Hematol, Oxford OX3 7LJ, England. [Bhole, Malini] Russells Hall Hosp, Dept Clin Immunol, Dudley, W Midlands, England. RP Dhalla, F (reprint author), John Radcliffe Hosp, Dept Clin Immunol, Oxford OX3 9DU, England. EM fatima.dhalla@doctors.org.uk OI sadaoka, tomohiko/0000-0001-7951-6904 FU Intramural NIH HHS NR 14 TC 7 Z9 7 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2015 VL 35 IS 2 BP 112 EP 118 DI 10.1007/s10875-014-0116-2 PG 7 WC Immunology SC Immunology GA CD2EE UT WOS:000350886300005 PM 25504528 ER PT J AU Buchbinder, D Baker, R Lee, YN Ravell, J Zhang, Y McElwee, J Nugent, D Coonrod, EM Durtschi, JD Augustine, NH Voelkerding, KV Csomos, K Rosen, L Browne, S Walter, JE Notarangelo, LD Hill, HR Kumanovics, A AF Buchbinder, David Baker, Rebecca Lee, Yu Nee Ravell, Juan Zhang, Yu McElwee, Joshua Nugent, Diane Coonrod, Emily M. Durtschi, Jacob D. Augustine, Nancy H. Voelkerding, Karl V. Csomos, Krisztian Rosen, Lindsey Browne, Sarah Walter, Jolan E. Notarangelo, Luigi D. Hill, Harry R. Kumanovics, Attila TI Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE RAG1; RAG deficiency; primary immunodeficiency; severe combined immune deficiency; common variable immunodeficiency disorder; exome sequencing; gene panel ID GRANULOMATOUS-DISEASE; AUTOIMMUNITY; DEFICIENCY; LYMPHOPENIA; CELLS AB Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A > G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G > T, p.W522C and (2) c.2689C > T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments. C1 [Buchbinder, David; Nugent, Diane] UC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USA. [Baker, Rebecca; Ravell, Juan; Rosen, Lindsey; Browne, Sarah] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lee, Yu Nee] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Zhang, Yu] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [McElwee, Joshua] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Walter, Jolan E.; Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Coonrod, Emily M.; Durtschi, Jacob D.; Augustine, Nancy H.; Voelkerding, Karl V.; Hill, Harry R.; Kumanovics, Attila] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT USA. [Augustine, Nancy H.; Voelkerding, Karl V.; Hill, Harry R.; Kumanovics, Attila] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA. [Hill, Harry R.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Csomos, Krisztian; Walter, Jolan E.] Harvard Univ, Sch Med, Pediat Allergy & Immunol, Boston, MA USA. [Csomos, Krisztian; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Buchbinder, David] CHOC Childrens Hosp, Div Hematol, Orange, CA 92868 USA. RP Buchbinder, D (reprint author), CHOC Childrens Hosp, Div Hematol, 1201 La Veta, Orange, CA 92868 USA. EM dbuchbinder@choc.org RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU Intramural NIH HHS; NIAID NIH HHS [1K08AI103035-03, 5P01AI076210-04, K08 AI103035, P01 AI076210, U54 AI082973, U54AI082973] NR 22 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD FEB PY 2015 VL 35 IS 2 BP 119 EP 124 DI 10.1007/s10875-014-0121-5 PG 6 WC Immunology SC Immunology GA CD2EE UT WOS:000350886300006 PM 25516070 ER PT J AU Strollo, SE Caserotti, P Ward, RE Glynn, NW Goodpaster, BH Strotmeyer, ES AF Strollo, S. E. Caserotti, P. Ward, R. E. Glynn, N. W. Goodpaster, B. H. Strotmeyer, E. S. TI A review of the relationship between leg power and selected chronic disease in older adults SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE Leg power; older adults; chronic disease; aging; muscle power ID NUTRITION EXAMINATION SURVEY; PERIPHERAL ARTERIAL-DISEASE; EXAMINATION SURVEY NHANES; MUSCLE POWER; SKELETAL-MUSCLE; BODY-COMPOSITION; HEART-FAILURE; GAIT SPEED; QUADRICEPS STRENGTH; KNEE OSTEOARTHRITIS AB This review investigates the relationship between leg muscle power and the chronic conditions of osteoarthritis, diabetes mellitus, and cardiovascular disease among older adults. Current literature assessing the impact of chronic disease on leg power has not yet been comprehensively characterized. Importantly, individuals with these conditions have shown improved leg power with training. A search was performed using PubMed to identify original studies published in English from January 1998 to August 2013. Leg power studies, among older adults a parts per thousand yen 50 years of age, which assessed associations with osteoarthritis, diabetes mellitus, and/or cardiovascular disease were selected. Studies concerning post-surgery rehabilitation, case studies, and articles that did not measure primary results were excluded. Sixteen studies met inclusion criteria, addressing osteoarthritis (n=5), diabetes mellitus (n=5), and cardiovascular disease (n=6). Studies generally supported associations of lower leg power among older adults with chronic disease, although small sample sizes, cross-sectional data, homogenous populations, varied disease definitions, and inconsistent leg power methods limited conclusions. Studies suggest that osteoarthritis, diabetes mellitus, and cardiovascular disease are associated with lower leg power compared to older adults without these conditions. These studies are limited, however, by the heterogeneity in study populations and a lack of standardized measurements of leg power. Future larger studies of more diverse older adults with well-defined chronic disease using standard measures of leg power and interventions to improve leg power in these older adults with chronic disease are needed. C1 [Strollo, S. E.] NIAID, NIH, Bethesda, MD 20892 USA. [Caserotti, P.] Univ Southern Denmark, Dept Sports Sci & Clin Biomech, Odense, Denmark. [Ward, R. E.] Boston Univ, Hlth & Disabil Res Inst, Spaulding Rehabil Hosp, Boston, MA 02215 USA. [Glynn, N. W.; Strotmeyer, E. S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Goodpaster, B. H.] Sanford Burnham Med Res Inst, Orlando, FL USA. RP Strotmeyer, ES (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 North Bellefield Ave,Room 515, Pittsburgh, PA 15213 USA. EM sara.strollo@nih.gov; pcaserotti@health.sdu.dk; rew27@bu.edu; glynnn@edc.pitt.edu; bgoodpaster@sanfordburnham.org; strotmeyere@edc.pitt.edu OI Strotmeyer, Elsa/0000-0002-4093-6036; Glynn, Nancy/0000-0003-2265-0162 FU Pittsburgh Claude D. Pepper Older Americans Independence Center; Research Registry, and Developmental Pilot Grant [NIH P30 AG024826, NIH P30 AG024827]; National Institute on Aging Professional Services [HHSN271201100605P]; NIA Aging Training Grant [T32 AG000181]; Intramural Research Program of the National Institute on Aging FX This work was supported by the Pittsburgh Claude D. Pepper Older Americans Independence Center, Research Registry, and Developmental Pilot Grant - NIH P30 AG024826 and NIH P30 AG024827; National Institute on Aging Professional Services Contract HHSN271201100605P; NIA Aging Training Grant T32 AG000181; and by the Intramural Research Program of the National Institute on Aging. NR 81 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 EI 1760-4788 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD FEB PY 2015 VL 19 IS 2 BP 240 EP 248 DI 10.1007/s12603-014-0528-y PG 9 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA CC4DH UT WOS:000350300500018 PM 25651453 ER PT J AU Torchia, DA AF Torchia, Dennis A. TI NMR studies of dynamic biomolecular conformational ensembles SO PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY LA English DT Review DE Spin; Relaxation; Residual dipolar coupling; Order parameter; Dynamics ID NUCLEAR-MAGNETIC-RESONANCE; SOLID-STATE NMR; RESIDUAL DIPOLAR COUPLINGS; CHEMICAL-SHIFT ANISOTROPY; LIQUID-CRYSTALLINE PHASE; MODEL-FREE APPROACH; PARAMAGNETIC RELAXATION ENHANCEMENT; PROTEIN-STRUCTURE DETERMINATION; PANCREATIC TRYPSIN-INHIBITOR; NONRIGID ROTATIONAL MOTION AB Multidimensional heteronuclear NMR approaches can provide nearly complete sequential signal assignments of isotopically enriched biomolecules. The availability of assignments together with measurements of spin relaxation rates, residual spin interactions, J-couplings and chemical shifts provides information at atomic resolution about internal dynamics on timescales ranging from ps to ms, both in solution and in the solid state. However, due to the complexity of biomolecules, it is not possible to extract a unique atomic-resolution description of biomolecular motions even from extensive NMR data when many conformations are sampled on multiple timescales. For this reason, powerful computational approaches are increasingly applied to large NMR data sets to elucidate conformational ensembles sampled by biomolecules. In the past decade, considerable attention has been directed at an important class of biomolecules that function by binding to a wide variety of target molecules. Questions of current interest are: "Does the free biomolecule sample a conformational ensemble that encompasses the conformations found when it binds to various targets; and if so, on what time scale is the ensemble sampled?" This article reviews recent efforts to answer these questions, with a focus on comparing ensembles obtained for the same biomolecules by different investigators. A detailed comparison of results obtained is provided for three biomolecules: ubiquitin, calmodulin and the HIV-1 trans-activation response RNA. Published by Elsevier B.V. C1 NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), NIH, 5 Mem Dr, Bethesda, MD 20892 USA. EM dtorchia@dir.nidcr.nih.gov FU NIH Intramural Research Program of the NIDCR; NIH Intramural Research Program of the NIDDK FX I thank Ad Bax, Marius Clore, Attila Szabo, Rob Tycko and Jinfa Ying for numerous helpful suggestions. This work was supported by the NIH Intramural Research Programs of the NIDCR and NIDDK. NR 173 TC 11 Z9 11 U1 12 U2 75 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6565 J9 PROG NUCL MAG RES SP JI Prog. Nucl. Magn. Reson. Spectrosc. PD FEB PY 2015 VL 84 BP 14 EP 32 DI 10.1016/j.pnmrs.2014.11.001 PG 19 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Physics; Spectroscopy GA CD8CJ UT WOS:000351322500002 PM 25669739 ER PT J AU Yang, QC Sun, X Wang, YM Wu, Q Feng, J Chen, BY AF Yang, Qing-chan Sun, Xin Wang, Yong-mei Wu, Qi Feng, Jing Chen, Bao-yuan TI Systematic and Endothelial Inflammation and Endothelial Progenitor Cell Levels in Emphysematous Rats Exposed to Intermittent Hypoxia SO RESPIRATORY CARE LA English DT Article DE intermittent hypoxia; emphysema; inflammation; endothelial dysfunction; endothelial progenitor cell ID OBSTRUCTIVE SLEEP-APNEA; INTIMA-MEDIA THICKNESS; PULMONARY-DISEASE; OVERLAP SYNDROME; LUNG-DISEASE; ATHEROSCLEROSIS; HYPERTENSION; MONOCYTES; ALPHA; COPD AB BACKGROUND: This study aimed to develop an overlap syndrome rat model with intermittent hypoxia (IH) exposure as seen in obstructive sleep apnea, on a base of preexisting emphysema caused by 16 wk of smoke exposure to determine whether IH and emphysema existing simultaneously play overlapped roles on systematic/endothelial inflammation and endothelial damage. METHODS: Sixty male Wistar rats were divided into 4 groups of 15 each, labeled according to exposure conditions as control, IH, emphysema, and overlap groups. In these animals, electroencephalogram monitoring and preliminary experiments to obtain arterial blood gas values were performed. Serum concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, TNF-alpha and IL-6 concentrations in the culture medium, Ras homology A mRNA expression levels of endothelial cells from right common carotid artery, and ratio of carotid intima-media thickness of whole thickness of vascular wall expressed in percent (C-IMT) (%) values were evaluated. Subsequently, circulating endothelial progenitor cells (EPCs) within rat peripheral blood and bone marrow were measured with flow cytometry. RESULTS: The serum and endothelial concentrations of TNF-alpha and IL-6 and the levels of endothelial Ras homology A mRNA have statistically significant results described as overlap > emphysema > IH > control. The levels of EPCs in rat peripheral blood and bone marrow have statistically significant results described as overlap > IH > emphysema > control. C-IMT (%) values from right common carotid artery are the highest in the overlap group and the lowest in the control group. There is no statistical difference when comparing the IH and the emphysema groups. CONCLUSIONS: Regardless of whether IH and emphysema exposure are mechanistically synergistic, this overlap elicits a more severe systematic/endothelial inflammation and endothelial damage; meanwhile, a robust mobilization of EPCs is demonstrated, which is not to mean a robust adherent and repairing capability. (C) 2015 Daedalus Enterprises C1 [Yang, Qing-chan; Sun, Xin; Wang, Yong-mei; Wu, Qi] Tianjin Haihe Hosp, Tianjin 300350, Peoples R China. [Feng, Jing; Chen, Bao-yuan] Tianjin Med Univ, Gen Hosp, Resp Dept, Tianjin 300052, Peoples R China. [Feng, Jing] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Feng, J (reprint author), Tianjin Med Univ, Gen Hosp, Resp Dept, Tianjin 300052, Peoples R China. EM tjshhyywym@126.com; zyyhxkfj@126.com FU National Natural Science Foundation of China [81270144, 30800507, 81170071]; Natural Science Foundation of Tianjin City [13JCYBJC22400, 13JCYBJC40000]; Tianjin Municipal Science and Technology Commission [09ZCZDSF04500] FX This study was supported by grants 81270144, 30800507, and 81170071 from the National Natural Science Foundation of China; by grants 13JCYBJC22400 and 13JCYBJC40000 from the Natural Science Foundation of Tianjin City; and by grant 09ZCZDSF04500 from the Tianjin Municipal Science and Technology Commission. The authors have disclosed no conflicts of interest. NR 40 TC 2 Z9 2 U1 10 U2 12 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD FEB PY 2015 VL 60 IS 2 BP 279 EP 289 DI 10.4187/respcare.03492 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CD2IC UT WOS:000350898900018 PM 25587169 ER PT J AU Apolo, AB Hoffman, V Kaag, MG Latini, DM Lee, CT Rosenberg, JE Knowles, M Theodorescu, D Czerniak, BA Efstathiou, JA Albert, ML Sridhar, SS Margulis, V Matin, SF Galsky, MD Hansel, D Kamat, AM Flaig, TW Smith, AB Messing, E Quale, DZ Lotan, Y AF Apolo, Andrea B. Hoffman, Vanessa Kaag, Matthew G. Latini, David M. Lee, Cheryl T. Rosenberg, Jonathan E. Knowles, Margaret Theodorescu, Dan Czerniak, Bogdan A. Efstathiou, Jason A. Albert, Matthew L. Sridhar, Srikala S. Margulis, Vitaly Matin, Surena F. Galsky, Matthew D. Hansel, Donna Kamat, Ashish M. Flaig, Thomas W. Smith, Angela B. Messing, Edward Quale, Diane Zipursky Lotan, Yair TI Summary of the 8th Annual Bladder Cancer Think Tank: Collaborating to move research forward SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Bladder cancer; BCAN; Think Tank; Targeted therapies; Sexual dysfunction; Gender disparities; Working groups ID TRACT UROTHELIAL CARCINOMA; UPPER URINARY-TRACT; TRANSITIONAL-CELL-CARCINOMA; THERAPY-ONCOLOGY-GROUP; RADICAL CYSTECTOMY; ANDROGEN RECEPTOR; ILEAL NEOBLADDER; SCREENING TRIAL; CLINICAL-TRIAL; LYMPH-NODES AB Objectives: The 8th Annual Bladder Cancer Think Tank (BCAN-TT) brought together a multidisciplinary group of clinicians, researchers, and patient advocates in an effort to advance bladder cancer research. Methods and Materials: With the theme of "Collaborating to Move Research Forward," the meeting included three panel presentations and seven small working groups. Results: The panel presentations and interactive discussions focused on three main areas: gender disparities, sexual dysfunction, and targeting novel pathways in bladder cancer. Small working groups also met to identify projects for the upcoming year, including: (1) improving enrollment and quality of clinical trials; (2) collecting data from multiple institutions for future research; (3) evaluating patterns of care for non-muscle-invasive bladder cancer; (4) improving delivery of care for muscle-invasive disease; (5) improving quality of life for survivors; (6) addressing upper tract disease; and (7) examining the impact of health policy changes on research and treatment of bladder cancer. Conclusions: The goal of the BCAN-TT is to advance the care of patients with bladder cancer and to promote collaborative research throughout the year. The meeting provided ample opportunities for collaboration among clinicians from multiple disciplines, patients and patient advocates, and industry representatives. (C) 2014 Elsevier Inc. All rights reserved. C1 [Apolo, Andrea B.] NCI, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. [Hoffman, Vanessa; Quale, Diane Zipursky] Bladder Canc Advocacy Network, Bethesda, MD USA. [Kaag, Matthew G.] Penn State Hershey Med Ctr, Dept Urol, Hershey, PA USA. [Latini, David M.] Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. [Lee, Cheryl T.] Univ Michigan Hlth Syst, Dept Urol, Ann Arbor, MI USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Knowles, Margaret] Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. [Theodorescu, Dan] Univ Colorado, Ctr Canc, Denver, CO 80202 USA. [Czerniak, Bogdan A.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Albert, Matthew L.] Inst Pasteur, Dept Immunol, F-75724 Paris, France. [Sridhar, Srikala S.] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Margulis, Vitaly; Lotan, Yair] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Matin, Surena F.; Kamat, Ashish M.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Galsky, Matthew D.] Mt Sinai Hosp, Dept Med Oncol, New York, NY 10029 USA. [Hansel, Donna] Univ Calif La Jolla, Dept Pathol, San Diego, CA USA. [Smith, Angela B.] Univ N Carolina, Dept Urol, Chapel Hill, NC USA. [Messing, Edward] Univ Rochester, Med Ctr, Dept Urol, Rochester, NY 14642 USA. RP Lotan, Y (reprint author), Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. EM yair.lotan@utsouthwestern.edu OI Latini, David/0000-0002-6161-4861; Rosenberg, Jonathan/0000-0003-2637-4249 NR 66 TC 2 Z9 2 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD FEB PY 2015 VL 33 IS 2 BP 53 EP 64 DI 10.1016/j.urolonc.2014.06.013 PG 12 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CD0PV UT WOS:000350777300001 PM 25065704 ER PT J AU Bernstein, SL Stoney, CM Rothman, RE AF Bernstein, Steven L. Stoney, Catherine M. Rothman, Richard E. TI Dissemination and Implementation Research in Emergency Medicine SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; BASE-LINE DESIGN; KNOWLEDGE TRANSLATION; PRIMARY-CARE; TIME; INTERVENTIONS; IMPROVEMENT; PROTOCOL; SCIENCE; MAP AB Published medical research takes years to change clinical practice. The reasons for this evidence-to-practice gap are many. To address this gap, in recent years the field of dissemination and implementation (D&I) science has grown dramatically. D&I studies design and test strategies to accelerate the movement of new evidence-based diagnostic and therapeutic maneuvers into real-world clinical practice. This article summarizes the proceedings of sessions at the 2011 and 2012 annual meetings of the Society for Academic Emergency Medicine that discussed D&I studies in emergency medicine. Examples of current studies are provided, along with a review of D&I methods, funding opportunities, and suggestions for future research. (C) 2015 by the Society for Academic Emergency Medicine C1 [Bernstein, Steven L.] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT 06520 USA. [Stoney, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Rothman, Richard E.] Johns Hopkins, Dept Emergency Med, Baltimore, MD USA. RP Bernstein, SL (reprint author), Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT 06520 USA. EM Steven.bernstein@yale.edu OI Rothman, Richard/0000-0002-1017-9505 FU National Heart, Lung and Blood Institute of the National Institutes of Health [R18HL105208] FX Supported in part by grant R18HL105208 from the National Heart, Lung and Blood Institute of the National Institutes of Health. The authors have no relevant financial information or potential conflicts to disclose. NR 36 TC 2 Z9 2 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD FEB PY 2015 VL 22 IS 2 BP 229 EP 236 DI 10.1111/acem.12588 PG 8 WC Emergency Medicine SC Emergency Medicine GA CC1LI UT WOS:000350101800016 PM 25640627 ER PT J AU Jennings, L Rompalo, AM Wang, J Hughes, J Adimora, AA Hodder, S Soto-Torres, LE Frew, PM Haley, DF AF Jennings, Larissa Rompalo, Anne M. Wang, Jing Hughes, James Adimora, Adaora A. Hodder, Sally Soto-Torres, Lydia E. Frew, Paula M. Haley, Danielle F. CA HIV Prevention Trials Network HPTN TI Prevalence and Correlates of Knowledge of Male Partner HIV Testing and Serostatus Among African-American Women Living in High Poverty, High HIV Prevalence Communities (HPTN 064) SO AIDS AND BEHAVIOR LA English DT Article DE Knowledge; Male sexual partner; HIV; Serostatus; African-American women ID UNPROTECTED ANAL INTERCOURSE; SEXUAL-BEHAVIOR; UNITED-STATES; CONDOM USE; MEN; RISK; PREVENTION; TRANSMISSION; NOTIFICATION; DISCLOSURE AB Knowledge of sexual partners' HIV infection can reduce risky sexual behaviors. Yet, there are no published studies to-date examining prevalence and characteristics associated with knowledge among African-American women living in high poverty communities disproportionately affected by HIV. Using the HIV Prevention Trial Network's (HPTN) 064 Study data, multivariable logistic regression was used to examine individual, partner, and partnership-level determinants of women's knowledge (n = 1,768 women). Results showed that women's demographic characteristics alone did not account for the variation in serostatus awareness. Rather, lower knowledge of partner serostatus was associated with having two or more sex partners (OR = 0.49, 95 % CI 0.37-0.65), food insecurity (OR = 0.68, 95 % CI 0.49-0.94), partner age > 35 years (OR = 0.68, 95 % CI 0.49-0.94), and partner concurrency (OR = 0.63, 95 % CI 0.49-0.83). Access to financial support (OR = 1.42, 95 % CI 1.05-1.92) and coresidence (OR = 1.43, 95 % CI 1.05-1.95) were associated with higher knowledge of partner serostatus. HIV prevention efforts addressing African-American women's vulnerabilities should employ integrated behavioral, economic, and empowerment approaches. C1 [Jennings, Larissa] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Social & Behav Intervent Program, Baltimore, MD 21205 USA. [Rompalo, Anne M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Wang, Jing; Hughes, James] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent SCHARP, Seattle, WA 98104 USA. [Hughes, James] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Adimora, Adaora A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Hodder, Sally] Rutgers New Jersey Med Sch, Newark, NJ USA. [Soto-Torres, Lydia E.] NIAID, Prevent Sci Program, DAIDS, NIH, Bethesda, MD 20892 USA. [Frew, Paula M.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Haley, Danielle F.] Family Hlth Int FHI 360, Durham, NC USA. [Haley, Danielle F.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. RP Jennings, L (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Social & Behav Intervent Program, 615 N Wolfe St,Room E5038, Baltimore, MD 21205 USA. EM ljenning@jhsph.edu FU University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; Clinical and Translational Science Award [UL1 RR025008]; Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit [5 UM1 AI069503-07]; Johns Hopkins Clinical and Translational Science Award [UL1 RR 25005]; HPTN Scholars Program - National Institute of Allergy and Infectious Diseases; National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse; National Institute of Mental Health [UM1 AI068619, UM 1AI068617, UM1-AI068613]; Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University [5U1Al069466]; University of North Carolina Clinical Trials Unit [AI069423]; University of North Carolina Center for AIDS Research [AI050410]; Emory University HIV/AIDS Clinical Trials Unit [5UO1AI069418]; Center for AIDS Research and Clinical and Translational Science Award [UL1 RR025008, P30 AI050409]; Johns Hopkins Adult AIDS Clinical Trial Unit [AI069465]; National Institute of Allergy and Infectious Diseases FX The authors wish to thank the study participants, community stakeholders, and staff from each study site. In particular, we acknowledge Lynda Emel, Jonathan Lucas, Nirupama Sista, Kathy Hinson, Elizabeth DiNenno, Ann O'Leary, Lisa Diane White, Waheedah Shabaaz-El, Quarraisha Abdool-Karim, Carlos del Rio, Chris Root, Valarie Hunter, Sten Vermund, Makisha Ruffin, Genda Dockery, Charlene Wylie, Adongo Tia-Okwee, Darrell Wheeler, Peter Winch, Magdalena Nelson, and Sam Griffith. By the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health (cooperative agreement no. UM1 AI068619, UM 1AI068617, and UM1-AI068613); Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University (5U1Al069466); University of North Carolina Clinical Trials Unit (AI069423); University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award (RR 025747); University of North Carolina Center for AIDS Research (AI050410); Emory University HIV/AIDS Clinical Trials Unit (5UO1AI069418), Center for AIDS Research (P30 AI050409), and Clinical and Translational Science Award (UL1 RR025008); The Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit(5 UM1 AI069503-07) and; The Johns Hopkins Adult AIDS Clinical Trial Unit (AI069465) and The Johns Hopkins Clinical and Translational Science Award (UL1 RR 25005). The primary author's work on this manuscript was supported through the HPTN Scholars Program funded by the National Institute of Allergy and Infectious Diseases. NR 31 TC 3 Z9 3 U1 2 U2 4 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 FEB PY 2015 VL 19 IS 2 BP 291 EP 301 DI 10.1007/s10461-014-0884-y PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CC4UL UT WOS:000350349300009 PM 25160901 ER PT J AU Mannisto, T Mendola, P Liu, DP Leishear, K Ying, Q Sundaram, R AF Maennistoe, Tuija Mendola, Pauline Liu, Danping Leishear, Kira Ying, Qi Sundaram, Rajeshwari TI Temporal variation in the acute effects of air pollution on blood pressure measured at admission to labor/delivery SO AIR QUALITY ATMOSPHERE AND HEALTH LA English DT Article DE Epidemiology; Blood pressure; Pregnancy; Air pollution; Temporal variation ID AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; PARTICULATE MATTER; SYSTEMIC INFLAMMATION; NORMAL-PREGNANCY; PULSE PRESSURE; HYPERTENSION; EXPOSURE; POPULATION; CONSTITUENTS AB Same day or recent air pollution exposure increases blood pressure in pregnant women. Temporal blood pressure variation associated with hourly air pollution is unstudied. We randomly selected 500 women (249 normotensive, 191 with hypertensive disorders, and 60 with chronic hypertension) with singleton pregnancies and blood pressure measured at labor/delivery admission from a large cohort, the Consortium on Safe Labor. Community multiscale air quality models estimated hourly air pollutant exposures for the admission hour (lag 0) and for the 24 h preceding labor/delivery admission (lags 1-24). Linear regression estimated the effect of 10 % increase in pollutants on blood pressure at each time point, adjusting for maternal characteristics, labor type, and time of day. Women with chronic hypertension had higher systolic blood pressure with exposure to particulate matter < 10 mu m (by 1.0-1.3 mmHg at 0-4 h), sulfur dioxide (by 0.7-0.9 mmHg at 0-3, 16-20, and 22-23 h) and with some air toxics. Diastolic blood pressure was higher in normotensive women with ozone exposure (by 0.1-0.4 mmHg at 0-1 and 23-24 h). Similar effects for systolic blood pressure were seen among women with hypertensive disorders (by 0.6 mmHg at 19-20 h), but most pollutants were associated with lower blood pressure in these women. Substantial variation in the impact of hourly air pollutant measures on blood pressure was observed during the day prior to labor/delivery admission, both by mothers' hypertensive status and by the lag time prior to BP measurement. Effects were largest near admission (lags 0-4) and among women with chronic hypertension. C1 [Maennistoe, Tuija; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, NIH, Rockville, MD 20852 USA. [Liu, Danping; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, NIH, Rockville, MD 20852 USA. [Leishear, Kira] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Ying, Qi] Texas A&M Univ, Zachry Dept Civil Engn, TAMU 3136, College Stn, TX 77843 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, NIH, 6100 Executive Blvd,7B05, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; [HHSN267200603425C]; [HHSN275200800002I]; [HHSN27500008] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The data included in this paper were obtained from the Consortium on Safe Labor and the Air Quality and Reproductive Health study, which were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The Consortium on Safe Labor was supported through Contract No. HHSN267200603425C, and the Air Quality and Reproductive Health study was supported through Contract No. HHSN275200800002I, Task Order No. HHSN27500008. Institutions involved in the Consortium include, in alphabetical order: Baystate Medical Center, Springfield, MA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA; Christiana Care Health System, Newark, DE; Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, IN; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, NY; MetroHealth Medical Center, Cleveland, OH.; Summa Health System, Akron City Hospital, Akron, OH; The EMMES Corporation, Rockville MD (data coordinating center); University of Illinois at Chicago, Chicago, IL; University of Miami, Miami, FL; and University of Texas Health Science Center at Houston, Houston, Texas. The authors also want to acknowledge the Texas A&M Supercomputing Facility (http://sc.tamu.edu) and the Texas Advanced Computing Center (http://www.tacc.utexas.edu/) for providing computing resources essential for completing the air quality simulations used for exposure estimations described in this study. NR 37 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1873-9318 EI 1873-9326 J9 AIR QUAL ATMOS HLTH JI Air Qual. Atmos. Health PD FEB PY 2015 VL 8 IS 1 BP 13 EP 28 DI 10.1007/s11869-014-0268-5 PG 16 WC Environmental Sciences SC Environmental Sciences & Ecology GA CC3FX UT WOS:000350232900002 ER PT J AU McDonald, PG O'Connell, M Suls, J AF McDonald, Paige Green O'Connell, Mary Suls, Jerry TI Cancer Control Falls Squarely Within the Province of the Psychological Sciences SO AMERICAN PSYCHOLOGIST LA English DT Article DE psychology; cancer prevention; cancer control; behavioral medicine ID METASTATIC BREAST-CANCER; UNITED-STATES; DECISION-MAKING; PSYCHOSOCIAL FACTORS; BEHAVIORAL-RESEARCH; PANCREATIC-CANCER; RANDOMIZED-TRIALS; PRONE PERSONALITY; PHYSICAL-ACTIVITY; COGNITIVE CHANGES AB Against the background of cancer as a contemporary public health challenge, this article presents a selective overview of psychological science contributions to cancer control research, practice, and policy. Initial contributions were circumscribed to awareness campaigns and the assessment of emotional responses to diagnosis and treatment. As evidence linking certain behaviors to cancer risk and outcomes accumulated, psychology emerged as a "hub science" in the Nation's cancer control program. Despite substantial accomplishments, new societal trends further challenge our ability to reduce risk, incidence, and deaths from cancer and enhance quality of life for cancer survivors. Evidence generated from psychological research conducted within each cell of Pasteur's quadrant continues to be relevant and necessary for effective 21st-century approaches to cancer prevention and control at the individual, clinical, and population levels. C1 [McDonald, Paige Green; O'Connell, Mary; Suls, Jerry] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP McDonald, PG (reprint author), 9609 Med Ctr Dr,MSC 9761, Rockville, MD 20850 USA. EM mcdonalp@mail.nih.gov OI Green, Paige/0000-0001-7886-8924 NR 187 TC 2 Z9 2 U1 0 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 61 EP 74 DI 10.1037/a0038873 PG 14 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800001 ER PT J AU McBride, CM Birmingham, WC Kinney, AY AF McBride, Colleen M. Birmingham, Wendy C. Kinney, Anita Y. TI Health Psychology and Translational Genomic Research Bringing Innovation to Cancer-Related Behavioral Interventions SO AMERICAN PSYCHOLOGIST LA English DT Article DE genomics; translational research; health psychology; cancer; behavior ID AT-RISK RELATIVES; NONPOLYPOSIS COLORECTAL-CANCER; RANDOMIZED CONTROLLED-TRIAL; SOCIAL-SCIENCES RESEARCH; BREAST-CANCER; HEREDITARY BREAST; OVARIAN-CANCER; GENETIC SUSCEPTIBILITY; FAMILY-HISTORY; LYNCH SYNDROME AB The past decade has witnessed rapid advances in human genome sequencing technology and in the understanding of the role of genetic and epigenetic alterations in cancer development. These advances have raised hopes that such knowledge could lead to improvements in behavioral risk reduction interventions, tailored screening recommendations, and treatment matching that together could accelerate the war on cancer. Despite this optimism, translation of genomic discovery for clinical and public health applications has moved relatively slowly. To date, health psychologists and the behavioral sciences generally have played a very limited role in translation research. In this report we discuss what we mean by genomic translational research and consider the social forces that have slowed translational research, including normative assumptions that translation research must occur downstream of basic science, thus relegating health psychology and other behavioral sciences to a distal role. We then outline two broad priority areas in cancer prevention, detection, and treatment where evidence will be needed to guide evaluation and implementation of personalized genomics: (a) effective communication, to broaden dissemination of genomic discovery, including patient-provider communication and familial communication, and (b) the need to improve the motivational impact of behavior change interventions, including those aimed at altering lifestyle choices and those focusing on decision making regarding targeted cancer treatments and chemopreventive adherence. We further discuss the role that health psychologists can play in interdisciplinary teams to shape translational research priorities and to evaluate the utility of emerging genomic discoveries for cancer prevention and control. C1 [McBride, Colleen M.] NHGRI, Bethesda, MD 20892 USA. [Birmingham, Wendy C.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Kinney, Anita Y.] Univ New Mexico, Ctr Canc, Dept Internal Med, Div Epidemiol Biostat & Prevent Med, Albuquerque, NM 87131 USA. RP McBride, CM (reprint author), NHGRI, Bldg 31,MSC 2073,31 Ctr Dr,Room B1B54, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov NR 122 TC 4 Z9 4 U1 1 U2 22 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 91 EP 104 DI 10.1037/a0036568 PG 14 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800003 PM 25730717 ER PT J AU Reyna, VF Nelson, WL Han, PK Pignone, MP AF Reyna, Valerie F. Nelson, Wendy L. Han, Paul K. Pignone, Michael P. TI Decision Making and Cancer SO AMERICAN PSYCHOLOGIST LA English DT Article DE heuristics and biases; decision aids; medical decision making; informed decision making; risk communication ID FUZZY-TRACE THEORY; SERVICES TASK-FORCE; BREAST-CANCER; PROSTATE-CANCER; RISK PERCEPTION; ACTIVE SURVEILLANCE; RECOMMENDATION STATEMENT; FERTILITY PRESERVATION; PERCEIVED AMBIGUITY; RATIONAL CHOICE AB We review decision making along the cancer continuum in the contemporary context of informed and shared decision making in which patients are encouraged to take a more active role in their health care. We discuss challenges to achieving informed and shared decision making, including cognitive limitations and emotional factors, but argue that understanding the mechanisms of decision making offers hope for improving decision support. Theoretical approaches to decision making that explain cognition, emotion, and their interaction are described, including classical psychophysical approaches, dual-process approaches that focus on conflicts between emotion versus cognition (or reason), and modern integrative approaches such as fuzzy-trace theory. In contrast to the earlier emphasis on rote use of numerical detail, modern approaches emphasize understanding the bottom-line gist of options (which encompasses emotion and other influences on meaning) and retrieving relevant social and moral values to apply to those gist representations. Finally, research on interventions to support better decision making in clinical settings is reviewed, drawing out implications for future research on decision making and cancer. C1 [Reyna, Valerie F.] Cornell Univ, Human Neurosci Inst, Ithaca, NY 14853 USA. [Reyna, Valerie F.] Cornell Univ, Ctr Behav Econ & Decis Res, Ithaca, NY 14853 USA. [Nelson, Wendy L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Han, Paul K.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [Pignone, Michael P.] Univ N Carolina, Div Gen Internal Med, Chapel Hill, NC USA. RP Reyna, VF (reprint author), Cornell Univ, Human Neurosci Inst, G331,Martha Van Rensselaer Hall, Ithaca, NY 14853 USA. EM vr53@cornell.edu OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute of the National Institutes of Health [R21CA149796]; National Institute of Nursing Research [RO1NR014368-01]; National Cancer Institute [K05 CA129166] FX Preparation of this manuscript was supported in part by awards from the National Cancer Institute of the National Institutes of Health (R21CA149796) and the National Institute of Nursing Research (RO1NR014368-01) to Valerie F. Reyna and by an Established Investigator Award from the National Cancer Institute (K05 CA129166) to Michael P. Pignone. NR 128 TC 22 Z9 22 U1 11 U2 37 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 105 EP 118 DI 10.1037/a0036834 PG 14 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800004 PM 25730718 ER PT J AU Stanton, AL Rowland, JH Ganz, PA AF Stanton, Annette L. Rowland, Julia H. Ganz, Patricia A. TI Life After Diagnosis and Treatment of Cancer in Adulthood Contributions From Psychosocial Oncology Research SO AMERICAN PSYCHOLOGIST LA English DT Article DE cancer; survivorship; psychosocial; quality of life; intervention ID QUALITY-OF-LIFE; POSTTRAUMATIC-STRESS-DISORDER; STAGE BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; LOCALIZED PROSTATE-CANCER; PROBLEM-SOLVING THERAPY; NON-HODGKIN-LYMPHOMA; LONG-TERM SURVIVORS; COLORECTAL-CANCER; DEPRESSIVE SYMPTOMS AB The number of individuals living with a history of cancer is estimated at 13.7 million in the United States and is expected to rise with the aging of the population. With expanding attention to the psychosocial and physical consequences of surviving illness, psychological science and evidence-based practice are making important contributions to addressing the pressing needs of cancer survivors. Research is demonstrating that adults diagnosed with cancer evidence generally positive psychosocial adjustment over time; however, a subset is at risk for compromised psychological and physical health stemming from long-term or late effects of cancer and its treatment. In this article, we characterize survivorship after medical treatment completion during the periods of reentry, early survivorship, and long-term survivorship. We describe the major psychosocial and physical sequelae facing adults during those periods, highlight promising posttreatment psychosocial and behavioral interventions, and offer recommendations for future research and evidence-based practice. C1 [Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Rowland, Julia H.] NCI, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Stanton, AL (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM astanton@ucla.edu NR 187 TC 12 Z9 13 U1 9 U2 26 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 159 EP 174 DI 10.1037/a0037875 PG 16 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800008 PM 25730722 ER PT J AU Hesse, BW Beckjord, E Rutten, LJF Fagerlin, A Cameron, LD AF Hesse, Bradford W. Beckjord, Ellen Rutten, Lila J. Finney Fagerlin, Angela Cameron, Linda D. TI Cancer Communication and Informatics Research Across the Cancer Continuum SO AMERICAN PSYCHOLOGIST LA English DT Article DE health communication; informatics; psycho-oncology; cancer ID DECISION-MAKING; SMOKING-CESSATION; MOBILE TECHNOLOGY; SOCIAL IMAGE; HEALTH-CARE; INTERVENTIONS; PATIENT; BREAST; IMPACT; PERSPECTIVE AB Over the past decade, dramatic changes brought about by a rapid diffusion of Internet technologies, cellular telephones, mobile devices, personal digital assistants, electronic health records, and data visualization have helped to create a revolution in health communication. To understand the implications of this communication revolution for cancer care, the National Cancer Institute launched an ambitious set of research priorities under its "extraordinary opportunities" program. We present an overview of some of the relevant behavioral research being conducted within the perspective of this extraordinary opportunity in cancer communication research. We begin by tracing the implications of this research for behavioral scientists across the continuum of cancer care from primary prevention (e.g., tobacco control, diet, exercise, sun protection, and immunization against human papilloma virus), to secondary prevention (e.g., screening for polyps, lesions, and early stage neoplasms), to diagnosis and treatment, post-treatment survivorship, and end of life. Along each point of the continuum, we describe a natural evolution of knowledge from studies on the traditional role of media to research on the changing role of new media and informatics, and we carefully highlight the role that psychological research has played in improving communication-and health-related outcomes along the way. We conclude with an appeal to psychologists of many different backgrounds to join with biomedical researchers, engineers, clinical practitioners, and others to accelerate progress against cancer. C1 [Hesse, Bradford W.] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Beckjord, Ellen] Univ Pittsburgh, Biobehav Med Oncol Program, Pittsburgh, PA 15260 USA. [Rutten, Lila J. Finney] Mayo Clin, Dept Hlth Sci Res, Populat Hlth Sci Program, Rochester, MN USA. [Fagerlin, Angela] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. [Fagerlin, Angela] VA Ctr Clin Management Res, Ann Arbor, MI USA. [Cameron, Linda D.] Univ Calif, Hlth Commun & Intervent Lab, Merced, CA USA. [Cameron, Linda D.] Univ Calif, Dept Psychol, Merced, CA USA. RP Hesse, BW (reprint author), NCI, Hlth Commun & Informat Res Branch, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM bradford.hesse@nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 110 TC 4 Z9 4 U1 4 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 198 EP 210 DI 10.1037/a0036852 PG 13 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800011 PM 25730725 ER PT J AU Rabin, B Glasgow, RE AF Rabin, Borsika Glasgow, Russell E. TI An Implementation Science Perspective on Psychological Science and Cancer What Is Known and Opportunities for Research, Policy, and Practice SO AMERICAN PSYCHOLOGIST LA English DT Article DE implementation; cancer; review; recommendations; psychological science ID PUBLIC-HEALTH; QUALITY-IMPROVEMENT; PRECISION MEDICINE; DIFFUSION-THEORY; TRANSLATION; CARE; DISSEMINATION; INTERVENTIONS; KNOWLEDGE; FUTURE AB We discuss the role of implementation science in cancer and summarize the need for this perspective. Following a summary of key implementation science principles and lessons learned, we review the literature on implementation of cancer prevention and control activities across the continuum from prevention to palliative care. We identified 10 unique relevant reviews, four of which were specific to cancer. Multicomponent implementation strategies were found to be superior to single-component interventions, but it was not possible to draw conclusions about specific strategies or the range of conditions across which strategies were effective. Particular gaps identified include the need for more studies of health policies and reports of cost, cost-effectiveness, and resources required. Following this review, we summarize the types of evidence needed to make research findings more actionable and discuss emerging implementation science opportunities for psychological research on cancer prevention and control. These include innovative study designs (i.e., rapid learning designs, simulation modeling, comparative effectiveness, pragmatic studies, mixed-methods research) and measurement science (i.e., development of context-relevant measures; practical, longitudinal measures to gauge improvement; cost-effectiveness data; and harmonized patient report data). We conclude by identifying a few grand challenges for psychologists that if successfully addressed would accelerate integration of evidence into cancer practice and policy more consistently and rapidly. C1 [Rabin, Borsika] Kaiser Permanente Colorado, CRN Canc Commun Res Ctr, Inst Hlth Res, Denver, CO USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Aurora, CO 80045 USA. RP Glasgow, RE (reprint author), Univ Colorado, Sch Med, Colorado Hlth Outcomes Program, 13199 East Montview Blvd,Suite 300,Mail Stop F443, Aurora, CO 80045 USA. EM russell.glasgow@ucdenver.edu FU National Cancer Institute Centers of Excellence in Cancer Communication Research [P20CA137219] FX Funding for the preparation of this manuscript was partially provided through the National Cancer Institute Centers of Excellence in Cancer Communication Research (Award P20CA137219). The opinions expressed in this article are those of the authors and do not necessarily represent those of the National Cancer Institute. NR 71 TC 2 Z9 2 U1 0 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 211 EP 220 DI 10.1037/a0036107 PG 10 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800012 PM 25730726 ER PT J AU Croyle, RT AF Croyle, Robert T. TI Risks and Opportunities for Psychology's Contribution to the War on Cancer SO AMERICAN PSYCHOLOGIST LA English DT Article DE cancer ID RECOMMENDATIONS AB This special issue of American Psychologist reviews a broad, diverse, and growing research literature that has established the discipline as an essential source of evidence concerning cancer prevention and control. Nevertheless, the history of psychological science that is intended to inform cancer control suggests a number of risks going forward that could attenuate the impact of this work. Fortunately, the field also faces new opportunities to contribute more substantially, especially if psychologists engage the broader biomedical and public health communities through rigorous, relevant, multilevel research that is informed by current knowledge of the disease and its treatment, the skills required to participate in large-scale transdisciplinary team science, and an appreciation of the economic, organizational, and policy context of cancer control at the local and national levels. C1 [Croyle, Robert T.] NCI, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM croyler@mail.nih.gov NR 17 TC 2 Z9 2 U1 1 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X EI 1935-990X J9 AM PSYCHOL JI Am. Psychol. PD FEB-MAR PY 2015 VL 70 IS 2 SI SI BP 221 EP 224 DI 10.1037/a0038869 PG 4 WC Psychology, Multidisciplinary SC Psychology GA CC7OE UT WOS:000350556800013 PM 25730727 ER PT J AU Ravenscroft, G Laing, NG Bonnemann, CG AF Ravenscroft, Gianina Laing, Nigel G. Boennemann, Carsten G. TI Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus SO BRAIN LA English DT Review DE congenital myopathy; pathophysiology; mitochondria; membrane remodelling; force generation; atrophy; autophagy; triad; excitation-contraction coupling ID MYOSIN HEAVY-CHAIN; ENZYME REPLACEMENT THERAPY; DUCHENNE MUSCULAR-DYSTROPHY; FIBER-TYPE DISPROPORTION; SKELETAL-MUSCLE ACTIN; RECESSIVE NEMALINE MYOPATHY; CAUSE DISTAL ARTHROGRYPOSIS; LINKED MYOTUBULAR MYOPATHY; BETA-TROPOMYOSIN MUTATION; DOMINANT ACTA1 DISEASE AB The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. C1 [Ravenscroft, Gianina; Laing, Nigel G.] Univ Western Australia, Harry Perkins Inst Med Res, Med Res Ctr, Nedlands, WA 6009, Australia. [Boennemann, Carsten G.] NINDS, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Bonnemann, CG (reprint author), NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35,Room 2A-116, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov FU National Health and Medical Research Council of Australia (NHRMC) Early Career Researcher Fellowship [APP1035955]; NHMRC Research Fellowship [APP1002147]; NINDS/NIH FX G.R. is supported by a National Health and Medical Research Council of Australia (NHRMC) Early Career Researcher Fellowship (APP1035955) and N.G.L. by a NHMRC Research Fellowship (APP1002147). C.G.B. is supported by intramural funds of NINDS/NIH. NR 212 TC 13 Z9 14 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD FEB 1 PY 2015 VL 138 BP 246 EP 268 DI 10.1093/brain/awu368 PN 2 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CC2YA UT WOS:000350209900016 PM 25552303 ER PT J AU Zeuner, KE Knutzen, A Granert, O Gotz, J Wolff, S Jansen, O Dressler, D Hefter, H Hallett, M Deuschl, G van Eimeren, T Witt, K AF Zeuner, Kirsten E. Knutzen, Arne Granert, Oliver Goetz, Julia Wolff, Stephan Jansen, Olav Dressler, Dirk Hefter, Harald Hallett, Mark Deuschl, Guenther van Eimeren, Thilo Witt, Karsten TI Increased volume and impaired function: the role of the basal ganglia in writer's cramp SO BRAIN AND BEHAVIOR LA English DT Article DE Focal hand dystonia; functional magnetic resonance imaging; motor learning; voxel-based morphometry; writer's cramp ID FOCAL HAND DYSTONIA; VOXEL-BASED MORPHOMETRY; PRIMARY MOTOR CORTEX; GRAY-MATTER CHANGES; EVENT-RELATED FMRI; FINGER MOVEMENTS; CEREBELLAR ACTIVATION; CERVICAL DYSTONIA; TASK COMPLEXITY; BRAIN AB IntroductionThe pathophysiology of writer's cramp, a task-specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients. MethodsWe applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI. With the asymptomatic left hand all participants learned a complex, sequential, five-element sequence-tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30sec) and rest (30sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel-based morphometry (VBM). ResultsWhile behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level-dependent (BOLD) activity in patients during the sequential finger-tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum. ConclusionThe results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait. C1 [Zeuner, Kirsten E.; Knutzen, Arne; Granert, Oliver; Goetz, Julia; Deuschl, Guenther; van Eimeren, Thilo; Witt, Karsten] Univ Kiel, Dept Neurol, D-24105 Kiel, Germany. [Wolff, Stephan; Jansen, Olav] Univ Kiel, Dept Neuroradiol, D-24105 Kiel, Germany. [Dressler, Dirk] Hannover Med Sch, Dept Neurol, Movement Disorders Sect, Hannover, Germany. [Hefter, Harald] Univ Dusseldorf, Dept Neurol, Dusseldorf, Germany. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zeuner, KE (reprint author), Univ Kiel, Dept Neurol, Arnold Heller Str 3,Haus 41, D-24105 Kiel, Germany. EM k.zeuner@neurologie.uni-kiel.de RI Deuschl, Gunther/A-7986-2010 FU Christian Albrechts-University of Kiel FX We are indebted to the patients and normal volunteers for participating in this study. This study has been supported by an intramural grant from the Christian Albrechts-University of Kiel. NR 77 TC 3 Z9 3 U1 1 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD FEB PY 2015 VL 5 IS 2 AR e00301 DI 10.1002/brb3.301 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CC3OZ UT WOS:000350260100003 PM 25642386 ER PT J AU Parameswaran, B Chiang, HC Lu, YZ Coates, J Deng, CX Baer, R Lin, HK Li, R Paull, TT Hu, YF AF Parameswaran, Balaji Chiang, Huai-Chin Lu, Yunzhe Coates, Julia Deng, Chu-Xia Baer, Richard Lin, Hui-Kuan Li, Rong Paull, Tanya T. Hu, Yanfen TI Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection SO CELL CYCLE LA English DT Article DE BRCA1; cell cycle; DNA double-strand break repair; end-resection; SCF ID STRAND-BREAK REPAIR; DNA-DAMAGE; CELL-CYCLE; HOMOLOGOUS RECOMBINATION; DEPENDENT PHOSPHORYLATION; GENOMIC STABILITY; COMPLEX-FORMATION; TUMOR-SUPPRESSOR; CTIP; CANCER AB The BRCA1 tumor suppressor plays an important role in homologous recombination (HR)-mediated DNA double-strand-break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinase upon gamma-irradiation, but the role of Chk2 phosphorylation is not understood. Here, we report that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and the dispersion of BRCA1 from DSBs but does not affect the assembly of Mre11/Rad50/NBS1 (MRN) and CtIP at DSBs. Moreover, we show that BRCA1 is ubiquitinated by SCFSkp2 and that abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggests that BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, but that Chk2 phosphorylation of BRCA1 also serves as a built-in clock for HR repair of DSBs. BRCA1 is known to inhibit Mre11 nuclease activity. SCFSkp2 activity appears at late G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removal of BRCA1 from DSBs by SCFSkp2-mediated degradation terminates BRCA1-mediated inhibition of Mre11 nuclease activity, allowing for end resection and restricting the initiation of HR to the S/G2 phases of the cell cycle. C1 [Parameswaran, Balaji; Chiang, Huai-Chin; Lu, Yunzhe; Li, Rong; Hu, Yanfen] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Coates, Julia] Wellcome Trust Res Labs, Cambridge, England. [Coates, Julia] Canc Res UK Gurdon Inst, Cambridge, England. [Coates, Julia] Univ Cambridge, Dept Zool, Cambridge, England. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Baer, Richard] Columbia Univ, Dept Pathol, Inst Canc Genet, New York, NY USA. [Lin, Hui-Kuan] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Paull, Tanya T.] Univ Texas Austin, Dept Mol Genet & Microbiol, Austin, TX 78712 USA. RP Hu, YF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. EM huy3@uthscsa.edu RI deng, chuxia/N-6713-2016; OI Parameswaran, Balaji/0000-0002-1665-4872 FU National Institutes of Health [R01CA118578]; cancer center support grant [P30CA054174] FX The study was supported by National Institutes of Health Grant (to YH) R01CA118578 and the cancer center support grant P30CA054174. NR 51 TC 4 Z9 6 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD FEB 1 PY 2015 VL 14 IS 3 BP 437 EP 448 DI 10.4161/15384101.2014.972901 PG 12 WC Cell Biology SC Cell Biology GA CC1WW UT WOS:000350137100022 PM 25659039 ER PT J AU Morozko, EL Nishio, A Ingham, NJ Chandra, R Fitzgerald, T Martelletti, E Borck, G Wilson, E Riordan, GP Wangemann, P Forge, A Steel, KP Liddle, RA Friedman, TB Belyantseva, IA AF Morozko, Eva L. Nishio, Ayako Ingham, Neil J. Chandra, Rashmi Fitzgerald, Tracy Martelletti, Elisa Borck, Guntram Wilson, Elizabeth Riordan, Gavin P. Wangemann, Philine Forge, Andrew Steel, Karen P. Liddle, Rodger A. Friedman, Thomas B. Belyantseva, Inna A. TI ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME MOUSE MODEL; INDUCED HEARING-LOSS; STRIA VASCULARIS; KNOCKOUT MICE; GUINEA-PIG; INTERCELLULAR-JUNCTIONS; FREEZE-FRACTURE; GENOME-WIDE; PROTEIN; BARRIER AB In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human non-syndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulinto tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs. C1 [Morozko, Eva L.; Wilson, Elizabeth; Riordan, Gavin P.; Friedman, Thomas B.; Belyantseva, Inna A.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20892 USA. [Nishio, Ayako] Natl Inst Deafness & Other Commun Disorders, Mol Biol & Genet Sect, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20892 USA. [Fitzgerald, Tracy] Natl Inst Deafness & Other Commun Disorders, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20892 USA. [Ingham, Neil J.; Martelletti, Elisa; Steel, Karen P.] Kings Coll London, Wolfson Ctr Age Related Dis, London SE1 1UL, England. [Chandra, Rashmi; Liddle, Rodger A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Borck, Guntram] Univ Ulm, Inst Human Genet, D-89081 Ulm, Germany. [Wangemann, Philine] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Forge, Andrew] UCL, Ctr Auditory Res, London WC1X 8EE, England. RP Belyantseva, IA (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, John Edward Porter Neurosci Res Ctr, 35A Convent Dr,Room 1F 141, Bethesda, MD 20892 USA. EM belyants@nidcd.nih.gov RI Borck, Guntram/F-1868-2015 FU Wellcome Trust [WT100669MA]; Medical Research Council; Rosetrees Trust; National Institutes of Health [DK098796, DK091946, NIH-R01-DC012151]; National Institute on Deafness and Other Communication Disorders Intramural Research Program [DC000060-14, DC000039-18]; NIDCD/NIH FX This work was supported in part by the Wellcome Trust (WT100669MA to K.P.S.), the Medical Research Council (to K.P.S.) and the Rosetrees Trust (A.F.). This work was supported by National Institutes of Health (DK098796 and DK091946 to R.A.L., NIH-R01-DC012151 to P.W.) and the National Institute on Deafness and Other Communication Disorders Intramural Research Program (DC000060-14 to A.N. and DC000039-18 to T.B.F.). Funding to pay the Open Access publication charges for this article was provided by the NIDCD/NIH from T.B.F.'s budget. NR 62 TC 6 Z9 6 U1 1 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 FEB 1 PY 2015 VL 24 IS 3 BP 609 EP 624 DI 10.1093/hmg/ddu474 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CC1XE UT WOS:000350137900002 PM 25217574 ER PT J AU Ilyushina, NA Haynes, BC Hoen, AG Khalenkov, AM Housman, ML Brown, EP Ackerman, ME Treanor, JJ Luke, CJ Subbarao, K Wright, PF AF Ilyushina, Natalia A. Haynes, Brenda C. Hoen, Anne G. Khalenkov, Alexey M. Housman, Molly L. Brown, Eric P. Ackerman, Margaret E. Treanor, John J. Luke, Catherine J. Subbarao, Kanta Wright, Peter F. TI Live Attenuated and Inactivated Influenza Vaccines in Children SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE influenza; vaccines; children ID WILD-TYPE VIRUS; YOUNG-CHILDREN; RESPIRATORY-TRACT; RELATIVE EFFICACY; TRIVALENT; COLD; ADULTS; RESISTANCE; CHALLENGE; INFECTION AB Background. Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. Methods. Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08). Results. Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)-numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. Conclusions. LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis. C1 [Ilyushina, Natalia A.; Haynes, Brenda C.; Khalenkov, Alexey M.; Wright, Peter F.] Geisel Sch Med Dartmouth, Dept Pediat, Lebanon, NH 03756 USA. [Hoen, Anne G.] Geisel Sch Med Dartmouth, Dept Commun & Family Med, Lebanon, NH 03756 USA. [Housman, Molly L.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Lebanon, NH 03756 USA. [Brown, Eric P.; Ackerman, Margaret E.] Thayer Sch Engn Dartmouth, Hanover, NH USA. [Treanor, John J.] Univ Rochester, Dept Med, Med Ctr, New York, NY USA. [Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wright, PF (reprint author), Geisel Sch Med Dartmouth, Dept Pediat, 1 Med Ctr Dr,Borwell 330 W, Lebanon, NH 03756 USA. EM peter.f.wright@hitchcock.org OI Brown, Eric/0000-0002-8438-6136 FU Division of Intramural Research of the NIAID, National Institutes of Health [HHSN272200900026C]; American Recovery and Reinvestment Act; Bill & Melinda Gates Foundation [OPP1032817] FX This work was supported by the Division of Intramural Research of the NIAID, National Institutes of Health (contract number HHSN272200900026C); American Recovery and Reinvestment Act funding (to P. F. W.); and the Bill & Melinda Gates Foundation (grant number OPP1032817 to M. E. A.). NR 21 TC 9 Z9 9 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 FEB 1 PY 2015 VL 211 IS 3 BP 352 EP 360 DI 10.1093/infdis/jiu458 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CG UT WOS:000350221500004 PM 25165161 ER PT J AU Brickley, EB Wood, AM Kabyemela, E Morrison, R Kurtis, JD Fried, M Duffy, PE AF Brickley, Elizabeth B. Wood, Angela M. Kabyemela, Edward Morrison, Robert Kurtis, Jonathan D. Fried, Michal Duffy, Patrick E. TI Fetal Origins of Malarial Disease: Cord Blood Cytokines as Risk Markers for Pediatric Severe Malarial Anemia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE malaria; anemia; cord blood; inflammation; cytokines; developmental programming; risk marker ID PLASMODIUM-FALCIPARUM MALARIA; SUSCEPTIBILITY; RESPONSES; CHILDREN; INTERLEUKIN-10; ERYTHROCYTES; EPIDEMIOLOGY; METAANALYSIS; COINFECTION; EXPRESSION AB Background. Severe malarial anemia (SMA) remains a major cause of pediatric illness and mortality in Sub-Saharan Africa. Here we test the hypothesis that prenatal exposures, reflected by soluble inflammatory mediators in cord blood, can condition an individual's susceptibility to SMA. Methods. In a Tanzanian birth cohort (n = 743), we measured cord blood concentrations of tumor necrosis factor (TNF), TNF receptors I and II (TNF-RI and TNF-RII), interleukin (IL)-1 beta, IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFN-gamma). After adjusting for conventional covariates, we calculated the hazard ratios (HR) for time to first SMA event with log(e) cytokine concentrations dichotomized at the median, by quartile, and per standard deviation (SD) increase. Results. Low levels of TNF, TNF-RI, IL-1 beta, and IL-5 and high levels of TNF-RII were associated statistically significantly and respectively with approximately 3-fold, 2-fold, 8-fold, 4-fold, and 3-fold increased risks of SMA (Hb < 50 g/L). TNF, TNF-RI, and IL-1 beta concentrations were inversely and log-linearly associated with SMA risk; the HR (95% confidence interval [CI]) per 1-SD increase were respectively 0.81 (.65, 1.02), 0.76 (.62, .92), and 0.50 (.40, .62). Conclusions. These data suggest that proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins. C1 [Brickley, Elizabeth B.; Morrison, Robert; Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Brickley, Elizabeth B.; Wood, Angela M.] Univ Cambridge, Strangeways Res Labs, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Kabyemela, Edward; Morrison, Robert] Seattle Biomed Res Inst, MOMS Project, Washington, DC USA. [Kabyemela, Edward] Muheza Designated Dist Hosp, Muheza, Tanzania. [Kurtis, Jonathan D.] Brown Univ, Dept Pathol & Lab Med, Rhode Isl Hosp, Sch Med, Providence, RI 02912 USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Room 1111,5640 Fishers Ln, Rockville, MD 20852 USA. EM patrick.duffy@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Bill & Melinda Gates Foundation [29202]; Foundation for NIH through the Grand Challenges in Global Health Initiative [1364]; National Institutes of Health Fogarty International Center [D43 TW005509]; National Institutes of Health [R01 AI52059] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Bill & Melinda Gates Foundation [grant number 29202], the Foundation for the NIH through the Grand Challenges in Global Health Initiative [grant 1364], the National Institutes of Health Fogarty International Center [grant D43 TW005509], and the National Institutes of Health [grant R01 AI52059], all grants to P. E. D. NR 32 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 FEB 1 PY 2015 VL 211 IS 3 BP 436 EP 444 DI 10.1093/infdis/jiu454 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CG UT WOS:000350221500013 PM 25139023 ER PT J AU Chen, Y Yeh, AJ Cheung, GYC Villaruz, AE Tan, VY Joo, HS Chatterjee, SS Yu, YS Otto, M AF Chen, Yan Yeh, Anthony J. Cheung, Gordon Y. C. Villaruz, Amer E. Tan, Vee Y. Joo, Hwang-Soo Chatterjee, Som S. Yu, Yunsong Otto, Michael TI Basis of Virulence in a Panton-Valentine Leukocidin-Negative Community-Associated Methicillin-Resistant Staphylococcus aureus Strain SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE alpha-toxin; community-associated infection; methicillin-resistant Staphylococcus aureus; Panton-Valentine leukocidin; phenol-soluble modulins ID PHENOL-SOLUBLE MODULINS; ALPHA-TOXIN; INFECTIONS; NEUTROPHILS; MRSA; AGR; IDENTIFICATION; DETERMINANTS; PATHOGENESIS; EXPRESSION AB Community-associated (CA) infections with methicillin-resistant Staphylococcus aureus (MRSA) are on a global rise. However, analysis of virulence characteristics has been limited almost exclusively to the US endemic strain USA300. CA-MRSA strains that do not produce Panton-Valentine leukocidin (PVL) have not been investigated on a molecular level. Therefore, we analyzed virulence determinants in a PVL-negative CA-MRSA strain, ST72, from Korea. Genome-wide analysis identified 3 loci that are unique to that strain, but did not affect virulence. In contrast, phenol-soluble modulins (PSMs) and the global virulence regulator Agr strongly affected lysis of neutrophils and erythrocytes, while alpha-toxin and Agr had a major impact on in vivo virulence. Our findings substantiate the general key roles these factors play in CA-MRSA virulence. However, our analyses also showed noticeable differences to strain USA300, inasmuch as alpha-toxin emerged as a much more important factor than PSMs in experimental skin infection caused by ST72. C1 [Chen, Yan; Yeh, Anthony J.; Cheung, Gordon Y. C.; Villaruz, Amer E.; Tan, Vee Y.; Joo, Hwang-Soo; Chatterjee, Som S.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Chen, Yan; Yu, Yunsong] Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Dept Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, Bldg 33,1W10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Chen, Yan/0000-0002-7679-1713; Otto, Michael/0000-0002-2222-4115; JOO, HWANG-SOO/0000-0003-4668-3225 FU National Institute of Allergy and Infectious Diseases [ZIA AI000904- 12]; China Scholarship Council FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (ZIA AI000904- 12 to M. O.) and the China Scholarship Council (to Y. C.). The authors thank Yuanjun Zhu for help with neutrophil isolation. NR 45 TC 6 Z9 6 U1 0 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 FEB 1 PY 2015 VL 211 IS 3 BP 472 EP 480 DI 10.1093/infdis/jiu462 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CG UT WOS:000350221500017 PM 25139021 ER PT J AU Luna, B Kubler, A Larsson, C Foster, B Bagci, U Mollura, DJ Jain, SK Bishai, WR AF Luna, Brian Kubler, Andre Larsson, Christer Foster, Brent Bagci, Ulas Mollura, Daniel J. Jain, Sanjay K. Bishai, William R. TI In Vivo Prediction of Tuberculosis-Associated Cavity Formation in Rabbits SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE CT; [F-18]-FDG; PET; tuberculosis ID MYCOBACTERIUM-TUBERCULOSIS AB The presence of cavitary lesions in patients with tuberculosis poses a significant clinical concern due to the risk of infectivity and the risk of antibiotic treatment failure. We describe 2 algorithms that use noninvasive positron emission tomography (PET) and computed tomography (CT) to predict the development of cavitary lesions in rabbits. Analysis of the PET region of interest predicted cavitary disease with 100% sensitivity and 76% specificity, and analysis of the CT region of interest predicted cavitary disease with 83.3% sensitivity and 76.9% specificity. Our results show that restricting our analysis to regions with high [F-18]-fluorodeoxyglucose uptake provided the best combination of sensitivity and specificity. C1 [Luna, Brian; Kubler, Andre; Larsson, Christer; Jain, Sanjay K.; Bishai, William R.] Johns Hopkins Univ, Sch Med, Johns Hopkins Ctr TB Res, Baltimore, MD USA. [Jain, Sanjay K.; Bishai, William R.] Johns Hopkins Univ, Sch Med, Ctr Infect & Inflammat Imaging Res, Baltimore, MD USA. [Jain, Sanjay K.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Foster, Brent; Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kubler, Andre] Univ London Imperial Coll Sci Technol & Med, Dept Med, London SW7 2AZ, England. RP Bishai, WR (reprint author), Johns Hopkins Sch Med, Johns Hopkins Ctr TB Res, 1550 Orleans,CRB2 St,Ste 103, Baltimore, MD 21231 USA. EM wbishai@jhmi.edu OI Larsson, Christer/0000-0002-5714-924X; Bagci, Ulas/0000-0001-7379-6829; Luna, PhD, Brian/0000-0001-6718-4551 FU Swedish Research Council; Swedish Society for Medical Research; National Institute of Allergy and Infectious Diseases [RO1AI079590]; National Institutes of Health [RO1A1035272]; Howard Hughes Medical Institute FX This work was supported by the Swedish Research Council, the Swedish Society for Medical Research, the National Institute of Allergy and Infectious Diseases (grant RO1AI079590), the National Institutes of Health (grant RO1A1035272), and the Howard Hughes Medical Institute. NR 15 TC 2 Z9 2 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 FEB 1 PY 2015 VL 211 IS 3 BP 481 EP 485 DI 10.1093/infdis/jiu449 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CC3CG UT WOS:000350221500018 PM 25117755 ER PT J AU Barnhill, A Miller, FG AF Barnhill, Anne Miller, Franklin G. TI Placebo and Deception: A Commentary SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Article DE deception; ethics; manipulation; placebo treatment ID CLINICAL-PRACTICE; ETHICS AB In a recent article in this Journal, Shlomo Cohen and Haim Shapiro (2013) introduce the concept of "comparable placebo treatments" (CPTs)-placebo treatments with biological effects similar to the drugs they replace-and argue that doctors are not being deceptive when they prescribe or administer CPTs without revealing that they are placebos. We critique two of Cohen and Shapiro's primary arguments. First, Cohen and Shapiro argue that offering undisclosed placebos is not lying to the patient, but rather is making a self-fulfilling prophecy-telling a "lie" that, ideally, will become true. We argue that offering undisclosed placebos is not a "lie" but is a straightforward case of deceptively misleading the patient. Second, Cohen and Shapiro argue that offering undisclosed CPTs is not equivocation. We argue that it typically is equivocation or deception of another sort. If justifiable, undisclosed placebo use will have to be justified as a practice that is deceptive in most instances. C1 [Barnhill, Anne] Univ Penn, Philadelphia, PA 19104 USA. [Miller, Franklin G.] NIH, Bethesda, MD 20892 USA. RP Barnhill, A (reprint author), Univ Penn, Dept Med Eth & Hlth Policy, 3401 Market St,Suite 320, Philadelphia, PA 19104 USA. EM anne.barnhill@gmail.com NR 15 TC 4 Z9 4 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 FEB PY 2015 VL 40 IS 1 BP 69 EP 82 DI 10.1093/jmp/jhu043 PG 14 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA CC3FK UT WOS:000350231500005 PM 25503605 ER PT J AU Zhang, F Xu, LY Xu, LX Xu, Q Li, DS Yang, YZ Karsenty, G Chen, CD AF Zhang, Feng Xu, Longyong Xu, Longxia Xu, Qing Li, Dangsheng Yang, Yingzi Karsenty, Gerard Chen, Charlie Degui TI JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice SO JOURNAL OF MOLECULAR CELL BIOLOGY LA English DT Article DE JMJD3; RUNX2; chondrocyte; endochondral bone formation ID EMBRYONIC STEM-CELLS; HISTONE LYSINE METHYLATION; DEMETHYLASE JMJD3; H3K27 DEMETHYLASE; GENE-EXPRESSION; METHYLTRANSFERASE ACTIVITY; DEVELOPMENTAL REGULATORS; CBFA1-DEFICIENT MICE; INDIAN-HEDGEHOG; GROWTH PLATES AB JMJD3 (KDM6B) is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression. However, the function of JMJD3 in vivo is not well understood. Here we show that JMJD3 is highly expressed in cells of the chondrocyte lineage, especially in prehypertrophic and hypertrophic chondrocytes, during endochondral ossification. Homozygous deletion of Jmjd3 results in severely decreased proliferation and delayed hypertrophy of chondrocytes, and thereby marked retardation of endochondral ossification in mice. Genetically, JMJD3 associates with RUNX2 to promote proliferation and hypertrophy of chondrocytes. Biochemically, JMJD3 associates with and enhances RUNX2 activity by derepression of Runx2 and Ihh transcription through its H3K27me3 demethylase activity. These results demonstrate that JMJD3 is a key epigenetic regulator in the process of cartilage maturation during endochondral bone formation. C1 [Zhang, Feng; Xu, Longyong; Xu, Longxia; Xu, Qing; Chen, Charlie Degui] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol,Shanghai Key Lab Mol Andro, Shanghai 200031, Peoples R China. [Zhang, Feng] Fourth Mil Med Univ, Xijing Hosp, Dept Pathol, State Key Lab Canc Biol, Xian 710032, Shaanxi, Peoples R China. [Li, Dangsheng] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Informat Ctr Life Sci, Shanghai 200031, Peoples R China. [Yang, Yingzi] NHGRI, NIH, Bethesda, MD 20892 USA. [Karsenty, Gerard] Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA. RP Chen, CD (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol,Shanghai Key Lab Mol Andro, Shanghai 200031, Peoples R China. EM cdchen@sibcb.ac.cn FU National Natural Science Foundation of China [91219304]; National Basic Research Program of China [2010CB529705, 2011CB510103, 2014CB943100]; Council of Shanghai Municipal Government for Science and Technology FX This work was supported by the National Natural Science Foundation of China (91219304), National Basic Research Program of China (2010CB529705, 2011CB510103, 2014CB943100), and the Council of Shanghai Municipal Government for Science and Technology. NR 52 TC 10 Z9 12 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1674-2788 EI 1759-4685 J9 J MOL CELL BIOL JI J. Mol. Cell Biol. PD FEB PY 2015 VL 7 IS 1 BP 23 EP 34 DI 10.1093/jmcb/mjv003 PG 12 WC Cell Biology SC Cell Biology GA CC3EO UT WOS:000350228600004 PM 25587042 ER PT J AU Ma, J Pawar, RS Grundel, E Mazzola, EP Ridge, CD Masaoka, T Le Grice, SFJ Wilson, J Beutler, JA Krynitsky, AJ AF Ma, Jun Pawar, Rahul S. Grundel, Erich Mazzola, Eugene P. Ridge, Clark D. Masaoka, Takashi Le Grice, Stuart F. J. Wilson, Jennifer Beutler, John A. Krynitsky, Alexander J. TI Sesquiterpenoid Tropolone Glycosides from Liriosma ovata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID RIBONUCLEASE-H ACTIVITY; DULACIA-GUIANENSIS; MANICOL; ASSAY AB Two new sesquiterpenoid tropolone glycosides, liriosmasides A (1) and B (2), along with two known compounds, secoxyloganin and oplopanpheside C, were isolated from a methanol extract of the roots of Liriosma ovata. The structures of 1 and 2 were elucidated by spectroscopic methods including 1D and 2D NMR and by high-resolution mass spectrometry involving an ultra-high-performance liquid chromatography-quadrupole-orbital ion trap mass spectrometric (UHPLC-Q-Orbitrap MS) method. Compound 1 showed weak inhibitory activity against HIV RNase H. C1 [Ma, Jun; Pawar, Rahul S.; Grundel, Erich; Mazzola, Eugene P.; Ridge, Clark D.; Krynitsky, Alexander J.] US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, College Pk, MD 20740 USA. [Masaoka, Takashi; Le Grice, Stuart F. J.] Natl Canc Inst, HIV Drug Resistance Program, RT Biochem Sect, Frederick, MD 21702 USA. [Wilson, Jennifer; Beutler, John A.] Natl Canc Inst, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21702 USA. RP Ma, J (reprint author), US FDA, Ctr Food Safety & Appl Nutr, Off Regulatory Sci, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM jun.ma@fda.hhs.gov NR 17 TC 1 Z9 1 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2015 VL 78 IS 2 BP 315 EP 319 DI 10.1021/np5006696 PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA CC4MX UT WOS:000350328600021 PM 25587934 ER PT J AU Wu, F Ourmanov, I Riddick, N Matsuda, K Whitted, S Plishka, RJ Buckler-White, A Starost, MF Hirsch, VM AF Wu, Fan Ourmanov, Ilnour Riddick, Nadeene Matsuda, Kenta Whitted, Sonya Plishka, Ronald J. Buckler-White, Alicia Starost, Matthew F. Hirsch, Vanessa M. TI TRIM5 alpha Restriction Affects Clinical Outcome and Disease Progression in Simian Immunodeficiency Virus-Infected Rhesus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID ZINC-FINGER NUCLEASES; HIV-1 INFECTION; ANTIRETROVIRAL THERAPY; IN-VITRO; T-CELLS; RESISTANCE; TRIM5; GENE; NEUTRALIZATION; POLYMORPHISMS AB Tripartite motif-containing protein 5 alpha (TRIM5 alpha) is considered to be a potential target for cell-based gene modification therapy against human immunodeficiency virus type 1 (HIV-1) infection. In the present study, we used a relevant rhesus macaque model of infection with simian immunodeficiency virus from sooty mangabey (SIVsm) to evaluate the effect of TRIM5 alpha restriction on clinical outcome. For macaques expressing a restrictive TRIM5 genotype, the disease outcomes of those infected with the wildtype TRIM-sensitive SIVsm strain and those infected with a virus with escape mutations in the capsid were compared. We found that TRIM5 alpha restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, supporting the feasibility of exploiting TRIM5 alpha as a target for gene therapy against HIV-1. Furthermore, we also found that preservation of memory CD4T cells was associated with protection by TRIM5 alpha restriction, suggesting memory CD4 T cells or their progenitor cells as an ideal target for gene modification. Despite the significant effect of TRIM5 alpha restriction on survival, SIV escape from TRIM5 alpha restriction was also observed; therefore, this may not be an effective stand-alone strategy and may require combination with other targets. IMPORTANCE Recent studies suggest that it may be feasible not only to suppress viral replication with antiviral drugs but also potentially to eliminate or "cure" human immunodeficiency virus (HIV) infection. One approach being explored is the use of gene therapy to introduce genes that can restrict HIV replication, including a restrictive version of the host factor TRIM5 alpha. TRIM5 was identified as a factor that restricts HIV replication in macaque cells. The rhesus gene is polymorphic, and some alleles are restrictive for primary SIVsm isolates, although escape mutations arise late in infection. Introduction of these escape mutations into the parental virus conferred resistance to TRIM5 on macaques. The present study evaluated these animals for long-term outcomes and found that TRIM5 alpha restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, suggesting that this could be a valid gene therapy approach that could be adapted for HIV. C1 [Wu, Fan; Ourmanov, Ilnour; Riddick, Nadeene; Matsuda, Kenta; Whitted, Sonya; Plishka, Ronald J.; Buckler-White, Alicia; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, Div Vet Resources, OD, ORS, Bethesda, MD 20892 USA. RP Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov FU federal funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported with federal funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 5 Z9 5 U1 0 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 FEB PY 2015 VL 89 IS 4 BP 2233 EP 2240 DI 10.1128/JVI.02978-14 PG 8 WC Virology SC Virology GA AZ9UT UT WOS:000348562800027 PM 25473059 ER PT J AU Carroll, JA Striebel, JF Race, B Phillips, K Chesebro, B AF Carroll, James A. Striebel, James F. Race, Brent Phillips, Katie Chesebro, Bruce TI Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction SO JOURNAL OF VIROLOGY LA English DT Article ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; ACUTE-PHASE RESPONSE; INTERLEUKIN-1 RECEPTOR ANTAGONIST; CREUTZFELDT-JAKOB-DISEASE; INTERFERON-GAMMA; NERVOUS-SYSTEM; CELL-DEATH; SPONGIFORM ENCEPHALOPATHIES; TRANSCRIPTIONAL ACTIVATION AB Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre- and post-clinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1 alpha, phosphorylated-STAT1 alpha (pSTAT1 alpha), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL-1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCE Prion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie-infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed. C1 [Carroll, James A.; Striebel, James F.; Race, Brent; Phillips, Katie; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Carroll, JA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM carrollja2@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 95 TC 4 Z9 4 U1 0 U2 3 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 FEB PY 2015 VL 89 IS 4 BP 2388 EP 2404 DI 10.1128/JVI.02952-14 PG 17 WC Virology SC Virology GA AZ9UT UT WOS:000348562800040 PM 25505076 ER PT J AU Evans, CM Raclawska, DS Ttofali, F Liptzin, DR Fletcher, AA Harper, DN McGing, MA McElwee, MM Williams, OW Sanchez, E Roy, MG Kindrachuk, KN Wynn, TA Eltzschig, HK Blackburn, MR Tuvim, MJ Janssen, WJ Schwartz, DA Dickey, BF AF Evans, Christopher M. Raclawska, Dorota S. Ttofali, Fani Liptzin, Deborah R. Fletcher, Ashley A. Harper, Daniel N. McGing, Maggie A. McElwee, Melissa M. Williams, Olatunji W. Sanchez, Elizabeth Roy, Michelle G. Kindrachuk, Kristen N. Wynn, Thomas A. Eltzschig, Holger K. Blackburn, Michael R. Tuvim, Michael J. Janssen, William J. Schwartz, David A. Dickey, Burton F. TI The polymeric mucin Muc5ac is required for allergic airway hyperreactivity SO NATURE COMMUNICATIONS LA English DT Article ID GOBLET CELL HYPERPLASIA; GROWTH-FACTOR RECEPTOR; SMOOTH-MUSCLE; N-ACETYLCYSTEINE; MUCOCILIARY CLEARANCE; MUCOUS METAPLASIA; MUCUS PRODUCTION; CYSTIC-FIBROSIS; CHALLENGED MICE; ACUTE ASTHMA AB In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced. C1 [Evans, Christopher M.; Raclawska, Dorota S.; Ttofali, Fani; Fletcher, Ashley A.; Harper, Daniel N.; McGing, Maggie A.; Janssen, William J.; Schwartz, David A.] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Liptzin, Deborah R.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [McElwee, Melissa M.; Sanchez, Elizabeth; Roy, Michelle G.; Tuvim, Michael J.; Dickey, Burton F.] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA. [Williams, Olatunji W.] Peyton Manning Childrens Hosp, Pediat, Indianapolis, IN 46260 USA. [Kindrachuk, Kristen N.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Program Barrier Immun & Repair, Bethesda, MD 20892 USA. [Eltzschig, Holger K.] Univ Colorado, Sch Med, Dept Anesthesiol, Aurora, CO 80045 USA. [Blackburn, Michael R.] Univ Texas Houston, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Janssen, William J.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. RP Evans, CM (reprint author), Univ Colorado, Sch Med, Dept Med, 12700 E 19th Ave,Mailstop 8611,Res Complex 2, Aurora, CO 80045 USA. EM Christopher.Evans@ucdenver.edu OI Liptzin, Deborah/0000-0002-3667-1856; Blackburn, Michael/0000-0002-1394-9966 FU National Institutes of Health [R01HL080396, R21ES023384, R21HL120770, UH2HL123442, R01HL097000, R01HL070952, R01DK097075, R01HL092188, R01HL098294, R01HL119837, P01HL114457, R01HL109517]; American Heart Association [14GRNT19990040]; Crohn's and Colitis Foundation of America; intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health; National Institutes of Health Cancer Center [P30CA016672]; University of Colorado [P30CA046934] FX We thank G. Francis, F. Benavides and J. Parker-Thornburg for their assistance in generating mutant and congenic mice. Discussions with Dr W. M. Foster of the Duke University Medical Center were helpful in the design of our aerosol system. This work was supported by the National Institutes of Health Grants R01HL080396 and R21ES023384 (C.M.E.); R21HL120770 (D.A.S.); UH2HL123442 (C.M.E. and D.A.S.); R01HL097000 (B.F.D.); R01HL070952 (M.R.B.); R01DK097075, R01HL092188, R01HL098294 and R01HL119837 (H.K.E.); P01HL114457 (M.R.B. and H.K.E.); R01HL109517 (W.J.J.); and grants by the American Heart Association 14GRNT19990040 (C.M.E.) and the Crohn's and Colitis Foundation of America (H.K.E.). T.A.W. was supported by the intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Additional support was provided by National Institutes of Health Cancer Center Support Grants P30CA016672 (M.D. Anderson Cancer Center, including the Research Animal Support Facility-Smithville, Animal Genetics Services) and P30CA046934 (University of Colorado). NR 67 TC 26 Z9 26 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6281 DI 10.1038/ncomms7281 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC3ZH UT WOS:000350289500012 PM 25687754 ER PT J AU Gao, YD Yang, P Shen, HM Yu, H Song, XM Zhang, LY Zhang, P Cheng, HZ Xie, ZJ Hao, S Dong, F Ma, SH Ji, Q Bartlow, P Ding, YH Wang, LR Liu, HB Li, YX Cheng, H Miao, WM Yuan, WP Yuan, YZ Cheng, T Xie, XQ AF Gao, Yingdai Yang, Peng Shen, Hongmei Yu, Hui Song, Xianmin Zhang, Liyan Zhang, Peng Cheng, Haizi Xie, Zhaojun Hao, Sha Dong, Fang Ma, Shihui Ji, Qing Bartlow, Patrick Ding, Yahui Wang, Lirong Liu, Haibin Li, Yanxin Cheng, Hui Miao, Weimin Yuan, Weiping Yuan, Youzhong Cheng, Tao Xie, Xiang-Qun TI Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells SO NATURE COMMUNICATIONS LA English DT Article ID SELF-RENEWAL; PROGENITOR CELLS; MAINTENANCE; RECEPTOR; DIFFERENTIATION; RESPONSIVENESS; PROLIFERATION; REPOPULATION; QUIESCENCE; P27(KIP1) AB Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel small-molecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC. C1 [Gao, Yingdai; Zhang, Liyan; Hao, Sha; Dong, Fang; Ma, Shihui; Ji, Qing; Ding, Yahui; Li, Yanxin; Cheng, Hui; Miao, Weimin; Yuan, Weiping; Yuan, Youzhong; Cheng, Tao] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China. [Gao, Yingdai; Zhang, Liyan; Hao, Sha; Dong, Fang; Ma, Shihui; Ji, Qing; Ding, Yahui; Li, Yanxin; Cheng, Hui; Miao, Weimin; Yuan, Weiping; Yuan, Youzhong; Cheng, Tao] Chinese Acad Med Sci, Blood Dis Hosp, Ctr Stem Cell Med, Tianjin 300020, Peoples R China. [Gao, Yingdai; Zhang, Liyan; Hao, Sha; Dong, Fang; Ma, Shihui; Ji, Qing; Ding, Yahui; Li, Yanxin; Cheng, Hui; Miao, Weimin; Yuan, Weiping; Yuan, Youzhong; Cheng, Tao] Peking Union Med Coll, Tianjin 300020, Peoples R China. [Yang, Peng; Zhang, Peng; Cheng, Haizi; Xie, Zhaojun; Bartlow, Patrick; Wang, Lirong; Liu, Haibin; Xie, Xiang-Qun] Drug Discovery Inst, Dept Pharmaceut Sci, Computat Chem Genom Screening Ctr, Sch Pharm,Natl Ctr Excellence Drug Abuse Res,NIH, Pittsburgh, PA 15260 USA. [Yang, Peng; Zhang, Peng; Cheng, Haizi; Xie, Zhaojun; Bartlow, Patrick; Wang, Lirong; Liu, Haibin; Xie, Xiang-Qun] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Shen, Hongmei; Yu, Hui] Univ Pittsburgh, Sch Med, Dept Radiat Oncol, Pittsburgh, PA 15260 USA. [Shen, Hongmei; Yu, Hui] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Song, Xianmin] Secondary Mil Med Univ, Changhai Hosp, Dept Hematol, Shanghai 200433, Peoples R China. RP Cheng, T (reprint author), Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China. EM chengtao@ihcams.ac.cn; xix15@pitt.edu OI Zhang, Peng/0000-0001-5574-0899 FU National Basic Research Program of China [2011CB964800, 2012CB966600]; National Natural Science Foundation of China (NSFC) [90913018, 81090410, 81421002, 30825017, 81170465]; key technologies R&D Program of Tianjin [13RCGFSF19500]; NIH [R21HL1096541] FX This work was funded by the National Basic Research Program of China (NO. 2011CB964800, 2012CB966600), the National Natural Science Foundation of China (NSFC 90913018, 81090410, 81421002, 30825017 and 81170465), the key technologies R&D Program of Tianjin (13RCGFSF19500) and NIH R21HL1096541. NR 37 TC 10 Z9 11 U1 5 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6328 DI 10.1038/ncomms7328 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC3ZZ UT WOS:000350291300004 PM 25692908 ER PT J AU Alexander, BM Galanis, E Yung, WKA Ballman, KV Boyett, JM Cloughesy, TF Degroot, JF Huse, JT Mann, B Mason, W Mellinghoff, IK Mikkelsen, T Mischel, PS O'Neill, BP Prados, MD Sarkaria, JN Tawab-Amiri, A Trippa, L Ye, XB Ligon, KL Berry, DA Wen, PY AF Alexander, Brian M. Galanis, Evanthia Yung, W. K. Alfred Ballman, Karla V. Boyett, James M. Cloughesy, Timothy F. Degroot, John F. Huse, Jason T. Mann, Bhupinder Mason, Warren Mellinghoff, Ingo K. Mikkelsen, Tom Mischel, Paul S. O'Neill, Brian P. Prados, Michael D. Sarkaria, Jann N. Tawab-Amiri, Abdul Trippa, Lorenzo Ye, Xiaobu Ligon, Keith L. Berry, Donald A. Wen, Patrick Y. TI Brain Malignancy Steering Committee clinical trials planning workshop: Report from the Targeted Therapies Working Group SO NEURO-ONCOLOGY LA English DT Article DE adaptive randomization; biomarkers; clinical trials; glioblastoma ID NEWLY-DIAGNOSED GLIOBLASTOMA; PROGRESSION-FREE SURVIVAL; INTEGRATED GENOMIC ANALYSIS; RANDOMIZED PHASE-III; I-SPY 2; ISOCITRATE DEHYDROGENASE; ADAPTIVE RANDOMIZATION; ADJUVANT TEMOZOLOMIDE; MUTATIONAL ANALYSIS; TUMOR SAMPLES AB Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting. C1 [Alexander, Brian M.; Trippa, Lorenzo; Ligon, Keith L.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Galanis, Evanthia; Ballman, Karla V.; O'Neill, Brian P.; Sarkaria, Jann N.] Mayo Clin, Rochester, MN USA. [Yung, W. K. Alfred; Degroot, John F.; Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Boyett, James M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Huse, Jason T.; Mellinghoff, Ingo K.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mann, Bhupinder; Tawab-Amiri, Abdul] Natl Canc Inst, Bethesda, MD USA. [Mason, Warren] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Mikkelsen, Tom] Henry Ford Hosp, Detroit, MI 48202 USA. [Mischel, Paul S.] Univ Calif San Diego, San Diego, CA 92103 USA. [Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ye, Xiaobu] Johns Hopkins Univ, Baltimore, MD USA. RP Alexander, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM brian_alexander@dfci.harvard.edu FU Pfizer; Novartis; Genentech; Basilea; Sanofi; Merck; EMD Serono FX WM reports advisory role for Roche, Lilly and Merck. TM reports advisory board role for Roche, Merck, and Celgene. MDP reports advisory board role for Roche and Novartis and clinical and laboratory research support from Pfizer and Novartis. JNS reports research funding from Genentech, Basilea, Sanofi, and Merck. KLL reports consulting fee from EMD Serono. DAB is co-owner of and statistical consultant with Berry Consultants, LLC, a company that designs Bayesian adaptive clinical trials for pharmaceutical and medical device companies and NIH cooperative groups. NR 47 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2015 VL 17 IS 2 BP 180 EP 188 DI 10.1093/neuonc/nou154 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC1XK UT WOS:000350138500003 PM 25165194 ER PT J AU Morikawa, A Peereboom, DM Thorsheim, HR Samala, R Balyan, R Murphy, CG Lockman, PR Simmons, A Weil, RJ Tabar, V Steeg, PS Smith, QR Seidman, AD AF Morikawa, Aki Peereboom, David M. Thorsheim, Helen R. Samala, Ramakrishna Balyan, Rajiv Murphy, Conleth G. Lockman, Paul R. Simmons, Ahkeem Weil, Robert J. Tabar, Viviane Steeg, Patricia S. Smith, Quentin R. Seidman, Andrew D. TI Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study SO NEURO-ONCOLOGY LA English DT Article DE blood-tumor barrier; brain metastases; breast cancer; capecitabine; lapatinib ID TYROSINE KINASE INHIBITOR; RESISTANCE PROTEIN ABCG2; P-GLYCOPROTEIN ABCB1; CNS METASTASES; LUNG-CANCER; PHASE-II; IN-VITRO; TISSUE; BARRIER; GROWTH AB Background. Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. Methods. Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. Results. Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 mM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio. Conclusions. This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678. C1 [Morikawa, Aki; Murphy, Conleth G.; Simmons, Ahkeem; Tabar, Viviane; Seidman, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Peereboom, David M.; Weil, Robert J.] Cleveland Clin, Cleveland, OH 44106 USA. [Thorsheim, Helen R.; Samala, Ramakrishna; Balyan, Rajiv; Lockman, Paul R.; Smith, Quentin R.] Texas Tech Univ, Hlth Sci Ctr, Amarillo, TX USA. [Steeg, Patricia S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Seidman, AD (reprint author), Mem Sloan Kettering Canc Ctr, Evelyn Lauder Breast Ctr, 300 East 66th St, New York, NY 10065 USA. EM seidmana@mskcc.org FU Department of Defense Center of Excellence Breast Cancer Research Program Award [W81XWH-06-0033]; Judah Gubbay Memorial Fund FX This work was supported by the Department of Defense Center of Excellence Breast Cancer Research Program Award (W81XWH-06-0033) and the Judah Gubbay Memorial Fund. NR 32 TC 31 Z9 31 U1 2 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2015 VL 17 IS 2 BP 289 EP 295 DI 10.1093/neuonc/nou141 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC1XK UT WOS:000350138500013 PM 25015089 ER PT J AU Walton, KM Abrams, DB Bailey, WC Clark, D Connolly, GN Djordjevic, MV Eissenberg, TE Fiore, MC Goniewicz, ML Haverkos, L Hecht, SS Henningfield, JE Hughes, JR Oncken, CA Postow, L Rose, JE Wanke, KL Yang, L Hatsukami, DK AF Walton, Kevin M. Abrams, David B. Bailey, William C. Clark, David Connolly, Gregory N. Djordjevic, Mirjana V. Eissenberg, Thomas E. Fiore, Michael C. Goniewicz, Maciej L. Haverkos, Lynne Hecht, Stephen S. Henningfield, Jack E. Hughes, John R. Oncken, Cheryl A. Postow, Lisa Rose, Jed E. Wanke, Kay L. Yang, Lucie Hatsukami, Dorothy K. TI NIH Electronic Cigarette Workshop: Developing a Research Agenda SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID ABUSE LIABILITY ASSESSMENT; NICOTINE DELIVERY-SYSTEMS; TOBACCO PRODUCTS; CARBONYL-COMPOUNDS; SMOKING REDUCTION; PREGNANT SMOKERS; UNITED-STATES; USERS; EXPOSURE; HEALTH AB Background: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. Purpose: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. Results and Conclusions: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences. C1 [Walton, Kevin M.] NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Bethesda, MD 20892 USA. [Abrams, David B.] Schroeder Inst Legacy, Washington, DC USA. [Abrams, David B.] Johns Hopkins Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Bailey, William C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Clark, David] Natl Inst Dent & Craniofacial Res, Behav & Social Sci Res Branch, NIH, Bethesda, MD USA. [Connolly, Gregory N.] Northeastern Univ, Sch Law, Boston, MA 02115 USA. [Connolly, Gregory N.] Northeastern Univ, Bouve Hlth Sci, Boston, MA 02115 USA. [Djordjevic, Mirjana V.] NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. [Eissenberg, Thomas E.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. [Fiore, Michael C.] Univ Wisconsin, Ctr Tobacco Res & Intervent, Madison, WI USA. [Goniewicz, Maciej L.] Roswell Pk Canc Inst, Dept Hlth Behav, Buffalo, NY 14263 USA. [Haverkos, Lynne] NICHHD, Child Dev & Behav Branch, NIH, Bethesda, MD 20892 USA. [Hecht, Stephen S.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Henningfield, Jack E.] Pinney Associates, Bethesda, MD USA. [Henningfield, Jack E.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Hughes, John R.] Univ Vermont, Coll Med, Dept Psychol Sci, Burlington, VT USA. [Oncken, Cheryl A.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Postow, Lisa] NHLBI, Airway Biol & Dis Branch, NIH, Bethesda, MD 20892 USA. [Rose, Jed E.] Duke Univ, Med Ctr, Ctr Smoking Cessat, Durham, NC USA. [Wanke, Kay L.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Yang, Lucie] US FDA, Div Nonprescript Clin Evaluat, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hatsukami, Dorothy K.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. RP Walton, KM (reprint author), NIDA, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM kevin.walton@nih.gov OI Hecht, Stephen/0000-0001-7228-1356 FU National Institutes of Health [P50 DA027840]; US Food and Drug Administration Center for Tobacco Products [U19 CA157345, P50 DA036105] FX This work was supported by the National Institutes of Health (P50 DA027840 to JER) and by the National Institutes of Health and US Food and Drug Administration Center for Tobacco Products (U19 CA157345 to DKH and P50 DA036105 to TEE). NR 103 TC 31 Z9 31 U1 7 U2 37 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 FEB PY 2015 VL 17 IS 2 SI SI BP 259 EP 269 DI 10.1093/ntr/ntu214 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA CC1YW UT WOS:000350142300022 PM 25335949 ER PT J AU Buonfrate, D Sequi, M Mejia, R Cimino, RO Krolewiecki, AJ Albonico, M Degani, M Tais, S Angheben, A Requena-Mendez, A Munoz, J Nutman, TB Bisoffi, Z AF Buonfrate, Dora Sequi, Marco Mejia, Rojelio Cimino, Ruben O. Krolewiecki, Alejandro J. Albonico, Marco Degani, Monica Tais, Stefano Angheben, Andrea Requena-Mendez, Ana Munoz, Jose Nutman, Thomas B. Bisoffi, Zeno TI Accuracy of Five Serologic Tests for the Follow up of Strongyloides stercoralis Infection SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID REAL-TIME PCR; EOSINOPHIL COUNT; DIAGNOSIS; ASSAY; IVERMECTIN; MANAGEMENT; HOOKWORM; PATTERNS; TOOL AB Background Traditional faecal-based methods have poor sensitivity for the detection of S. stercoralis, therefore are inadequate for post-treatment evaluation of infected patients who should be carefully monitored to exclude the persistence of the infection. In a previous study, we demonstrated high accuracy of five serology tests for the screening and diagnosis of strongyloidiasis. Aim of this study is to evaluate the performance of the same five tests for the follow up of patients infected with S. stercoralis. Methods Retrospective study on anonymized, cryo-preserved samples available at the Centre for Tropical Diseases (Negrar, Verona, Italy). Samples were collected before and from 3 to 12 months after treatment. The samples were tested with two commercially-available ELISA tests (IVD, Bordier), two techniques based on a recombinant antigen (NIE-ELISA and NIE-LIPS) and one in-house IFAT. The results of each test were evaluated both in relation to the results of fecal examination and to those of a composite reference standard (classifying as positive a sample with positive stools and/or at least three positive serology tests). The associations between the independent variables age and time and the dependent variable value of serological test (for all five tests), were analyzed by linear mixed-effects regression model. Results A high proportion of samples demonstrated for each test a seroreversion or a relevant decline (optical density/relative light units halved or decrease of at least two titers for IFAT) at follow up, results confirmed by the linear mixed effects model that showed a trend to seroreversion over time for all tests. In particular, IVD-ELISA (almost 90% samples demonstrated relevant decline) and IFAT (almost 87%) had the best performance. Considering only samples with a complete negativization, NIE-ELISA showed the best performance (72.5% seroreversion). Conclusions Serology is useful for the follow up of patients infected with S. stercoralis and determining test of cure. C1 [Buonfrate, Dora; Albonico, Marco; Degani, Monica; Tais, Stefano; Angheben, Andrea; Bisoffi, Zeno] Sacro Cuore Hosp, CTD, Verona, Italy. [Buonfrate, Dora; Albonico, Marco; Angheben, Andrea; Requena-Mendez, Ana; Munoz, Jose; Bisoffi, Zeno] Commiss European Communities, Coordinating Resources Assess & Improve Hlth Stat, Hlth Cooperat Work Programme, FP7,GA 261495, Milan, Italy. [Sequi, Marco] IRCCS Mario Negri Inst Pharmacol Res, Dept Publ Hlth, Milan, Italy. [Mejia, Rojelio; Nutman, Thomas B.] NIAID, NIH, Bethesda, MD 20892 USA. [Cimino, Ruben O.; Krolewiecki, Alejandro J.] Univ Nacl Salta, CONICET, Inst Invest Enfermedades Trop, Oran, Argentina. [Requena-Mendez, Ana; Munoz, Jose] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res CRESIB, Barcelona, Spain. RP Buonfrate, D (reprint author), Sacro Cuore Hosp, CTD, Verona, Italy. EM dora.buonfrate@sacrocuore.it OI Munoz Gutierrez, Jose/0000-0002-0945-1735; ALBONICO, Marco/0000-0002-7805-2391 FU EC within the 7th Framework Programme under the COHEMI project [FP7-GA-261495]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID) FX This work has been partly supported by the EC within the 7th Framework Programme under the COHEMI project - grant agreement n. FP7-GA-261495. The work performed by RM, ROC, and TBN was funded in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID). We thank Bordier Affinity Products SA for donating the Bordier ELISA kits. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 15 Z9 15 U1 7 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2015 VL 9 IS 2 AR UNSP e0003491 DI 10.1371/journal.pntd.0003491 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CD3PW UT WOS:000350992500035 PM 25668740 ER PT J AU Mondragon-Shem, K Al-Salem, WS Kelly-Hope, L Abdeladhim, M Al-Zahrani, MH Valenzuela, JG Acosta-Serrano, A AF Mondragon-Shem, Karina Al-Salem, Waleed S. Kelly-Hope, Louise Abdeladhim, Maha Al-Zahrani, Mohammed H. Valenzuela, Jesus G. Acosta-Serrano, Alvaro TI Severity of Old World Cutaneous Leishmaniasis Is Influenced by Previous Exposure to Sandfly Bites in Saudi Arabia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CANINE ANTIBODY-RESPONSE; PHLEBOTOMUS-PAPATASI; VISCERAL LEISHMANIASIS; IMMUNE-RESPONSE; LUTZOMYIA-LONGIPALPIS; SALIVARY ANTIGEN; MICE BITTEN; FLY SALIVA; VECTOR; INFECTION AB Background The sandfly Phlebotomus papatasi is the vector of Leishmania major, the main causative agent of Old World cutaneous leishmaniasis (CL) in Saudi Arabia. Sandflies inject saliva while feeding and the salivary protein PpSP32 was previously shown to be a biomarker for bite exposure. Here we used recombinant PpSP32 to evaluate human exposure to Ph. papatasi bites, and study the association between antibody response to saliva and CL in endemic areas in Saudi Arabia. Methodology/Principal Findings In this observational study, anti-PpSP32 antibodies, as indicators of exposure to sandfly bites, were measured in sera from healthy individuals and patients from endemic regions in Saudi Arabia with active and cured CL. Ph. papatasi was identified as the primary CL vector in the study area. Anti-PpSP32 antibody levels were significantly higher in CL patients presenting active infections from all geographical regions compared to CL cured and healthy individuals. Furthermore, higher anti-PpSP32 antibody levels correlated with the prevalence and type of CL lesions (nodular vs. papular) observed in patients, especially non-local construction workers. Conclusions Our findings suggest a possible correlation between the type of immunity generated by the exposure to sandfly bites and disease outcome. C1 [Mondragon-Shem, Karina; Al-Salem, Waleed S.; Kelly-Hope, Louise; Acosta-Serrano, Alvaro] Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England. [Al-Salem, Waleed S.; Al-Zahrani, Mohammed H.] Saudi Minist Hlth, Dept Vector Borne Dis, Riyadh, Saudi Arabia. [Kelly-Hope, Louise] Univ Liverpool, Liverpool Sch Trop Med, Ctr Neglected Trop Dis, Liverpool L3 5QA, Merseyside, England. [Abdeladhim, Maha; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, NIH, Bethesda, MD 20892 USA. [Acosta-Serrano, Alvaro] Univ Liverpool, Liverpool Sch Trop Med, Dept Vector Biol, Liverpool L3 5QA, Merseyside, England. RP Mondragon-Shem, K (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England. EM alvaro.acosta-serrano@lstmed.ac.uk RI Acosta-Serrano, Alvaro/L-5503-2015; OI Acosta-Serrano, Alvaro/0000-0002-2576-7959; Mondragon-Shem, Karina/0000-0002-0997-5600 FU Ministry of Health of the Kingdom of Saudi Arabia; Colombian Department of Science, Technology and Innovation (Colciencias) through the scholarship programme "Francisco Jose de Caldas"; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported in part by a Ph.D. studentship from the Ministry of Health of the Kingdom of Saudi Arabia (to WSAS); by the Colombian Department of Science, Technology and Innovation (Colciencias) through the scholarship programme "Francisco Jose de Caldas" (to KMS); and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to MA and JGV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 7 Z9 8 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2015 VL 9 IS 2 AR e0003449 DI 10.1371/journal.pntd.0003449 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CD3PW UT WOS:000350992500016 PM 25646796 ER PT J AU Nutting, CS Eversole, RR Blair, K Specht, S Nutman, TB Klion, AD Wanji, S Boussinesq, M Mackenzie, CD AF Nutting, Chuck S. Eversole, Rob R. Blair, Kevin Specht, Sabine Nutman, Thomas B. Klion, Amy D. Wanji, Samuel Boussinesq, Michel Mackenzie, Charles D. TI Analysis of Nematode Motion Using an Improved Light-Scatter Based System SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DRUGS; ONCHOCERCIASIS; ELIMINATION; INFECTION; MOTILITY; FILARIAE AB Background The detailed assessment of nematode activity and viability still remains a relatively undeveloped area of biological and medical research. Computer-based approaches to assessing the motility of larger nematode stages have been developed, yet these lack the capability to detect and analyze the more subtle and important characteristics of the motion of nematodes. There is currently a need to improved methods of assessing the viability and health of parasitic worms. Methods We describe here a system that converts the motion of nematodes through a light-scattering system into an electrical waveform, and allows for reproducible, and wholly non-subjective, assessment of alterations in motion, as well as estimation of the number of nematode worms of different forms and sizes. Here we have used Brugia sp. microfilariae (L1), infective larvae (L3) and adults, together with the free-living nematode Caenorhabditis elegans. Results The motion of worms in a small (200ul) volume can be detected, with the presence of immotile worms not interfering with the readings at practical levels (up to at least 500 L1 /200ul). Alterations in the frequency of parasite movement following the application of the anti-parasitic drugs, (chloroquine and imatinib); the anti-filarial effect of the latter agent is the first demonstrated here for the first time. This system can also be used to estimate the number of parasites, and shortens the time required to estimate parasites numbers, and eliminates the need for microscopes and trained technicians to provide an estimate of microfilarial sample sizes up to 1000 parasites/ml. Alterations in the form of motion of the worms can also be depicted. Conclusions This new instrument, named a "WiggleTron", offers exciting opportunities to further study nematode biology and to aid drug discovery, as well as contributing to a rapid estimate of parasite numbers in various biological samples. C1 [Nutting, Chuck S.; Eversole, Rob R.; Blair, Kevin; Mackenzie, Charles D.] Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA. [Blair, Kevin] Western Michigan Univ, Dept Chem, Kalamazoo, MI 49008 USA. [Specht, Sabine] Univ Hosp Bonn, Inst Med Microbiol, Bonn, Germany. [Nutman, Thomas B.; Klion, Amy D.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Wanji, Samuel] Inst Rech Dev, Montpellier, France. [Boussinesq, Michel] Univ Buea, Res Fdn Trop Dis & Environm, Buea, Cameroon. [Mackenzie, Charles D.] Michigan State Univ, Dept Pathobiol & Diagnost Invest, E Lansing, MI 48824 USA. RP Nutting, CS (reprint author), Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA. EM mackenz8@msu.edu RI Boussinesq, Michel/J-7256-2016; OI Boussinesq, Michel/0000-0001-6312-0681; Klion, Amy/0000-0002-4986-5326 FU Bill and Melinda Gates Foundation FX This work was supported The Bill and Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 1 Z9 1 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD FEB PY 2015 VL 9 IS 2 AR e0003523 DI 10.1371/journal.pntd.0003523 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CD3PW UT WOS:000350992500049 PM 25695776 ER PT J AU Blackshear, PE Pandiri, AR Nagai, H Bhusari, S Hong, HH Ton, TVT Clayton, NP Wyde, M Shockley, KR Peddada, SD Gerrish, KE Sills, RC Hoenerhoff, MJ AF Blackshear, Pamela E. Pandiri, Arun R. Nagai, Hiroaki Bhusari, Sachin Hong, Hue-Hua Ton, Thai-Vu T. Clayton, Natasha P. Wyde, Michael Shockley, Keith R. Peddada, Shyamal D. Gerrish, Kevin E. Sills, Robert C. Hoenerhoff, Mark J. TI Gene Expression of Mesothelioma in Vinylidene Chloride-exposed F344/N Rats Reveal Immune Dysfunction, Tissue Damage, and Inflammation Pathways SO TOXICOLOGIC PATHOLOGY LA English DT Article DE vinylidene chloride; mesothelioma; F344; N rat; National Toxicology Program; microarray; gene expression; mesothelial cell; Fred-PE cells ID MALIGNANT PLEURAL MESOTHELIOMA; NATURAL-KILLER-CELLS; PULMONARY ADENOCARCINOMA; SIGNAL-TRANSDUCTION; MOLECULAR PATHWAYS; TUNICA VAGINALIS; GAMMA-SYNUCLEIN; PROBE LEVEL; IN-VIVO; CANCER AB A majority (approximate to 80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma. C1 [Blackshear, Pamela E.; Pandiri, Arun R.; Nagai, Hiroaki; Bhusari, Sachin; Hong, Hue-Hua; Ton, Thai-Vu T.; Clayton, Natasha P.; Sills, Robert C.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Blackshear, Pamela E.] Integrated Syst Lab Inc, Res Triangle Pk, NC USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Wyde, Michael] NIEHS, Expt Toxicol Grp, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Shockley, Keith R.; Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin E.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), Univ Michigan, Sch Med, Unit Lab Anim Med, North Campus Res Complex,2800 Plymouth Rd, Ann Arbor, MI 48103 USA. EM hoenerho@med.umich.edu FU Intramural NIH HHS [Z99 ES999999] NR 62 TC 1 Z9 1 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2015 VL 43 IS 2 BP 171 EP 185 DI 10.1177/0192623314537885 PG 15 WC Pathology; Toxicology SC Pathology; Toxicology GA CC4RO UT WOS:000350341100002 PM 24958746 ER PT J AU Kaess, BM Harris, WS Lacey, S Larson, MG Hamburg, NM Vita, JA Robins, SJ Benjamin, EJ Mitchell, GF Vasan, RS AF Kaess, Bernhard M. Harris, William S. Lacey, Sean Larson, Martin G. Hamburg, Naomi M. Vita, Joseph A. Robins, Sander J. Benjamin, Emelia J. Mitchell, Gary F. Vasan, Ramachandran S. TI The relation of red blood cell fatty acids with vascular stiffness, cardiac structure and left ventricular function: The Framingham Heart Study SO VASCULAR MEDICINE LA English DT Article DE aortic stiffness; fatty acids ID LONG-CHAIN OMEGA-3-FATTY-ACIDS; INTIMA-MEDIA THICKNESS; GISSI-HF TRIAL; CARDIOVASCULAR-DISEASE; ARTERIAL STIFFNESS; EICOSAPENTAENOIC ACID; FISH CONSUMPTION; DOCOSAHEXAENOIC ACID; SECONDARY PREVENTION; AORTIC STIFFNESS AB Polyunsaturated fatty acids have been associated with beneficial influences on cardiovascular health. However, the underlying mechanisms are not clear, and data on the relations of polyunsaturated fatty acids to subclinical disease measures such as vascular stiffness and cardiac function are sparse and inconclusive. In a large community-based cohort, we examined the relations of omega-3 and other fatty acids to a comprehensive panel of vascular function measures (assessing microvascular function and large artery stiffness), cardiac structure and left ventricular function. Red blood cell (RBC) membrane fatty acid composition, a measure of long-term fatty acid intake, was assessed in participants of the Framingham Offspring Study and Omni cohorts and related to tonometry-derived measures of vascular stiffness and to a panel of echocardiographic traits using partial correlations. Up to n=3055 individuals (56% women, mean age 66 years) were available for analyses. In age- and sex-adjusted models, higher RBC omega-3 content was moderately associated (p0.002) with several measures of vascular stiffness and function in a protective direction. However, after multivariable adjustment, only an association of higher RBC omega-3 content with lower carotid-femoral pulse wave velocity (a measure of aortic stiffness) remained significant (r = -0.06, p=0.002). In secondary analyses, higher linoleic acid, the major nutritional omega-6 fatty acid, was associated with smaller left atrial size, even after multivariable adjustment (r = -0.064, p<0.001). In conclusion, in our cross-sectional community-based study, we found several associations consistent with the notion of protective effects of omega-3 and linoleic acid. The clinical significance of these modest associations remains to be elucidated. C1 [Kaess, Bernhard M.; Larson, Martin G.; Robins, Sander J.; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham, MA USA. [Kaess, Bernhard M.; Larson, Martin G.; Robins, Sander J.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Kaess, Bernhard M.] Tech Univ Munich, Deutsch Herzzentrum, D-80290 Munich, Germany. [Harris, William S.] Univ S Dakota, Sanford Sch Med, Dept Med, Sioux Falls, SD USA. [Harris, William S.] Hlth Diagnost Lab Inc, Richmond, VA USA. [Lacey, Sean; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.; Benjamin, Emelia J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Kaess, BM (reprint author), Deutsch Herzzentrum Munich, Lazarettstr 36, D-80636 Munich, Germany. EM bernhard_kaess@gmx.de OI Benjamin, Emelia/0000-0003-4076-2336; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL089590]; Framingham Heart Study (NHLBI) [N01-HC-25195]; Boston University School of Medicine; [HL076784]; [G028321]; [HL070100]; [HL060040]; [HL080124]; [HL071039]; [HL077447]; [HL107385]; [2-K24-HL04334] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI; R01 HL089590) and by contract N01-HC-25195, the Framingham Heart Study (NHLBI) and Boston University School of Medicine, and by HL076784, G028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, and 2-K24-HL04334. NR 54 TC 4 Z9 4 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD FEB PY 2015 VL 20 IS 1 BP 5 EP 13 DI 10.1177/1358863X14560808 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CC6JY UT WOS:000350472400002 PM 25520318 ER PT J AU Massimelli, MJ Majerciak, V Kang, JG Liewehr, DJ Steinberg, SM Zheng, ZM AF Massimelli, Maria Julia Majerciak, Vladimir Kang, Jeong-Gu Liewehr, David J. Steinberg, Seth M. Zheng, Zhi-Ming TI Multiple Regions of Kaposi's Sarcoma-Associated Herpesvirus ORF59 RNA are Required for Its Expression Mediated by Viral ORF57 and Cellular RBM15 SO VIRUSES-BASEL LA English DT Article ID PROCESSIVITY FACTOR ORF59; PROTEIN INTERACTS; GENE-EXPRESSION; DNA-REPLICATION; ELEMENT; RTA; TRANSACTIVATOR; POLYMERASE; REGULATOR; INFECTION AB KSHV ORF57 (MTA) promotes RNA stability of ORF59, a viral DNA polymerase processivity factor. Here, we show that the integrity of both ORF59 RNA ends is necessary for ORF57-mediated ORF59 expression and deletion of both 5' and 3' regions, or one end region with a central region, of ORF59 RNA prevents ORF57-mediated translation of ORF59. The ORF59 sequence between nt 96633 and 96559 resembles other known MTA-responsive elements (MREs). ORF57 specifically binds to a stem-loop region from nt 96596-96572 of the MRE, which also binds cellular RBM15. Internal deletion of the MRE from ORF59 led to poor export, but accumulation of nuclear ORF59 RNA in the presence of ORF57 or RBM15. Despite of being translatable in the presence of ORF57, this deletion mutant exhibits translational defect in the presence of RBM15. Together, our results provide novel insight into the roles of ORF57 and RBM15 in ORF59 RNA accumulation and protein translation. C1 [Massimelli, Maria Julia; Majerciak, Vladimir; Kang, Jeong-Gu; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res,NIH, 1050 Boyles St, Frederick, MD 21702 USA. EM julia.massimelli@uci.edu; majerciv@mail.nih.gov; jkang@jkbiopharma.com; liewehrd@mail.nih.gov; steinbes@mail.nih.gov; zhengt@exchange.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. We thank Barbara Felber at NCI for RBM15 plasmid and Jae Jung of the University of Southern California for inducible TREx BCBL1-RTA and -vector cell lines. NR 30 TC 4 Z9 4 U1 0 U2 0 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2015 VL 7 IS 2 BP 496 EP 510 DI 10.3390/v7020496 PG 15 WC Virology SC Virology GA CC9EL UT WOS:000350670800003 PM 25690794 ER PT J AU Judson, S Prescott, J Munster, V AF Judson, Seth Prescott, Joseph Munster, Vincent TI Understanding Ebola Virus Transmission SO VIRUSES-BASEL LA English DT Review ID HEMORRHAGIC-FEVER; RHESUS-MONKEYS; RISK-FACTORS; INFECTION; EXPOSURE; AEROSOL; ZAIRE; PATHOLOGY; SURVIVAL; KIKWIT AB An unprecedented number of Ebola virus infections among healthcare workers and patients have raised questions about our understanding of Ebola virus transmission. Here, we explore different routes of Ebola virus transmission between people, summarizing the known epidemiological and experimental data. From this data, we expose important gaps in Ebola virus research pertinent to outbreak situations. We further propose experiments and methods of data collection that will enable scientists to fill these voids in our knowledge about the transmission of Ebola virus. C1 [Judson, Seth; Prescott, Joseph; Munster, Vincent] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. RP Munster, V (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM sethdjudson@gmail.com; prescottjb@niaid.nih.gov; munstervj@niaid.nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We would like to thank Austin Athman, Ryan Kissinger and Anita Mora (RTB, DIR, NIAID, NIH) for help creating the Figure. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 24 TC 17 Z9 17 U1 2 U2 40 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2015 VL 7 IS 2 BP 511 EP 521 DI 10.3390/v7020511 PG 11 WC Virology SC Virology GA CC9EL UT WOS:000350670800004 PM 25654239 ER PT J AU Majerciak, V Zheng, ZM AF Majerciak, Vladimir Zheng, Zhi-Ming TI KSHV ORF57, a Protein of Many Faces SO VIRUSES-BASEL LA English DT Review ID SARCOMA-ASSOCIATED HERPESVIRUS; MESSENGER-RNA EXPORT; SIMPLEX-VIRUS ICP27; POLYADENYLATED NUCLEAR-RNA; KINASE CK2 PHOSPHORYLATION; LYTIC GENE-EXPRESSION; EXON-JUNCTION COMPLEX; ARGININE-RICH MOTIFS; LONG NONCODING RNA; REGULATORY PROTEIN AB Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein (also known as mRNA transcript accumulation (Mta)) is a potent posttranscriptional regulator essential for the efficient expression of KSHV lytic genes and productive KSHV replication. ORF57 possesses numerous activities that promote the expression of viral genes, including the three major functions of enhancement of RNA stability, promotion of RNA splicing, and stimulation of protein translation. The multifunctional nature of ORF57 is driven by its ability to interact with an array of cellular cofactors. These interactions are required for the formation of ORF57-containing ribonucleoprotein complexes at specific binding sites in the target transcripts, referred as Mta-responsive elements (MREs). Understanding of the ORF57 protein conformation has led to the identification of two structurally-distinct domains within the ORF57 polypeptide: an unstructured intrinsically disordered N-terminal domain and a structured alpha-helix-rich C-terminal domain. The distinct structures of the domains serve as the foundation for their unique binding affinities: the N-terminal domain mediates ORF57 interactions with cellular cofactors and target RNAs, and the C-terminal domain mediates ORF57 homodimerization. In addition, each domain has been found to contribute to the stability of ORF57 protein in infected cells by counteracting caspase- and proteasome-mediated degradation pathways. Together, these new findings provide insight into the function and biological properties of ORF57 in the KSHV life cycle and pathogenesis. C1 [Majerciak, Vladimir; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, Gene Regulat & Chromosome Biol Lab, NIH, 1050 Boyles St, Frederick, MD 21702 USA. EM Vladimir.Majerciak@nih.gov; zhengt@exchange.nih.gov FU National Cancer Institute, Center for Cancer Research, NIH FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 119 TC 4 Z9 4 U1 2 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2015 VL 7 IS 2 BP 604 EP 633 DI 10.3390/v7020604 PG 30 WC Virology SC Virology GA CC9EL UT WOS:000350670800009 PM 25674768 ER PT J AU Sun, XL Cai, WB Chen, XY AF Sun, Xiaolian Cai, Weibo Chen, Xiaoyuan TI Positron Emission Tomography Imaging Using Radio labeled Inorganic Nanomaterials SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID IRON-OXIDE NANOPARTICLES; IN-VIVO; THERANOSTIC NANOPARTICLES; TUMOR VASCULATURE; CARBON NANOTUBES; QUANTUM DOTS; CANCER; PET; THERAPY; RADIOPHARMACEUTICALS AB Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochemical) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clinical research, only very few have moved to humans. One major reason is the lack of understanding of the biological behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal molecular imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time. C1 [Sun, Xiaolian] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiamen 361102, Peoples R China. [Sun, Xiaolian; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Cai, Weibo] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Cai, Weibo] Univ Wisconsin, Dept Phys Med, Madison, WI 53706 USA. RP Sun, XL (reprint author), Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Ctr Mol Imaging & Translat Med, Xiangan South Rd, Xiamen 361102, Peoples R China. EM xiaolian.sun@nih.gov; WCai@uwhealth.org; shawn.chen@nih.gov FU intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); University of Wisconsin-Madison; National Institutes of Health [NIBIB/NCI 1R01CA169365]; Department of Defense [W81XWH-11-1-0644]; American Cancer Society [125246-RSG-13-099-01-CCE] FX We thank the intramural research program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the University of Wisconsin-Madison, the National Institutes of Health (Grant NIBIB/NCI 1R01CA169365), the Department of Defense (Grant W81XWH-11-1-0644), and the American Cancer Society (Grant 125246-RSG-13-099-01-CCE) for the support of this work. NR 56 TC 37 Z9 37 U1 17 U2 93 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 EI 1520-4898 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD FEB PY 2015 VL 48 IS 2 BP 286 EP 294 DI 10.1021/ar500362y PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA CB7KS UT WOS:000349806300016 PM 25635467 ER PT J AU Breslow, RA Dong, CH White, A AF Breslow, Rosalind A. Dong, Chuanhui White, Aaron TI Prevalence of Alcohol-Interactive Prescription Medication Use Among Current Drinkers: United States, 1999 to 2010 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Consumption; Drinking Patterns; Drinking Behavior; Drugs; Medications; Prescription Medications; Cross-Sectional Survey; National Health and Nutrition Examination Survey AB BackgroundThe majority of Americans consume alcoholic beverages. Alcohol interacts negatively with numerous commonly prescribed medications. Yet, on a population level, little is known about use of alcohol-interactive (AI) prescription medications among drinkers. The purpose of our study was to determine the prevalence of AI prescription medication use among current drinkers in the U.S. population. MethodsData were from the National Health and Nutrition Examination Survey (NHANES 1999 to 2010); 26,657 adults aged 20years had data on past year alcohol consumption and past month prescription medication use. Analyses were adjusted for covariates: age, race/ethnicity, education, marital status, and smoking. Statistical procedures accounted for survey stratification, clustering, and nonresponse. Analyses were weighted to be nationally representative. ResultsThe unadjusted total prevalence of AI medication use was 42.8% (95% confidence interval [CI] 41.5 to 44.0). Among current drinkers, adjusted prevalence was 41.5% (CI 40.3 to 42.7). Among participants aged 65 total prevalence of AI medication use was 78.6% (CI 77.3 to 79.9) and adjusted prevalence among current drinkers was 77.8% (CI 75.7 to 79.7). The AI medications most commonly used by current drinkers were cardiovascular agents, central nervous system agents, and metabolic agents. ConclusionsOur results suggest that there could be substantial simultaneous exposure to alcohol and AI prescription medications in the U.S. population. Given the adverse health risks of combining alcohol with AI prescription medications, future efforts are needed to collect data to determine actual simultaneous prevalence. C1 [Breslow, Rosalind A.; White, Aaron] NIAAA, Div Epidemiol & Prevent Res, NIH, Rockville, MD 20892 USA. [Dong, Chuanhui] CSR Inc, Arlington, VA USA. RP Breslow, RA (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2071, Rockville, MD 20892 USA. EM rbreslow@mail.nih.gov FU Intramural NIH HHS [Z99 AA999999] NR 22 TC 9 Z9 9 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2015 VL 39 IS 2 BP 371 EP 379 DI 10.1111/acer.12633 PG 9 WC Substance Abuse SC Substance Abuse GA CC1KZ UT WOS:000350100900020 PM 25597432 ER PT J AU Ahrens, KA Cole, SR Westreich, D Platt, RW Schisterman, EF AF Ahrens, K. A. Cole, S. R. Westreich, D. Platt, R. W. Schisterman, E. F. TI A Cautionary Note About Estimating Effects of Secondary Exposures in Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); cohort studies; directed acyclic graph; epidemiologic methods; oversampling ID CAUSAL DIAGRAMS; MODELS; EPIDEMIOLOGY; ADJUSTMENT; BIAS AB Cohort studies are often enriched for a primary exposure of interest to improve cost-effectiveness, which presents analytical challenges not commonly discussed in epidemiology. In this paper, we use causal diagrams to represent exposure-enriched cohort studies, illustrate a scenario wherein the risk ratio for the effect of a secondary exposure on an outcome is biased, and propose an analytical method for correcting for such bias. In our motivating example, maternal smoking (Z) is a cause of fetal growth restriction (X), which subsequently affects preterm birth (Y) (i.e., Z -> X -> Y); strong positive associations exist between both Z, X and X, Y; and enrichment for X increases its prevalence from 10% to 50%. In the X-enriched cohort, unadjusted and X-adjusted analyses lead to bias in the risk ratio for the total effect of Z on Y. After application of inverse probability weights, the bias is corrected, with a small loss of efficiency in comparison with a same-sized study without X-enrichment. With increasing interest in conducting secondary analyses to reduce research costs, caution should be employed when analyzing studies that have already been enriched, intentionally or unintentionally, for a primary exposure of interest. Causal diagrams can help identify scenarios in which secondary analyses may be biased. Inverse probability weights can be used to remove the bias. C1 [Ahrens, K. A.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Cole, S. R.; Westreich, D.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Platt, R. W.] McGill Univ, Fac Med, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health; National Institute of Allergy and Infectious Diseases, US National Institutes of Health [R01-AI 100654]; Chercheur National Award from the Fonds de Recherche en Sante du Quebec; Fonds de Recherche en Sante du Quebec FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health (E.F.S. and K.A.A.); the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (grant R01-AI 100654 to S.R.C.); the Chercheur National Award from the Fonds de Recherche en Sante du Quebec (R.W.P.); and core support provided to the Montreal Children's Hospital Research Institute from the Fonds de Recherche en Sante du Quebec (R.W.P.). NR 26 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2015 VL 181 IS 3 BP 198 EP 203 DI 10.1093/aje/kwu276 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB4XK UT WOS:000349631500004 PM 25589243 ER PT J AU Wilcox, AJ Weinberg, CR Basso, O Harmon, QE AF Wilcox, Allen J. Weinberg, Clarice R. Basso, Olga Harmon, Quaker E. TI RE: "ANALYZING RISKS OF ADVERSE PREGNANCY OUTCOMES" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Wilcox, Allen J.; Harmon, Quaker E.] NIEHS, Epidemiol Branch, Durham, NC 27713 USA. [Weinberg, Clarice R.] NIEHS, Biostat Branch, Durham, NC USA. [Basso, Olga] McGill Univ, Royal Victoria Hosp, Dept Obstet & Gynecol, Ctr Hlth, Montreal, PQ H3A 1A1, Canada. [Basso, Olga] McGill Univ, Fac Med, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, Durham, NC 27713 USA. EM wilcox@niehs.nih.gov OI Harmon, Quaker/0000-0002-5866-848X; Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 4 TC 1 Z9 1 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2015 VL 181 IS 3 BP 218 EP 218 DI 10.1093/aje/kwu463 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB4XK UT WOS:000349631500007 PM 25612573 ER PT J AU Yu, YK Capra, JA Stojmirovic, A Landsman, D Altschul, SF AF Yu, Yi-Kuo Capra, John A. Stojmirovic, Aleksandar Landsman, David Altschul, Stephen F. TI Log-odds sequence logos SO BIOINFORMATICS LA English DT Article ID ACID SUBSTITUTION MATRICES; CONSENSUS SEQUENCES; INFORMATION-CONTENT; DIRICHLET MIXTURES; BINDING-SITES; PSI-BLAST; DNA; PROTEINS; VISUALIZATION; ALIGNMENTS AB Motivation: DNA and protein patterns are usefully represented by sequence logos. However, the methods for logo generation in common use lack a proper statistical basis, and are non-optimal for recognizing functionally relevant alignment columns. Results: We redefine the information at a logo position as a per-observation multiple alignment log-odds score. Such scores are positive or negative, depending on whether a column's observations are better explained as arising from relatedness or chance. Within this framework, we propose distinct normalized maximum likelihood and Bayesian measures of column information. We illustrate these measures on High Mobility Group B (HMGB) box proteins and a dataset of enzyme alignments. Particularly in the context of protein alignments, our measures improve the discrimination of biologically relevant positions. C1 [Yu, Yi-Kuo; Stojmirovic, Aleksandar; Landsman, David; Altschul, Stephen F.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Capra, John A.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Capra, John A.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. RP Altschul, SF (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM altschul@ncbi.nlm.nih.gov OI Landsman, David/0000-0002-9819-6675 FU Intramural Research Program of the National Library of Medicine of the National Institutes of Health; Vanderbilt University FX Y.K.Y., A.S., D.L. and S.F.A. were supported by the Intramural Research Program of the National Library of Medicine of the National Institutes of Health; J.A.C. was supported by institutional funds from Vanderbilt University. NR 40 TC 2 Z9 2 U1 1 U2 6 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 FEB 1 PY 2015 VL 31 IS 3 BP 324 EP 331 DI 10.1093/bioinformatics/btu634 PG 8 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 CC0WG UT WOS:000350058800005 PM 25294922 ER PT J AU Nakamura, N Inselman, AL White, GA Chang, CW Trbojevich, RA Sephr, E Voris, KL Patton, RE Bryant, MS Harrouk, W McIntyre, BS Foster, PMD Hansen, DK AF Nakamura, Noriko Inselman, Amy L. White, Gene A. Chang, Ching-Wei Trbojevich, Raul A. Sephr, Estatira Voris, Kristie L. Patton, Ralph E. Bryant, Matthew S. Harrouk, Wafa McIntyre, Barry S. Foster, Paul M. D. Hansen, Deborah K. TI Effects of Maternal and Lactational Exposure to 2-Hydroxy-4-Methoxybenzone on Development and Reproductive Organs in Male and Female Rat Offspring SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE 2-hydroxy-4-methoxybenzophenone; body weight; rats; offspring; testes; ovary; fetal exposure ID ENDOCRINE-DISRUPTING CHEMICALS; TANDEM MASS-SPECTROMETRY; BODY TOPICAL APPLICATION; UV FILTERS; CELL APOPTOSIS; LIQUID-CHROMATOGRAPHY; ESTROGENIC ACTIVITY; SURFACE WATERS; SWISS LAKES; BENZOPHENONE-3 AB BACKGROUND2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODSTo determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSIONExposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats C1 [Nakamura, Noriko; Inselman, Amy L.; White, Gene A.; Hansen, Deborah K.] US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Chang, Ching-Wei] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Trbojevich, Raul A.; Sephr, Estatira; Bryant, Matthew S.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Voris, Kristie L.; Patton, Ralph E.] Toxicol Pathol Associates, Jefferson, AR USA. [Harrouk, Wafa] US FDA, Ctr Drug Evaluat & Res, Jefferson, AR 72079 USA. [McIntyre, Barry S.; Foster, Paul M. D.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Nakamura, N (reprint author), US FDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Noriko.Nakamura@fda.hhs.gov FU NCTR [E0745502]; FDA/NCTR [FDA 224-12-0003]; NIEHS/NTP [NIH AES12013] FX Grant sponsor: NCTR; Grant number: E0745502; Grant sponsor: FDA/NCTR; Grant number: FDA 224-12-0003; Grant sponsor: NIEHS/NTP; Grant number: NIH AES12013. NR 51 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-9733 EI 1542-9741 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD FEB PY 2015 VL 104 IS 1 BP 35 EP 51 DI 10.1002/bdrb.21137 PG 17 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA CC1ZX UT WOS:000350145200004 PM 25707689 ER PT J AU Kabisch, M Bermejo, JL Duennebier, T Ying, SB Michailidou, K Bolla, MK Wang, Q Dennis, J Shah, M Perkins, BJ Czene, K Darabi, H Eriksson, M Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Lambrechts, D Neven, P Peeters, S Weltens, C Couch, FJ Olson, JE Wang, XS Purrington, K Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Peto, J dos-Santos-Silva, I Johnson, N Fletcher, O Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Schmidt, MK Broeks, A Cornelissen, S Hogervorst, FBL Li, JM Brand, JS Humphreys, K Guenel, P Truong, T Menegaux, F Sanchez, M Burwinkel, B Marme, F Yang, RX Bugert, P Gonzalez-Neira, A Benitez, J Zamora, MP Perez, JIA Cox, A Cross, SS Reed, MWR Andrulis, IL Knight, JA Glendon, G Tchatchou, S Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Haiman, CA Schumacher, F Henderson, BE Le Marchand, L Lindblom, A Margolin, S Hooning, MJ Hollestelle, A Kriege, M Koppert, LB Hopper, JL Southey, MC Tsimiklis, H Apicella, C Slettedahl, S Toland, AE Vachon, C Yannoukakos, D Giles, GG Milne, RL McLean, C Fasching, PA Ruebner, M Ekici, AB Beckmann, MW Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Ashworth, A Orr, N Schoemaker, MJ Swerdlow, A Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Goldberg, MS Labreche, F Dumont, M Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Brauch, H Bruning, T Ko, YD Radice, P Peterlongo, P Scuvera, G Fortuzzi, S Bogdanova, N Dork, T Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Devilee, P Tollenaar, RAEM Seynaeve, C Van Asperen, CJ Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Zheng, W Shrubsole, MJ Cai, QY Torres, D Anton-Culver, H Kristensen, V Bacot, F Tessier, DC Vincent, D Luccarini, C Baynes, C Ahmed, S Maranian, M Simard, J Chenevix-Trench, G Hall, P Pharoah, PDP Dunning, AM Easton, DF Hamann, U AF Kabisch, Maria Bermejo, Justo Lorenzo Duennebier, Thomas Ying, Shibo Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Shah, Mitul Perkins, Barbara J. Czene, Kamila Darabi, Hatef Eriksson, Mikael Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Lambrechts, Diether Neven, Patrick Peeters, Stephanie Weltens, Caroline Couch, Fergus J. Olson, Janet E. Wang, Xianshu Purrington, Kristen Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Peto, Julian dos-Santos-Silva, Isabel Johnson, Nichola Fletcher, Olivia Nevanlinna, Heli Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Schmidt, Marjanka K. Broeks, Annegien Cornelissen, Sten Hogervorst, Frans B. L. Li, Jingmei Brand, Judith S. Humphreys, Keith Guenel, Pascal Truong, Therese Menegaux, Florence Sanchez, Marie Burwinkel, Barbara Marme, Frederik Yang, Rongxi Bugert, Peter Gonzalez-Neira, Anna Benitez, Javier Pilar Zamora, M. Arias Perez, Jose I. Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Le Marchand, Loic Lindblom, Annika Margolin, Sara Hooning, Maartje J. Hollestelle, Antoinette Kriege, Mieke Koppert, Linetta B. Hopper, John L. Southey, Melissa C. Tsimiklis, Helen Apicella, Carmel Slettedahl, Seth Toland, Amanda E. Vachon, Celine Yannoukakos, Drakoulis Giles, Graham G. Milne, Roger L. McLean, Catriona Fasching, Peter A. Ruebner, Matthias Ekici, Arif B. Beckmann, Matthias W. Brenner, Hermann Dieffenbach, Aida K. Arndt, Volker Stegmaier, Christa Ashworth, Alan Orr, Nicholas Schoemaker, Minouk J. Swerdlow, Anthony Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Goldberg, Mark S. Labreche, France Dumont, Martine Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Radice, Paolo Peterlongo, Paolo Scuvera, Giulietta Fortuzzi, Stefano Bogdanova, Natalia Doerk, Thilo Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Van Asperen, Christi J. Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Zheng, Wei Shrubsole, Martha J. Cai, Qiuyin Torres, Diana Anton-Culver, Hoda Kristensen, Vessela Bacot, Francois Tessier, Daniel C. Vincent, Daniel Luccarini, Craig Baynes, Caroline Ahmed, Shahana Maranian, Mel Simard, Jacques Chenevix-Trench, Georgia Hall, Per Pharoah, Paul D. P. Dunning, Alison M. Easton, Douglas F. Hamann, Ute CA kConFab Investigators Australian Ovarian Canc Study Grp GENICA Network TI Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer SO CARCINOGENESIS LA English DT Article ID AURORA-B; CLEAVAGE FURROW; SURVIVIN; KINASE; CYTOKINESIS; MAMMAGLOBIN; SEGREGATION; METAPHASE; MITOSIS; MIDBODY AB The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3E(1) untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. C1 [Kabisch, Maria; Duennebier, Thomas; Ying, Shibo; Torres, Diana; Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany. [Bermejo, Justo Lorenzo] Univ Heidelberg Hosp, Inst Med Biometry & Informat, D-69120 Heidelberg, Germany. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Shah, Mitul; Perkins, Barbara J.; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. [Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S.; Humphreys, Keith; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Copenhagen Gen Populat Study, Herlev Hosp, DK-2730 Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, DK-2730 Herlev, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Dept Breast Surg, Herlev Hosp, DK-2730 Herlev, Denmark. [Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Lab Translat Genet, Dept Oncol, B-3000 Leuven, Belgium. [Neven, Patrick; Peeters, Stephanie; Weltens, Caroline] Univ Leuven, KU Leuven, Dept Oncol, Multidisciplinary Breast Ctr,Univ Hosp Leuven, B-3000 Leuven, Belgium. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Olson, Janet E.; Slettedahl, Seth; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Purrington, Kristen] Karmanos Canc Inst, Detroit, MI 48201 USA. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany. [Peto, Julian; dos-Santos-Silva, Isabel] Univ London London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1E 7HT, England. [Johnson, Nichola; Fletcher, Olivia; Ashworth, Alan; Orr, Nicholas; Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, FI-00029 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland. [Blomqvist, Carl] Helsinki Univ Cent Hosp, D-69120 Heidelberg, Germany. [Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten; Hogervorst, Frans B. L.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Li, Jingmei] Genome Inst Singapore, Human Genet Div, Singapore 138672, Singapore. [Guenel, Pascal; Truong, Therese; Menegaux, Florence; Sanchez, Marie] Natl Inst Hlth & Med Res, Ctr Res Epidemiol & Populat Hlth Environm Epidemi, F-94807 Villejuif, France. [Guenel, Pascal; Truong, Therese; Menegaux, Florence; Sanchez, Marie] Univ Paris 11, F-94807 Villejuif, France. [Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Burwinkel, Barbara; Yang, Rongxi] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Bugert, Peter] Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, D-68167 Mannheim, Germany. [Gonzalez-Neira, Anna; Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Madrid 28029, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid 28029, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia 46010, Spain. [Pilar Zamora, M.] Hosp Univ La Paz, Serv Oncol Med, Madrid 28046, Spain. [Arias Perez, Jose I.; Pharoah, Paul D. P.; Easton, Douglas F.] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo 33012, Spain. [Cox, Angela; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Sheffield S10 2RX, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield S10 2HQ, S Yorkshire, England. [Andrulis, Irene L.; Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. [Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, ON Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England. [Kerin, Michael J.; Miller, Nicola] Univ Hosp Galway, Clin Sci Inst, Galway, Ireland. [kConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [Australian Ovarian Canc Study Grp] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96813 USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, SE-17177 Stockholm, Sweden. [Hooning, Maartje J.; Hollestelle, Antoinette; Kriege, Mieke; Seynaeve, Caroline] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. [Koppert, Linetta B.] Erasmus MC Canc Inst, Dept Surg Oncol, NL-3008 AE Rotterdam, Netherlands. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Southey, Melissa C.; Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Aghia Paraskevi Attikis, Athens 15310, Greece. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3053, Australia. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic 3004, Australia. [Fasching, Peter A.; Ruebner, Matthias; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.] Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida K.] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, D-66119 Saarbrucken, Germany. [Schoemaker, Minouk J.; Swerdlow, Anthony; Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton SM2 5NG, Surrey, England. [Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada. [Goldberg, Mark S.] Royal Victoria Hosp, McGill Univ Hlth Ctr, Div Clin Epidemiol, Montreal, PQ H3G 2M1, Canada. [Labreche, France] Univ Montreal, Ecole Sante Publ, Dept Med Sociale & Prevent, Dept Sante Environm & Sante Travail, Montreal, PQ H3T 1A8, Canada. [Dumont, Martine; Simard, Jacques] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Quebec City, PQ G1V 4G2, Canada. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Oulu Univ Hosp, Dept Clin Chem,NordLab Oulu, FI-90220 Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Oulu Univ Hosp, Bioctr Oulu,NordLab Oulu, FI-90220 Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, FI-90220 Oulu, Finland. [Grip, Mervi] Univ Oulu, Oulu Univ Hosp, Dept Surg, FI-90220 Oulu, Finland. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, D-72074 Tubingen, Germany. [Brauch, Hiltrud] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Brauch, Hiltrud] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med German Social Accident, D-44789 Bochum, Germany. [Ko, Yon-Dschun] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany. Univ Bonn, Fac Med, Inst Pathol, D-53127 Bonn, Germany. [GENICA Network] Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, D-20246 Hamburg, Germany. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy. [Peterlongo, Paolo; Fortuzzi, Stefano] Fdn Ist FIRC Oncol Mol, IFOM, I-20139 Milan, Italy. [Scuvera, Giulietta] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy. [Fortuzzi, Stefano] Cogentech Canc Genet Test Lab, I-20139 Milan, Italy. [Bogdanova, Natalia] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany. [Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, D-30625 Hannover, Germany. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, FI-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, FI-70211 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Sch Med, Oncol, FI-70211 Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, FI-70210 Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, FI-40620 Jyvaskyla, Finland. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands. [Tollenaar, Robert A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2333 ZC Leiden, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Zheng, Wei; Shrubsole, Martha J.; Cai, Qiuyin] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Vanderbilt Epidemiol Ctr,Sch Med, Nashville, TN 37203 USA. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota 11001000, Colombia. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. [Kristensen, Vessela] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Inst Clin Med, N-0450 Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Dept Clin Mol Biol EpiGen, N-0450 Oslo, Norway. [Bacot, Francois; Tessier, Daniel C.; Vincent, Daniel] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Bacot, Francois; Tessier, Daniel C.; Vincent, Daniel] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Bacot, Francois; Tessier, Daniel C.; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4006, Australia. RP Hamann, U (reprint author), German Canc Res Ctr, Mol Genet Breast Canc B072, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. EM u.hamann@dkfz-heidelberg.de RI Shrubsole, Martha/K-5052-2015; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Brenner, Hermann/B-4627-2017; Gonzalez-Neira, Anna/C-5791-2015; Hartikainen, Jaana/E-6256-2015; Li, Jingmei/I-2904-2012; Garcia-Closas, Montserrat /F-3871-2015; Knight, Julia/A-6843-2012; OI Shrubsole, Martha/0000-0002-5591-7575; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Fortuzzi, Stefano/0000-0002-5662-3800; Schoemaker, Minouk/0000-0001-8403-2234; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Dunning, Alison Margaret/0000-0001-6651-7166; dos Santos Silva, Isabel/0000-0002-6596-8798; Ying, Shibo/0000-0001-5275-9383; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808 FU National Health and Medical Research Council; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA); Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C490/A10124]; European Community [223175, HEALTH-F2-2009-223175, 223175 (HEALTH-F2-2009-223175)]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative (GAME-ON initiative) [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Marit and Hans Rausings Initiative Against Breast Cancer.; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council and Herlev Hospital; 'Stichting tegen Kanker' [232-2008, 196-2010]; FWO; NIH [CA128978, CA116167, CA176785, CA116201, CA63464, CA54281, CA098758, CA132839]; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Cancer Research UK; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Dutch Cancer Society [NKI 2007-3839, 2009 4363]; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; Oxford Biomedical Research Centre; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; National Cancer Institute (USA) [UM1 CA164920]; NHMRC of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; CCSG Share Resource by National Institutes of Health [P30 CA016056]; Hellenic Cooperative Oncology Group [HR R_BG/04]; Australian NHMRC [209057, 251553, 504711]; German Cancer Aid (Deutsche Krebshilfe); Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Finnish Cancer Foundation, the Academy of Finland [250083, 122715]; Finnish Cancer Foundation, the Academy of Finland (Center of Excellence) [251314]; Finnish Cancer Foundation; Federal Ministry of Education and Research (BMBF) [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Fondazione IRCCS Istituto Nazionale Tumori; Government Funding (EVO) of Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; NIH grant [R01CA100374, R01 CA77398]; California Breast Cancer Research Fund [97-10500]; California Department of Public Health [103885]; Lon V Smith Foundation [LVS39420]; Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]; Swizz Bridge Award; [KULPFV/10/016-SymBioSysII]; [PBZ_KBN_122/P05/2004]; [P30 CA68485]; Associazione Italiana per la Ricerca sul Cancro FX The results shown in this article are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov; the ENCODE Consortium and the ENCODE production laboratory(s): http://genome.ucsc.edu/ENCODE; the Gene Expression Omnibus contributors: http://www.ncbi.nlm.nih.gov/geo and the 1000 Genomes Project Consortium: http://www.1000genomes.org/home.BCAC: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. COGS: This study would not have been possible without the contributions of the following: PH (COGS); DFE, PP, KM, MKB, QW (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, DFE, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), GCT, Antonis Antoniou, Lesley McGuffog, FJC and Ken Offit (CIMBA), JD, AMD, Andrew Lee, and Ed Dicks, CL and the staff of the Centre for Genetic Epidemiology Laboratory, JB, AGN and the staff of the CNIO genotyping unit, JS and DCT, FB, DV, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, SEB, SFN, BGN, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. SEARCH: The SEARCH and EPIC teams. pKARMA: The Swedish Medical Research Counsel. CGPS: Staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen. The Danish Breast Cancer Group (DBCG) is acknowledged for the tumor information. LMBC: Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. MARIE: Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers, Stefan Nickels. BBCS: Eileen Williams, Elaine Ryder-Mills, Kara Sargus. HEBCS: Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen, Irja Erkkila. ABCS: Sten Cornelissen, Richard van Hien, Linde Braaf, FBLH, Senno Verhoef, Laura van 't Veer, Emiel Rutgers, Ellen van der Schoot, Femke Atsma. SASBAC: The Swedish Medical Research Counsel. BSUCH: Medical Faculty Mannheim, Germany (PB). CNIO-BCS: Guillermo Pita, Charo Alonso, Daniel Herrero, Nuria Alvarez, MPZ, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO). SBCS: Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian and Dan Connley. OFBCR: Teresa Selander, Nayana Weerasooriya. BIGGS: Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. kConFab/AOCS: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the National Health and Medical Research Council, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA) for their contributions to this resource, and the many families who contribute to kConFab. RBCS: Petra Bos, Jannet Blom, Ellen Crepin, Anja Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic. ABCFS: Maggie Angelakos, Judi Maskiell, Gillian Dite. TNBCC: Robert Pilarski and Charles Shapiro were instrumental in the formation of the OSU Breast Cancer Tissue Bank. We thank the Human Genetics Sample Bank for processing of samples and providing OSU Columbus area control samples. BBCC: Silke Landrith, Alexander Hein, Sonja Oeser, Michael Schneider.; ESTHER: Hartwig Ziegler, Sonja Wolf, Volker Hermann. UKBGS: We thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge National Health Service (NHS) funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. PBCS: Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. MTLGEBCS: We would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Centre, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. OBCS: Meeri Otsukka, Kari Mononen. GENICA: The GENICA Network: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany; (HBra, Wing-Yee Lo, Christina Justenhoven), Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (YDK, Christian Baisch), Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer), Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (UH) and Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (TB, Beate Pesch, Sylvia Rabstein, Anne Lotz); Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). MBCSG: Siranoush Manoukian, Bernard Peissel and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and Loris Bernard the personnel of the Cogentech Cancer Genetic Test Laboratory. HMBCS: Peter Hillemanns, Hans Christiansen and Johann H. Karstens. KBCP: Eija Myohanen, Helena Kemilainen. ORIGO: We thank E. Krol-Warmerdam and J. Blom for patient accrual, administering questionnaires and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr J. Molenaar. NBHS: We thank study participants and research staff for their contributions and commitment to this study. SKKDKFZS: We thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. CTS: The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, and HAC, Argyrios Ziogas, and Hannah Park at the University of California Irvine. NBCS: NBCS includes the following clinical collaborators: Prof. Per Eystein Lonning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), Prof. Em. Sophie D.; Fossa, MD (National Resource Centre for Longterm Studies after Cancer, Rikshospitalet-Radiumhospitalet Cancer Clinic Montebello, Oslo, Norway), Head physician Tone Ikdahl, MD (Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr Lars Ottestad, MD (Department of Genetics and Department of Oncology, Oslo University Hospital Radiumhospitalet), Dr Marit Muri Holmen, MD (Department of Radiology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr Vilde Haakensen, MD (Department of Genetics and Department of Oncology, Oslo University Hospital Radiumhospitalet and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Prof. Bjorn Naume, MD (Division of Cancer Medicine and Radiotherapy, Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Associate Prof. Aslaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Prof. Inger Torhild Gram, MD (Department of Community Medicine, Faculty of Health Sciences, University of Tromso and Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromso, Norway), Prof. Em. Rolf Karesen, MD (Department of Breast and Endocrine Surgery, Institute for Clinical Medicine, Ullevaal Hospital, Oslo University Hospital and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Dr Ellen Schlichting, MD (Department for Breast and Endocrine Surgery, Oslo University Hospital Ullevaal, Oslo, Norway), Prof. Toril Sauer, MD (Department of Pathology at Akershus University Hospital, Lorenskog, Norway), Dr Olav Engebraten, MD (Institute for Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr Margit Riis, MD (Department of Surgery, Akershus University Hospital and Department of Clinical Molecular Biology (EpiGen), Institute of Clinical Medicine, Akershus University Hospital, University of Oslo, Lorenskog, Norway).; This work was supported by the following: BCAC: Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). iCOGS: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. SEARCH: Cancer Research UK [C490/A10124] and UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. pKARMA: Marit and Hans Rausings Initiative Against Breast Cancer. CGPS: Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. LMBC: 'Stichting tegen Kanker' (232-2008 and 196-2010). D.L. is supported by the FWO and the KULPFV/10/016-SymBioSysII. MCBCS: NIH grants CA128978, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MARIE: Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. BBCS: Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). HEBCS: Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. ABCS: Dutch Cancer Society [grants NKI 2007-3839 and 2009 4363]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. SASBAC: Agency for Science, Technology and Research of Singapore (A*STAR), the United States National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. CECILE: Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). BSUCH: Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). CNIO-BCS: Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by the Instituto de Salud Carlos III. SBCS: Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. Ontario Familial Breast Cancer Registry (OFBCR): UM1 CA164920 from the National Cancer Institute (USA).; The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the USA Government or the BCFR. BIGGS ES: NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London, UK. I. T. is supported by the Oxford Biomedical Research Centre. kConFab: National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MEC: NIH grants CA63464, CA54281, CA098758 and CA132839. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. RBCS: Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the NHMRC of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a NHMRC Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a NHMRC senior research fellow and a Victorian Breast Cancer Research Consortium Group Leader. TNBCC: Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-ARISTEIA. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. BBCC: ELAN-Fond of the University Hospital of Erlangen. ESTHER: Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). UKBGS: Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. PBCS: Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.; MTLGEBCS: Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade-grant # PSR-SIIRI-701. OBCS: Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. GENICA: Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. MBCSG: Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). HMBCS: Friends of Hannover Medical School and by the Rudolf Bartling Foundation. KBCP: Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations and by the strategic funding of the University of Eastern Finland. ORIGO: Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The SZBCS was supported by grant PBZ_KBN_122/P05/2004. NBHS: NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. SKKDKFZS: DKFZ. CTS: California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). NBCS: Norwegian Research council, 155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and a Swizz Bridge Award to ALBD. NR 51 TC 2 Z9 2 U1 2 U2 18 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 FEB PY 2015 VL 36 IS 2 BP 256 EP 271 DI 10.1093/carcin/bgu326 PG 16 WC Oncology SC Oncology GA CC2ZX UT WOS:000350214900010 PM 25586992 ER PT J AU Musani, SK Fox, ER Kraja, A Bidulescu, A Lieb, W Lin, HH Beecham, A Chen, MH Felix, JF Fox, CS Kao, WHL Kardia, SLR Liu, CT Nalls, MA Rundek, T Sacco, RL Smith, J Sun, YV Wilson, G Zhang, ZG Mosley, TH Taylor, HA Vasan, RS AF Musani, Solomon K. Fox, Ervin R. Kraja, Aldi Bidulescu, Aurelian Lieb, Wolfgang Lin, Honghuang Beecham, Ashley Chen, Ming-Huei Felix, Janine F. Fox, Caroline S. Kao, W. H. Linda Kardia, Sharon L. R. Liu, Ching-Ti Nalls, Mike A. Rundek, Tatjana Sacco, Ralph L. Smith, Jennifer Sun, Yan V. Wilson, Gregory Zhang, Zhaogong Mosley, Thomas H. Taylor, Herman A. Vasan, Ramachandran S. TI Genome-Wide Association Analysis of Plasma B-Type Natriuretic Peptide in Blacks The Jackson Heart Study SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetic association studies; genetics; genome-wide association study; genotype ID STAGE RENAL-DISEASE; BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; BNP LEVELS; GENE; COMMON; POLYMORPHISM; VARIANTS; FAILURE; RISK AB Background-Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective; however, in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass. Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. Methods and Results-We performed a meta-analysis of 2 genome-wide association results from a total of 2790 blacks. We assumed an additive genetic model in an association analysis of imputed 2.5 million single-nucleotide polymorphism dosages with residuals generated from multivariable-adjusted logarithmically transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, P=1.18x10(-09)) and a novel missense variant in the KLKB1 locus (rs3733402, P=1.75x10(-11)) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, and an average of 8.1 pg/mL increase was associated with 2 allele copies. In a companion study, single-nucleotide polymorphisms in this loci were cross-checked with genome-wide association results for the aldosterone/renin ratio in individuals of European ancestry, and rs3733402 was genome-wide significant (P<5.0x10(-8)), suggesting possible shared genetic architecture for these 2 pathways. Other statistically significant relations for these single-nucleotide polymorphisms included the following: rs198389 with systolic blood pressure in blacks (COGENT consortium) and rs198389 and rs3733402 with left ventricular mass in whites (EchoGEN consortium). Conclusions-These findings improve our knowledge of the genetic basis of BNP variation in blacks, demonstrate a possible shared allelic architecture for BNP with aldosterone-renin ratio, and motivate further studies of underlying mechanisms. C1 [Musani, Solomon K.; Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39213 USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS 39213 USA. [Kraja, Aldi] Washington Univ, Sect Stat Genom, St Louis, MO 63130 USA. [Bidulescu, Aurelian] Indiana Univ, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Lieb, Wolfgang] Univ Kiel, Kiel, Germany. [Lieb, Wolfgang; Felix, Janine F.; Fox, Caroline S.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Sacco, Ralph L.] Univ Miami, Dept Neurol, Coral Gables, FL 33124 USA. Univ Miami, John P Hussman Inst Human Genom, Miller Sch Med, Coral Gables, FL 33124 USA. [Rundek, Tatjana] Univ Miami, Dept Publ Hlth Serv, Coral Gables, FL 33124 USA. [Beecham, Ashley; Sacco, Ralph L.] Univ Miami, Coral Gables, FL 33124 USA. [Felix, Janine F.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Felix, Janine F.] Netherlands Consortium Hlth Aging NGI NCHA, Genom Initiat, Leiden, Netherlands. [Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kardia, Sharon L. R.; Smith, Jennifer] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Liu, Ching-Ti] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Nalls, Mike A.] NIA, Mol Genet Sect, Bethesda, MD 20892 USA. [Sun, Yan V.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Wilson, Gregory] Jackson State Univ, Coll Publ Serv, Jackson, MS USA. [Zhang, Zhaogong] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. Morehouse Sch Med, Cardiovasc Res Ctr, Atlanta, GA 30310 USA. RP Musani, SK (reprint author), Univ Mississippi, Med Ctr, 350 W Woodrow Wilson Ave,Suite 701, Jackson, MS 39213 USA. EM smusani@umc.edu RI Lieb, Wolfgang/C-1990-2012; OI Felix, Janine/0000-0002-9801-5774; Lin, Honghuang/0000-0003-3043-3942; Ramachandran, Vasan/0000-0001-7357-5970; Smith, Jennifer/0000-0002-3575-5468 FU National Heart, Lung, and Blood Institute on Minority Health and Health Disparities [HSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C] FX The Jackson Heart Study is supported by contracts HSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute on Minority Health and Health Disparities. NR 46 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD FEB PY 2015 VL 8 IS 1 BP 122 EP 130 DI 10.1161/CIRCGENETICS.114.000900 PG 9 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA CB8IW UT WOS:000349873200017 PM 25561047 ER PT J AU Gronholm, J Lenardo, MJ AF Groenholm, Juha Lenardo, Michael J. TI Novel diagnostic and therapeutic approaches for autoimmune diabetes - A prime time to treat insulitis as a disease SO CLINICAL IMMUNOLOGY LA English DT Review DE Autoantibody; Insulitis; Type 1 diabetes; Tolerance ID RANDOMIZED CONTROLLED-TRIAL; HEAT-SHOCK-PROTEIN; BETA-CELL FUNCTION; ANTIBODY STANDARDIZATION PROGRAM; GLUTAMIC-ACID DECARBOXYLASE; RECENT-ONSET; DOUBLE-BLIND; 1ST-DEGREE RELATIVES; GENERAL-POPULATION; COXSACKIEVIRUS B1 AB Type 1 diabetes is a progressive autoimmune disease with no curative treatment, making prevention critical. At the time of diagnosis, a majority of the insulin secreting beta-cells have already been destroyed. Insulitis, lymphocytic infiltration to the pancreatic islets, is believed to begin months to years before the clinical symptoms of insulin deficiency appear. Insulitis should be treated as its own disease, for it is a known precursor to autoimmune diabetes. Because it is difficult to detect insulitic cellular infiltrates noninvasively, considerable interest has been focused on the levels of islet autoantibodies in blood as measurable diagnostic markers for islet autoimmunity. The traditional islet autoantibody detection assays have many limitations. New electrochemiluminescence-based autoantibody detection assays have the potential to overcome these challenges and they offer promising, cost-effective screening tools in identifying high-risk individuals for trials of preventive interventions. Here, we outline diagnostic and therapeutic strategies to overcome pancreatic beta-cell destroying insulitis. (C) 2014 Elsevier Inc. All rights reserved. C1 [Groenholm, Juha; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, Clin Genom Program,NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Immunol Lab, Clin Genom Program,NIH, Bldg 10,Room 11D14,Ctr Dr, Bethesda, MD 20892 USA. EM juhapetrikristian.gronholm@nih.gov; lenardo@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Clinical Center; National Human Genome Research Institute, National Institutes of Health; Sigrid Juselius Foundation; Emil Aaltonen Foundation FX We thank Anthony Venida for the careful review of our manuscript as well as Prof. David Harlan and Dr. Kimberly Shafer-Weaver on their valuable comments on the manuscript. Dr. Samuli Rounioja is acknowledged for providing us the IAA-RIA protocol. This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Human Genome Research Institute, National Institutes of Health. J.G. was supported by a fellowship grant from Sigrid Juselius Foundation and by Emil Aaltonen Foundation. Wellstat Diagnostics LLC and Novo Nordisk are acknowledged for their collaboration. NR 87 TC 2 Z9 2 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2015 VL 156 IS 2 BP 109 EP 118 DI 10.1016/j.clim.2014.11.007 PG 10 WC Immunology SC Immunology GA CC2QL UT WOS:000350189600003 PM 25486604 ER PT J AU McCully, CML Bacher, J MacAllister, RP Steffen-Smith, EA Saleem, K Thomas, ML Cruz, R Warren, KE AF McCully, Cynthia M. Lester Bacher, John MacAllister, Rhonda P. Steffen-Smith, Emilie A. Saleem, Kadharbatcha Thomas, Marvin L., III Cruz, Rafael Warren, Katherine E. TI Development of a Cerebrospinal Fluid Lateral Reservoir Model in Rhesus Monkeys (Macaca mulatta) SO COMPARATIVE MEDICINE LA English DT Article ID DRUGS AB Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates. C1 [McCully, Cynthia M. Lester; MacAllister, Rhonda P.; Steffen-Smith, Emilie A.; Cruz, Rafael; Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. [Bacher, John; Thomas, Marvin L., III] Off Res Serv, Bethesda, MD USA. [Saleem, Kadharbatcha] NIMH, Bethesda, MD 20892 USA. RP McCully, CML (reprint author), NCI, Bethesda, MD 20892 USA. EM mccullyc@mail.nih.gov NR 6 TC 1 Z9 1 U1 1 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD FEB PY 2015 VL 65 IS 1 BP 77 EP 82 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA CC0FD UT WOS:000350010300010 ER PT J AU Ashish, N Bamman, MM Cerny, FJ Cooper, DM D'Hemecourt, P Eisenmann, JC Ericson, D Fahey, J Falk, B Gabriel, D Kahn, MG Kemper, HCG Leu, SY Liem, RI McMurray, R Nixon, PA Olin, JT Pianosi, PT Purucker, M Radom-Aizik, S Taylor, A AF Ashish, Naveen Bamman, Marcas M. Cerny, Frank J. Cooper, Dan M. D'Hemecourt, Pierre Eisenmann, Joey C. Ericson, Dawn Fahey, John Falk, Bareket Gabriel, Davera Kahn, Michael G. Kemper, Han C. G. Leu, Szu-Yun Liem, Robert I. McMurray, Robert Nixon, Patricia A. Olin, J. Tod Pianosi, Paolo T. Purucker, Mary Radom-Aizik, Shlomit Taylor, Amy TI The Clinical Translation Gap in Child Health Exercise Research: A Call for Disruptive Innovation SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE exercise; clinical trials; pediatrics; data harmonization; cardiopulmonary exercise testing ID MAXIMAL OXYGEN-UPTAKE; PHYSICAL-ACTIVITY; AEROBIC FITNESS; ADOLESCENTS; DISEASE; ASTHMA; OBESITY; YOUTH; VO2 AB In children, levels of play, physical activity, and fitness are key indicators of health and disease and closely tied to optimal growth and development. Cardiopulmonary exercise testing (CPET) provides clinicians with biomarkers of disease and effectiveness of therapy, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response that is hidden when the child is at rest. Yet the growth of clinical trials utilizing CPET in pediatrics remains stunted despite the current emphasis on preventative medicine and the growing recognition that therapies used in children should be clinically tested in children. There exists a translational gap between basic discovery and clinical application in this essential component of child health. To address this gap, the NIH provided funding through the Clinical and Translational Science Award (CTSA) program to convene a panel of experts. This report summarizes our major findings and outlines next steps necessary to enhance child health exercise medicine translational research. We present specific plans to bolster data interoperability, improve child health CPET reference values, stimulate formal training in exercise medicine for child health care professionals, and outline innovative approaches through which exercise medicine can become more accessible and advance therapeutics across the broad spectrum of child health. C1 [Ashish, Naveen] Univ So Calif, Dept Neurol, Los Angeles, CA 90089 USA. [Bamman, Marcas M.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. [Cerny, Frank J.] SUNY Buffalo, Dept Pediat, Womens & Childrens Hosp Buffalo, Buffalo, NY USA. [Cooper, Dan M.; Leu, Szu-Yun; Radom-Aizik, Shlomit] Univ Calif Irvine, Inst Clin & Translat Sci, Dept Pediat, Pediat Exercise & Genom Res Ctr, Irvine, CA 92697 USA. [D'Hemecourt, Pierre] Boston Childrens Hosp, Div Sports Med, Boston, MA USA. [Eisenmann, Joey C.] Michigan State Univ, Coll Osteopath Med, E Lansing, MI 48824 USA. [Ericson, Dawn] Boston Childrens Hosp, Dept Pulm Med, Boston, MA USA. [Fahey, John] Yale Univ, New Haven, CT USA. [Falk, Bareket] Brock Univ, Dept Kinesiol, St Catharines, ON L2S, Canada. [Gabriel, Davera] Univ Calif Davis, Ctr Hlth Technol, Davis, CA 95616 USA. [Kahn, Michael G.] Univ Colorado, Dept Pediat, Aurora, CO USA. [Kemper, Han C. G.] Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Liem, Robert I.] Northwestern Univ Feinberg Sch Med, Div Pediat Hematol, Chicago, IL USA. [McMurray, Robert] Univ N Carolina, Dept Exercise & Sport Sci, Chapel Hill, NC USA. [Nixon, Patricia A.] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Olin, J. Tod] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Pianosi, Paolo T.] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN USA. [Purucker, Mary] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Taylor, Amy] Childrens Hosp Colorado, Childrens Clin Res Org & Pediat Cardiol, Aurora, CO USA. RP Cooper, DM (reprint author), Univ Calif Irvine, Inst Clin & Translat Sci, Dept Pediat, Pediat Exercise & Genom Res Ctr, Irvine, CA 92697 USA. EM dcooper@uci.edu FU NIH through the Clinical and Translational Science Award (CTSA) at the University of California, Irvine [3UL1RR031985]; Mechanisms of Health Effects of Exercise in Children [P01HD-048721] FX This effort was supported by NIH through the Clinical and Translational Science Award (CTSA) at the University of California, Irvine (Grant 3UL1RR031985) and a program project grant, Mechanisms of Health Effects of Exercise in Children (P01HD-048721). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. NR 52 TC 4 Z9 5 U1 2 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2015 VL 8 IS 1 BP 67 EP 76 DI 10.1111/cts.12194 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CC0BT UT WOS:000350000700015 PM 25109386 ER PT J AU Nash, TE Mahanty, S Loeb, JA Theodore, WH Friedman, A Sander, JW Singh, G Cavalheiro, E Del Brutto, OH Takayanagui, OM Fleury, A Verastegui, M Preux, PM Montano, S Pretell, EJ White, AC Gonzales, AE Gilman, RH Garcia, HH AF Nash, Theodore E. Mahanty, Siddhartha Loeb, Jeffrey A. Theodore, William H. Friedman, Alon Sander, Josemir W. Singh, Gagandeep Cavalheiro, Esper Del Brutto, Oscar H. Takayanagui, Osvaldo M. Fleury, Agnes Verastegui, Manuela Preux, Pierre-Marie Montano, Silvia Pretell, E. Javier White, A. Clinton Gonzales, Armando E. Gilman, Robert H. Garcia, Hector H. TI Neurocysticercosis: A natural human model of epileptogenesis SO EPILEPSIA LA English DT Article DE Epilepsy; Seizure; Taenia solium; Helminth ID TEMPORAL-LOBE EPILEPSY; TERM-FOLLOW-UP; CALCIFIED NEUROCYSTICERCOSIS; PERILESIONAL EDEMA; HIPPOCAMPAL SCLEROSIS; CALCIFICATIONS; ASSOCIATION AB ObjectiveTo develop a better understanding of mechanisms of seizures and long-term epileptogenesis using neurocysticercosis. MethodsA workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis. ResultsHuman neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis. SignificanceNaturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world's most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state. C1 [Nash, Theodore E.; Mahanty, Siddhartha] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Parasit Dis Lab, Bethesda, MD USA. [Loeb, Jeffrey A.] Univ Illinois, Dept Neurol & Rehabil, Chicago, IL USA. [Theodore, William H.] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Epilepsy Sect, Bethesda, MD USA. [Friedman, Alon] Ben Gurion Univ Negev, Zlotowski Ctr Neuroscience, Negev, Beer Sheva, Israel. [Friedman, Alon] Dalhousie Univ, Dept Med Neuroscience, Halifax, NS, Canada. [Sander, Josemir W.] UCL Inst Neurol, NIHR UCL Hosp Biomed Res Ctr, Dept Clin Expt Epilepsy, London, United Kingdom. [Sander, Josemir W.] Netherlands Fdn, Epilepsy Inst, Heemstede, Netherlands. [Singh, Gagandeep] Dept Neurol, Dayan & Med Coll, Ludhiana, Punjab, India. [Cavalheiro, Esper] Univ Fed Sao Paulo, Dept Neurol & Neurosurgery, Sao Paulo, Brazil. [Del Brutto, Oscar H.] Univ Espiritu Santo, Sch Med, Guayaquil, Ecuador. [Takayanagui, Osvaldo M.] RibeirAo Preto Med Sch Univ SAo Paulo, Dept Neurosciences & Behav, Ribeirao Preto, Brazil. [Fleury, Agnes] Natl Autonomous Univ Mexico & Natl Inst Neurol &, Inst Biomed Res, Mexico City, DF, Mexico. [Verastegui, Manuela] Univ Peruana Cayetano Heredia, Fac Sci & Philosophy, Dept Cellular & Mol Sci, Lima, Peru. [Preux, Pierre-Marie] Univ Limoges, Inst Neuroepidemiol & Trop Neurol, INSERM, CHU Limoges, Limoges, France. [Montano, Silvia] US Naval Med Res Unit 6, Callao, Peru. [Pretell, E. Javier] Hosp Alberto Sabogal, Dept Neurol, Callao, Peru. [White, A. Clinton] Univ Texas, Div Infect Dis, Dept Internal Med, Galveston, TX USA. [Gonzales, Armando E.] Natl Univ San Marcos, Sch Vet Med, Dept Vet Publ Hlth, Lima, Peru. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Garcia, Hector H.] Inst Neurol Dis, Cysticercosis Unit, Lima, Peru. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Univ Peruana Cayetano Heredia, Dept Microbiol, Ctr Global Hlth Tumbes, Lima, Peru. RP Nash, TE (reprint author), 9000 Rockville Pike,Bldg 4, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov RI Sander, Josemir/C-1576-2008; PREUX, Pierre-Marie/B-8393-2014; Takayanagui, Osvaldo/C-8159-2013; OI Sander, Josemir/0000-0001-6041-9661; PREUX, Pierre-Marie/0000-0002-2171-2977; Takayanagui, Osvaldo/0000-0002-8190-0275; White, A Clinton/0000-0002-9668-4632; Mahanty, Siddhartha/0000-0003-1068-0524 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases from the National Institutes of Health; Office of Rare Diseases Research from the National Institutes of Health; National Center for Advancing Translational Sciences from the National Institutes of Health; Fogarty International Center Training Grant from the National Institutes of Health [D43 TW00114]; Wellcome Trust Senior International Research Fellowship in Tropical Medicine and Public Health FX Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases Research, the National Center for Advancing Translational Sciences, and Fogarty International Center Training Grant D43 TW00114, all from the National Institutes of Health. H.G. is supported by a Wellcome Trust Senior International Research Fellowship in Tropical Medicine and Public Health. NR 29 TC 11 Z9 11 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD FEB PY 2015 VL 56 IS 2 BP 177 EP 183 DI 10.1111/epi.12849 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CC2AH UT WOS:000350146300013 PM 25534640 ER PT J AU Welch, RD Nicholas, K Durkalski-Mauldin, VL Lowenstein, DH Conwit, R Mahajan, PV Lewandowski, C Silbergleit, R AF Welch, Robert D. Nicholas, Katherine Durkalski-Mauldin, Valerie L. Lowenstein, Daniel H. Conwit, Robin Mahajan, Prashant V. Lewandowski, Christopher Silbergleit, Robert CA Neurological Emergencies Treatment TI Intramuscular midazolam versus intravenous lorazepam for the prehospital treatment of status epilepticus in the pediatric population SO EPILEPSIA LA English DT Article DE Status epilepticus; Prehospital treatment; Pediatrics ID RANDOMIZED CLINICAL-TRIAL; DIAZEPAM; CHILDREN; RESUSCITATION; MANAGEMENT; SEIZURES; ADULTS AB ObjectiveTo examine the effectiveness of intramuscular (IM) midazolam versus intravenous (IV) lorazepam for the treatment of pediatric patients with status epilepticus (SE) in the prehospital care setting. MethodsThis multicenter clinical trial randomized patients diagnosed with SE to receive either IM midazolam or IV lorazepam administered by paramedics in the prehospital care setting. Included in this secondary analysis were only patients younger than 18years of age. Evaluated were the associations of the treatment group (IM vs. IV) with the primary outcome, defined as seizure cessation prior to emergency department (ED) arrival, and with patient characteristics, time to important events, and adverse events. Descriptive statistics and 99% confidence intervals (CIs) were used for the analysis. ResultsOf 893 primary study subjects, 120 met criteria for this study (60 in each treatment group). There were no differences in important baseline characteristics or seizure etiologies between groups. The primary outcome was met in 41 (68.3%) and 43 (71.7%) of subjects in the IM and IV groups, respectively (risk difference [RD] -3.3%, 99% CI -24.9% to 18.2%). Similar results were noted for those younger than 11years (RD -1.3%, 99% CI -25.7% to 23.1%). Time from initiating the treatment protocol was shorter for children who received IM midazolam, mainly due to the shorter time to administer the active treatment. Safety profiles were similar. SignificanceIM midazolam can be rapidly administered and appears to be safe and effective for the management of children with SE treated in the prehospital setting. The results must be interpreted in the context of the secondary analysis design and sample size of the study. C1 [Welch, Robert D.] Wayne State Univ Sch Med, Dept Emergency Med, Detroit, MI USA. [Welch, Robert D.] Wayne State Univ Sch Med, Cardiovasc Res Inst, Detroit, MI USA. [Nicholas, Katherine; Durkalski-Mauldin, Valerie L.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Lowenstein, Daniel H.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. [Mahajan, Prashant V.] Wayne State Univ Sch Med, Dept Pediat, Detroit, MI USA. [Lewandowski, Christopher] Henry Ford Hlth Syst, Dept Emergency Med, Detroit, MI USA. [Silbergleit, Robert] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. RP Welch, RD (reprint author), Wayne State Univ Sch Med, Detroit Receiving Hosp UHC 6G, Dept Emergency Med, 4201 St Antoine, Detroit, MI 48201 USA. EM rwelch@med.wayne.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [U01NS056975, U01NS059041]; National Institutes of Health Office of the Director CounterACT Program FX Grant Support: National Institute of Neurological Disorders and Stroke (NINDS) (U01NS056975 and U01NS059041); National Institutes of Health Office of the Director CounterACT Program; Biomedical Advanced Research and Development Authority of the Assistant Secretary for Preparedness and Response. NR 15 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD FEB PY 2015 VL 56 IS 2 BP 254 EP 262 DI 10.1111/epi.12905 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CC2AH UT WOS:000350146300023 PM 25597369 ER PT J AU Yi, F DeCan, E Stoll, K Marceau, E Deisseroth, K Lawrence, JJ AF Yi, Feng DeCan, Evan Stoll, Kurt Marceau, Eric Deisseroth, Karl Lawrence, J. Josh TI Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures SO EPILEPSIA LA English DT Article DE Pilocarpine; Muscarinic; Acetylcholine; Hippocampus; Seizures ID TEMPORAL-LOBE EPILEPSY; PROTEIN-COUPLED RECEPTORS; GAMMA OSCILLATIONS; CHOLINERGIC MODULATION; MOUSE HIPPOCAMPUS; PYRAMIDAL CELLS; M1 RECEPTOR; IN-VITRO; MODEL; MICE AB ObjectiveA common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (mAChR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine-induced seizures (PISs) remain unclear. Global M-1 mAChR (M1R) knockout mice are resistant to PISs, implying that M1R activation disrupts excitation/inhibition balance. Parvalbumin-positive (PV) inhibitory neurons express M(1)Rs, participate in cholinergically induced oscillations, and can enter a state of depolarization block (DB) during epileptiform activity. Here, we test the hypothesis that pilocarpine activation of M(1)Rs expressed on PV cells contributes to PISs. MethodsCA1 PV cells in PV-CRE mice were visualized with a floxed YFP or hM3Dq-mCherry adeno-associated virus, or by crossing PV-CRE mice with the RosaYFP reporter line. To eliminate M(1)Rs from PV cells, we generated PV-M(1)knockout (KO) mice by crossing PV-CRE and floxed M-1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200m). In behavioral experiments, locomotion and seizure symptoms were recorded in wild-type (WT) or PV-M1KO mice during PISs. ResultsPilocarpine significantly increased AP frequency in CA1 PV cells into the gamma range. In the continued presence of pilocarpine, a subset (5/7) of PV cells progressed to DB, which was mimicked by hM3Dq activation of Gq-receptor signaling. Pilocarpine-induced depolarization, AP firing at gamma frequency, and progression to DB were prevented in CA1 PV cells of PV-M1KO mice. Finally, compared to WT mice, PV-M1KO mice were associated with reduced severity of PISs. SignificancePilocarpine can directly depolarize PV+ cells via M1R activation, but a subset of these cells progress to DB. Our electrophysiologic and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV-mediated -aminobutyric acid (GABA)ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs. C1 [Yi, Feng; DeCan, Evan; Stoll, Kurt; Marceau, Eric; Lawrence, J. Josh] Univ Montana, COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. [Yi, Feng; DeCan, Evan; Stoll, Kurt; Marceau, Eric; Lawrence, J. Josh] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [DeCan, Evan] Univ Montana, Davidson Honors Coll, Missoula, MT 59812 USA. [Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. RP Lawrence, JJ (reprint author), Univ Montana, Dept Biomed & Pharmaceut Sci, COBRE Ctr Struct & Funct Neurosci, 391 Skaggs Bldg,32 Campus Dr, Missoula, MT 59812 USA. EM josh.lawrence@umontana.edu FU National Institutes of Health (NIH) [R01 NS069689]; NCRR [P20RR015583]; Epilepsy Foundation; Davidson Honors College Undergraduate Research Award; NSF National Science Foundation Experimental Program to Stimulate Competitive Research (EPSCoR); University of Montana Small Grants Program; Montana State University Mountains and Minds Research Experiences for Undergraduates Program [NSF REU 1156855]; National Center for Research Resources [P20RR015583, P20RR017670, P20GM10356] FX We thank Drs. Susumu Tonegawa and David Gerber (MIT) for floxed M1 mice, Ed Calloway (Salk Institute) and Silvia Arber (University of Basel, Switzerland) for PV-CRE mice, Dr. Bryan Roth (University of North Carolina-Chapel Hill) for hM3Dq-mCherry AAV, Miriam Rose Baker for preliminary data on PIS experiments, Alison Hixon for help with genotyping, and Drs. Laura Ewell, Debbie Smith, and Neil Nathanson for critically reviewing the manuscript. Funding was from the National Institutes of Health (NIH) R01 NS069689 (JJL), NCRR P20RR015583 (JJL), the Epilepsy Foundation (JJL), a Davidson Honors College Undergraduate Research Award (ED), NSF National Science Foundation Experimental Program to Stimulate Competitive Research (EPSCoR) (KES), the University of Montana Small Grants Program (JJL and KES), and the Montana State University Mountains and Minds Research Experiences for Undergraduates Program (NSF REU 1156855; EM). ED was a Center for Structural and Functional Neuroscience Summer Undergraduate Research Fellow. National Center for Research Resources P20RR015583, P20RR017670, and P20GM10356 grants supported core imaging and behavioral facilities. NR 55 TC 8 Z9 8 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD FEB PY 2015 VL 56 IS 2 BP 297 EP 309 DI 10.1111/epi.12883 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA CC2AH UT WOS:000350146300028 PM 25495999 ER PT J AU Kirsch, M Mitchell, SA Dobbels, F Stussi, G Basch, E Halter, JP De Geest, S AF Kirsch, Monika Mitchell, Sandra A. Dobbels, Fabienne Stussi, Georg Basch, Ethan Halter, Jorg P. De Geest, Sabina TI Linguistic and content validation of a German-language PRO-CIVAE-based patient-reported outcomes instrument to evaluate the late effect symptom experience after allogeneic hematopoietic stem cell transplantation SO EUROPEAN JOURNAL OF ONCOLOGY NURSING LA English DT Article DE Patient-reported outcomes; Stem cell transplantation; PRO-CTCAE; Survivorship; Late effects; Validity; Mixed methods; Symptom experience ID QUALITY-OF-LIFE; VERSUS-HOST-DISEASE; TASK-FORCE REPORT; CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; LONG-TERM SURVIVORS; CLINICAL-TRIALS; CANCER-PATIENTS; CARE AB Purpose: The aim of this sequential mixed methods study was to develop a PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events)-based measure of the symptom experience of late effects in German speaking long-term survivors of allogeneic stem cell transplantation (SCT), and to examine its content validity. Methods: The US National Cancer Institute's PRO-CTAE item library was translated into German and linguistically validated. PRO-CTCAE symptoms prevalent in >50% of survivors (n = 15) and recognized in its importance by SCT experts (n = 9) were identified. Additional concepts relevant to the symptom experience and its consequences were elicited. Content validity of the PROVIVO (Patient-Reported Outcomes of long-term survivors after allogeneic SCT) instrument was assessed through an additional round of cognitive debriefing in 15 patients, and item and scale content validity indices by 9 experts. Results: PROVIVO is comprised of a total of 49 items capturing the experience of physical, emotional and cognitive symptoms. To improve the instrument's utility for clinical decision-making, questions soliciting limitations in activities of daily living, frequent infections, and overall well-being were added. Cognitive debriefings demonstrated that items were well understood and relevant to the SCT survivor experience. Scale Content Validity Index (CVI) (0.94) and item CVI (median = 1; range 0.75-1) were very high. Conclusions: Qualitative and quantitative data provide preliminary evidence supporting the content validity of PROVIVO and identify a PRO-CTCAE item bundle for use in SCT survivors. A study to evaluate the measurement properties of PROVIVO and to examine its capacity to improve survivorship care planning is underway. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kirsch, Monika; De Geest, Sabina] Univ Basel, Inst Nursing Sci, CH-4056 Basel, Switzerland. [Kirsch, Monika; Halter, Jorg P.] Univ Basel Hosp, Dept Haematol, Basel, Switzerland. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Bethesda, MD 20892 USA. [Dobbels, Fabienne; De Geest, Sabina] Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Hlth Serv & Nursing Res, Leuven, Belgium. [Stussi, Georg] Oncol Inst Southern Switzerland, Dept Haematol, Bellinzona, Switzerland. [Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Canc Outcomes Res Program, Chapel Hill, NC 27515 USA. RP De Geest, S (reprint author), Univ Basel, Inst Nursing Sci, Bernoullistr 28, CH-4056 Basel, Switzerland. EM sabina.degeest@unibas.ch FU Foundation Cancer Research Switzerland [KFS 2705-08-2010]; Stiftung zur Krebsbekampfung [2010/280] FX This study was supported by grants from the Foundation Cancer Research Switzerland (KFS 2705-08-2010) and the 'Stiftung zur Krebsbekampfung' (2010/280). NR 38 TC 4 Z9 4 U1 3 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1462-3889 EI 1532-2122 J9 EUR J ONCOL NURS JI Eur. J. Oncol. Nurs. PD FEB PY 2015 VL 19 IS 1 BP 66 EP 74 DI 10.1016/j.ejon.2014.07.007 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA CC1AW UT WOS:000350074400012 PM 25190633 ER PT J AU Gu, J Lei, Y Huang, YP Zhao, YY Li, J Huang, T Zhang, JJ Wang, JP Deng, XD Chen, ZS Korteweg, C Deng, RS Yan, ML Xu, Q Dong, SN Cai, MH Luo, LL Huang, GW Wang, Y Li, Q Lin, CM Su, M Yang, CZ Zhuang, ZP AF Gu, Jiang Lei, Yu Huang, Yuanping Zhao, Yingying Li, Jing Huang, Tao Zhang, Junjun Wang, Juping Deng, Xiaodong Chen, Zhengshan Korteweg, Christine Deng, Ruishu Yan, Meiling Xu, Qian Dong, Shengnan Cai, Monghong Luo, Lili Huang, Guowei Wang, Yun Li, Qian Lin, Changmei Su, Meng Yang, Chunzhang Zhuang, Zhengping TI Fab fragment glycosylated IgG may play a central role in placental immune evasion SO HUMAN REPRODUCTION LA English DT Article DE asymmetric immunoglobulin G; placenta; immune evasion; leukocyte; fetus ID IMMUNOGLOBULIN-G EXPRESSION; NEWLY SYNTHESIZED PROTEINS; CANCER-CELL-LINES; ASYMMETRIC ANTIBODIES; CHORIONIC VILLI; FC-RECEPTORS; PREGNANCY; TRANSMISSION; NEURONS; BINDING AB STUDY QUESTION: How does the placenta protect the fetus from immune rejection by the mother? SUMMARY ANSWER: The placenta can produce IgG that is glycosylated at one of its Fab arms (asymmetric IgG; aIgG) which can interact with other antibodies and certain leukocytes to affect local immune reactions at the junction between the two genetically distinct entities. WHAT IS KNOWN ALREADY: The placenta can protect the semi-allogenic fetus from immune rejection by the immune potent mother. aIgG in serum is increased during pregnancy and returns to the normal range after giving birth. aIgG can react to antigens to form immune complexes which do not cause a subsequent immune effector reaction, including fixing complements, inducing cytotoxicity and phagocytosis, and therefore has been called 'blocking antibody'. STUDY DESIGN, SIZE, DURATION: Eighty-eight human placentas, four trophoblast cell lines (TEV-1, JAR, JEG and BeWo), primary culture of human placental trophoblasts and a gene knock-out mouse model were investigated in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The general approach included the techniques of cell culture, immunohistochemistry, in situ hybridization, immuno-electron microscopy, western blot, quantitative PCR, protein isolation, glycosylation analysis, enzyme digestion, gene sequencing, mass spectrophotometry, laser-guided microdissection, enzyme-linked immunosorbent assay, pulse chase assay, double and multiple staining to analyze protein and DNA and RNA analysis at the cellular and molecular levels. MAIN RESULTS AND THE ROLE OF CHANCE: Three major discoveries were made: (i) placental trophoblasts and endothelial cells are capable of producing IgG, a significant portion of which is aberrantly glycosylated at one of its Fab arms to form aIgG; (ii) the asymmetrically glycosylated IgG produced by trophoblasts and endothelial cells can react to immunoglobulin molecules of human, rat, mouse, goat and rabbit at the Fc portion; (iii) asymmetrically glycosylated IgG can react to certain leukocytes in the membrane and cytoplasm, while symmetric IgG from the placenta does not have this property. LIMITATIONS, REASONS FOR CAUTION: Most of the experiments were performed in vitro. The proposed mechanism calls for verification in normal and abnormal pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This study identified a number of new phenomena suggesting that aIgG produced by the placenta would be able to react to detrimental antibodies and leukocytes and interfere with their immune reactions against the placenta and the fetus. This opens a new dimension for further studies on pregnancy physiology and immunology. Should the mechanism proposed here be confirmed, it will have a direct impact on our understanding of the physiology and pathology of human reproduction and offer new possibilities for the treatment of many diseases including spontaneous abortion, infertility and pre-eclampsia. It also sheds light on the mechanism of immune evasion in general including that of cancer. C1 [Gu, Jiang; Lei, Yu; Huang, Yuanping; Zhao, Yingying; Li, Jing; Huang, Tao; Zhang, Junjun; Wang, Juping; Deng, Xiaodong; Chen, Zhengshan; Korteweg, Christine; Deng, Ruishu; Yan, Meiling; Xu, Qian; Dong, Shengnan; Huang, Guowei; Wang, Yun; Li, Qian; Su, Meng] Shantou Univ Med Coll, Dept Pathol, Shantou 515041, Guangdong, Peoples R China. [Gu, Jiang; Lei, Yu; Huang, Yuanping; Zhao, Yingying; Li, Jing; Huang, Tao; Zhang, Junjun; Wang, Juping; Deng, Xiaodong; Chen, Zhengshan; Korteweg, Christine; Deng, Ruishu; Yan, Meiling; Xu, Qian; Dong, Shengnan; Huang, Guowei; Wang, Yun; Li, Qian; Su, Meng] Shantou Univ Med Coll, Prov Key Lab Infect Dis & Immunopathol, Shantou 515041, Guangdong, Peoples R China. [Gu, Jiang; Zhao, Yingying; Deng, Ruishu; Su, Meng] Beijing Univ Hlth Sci Ctr, Dept Pathol, Beijing 100083, Peoples R China. [Gu, Jiang; Cai, Monghong] Shantou Univ Med Coll, Affiliated Hosp 2, Translat Med Ctr, Shantou, Peoples R China. [Luo, Lili] Shantou Univ Med Coll, Affiliated Hosp 1, Dept Gynecol & Obstetrician, Shantou, Peoples R China. [Lin, Changmei] Haidian Maternal & Child Hlth Hosp, Dept Fertil, Beijing 100080, Peoples R China. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Gu, J (reprint author), Shantou Univ Med Coll, Dept Pathol & Pathophysiol, Shantou, Peoples R China. EM 2523381625@qq.com FU National Nature Science Foundation of China [30971150, 81030033]; Li KaShing Foundation FX This work was supported by grants from the National Nature Science Foundation of China (No. 30971150 and 81030033 to J.G.) and The Li KaShing Foundation. NR 50 TC 6 Z9 6 U1 2 U2 15 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 FEB PY 2015 VL 30 IS 2 BP 380 EP 391 DI 10.1093/humrep/deu323 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CC2AK UT WOS:000350146600016 PM 25505012 ER PT J AU Eisenberg, ML Kim, S Chen, Z Sundaram, R Schisterman, EF Louis, GMB AF Eisenberg, Michael L. Kim, Sungduk Chen, Zhen Sundaram, Rajeshwari Schisterman, Enrique F. Louis, Germaine M. Buck TI The relationship between male BMI and waist circumference on semen quality: data from the LIFE study (vol 29, pg 193, 2014) SO HUMAN REPRODUCTION LA English DT Correction C1 [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA. [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Obstet, Stanford, CA 94305 USA. [Eisenberg, Michael L.] Stanford Univ, Sch Med, Dept Gynecol, Stanford, CA 94305 USA. [Kim, Sungduk; Chen, Zhen; Sundaram, Rajeshwari; Schisterman, Enrique F.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Eisenberg, ML (reprint author), Stanford Univ, Sch Med, Dept Urol, 300 Pasteur Dr, Stanford, CA 94305 USA. EM eisenberg@stanford.edu OI Eisenberg, Michael/0000-0001-5482-0141 NR 2 TC 0 Z9 3 U1 0 U2 0 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 FEB PY 2015 VL 30 IS 2 BP 493 EP 494 DI 10.1093/humrep/deu322 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CC2AK UT WOS:000350146600031 PM 25516559 ER PT J AU Spieker, EA Sbrocco, T Theim, KR Maurer, D Johnson, D Bryant, E Bakalar, JL Schvey, NA Ress, R Seehusen, D Klein, DA Stice, E Yanovski, JA Chan, L Gentry, S Ellsworth, C Hill, JW Tanofsky-Kraff, M Stephens, MB AF Spieker, Elena A. Sbrocco, Tracy Theim, Kelly R. Maurer, Douglas Johnson, Dawn Bryant, Edny Bakalar, Jennifer L. Schvey, Natasha A. Ress, Rachel Seehusen, Dean Klein, David A. Stice, Eric Yanovski, Jack A. Chan, Linda Gentry, Shari Ellsworth, Carol Hill, Joanne W. Tanofsky-Kraff, Marian Stephens, Mark B. TI Preventing Obesity in the Military Community (POMC): The Development of a Clinical Trials Research Network SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article ID RANDOMIZED EFFICACY TRIAL; EATING-DISORDER; ADULT OBESITY; INTERPERSONAL PSYCHOTHERAPY; DESERT-STORM; HIGH-RISK; METABOLIC SYNDROME; ADOLESCENT GIRLS; WEIGHT-GAIN; BODY-WEIGHT AB Obesity impacts the U.S. military by affecting the health and readiness of active duty service members and their families. Preventing Obesity in Military Communities (POMC) is a comprehensive research program within Patient Centered Medical Homes (PCMHs) in three Military Training Facilities. This paper describes three pilot randomized controlled trials that target critical high risk periods for unhealthy weight gain from birth to young adulthood: (1) pregnancy and early infancy (POMC-Mother-Baby), (2) adolescence (POMC-Adolescent), and (3) the first tour of duty after boot camp (POMC-Early Career). Each study employs a two-group randomized treatment or prevention program with follow up. POMC offers a unique opportunity to bring together research and clinical expertise in obesity prevention to develop state-of-the-art programs within PCMHs in Military Training Facilities. This research builds on existing infrastructure that is expected to have immediate clinical benefits to DoD and far-reaching potential for ongoing collaborative work. POMC may offer an economical approach for widespread obesity prevention, from conception to young adulthood, in the U.S. military as well as in civilian communities. C1 [Spieker, Elena A.; Maurer, Douglas] Madigan Army Med Ctr, Dept Family Med, Tacoma, WA 98431 USA. [Spieker, Elena A.; Sbrocco, Tracy; Theim, Kelly R.; Johnson, Dawn; Bryant, Edny; Bakalar, Jennifer L.; Schvey, Natasha A.; Ress, Rachel; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Spieker, Elena A.; Theim, Kelly R.; Bakalar, Jennifer L.; Schvey, Natasha A.; Ress, Rachel] Henry M Jackson Fdn Adv Mil Med Inc, Bethesda, MD 20817 USA. [Seehusen, Dean] Dept Family & Community Med, Ft Gordon, GA 30905 USA. [Klein, David A.] Ft Belvoir Community Hosp, Dept Family Med, Ft Belvoir, VA 22060 USA. [Stice, Eric] Oregon Res Inst, Eugene, OR 97403 USA. [Yanovski, Jack A.; Tanofsky-Kraff, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Chan, Linda] Naval Hosp Camp Lejeune, Dept Obstet & Gynecol, Camp Lejeune, NC 28547 USA. [Gentry, Shari; Ellsworth, Carol] Naval Hosp Camp Lejeune, Dept Family Med, Camp Lejeune, NC 28547 USA. [Hill, Joanne W.] Naval Hosp Camp Lejeune, Dept Res, Camp Lejeune, NC 28547 USA. [Stephens, Mark B.] Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. RP Sbrocco, T (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM elena.a.spieker.ctr@mail.mil; tracy.sbrocco@usuhs.edu; kelly.theim.ctr@usuhs.edu; douglas.m.maurer.mil@mail.mil; dawn.johnson@usuhs.edu; edny.joseph@usuhs.edu; Jennifer.bakalar@usuhs.edu; natasha.schvey.ctr@usuhs.edu; rachel.ress.ctr@usuhs.edu; Dean.A.Seehusen.mil@health.mil; david.a.klein26.mil@mail.mil; estice@ori.org; yanovskj@mail.nih.gov; Linda.Chan@med.navy.mil; shari.gentry@med.navy.mil; carol.ellsworth@med.navy.mil; Joanne.Hill@med.navy.mil; marian.tanofsky-kraff@usuhs.edu; mark.stephens@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637 FU Uniformed Services University [USUHS72NC-01]; NICHD [Z1aHD00641]; [F172NC-02] FX Research support provided by a grant from the Uniformed Services University (USUHS72NC-01) to Tracy Sbrocco and intramural support from NICHD (Z1aHD00641) to Jack A. Yanovski, a Commissioned Officer in the United States Public Health Service. This manuscript was developed within the scope of work for the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., by authors Elena A. Spieker, Kelly R. Theim supported by grant F172NC-02. NR 57 TC 3 Z9 3 U1 3 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD FEB PY 2015 VL 12 IS 2 BP 1174 EP 1195 DI 10.3390/ijerph120201174 PG 22 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA CC2XZ UT WOS:000350209800008 PM 25648176 ER PT J AU Phelan, S Kanaya, AM Ma, Y Vittinghoff, E Barrett-Connor, E Wing, R Kusek, JW Orchard, TJ Crandall, JP Montez, MG Brown, JS AF Phelan, Suzanne Kanaya, Alka M. Ma, Yong Vittinghoff, Eric Barrett-Connor, Elizabeth Wing, Rena Kusek, John W. Orchard, Trevor J. Crandall, Jill P. Montez, Maria G. Brown, Jeanette S. CA Diabet Prevention Program Res Grp TI Long-term prevalence and predictors of urinary incontinence among women in the Diabetes Prevention Program Outcomes Study SO INTERNATIONAL JOURNAL OF UROLOGY LA English DT Article DE Diabetes Prevention Program Outcomes Study; lifestyle intervention; urinary incontinence; weight loss ID LIFE-STYLE INTERVENTION; WEIGHT-LOSS; EPIDEMIOLOGIC SURVEY; EXERCISE; RISK; CLASSIFICATION; POPULATION; REMISSION; MELLITUS; STRESS AB ObjectivesTo examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study, a follow-up study of the Diabetes Prevention Program randomized clinical trial of overweight adults with impaired glucose tolerance. MethodsThis analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been randomly assigned during the Diabetes Prevention Program to intensive lifestyle intervention (n=582), metformin (n=589) or placebo (n=607). The study participants completed semi-annual assessments after the final Diabetes Prevention Program visit and for 6years until October 2008. ResultsAt the study entry, the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups (44.2% vs 51.8%, 48.0% urinary incontinence/week, P=0.04); during the 6-year follow-up period, these lower rates in intensive lifestyle intervention were maintained (46.7%, 53.1%, 49.9% urinary incontinence/week; P=0.03). Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program, the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study. Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index (odds ratio 0.988, 95% confidence interval 0.982-0.994) and greater physical activity (odds ratio 0.999, 95% confidence interval 0.998-1.000) at the Diabetes Prevention Program Outcomes Study entry, and greater reductions in body mass index (odds ratio 0.75, 95% confidence interval 0.60-0.94) and waist circumference (odds ratio 0.998, 95% confidence interval 0.996-1.0) during the Diabetes Prevention Program Outcomes Study. Diabetes was not significantly related to urinary incontinence. ConclusionsIntensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence, and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance. C1 [Phelan, Suzanne] Calif Polytech State Univ San Luis Obispo, Kinesiol Dept, San Luis Obispo, CA 93407 USA. [Kanaya, Alka M.] Univ Calif San Francisco, Dept Gen Internal Med, San Francisco, CA 94143 USA. [Ma, Yong] George Washington Univ, Biostat Ctr, Rockville, MD 20852 USA. [Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Div Epidemiol, San Diego, CA 92103 USA. [Wing, Rena] Brown Univ, Warren Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Wing, Rena] Miriam Hosp, Providence, RI 02906 USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Orchard, Trevor J.] Univ Pittsburgh, Pittsburgh, PA USA. [Crandall, Jill P.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Brown, Jeanette S.] UCSF Womens Hlth Clin Res Ctr, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Brown, Jeanette S.] UCSF Womens Hlth Clin Res Ctr, Dept Urol, San Francisco, CA USA. [Brown, Jeanette S.] UCSF Womens Hlth Clin Res Ctr, Dept Epidemiol, San Francisco, CA USA. RP Phelan, S (reprint author), George Washington Univ, Biostat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu OI orchard, trevor/0000-0001-9552-3215 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Southwestern American Indian Centers; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute, the National Heart Lung and Blood Institute; Office of Women's Health; National Center for Minority Health and Human Disease; Centers for Disease Control and Prevention; American Diabetes Association FX This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as a cooperative agreement. We thank the participants of the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study for their commitment and dedication; the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health for funding to the clinical and coordinating centers that designed and undertook the study, and collected, managed, analyzed and interpreted the data; and the General Clinical Research Center Program and the National Center for Research Resources for support of data collection at many of the clinical centers. The Southwestern American Indian Centers were supported directly by the National Institute of Diabetes and Digestive and Kidney Diseases, including its Intramural Research Program, and by the Indian Health Service. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Women's Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, and the American Diabetes Association. Lipha (Merck-Sante) provided medicines, and LifeScan donated materials. The opinions expressed are those of the investigators, and do not necessarily reflect the views of the funding agencies. Comments by three anonymous reviewers are gratefully acknowledged. NR 37 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0919-8172 EI 1442-2042 J9 INT J UROL JI Int. J. Urol. PD FEB PY 2015 VL 22 IS 2 BP 206 EP 212 DI 10.1111/iju.12654 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CB9TU UT WOS:000349976800021 PM 25352018 ER PT J AU Takeshita, J Wang, SW Shin, DB Mehta, NN Kimmel, SE Margolis, DJ Troxel, AB Gelfand, JM AF Takeshita, Junko Wang, Shuwei Shin, Daniel B. Mehta, Nehal N. Kimmel, Stephen E. Margolis, David J. Troxel, Andrea B. Gelfand, Joel M. TI Effect of Psoriasis Severity on Hypertension Control A Population-Based Study in the United Kingdom SO JAMA DERMATOLOGY LA English DT Article ID II-INDUCED HYPERTENSION; ANGIOTENSIN-II; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; RISK-FACTORS; VASCULAR DYSFUNCTION; BLOOD-PRESSURE; METAANALYSIS; PREVALENCE; COMORBIDITIES AB IMPORTANCE Hypertension is prevalent among patients with psoriasis. The effect of psoriasis and its severity on hypertension control is unknown. OBJECTIVE To determine the association between uncontrolled blood pressure and psoriasis, both overall and according to objectively measured psoriasis severity, among patients with diagnosed hypertension. DESIGN, SETTING, AND PARTICIPANTS Population-based cross-sectional study nested in a prospective cohort drawn from The Health Improvement Network (THIN), an electronic medical records database broadly representative of the general population in the United Kingdom. The study population included a random sample of patients with psoriasis (n = 1322) between the ages of 25 and 64 years in THIN who were included in the Incident Health Outcomes and Psoriasis Events prospective cohort and their age-and practice-matched controls without psoriasis (n = 11 977). All included patients had a diagnosis of hypertension; their psoriasis diagnosis was confirmed and disease severity was classified by their general practitioners. MAIN OUTCOMES AND MEASURES Uncontrolled hypertensionwas defined as a systolic blood pressure of 140mmHg or higher or a diastolic blood pressure of 90mmHg or higher based on the blood pressure recorded closest in time to the assessment of psoriasis severity. RESULTS There was a significant positive dose-response relationship between uncontrolled hypertension and psoriasis severity as objectively determined by the affected body surface area in both unadjusted and adjusted analyses that controlled for age, sex, body mass index, smoking and alcohol use status, presence of comorbid conditions, and current use of antihypertensive medications and nonsteroidal anti-inflammatory drugs (adjusted odds ratio [aOR], 0.97; 95% CI, 0.82-1.14 for mild psoriasis; aOR, 1.20; 95% CI, 0.99-1.45 for moderate psoriasis; and aOR, 1.48; 95% CI, 1.08-2.04 for severe psoriasis; P =.01 for trend). The likelihood of uncontrolled hypertension among psoriasis overall was also increased, although not statistically significantly so (aOR, 1.10; 95% CI, 0.98-1.24). CONCLUSIONS AND RELEVANCE Among patients with hypertension, psoriasiswas associated with a greater likelihood of uncontrolled hypertension in a dose-dependent manner, with the greatest likelihood observed among those with moderate to severe psoriasis defined by 3% or more of the body surface area affected. Our data suggest a need for more effective C1 [Takeshita, Junko; Shin, Daniel B.; Margolis, David J.; Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Takeshita, Junko; Shin, Daniel B.; Kimmel, Stephen E.; Margolis, David J.; Troxel, Andrea B.; Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA USA. [Wang, Shuwei] Thomas Jefferson Univ, Div Internal Med, Philadelphia, PA 19107 USA. [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD 20892 USA. [Kimmel, Stephen E.] Univ Penn, Perelman Sch Med, Div Cardiol, Philadelphia, PA USA. RP Takeshita, J (reprint author), Univ Penn, Perelman Sch Med, Dept Dermatol, 1463 Penn Tower,One Convent Ave, Philadelphia, PA 19104 USA. EM junko.takeshita@uphs.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU National Heart, Lung, and Blood Institute [RO1-HLO89744]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24-ARO6431O]; Dermatology Foundation Career Development Award; National Psoriasis Foundation Fellowship Award FX This study was supported by grant RO1-HLO89744 from the National Heart, Lung, and Blood Institute (Dr Gelfand), grant K24-ARO6431O from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Dr Gelfand), a Dermatology Foundation Career Development Award (Dr Takeshita), and a National Psoriasis Foundation Fellowship Award (Dr Takeshita). NR 46 TC 11 Z9 11 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD FEB PY 2015 VL 151 IS 2 BP 161 EP 169 DI 10.1001/jamadermatol.2014.2094 PG 9 WC Dermatology SC Dermatology GA CB6RL UT WOS:000349754200010 PM 25322196 ER PT J AU Zuo, RC Apolo, AB DiGiovanna, JJ Parnes, HL Keen, CM Nanda, S Dahut, WL Cowen, EW AF Zuo, Rena C. Apolo, Andrea B. DiGiovanna, John J. Parnes, Howard L. Keen, Corrine M. Nanda, Swati Dahut, William L. Cowen, Edward W. TI Cutaneous Adverse Effects Associated With the Tyrosine-Kinase Inhibitor Cabozantinib SO JAMA DERMATOLOGY LA English DT Article ID FOOT SKIN REACTION; PALMAR-PLANTAR ERYTHRODYSESTHESIA; MESYLATE CAUSES HYPOPIGMENTATION; SUBUNGUAL SPLINTER HEMORRHAGES; MEDULLARY-THYROID CANCER; RENAL-CELL CARCINOMA; PROSTATE-CANCER; VITAMIN-E; SUNITINIB; SORAFENIB AB IMPORTANCE Cabozantinib S-malate is a vascular endothelial growth factor receptor 2, c-MET, and RET multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumorigenic properties with potential efficacy for the treatment of several cancers. Cutaneous reactions, one of the most frequently observed adverse effects associated with tyrosine kinase inhibitors, can significantly affect patients' quality of life and drug adherence and represent a major therapeutic challenge to maximizing the efficacy of targeted cancer therapy. OBJECTIVE To describe the frequency and spectrum of skin reactions in patients with urothelial carcinoma receiving cabozantinib as monotherapy. DESIGN, SETTING, AND PARTICIPANTS A single-institution study at the Clinical Research Center at the National Institutes of Health included 41 consecutive adults with metastatic, progressive urothelial carcinoma enrolled in a National Cancer Institute open-label, nonrandomized, phase 2 clinical trial. Patients receiving cabozantinib were evaluated for the development of skin reactions at each treatment visit from October 2012 to June 2014 by the primary oncology team and referred for dermatologic evaluation as appropriate. MAIN OUTCOMES AND MEASURES A detailed history, full-body physical examination, and clinical photographs of cutaneous lesions were obtained. RESULTS Of 41 consecutive patients who received cabozantinib, 30 (73%) developed 1 or more cutaneous toxic effects. Adverse events included hand-foot skin reaction (22 [54%]), generalized pigment dilution and/or hair depigmentation (18 [44%]), xerosis (8 [20%]), scrotal erythema/ulceration (6 [15%]), and nail splinter hemorrhages (5 [12%]). Eighteen patients (44%) had 2 or more cutaneous adverse events. Reactions developed in 17 of 30 patients (57%) during the first month of cabozantinib treatment and in 24 of 30 (80%) by the second month. Of patients with skin toxic effects, dose reduction was required for symptom management in 9 of 30 patients (30%), and treatment discontinuation was required in 4 of 30 (13%). CONCLUSIONS AND RELEVANCE Cabozantinib monotherapy is associated with 1 or more cutaneous adverse events in most patients. Early detection and prompt treatment may increase patients' adherence to tyrosine kinase inhibitor therapy. C1 [Zuo, Rena C.; DiGiovanna, John J.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apolo, Andrea B.; Keen, Corrine M.; Nanda, Swati; Dahut, William L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Prostate & Urol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1908,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute; Medical Research Scholars Program; NIH; Pfizer Inc; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, and the Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the National Institutes of Health from Pfizer Inc, the Doris Duke Charitable Foundation, the Alexandria Real Estate Equities, Inc, Mr and Mrs Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. NR 53 TC 4 Z9 4 U1 2 U2 7 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 FEB PY 2015 VL 151 IS 2 BP 170 EP 177 DI 10.1001/jamadermatol.2014.2734 PG 8 WC Dermatology SC Dermatology GA CB6RL UT WOS:000349754200012 PM 25427282 ER PT J AU Moraitis, AG Freeman, LA Shamburek, RD Wesley, R Wilson, W Grant, CM Price, S Demosky, S Thacker, SG Zarzour, A Hornung, RL Pucino, F Csako, G Yarboro, C McInnes, IB Kuroiwa, T Boumpas, D Rao, VK Illei, GG Remaley, AT AF Moraitis, Andreas G. Freeman, Lita A. Shamburek, Robert D. Wesley, Robert Wilson, Wyndham Grant, Cliona M. Price, Susan Demosky, Stephen Thacker, Seth G. Zarzour, Abdalrahman Hornung, Ronald L. Pucino, Frank Csako, Gyorgy Yarboro, Cheryl McInnes, Iain B. Kuroiwa, Takashi Boumpas, Dimitrios Rao, V. Koneti Illei, Gabor G. Remaley, Alan T. TI Elevated interleukin-10: A new cause of dyslipidemia leading to severe HDL deficiency SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE "Disappearing HDL syndrome"; Severe HDL deficiency; Hypertriglyceridemia; Dyslipidemia; B-cell lymphoma; Intravascular large B-cell lymphoma; ALPS; Psoriasis; IL-10; LCAT ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; LECITHIN-CHOLESTEROL ACYLTRANSFERASE; DENSITY-LIPOPROTEIN-DEFICIENCY; INTESTINAL EPITHELIAL-CELLS; FAS GENE-MUTATIONS; INHIBITS ATHEROSCLEROSIS; VISCERAL LEISHMANIASIS; DISEASE; INFLAMMATION; LYMPHOMA AB BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. Investigating mechanisms underlying acquired severe HDL deficiency in noncritically ill patients ("disappearing EIDL syndrome") could provide new insights into HDL metabolism. OBJECTIVE: To determine the cause of low HDL-C in patients with severe acquired HDL deficiency. METHODS AND RESULTS: Patients with intravascular large B-cell lymphoma (n = 2), diffuse large B-cell lymphoma (n = 1), and autoimmune lymphoproliferative syndrome (n = 1) presenting with markedly decreased EIDL-C, low low-density lipoprotein cholesterol (LDL-C), and elevated triglycerides were identified. The abnormal lipoprotein profile returned to normal after therapy in all 4 patients. All patients were found to have markedly elevated serum interleukin-10 (IL-10) levels that also normalized after therapy. In a cohort of autoimmune lymphoproliferative syndrome patients (n = 93), IL-10 showed a strong inverse correlation with HDL-C (R-2 = 0.3720, P < .0001). A direct causal role for increased serum IL-10 in inducing the observed changes in lipoproteins was established in a randomized, placebo-controlled clinical trial of recombinant human IL-10 in psoriatic arthritis patients (n = 18). Within a week of initiating subcutaneous recombinant human IL-10 injections, HDL-C precipitously decreased to near-undetectable levels. LDL-C also decreased by more than 50% (P < .0001) and triglycerides increased by approximately 2-fold (P < .005). All values returned to baseline after discontinuing IL-10 therapy. CONCLUSION: Increased IL-10 causes severe HDL-C deficiency, low LDL-C, and elevated triglycerides. IL-10 is thus a potent modulator of lipoprotein levels, a potential new biomarker for B-cell disorders, and a novel cause of disappearing HDL syndrome. Published by Elsevier Inc. on behalf of National Lipid Association. C1 [Moraitis, Andreas G.] Univ Michigan, Endocrine Oncol Program, Ann Arbor, MI 48109 USA. [Freeman, Lita A.; Shamburek, Robert D.; Demosky, Stephen; Thacker, Seth G.; Zarzour, Abdalrahman; Remaley, Alan T.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Hosp Epidemiol, Bethesda, MD 20892 USA. [Wilson, Wyndham; Grant, Cliona M.] NCI, NIH, Bethesda, MD 20892 USA. [Price, Susan; Rao, V. Koneti] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Hornung, Ronald L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Serv Program, Frederick, MD USA. [Pucino, Frank; Yarboro, Cheryl; McInnes, Iain B.; Kuroiwa, Takashi; Boumpas, Dimitrios; Illei, Gabor G.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Csako, Gyorgy; Remaley, Alan T.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [McInnes, Iain B.] Univ Glasgow, Coll Med, Vet Med & Life Sci, Glasgow, Lanark, Scotland. [Boumpas, Dimitrios] Univ Athens, Sch Med, GR-10679 Athens, Greece. RP Remaley, AT (reprint author), NIH, Bldg 10,Rm 2C-433, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov OI McInnes, Iain/0000-0002-6462-4280 FU National Cancer Institute, National Institutes of Health [HHSN261200800001 E]; National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001 E and from intramural research funds from the National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 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 52 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD FEB PY 2015 VL 9 IS 1 BP 81 EP 90 DI 10.1016/j.jacl.2014.09.014 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC1IB UT WOS:000350093300012 PM 25670364 ER PT J AU Abramson, K Keefe, B Chou, WYS AF Abramson, Karley Keefe, Brian Chou, Wen-Ying Sylvia TI Communicating About Cancer Through Facebook: A Qualitative Analysis of a Breast Cancer Awareness Page SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article AB Social media channels are increasingly being used for health communication and promotion. Social networking sites such as Facebook have become popular platforms for organizations to communicate health messages and encourage user participation around health topics. While the evaluation of social media's effectiveness in health promotion is beginning to emerge in the literature, few studies have examined actual interactions and user behaviors on Facebook Pages hosted by health organizations. The authors present a qualitative case study of a popular Facebook Page from a nonprofit organization devoted to raising awareness about breast cancer. With the goal of identifying the functions and uses of the Page, our study analyzes the content of Wall posts during Breast Cancer Awareness Month, October 2010. Common themes and characteristics are identified, including open mic communication, scarcity of health information, the commodification of breast cancer, unpredictable locations of conversation, and the use of gendered images and language. The findings have potential implications for health promotion efforts using social media platforms. C1 [Abramson, Karley] Univ Michigan, Sch Law, Ann Arbor, MI 48109 USA. [Keefe, Brian] ICF Int, Rockville, MD 20850 USA. [Chou, Wen-Ying Sylvia] NCI, Behav Res Program, Rockville, MD USA. RP Keefe, B (reprint author), ICF Int, 530 Gaither Rd, Rockville, MD 20850 USA. EM brian.keefe@icfi.com NR 24 TC 5 Z9 6 U1 5 U2 23 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD FEB 1 PY 2015 VL 20 IS 2 BP 237 EP 243 DI 10.1080/10810730.2014.927034 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CC4QS UT WOS:000350338700014 PM 25495200 ER PT J AU Dauer, LT Miller, DL Schueler, B Silberzweig, J Balter, S Bartal, G Chambers, C Collins, JD Damilakis, J Dixon, RG Marx, MV Stocker, MS Vano, E Venkatesan, AM Nikolic, B AF Dauer, Lawrence T. Miller, Donald L. Schueler, Beth Silberzweig, James Balter, Stephen Bartal, Gabriel Chambers, Charles Collins, Jeremy D. Damilakis, John Dixon, Robert G. Marx, M. Victoria Stocker, Michael S. Vano, Eliseo Venkatesan, Aradhana M. Nikolic, Boris CA Soc Interventional Radiology Safet Cardiovasc & Interventional Radiol TI Occupational Radiation Protection of Pregnant or Potentially Pregnant Workers in IR: A Joint Guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID CARDIAC-CATHETERIZATION PROCEDURES; DIAGNOSTIC-RADIOLOGY; PROGRAM GUIDELINES; WOMEN-RADIOLOGISTS; SAFETY PROGRAM; HEALTH HAZARDS; EXPOSURE; PATIENT; CARDIOLOGY; STAFF C1 [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Dauer, Lawrence T.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Silberzweig, James] Beth Israel Deaconess Med Ctr, Dept Radiol, New York, NY 10003 USA. [Balter, Stephen] Columbia Univ, Med Ctr, Dept Radiol, New York, NY 10003 USA. [Balter, Stephen] Columbia Univ, Med Ctr, Dept Med, New York, NY 10003 USA. [Nikolic, Boris] Stratton Med Ctr, Dept Radiol, Albany, NY USA. [Miller, Donald L.] Food & Drug Adm, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Venkatesan, Aradhana M.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Schueler, Beth] Mayo Clin, Dept Radiol, Rochester, MN USA. [Chambers, Charles] Penn State Hershey Med Ctr, Penn State Hershey Heart & Vasc Inst, Hershey, PA USA. [Collins, Jeremy D.] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Dixon, Robert G.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Marx, M. Victoria] Los Angeles Cty & Univ So Calif, Med Ctr, Dept Radiol, Los Angeles, CA USA. [Stocker, Michael S.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Bartal, Gabriel] Meir Med Ctr, Dept Diagnost & Intervent Radiol, Kefar Sava, Israel. [Damilakis, John] Univ Crete, Fac Med, Dept Med Phys, Iraklion, Greece. [Vano, Eliseo] Univ Complutense, Dept Radiol, E-28040 Madrid, Spain. RP Dauer, LT (reprint author), SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM dauerl@mskcc.org OI Dauer, Lawrence/0000-0002-5629-8462 NR 99 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2015 VL 26 IS 2 BP 171 EP 181 DI 10.1016/j.jvir.2014.11.026 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA CB6MZ UT WOS:000349742400004 PM 25645407 ER PT J AU Abi-Jaoudeh, N Venkatesan, AM Van der Sterren, W Radaelli, A Carelsen, B Wood, BJ AF Abi-Jaoudeh, Nadine Venkatesan, Aradhana M. Van der Sterren, William Radaelli, Alessandro Carelsen, Bart Wood, Bradford J. TI Clinical Experience with Cone-Beam CT Navigation for Tumor Ablation SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; RADIOFREQUENCY ABLATION; PERCUTANEOUS ABLATION; SURGICAL RESECTION; GUIDANCE; ACCURACY; FUSION; BIOPSY; FEASIBILITY; FLUOROSCOPY AB Purpose: To describe clinical use and potential benefits of cone-beam -computed tomography (CT) navigation to perform image-guided percutaneous tumor.ablation. Materials and Methods: All ablations performed between February 2011 and February 2013 using cone-bearn CT navigation Were included. There Were 16 Patients who uriderWent 20 ablations for 29 lesions. Cone-beam. CT ablation planning Cap a bilities include multimodality image fusion and tumor segmentation for visualization, depiction of the predicted ablation zones for intraprocedural planning, and segmentation of the ablated area for immediate verification after treatment Number and purpose of cone-beam CT scans were, examined. The, initial ablation plan, defined as number of probes and duration of energy delivery, was recorded for the 26 of the 29 lesions ablated. Technical success and local recurrenCes were recotded: Primary and secondary effectiVeness rates were calculated. Results: Image fusion was Used. for 16 lesions, and inttaprocedural ultrasound was used for 4 lesions. Of the 20 ablations, where the ablation plans Were recorded, there was no deviation from the plan in 14 ablations. In the remaining 6 ablations, iterative planning was needed for Coinplete tumot coverage. An. average of 8:7 cone-beam CT scans +/- 3.2 were performed per procedure, including 1.3 +/- 0.5 for tumot segmentation and planning, 1.7 +/- 0.7 for probe position confirmation, and 3.9 +/- 2 to ensure complete coverage. Mean follow-up time was 18,6, months +/- 6.5. Ablations for 28, of 29 lesions were technically successful (96.5%). Of ablations performed with curative intent, technical effectiveness at 1 month was 25 of 26, lesions (96.1%) and 22 of 26 lesions (84.6%) at last follow up Local tumor progression was observed in 11.5% (3 of 26 lesions). Conclusions: Cone-beam CT navigation may add information to assist and improve ablation guidance and monitoring. C1 [Abi-Jaoudeh, Nadine; Venkatesan, Aradhana M.; Wood, Bradford J.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Van der Sterren, William; Radaelli, Alessandro; Carelsen, Bart] Philips Healthcare, iXR Div, Best, Netherlands. RP Abi-Jaoudeh, N (reprint author), NIH, Dept Radiol & Imaging Sci, Room 1C365 Bldg 10 MSC 1182,9000 Rockville Pike, Bethesda, MD 20892 USA. EM naj@mail.nih.gov FU National Institutes of Health Center for Interventional Oncology; Intramural Research Program of the National Institutes of Health [ZID BC 011242-06]; National Institutes of Health; Philips Healthcare FX This work was supported by the National Institutes of Health Center for Interventional Oncology and the Intramural Research Program of the National Institutes of Health (grant no. ZID BC 011242-06) and by a collaborative research and development agreement between the National Institutes of Health and Philips Healthcare. NR 20 TC 5 Z9 5 U1 0 U2 1 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 FEB PY 2015 VL 26 IS 2 BP 214 EP 219 DI 10.1016/j.jvir.2014.10.049 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA CB6MZ UT WOS:000349742400011 PM 25645409 ER PT J AU Fragala, MS Dam, TTL Barber, V Judge, JO Studenski, SA Cawthon, PM McLean, RR Harris, TB Ferrucci, L Guralnik, JM Kiel, DP Kritchevsky, SB Shardell, MD Vassileva, MT Kenny, AM AF Fragala, Maren S. Dam, Thuy-Tien L. Barber, Vanessa Judge, James O. Studenski, Stephanie A. Cawthon, Peggy M. McLean, Robert R. Harris, Tamara B. Ferrucci, Luigi Guralnik, Jack M. Kiel, Douglas P. Kritchevsky, Stephen B. Shardell, Michelle D. Vassileva, Maria T. Kenny, Anne M. TI Strength and Function Response to Clinical Interventions of Older Women Categorized by Weakness and Low Lean Mass Using Classifications From the Foundation for the National Institute of Health Sarcopenia Project SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Strength; Function; Sarcopenia; Gait speed; Clinical trials ID RANDOMIZED CONTROLLED-TRIAL; MUSCLE STRENGTH; PHYSICAL PERFORMANCE; VITAMIN-D; BODY-COMPOSITION; RELEVANT WEAKNESS; RISK-FACTORS; FRAILTY; ADULTS; SUPPLEMENTATION AB Background. The Foundation for the National Institutes of Health Sarcopenia Project developed data-driven cutpoints for clinically meaningful weakness and low lean body mass. This analysis describes strength and function response to interventions based on these classifications. Methods. In data from four intervention studies, 378 postmenopausal women with baseline and 6-month data were evaluated for change in grip strength, appendicular lean mass corrected for body mass index, leg strength and power, and short physical performance battery (SPPB). Clinical interventions included hormones, exercise, and nutritional supplementation. Differences in outcomes were evaluated between (i) those with and without weakness and (ii) those with weakness and low lean mass or with one but not the other. We stratified analyses by slowness (walking speed <= 0.8 m/s) and by treatment assignment. Results. The women (72 +/- 7 years; body mass index of 26 +/- 5 kg/m(2)) were weak (33%), had low lean mass (14%), or both (6%). Those with weakness increased grip strength, lost less leg power, and gained SPPB score (p<.05) compared with nonweak participants. Stratified analyses were similar for grip strength and SPPB. With lean mass in the analysis, individuals with weakness had larger gains in grip strength and SPPB scores regardless of low lean mass (p<.01). Conclusions. Older women with clinically meaningful muscle weakness increased grip strength and SPPB, regardless of the presence of low lean mass following treatment with interventions for frailty. Thus, results suggest that muscle weakness, as defined by the Foundation for the National Institutes of Health Sarcopenia Project, appears to be a treatable symptom. C1 [Fragala, Maren S.] Univ Cent Florida, Orlando, FL 32816 USA. [Dam, Thuy-Tien L.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Barber, Vanessa; Judge, James O.; Kenny, Anne M.] Univ Connecticut, Ctr Hlth, Farmington, CT 06030 USA. [Studenski, Stephanie A.; Harris, Tamara B.; Ferrucci, Luigi] NIA, NIH, Bethesda, MD 20892 USA. [Cawthon, Peggy M.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [McLean, Robert R.; Kiel, Douglas P.] Hebrew Senior Life Inst Aging Res, Boston, MA USA. [McLean, Robert R.; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Guralnik, Jack M.; Shardell, Michelle D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Vassileva, Maria T.] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Kenny, AM (reprint author), Univ Connecticut, Ctr Hlth, Farmington, CT 06030 USA. EM kenny@uchc.edu OI Kiel, Douglas/0000-0001-8474-0310 FU National Institute on Aging [1U13AG041583, P30 AG024827]; Food and Drug Administration; Foundation for the NIH; Abbott Nutrition; Amgen; Eli Lilly; Merck; Novartis; Dairy Research Institute FX Funding support for the conference and the work of the consortium was provided by the National Institute on Aging (1U13AG041583 and P30 AG024827), the Food and Drug Administration, and through grants from the Foundation for the NIH, made possible by funding from Abbott Nutrition, Amgen, Eli Lilly, Merck, Novartis, and The Dairy Research Institute. NR 49 TC 10 Z9 10 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2015 VL 70 IS 2 BP 202 EP 209 DI 10.1093/gerona/glu110 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CC1RR UT WOS:000350121100008 PM 25135999 ER PT J AU Felisiak-Golabek, A Wasag, B Coates, T Lasota, JP Miettinen, M AF Felisiak-Golabek, Anna Wasag, Bartosz Coates, Tiffany Lasota, Jerzy P. Miettinen, Markku TI Frequency and Clinicopathologic Profile of PIK3CA Mutant GISTs SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Med Univ, Gdansk, Poland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 54 BP 17A EP 17A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200055 ER PT J AU Hsi, A Brown, G Lee, CC Schaffer, A AF Hsi, Andy Brown, Gregory Lee, Chyi-Chia Schaffer, Andras TI Expression of Master Regulators of Mature T-Cell Differentiation FOXP3, T-Bet, and GATA-3 in Cutaneous Adult T-Cell Leukemia/Lymphoma By Immunohistochemistry SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Washington Univ, Sch Med, St Louis, MO USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 471 BP 121A EP 121A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502200471 ER PT J AU Giubellino, A Li, A Lara-Otero, K Linehan, M Merino, M AF Giubellino, Alessio Li, Ang Lara-Otero, Karlena Linehan, Marston Merino, Maria TI MicroRNA Profiling of Morphologically Heterogeneous Clear Renal Cell Carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Giubellino, Alessio; Li, Ang; Lara-Otero, Karlena; Linehan, Marston; Merino, Maria] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 886 BP 223A EP 223A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201224 ER PT J AU Merino, M Ghosh, A Schmidt, L Linehan, M AF Merino, Maria Ghosh, Arunima Schmidt, Laura Linehan, Marston TI Clonal Analysis of Multi-Focal Tumors in Patients With Birt-Hogg-Dube Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Frederick Natl Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 975 BP 245A EP 245A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201313 ER PT J AU Moreno, V Metwali, A Linehan, WM Merino, M AF Moreno, Vanessa Metwali, Adam Linehan, W. Marston Merino, Maria TI New and Old Testicular Lesions Associated With VHL Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Moreno, Vanessa; Metwali, Adam; Linehan, W. Marston; Merino, Maria] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 979 BP 246A EP 246A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201317 ER PT J AU Yan, WS Young, D Song, YJ Chen, YM Katta, S Ravindranath, L Lee, J Srinivasan, A Cullen, J Kagan, J Srivastava, S Dobi, A Rosner, I McLeod, D Sesterhenn, I Srivastava, S Petrovics, G AF Yan, Wusheng Young, Denise Song, Yingjie Chen, Yongmei Katta, Shilpa Ravindranath, Lakshmi Lee, Jocelyn Srinivasan, Alagarsamy Cullen, Jennifer Kagan, Jacob Srivastava, Sudhir Dobi, Albert Rosner, Inger McLeod, David Sesterhenn, Isabell Srivastava, Shiv Petrovics, Gyorgy TI Optimization of Nanostring Platform for Evaluation of Prostate Cancer Biomarkers and Therapeutic Targes in FFPE Specimens SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Uniformed Serv Univ Hlth Sci, Rockville, MD USA. NCI, Rockville, MD USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. Joint Pathol Ctr, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1070 BP 268A EP 269A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201408 ER PT J AU Yang, ZM Li, A Pinto, P Merino, M AF Yang, Zhiming Li, Ang Pinto, Peter Merino, Maria TI microRNA Profiling of Prostate Cancer in Young and Older Man, One or Two Diseases? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Yang, Zhiming; Li, Ang; Pinto, Peter; Merino, Maria] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1072 BP 269A EP 269A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201410 ER PT J AU Zheng, XY Mao, Y Huang, WH Kamalakaran, S Yang, YF Linehan, WM Merino, MJ Zhong, MH Dimitrova, N Fallon, J AF Zheng, Xiaoyong Mao, Yong Huang, Weihua Kamalakaran, Sitharthan Yang, Youfeng Linehan, W. Marston Merino, Maria J. Zhong, Minghao Dimitrova, Nevenka Fallon, John TI Detecting Additional Chromosomal Translocations in TFE3 Translocation Renal Cell RCC By RNA-Seq SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 New York Med Coll, Westchester Cty Med Ctr, Valhalla, NY 10595 USA. Philips Res North Amer, Briarcliff Manor, NY 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1080 BP 271A EP 271A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502201418 ER PT J AU Gong, SY Dumitriu, B Young, N Maric, I AF Gong, Shunyou Dumitriu, Bogdan Young, Neal Maric, Irina TI Evaluation of Phospho-STAT3 Immunohistochemical Stain in Diagnosis of Marrow Involvement By Large Granular Lymphocytic Leukemia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1385 BP 346A EP 346A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202094 ER PT J AU Gong, SY Townsley, D Hsu, A Arthur, D Giri, N Alter, B Hickstein, D Young, N Braylan, R Holland, S Calvo, K AF Gong, Shunyou Townsley, Danielle Hsu, Amy Arthur, Diane Giri, Neelam Alter, Blanche Hickstein, Dennis Young, Neal Braylan, Raul Holland, Steven Calvo, Katherine TI Atypical Myelofibrosis in Patients Harboring Germline GATA2 Mutations SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Gong, Shunyou; Townsley, Danielle; Hsu, Amy; Arthur, Diane; Giri, Neelam; Alter, Blanche; Hickstein, Dennis; Young, Neal; Braylan, Raul; Holland, Steven; Calvo, Katherine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1384 BP 346A EP 346A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202093 ER PT J AU King, R Dao, LD McPhail, E Jaffe, E Said, J Swerdlow, S Sidhu, J Hsi, E Karikehalli, S Jiang, LY Gibson, S Ondrejka, S Nicolae, A Macon, W Castellar, EP Feldman, AL AF King, Rebecca Dao, Linda McPhail, Ellen Jaffe, Elaine Said, Jonathan Swerdlow, Steven Sidhu, Jagnzohan Hsi, Eric Karikehalli, Shridevi Jiang, Liuyan Gibson, Sarah Ondrejka, Sarah Nicolae, Alina Macon, William Castellar, Edgardo Parrilla Feldman, Andrew L. TI Morphology of ALK-Negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. United Hlth Serv Hopsitals, Binghamton, NY USA. Cleveland Clin, Cleveland, OH 44106 USA. Centrex Clin Labs, Utica, NY USA. Univ Washington, Seattle, WA 98195 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1416 BP 355A EP 355A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202125 ER PT J AU Nicolae, A Ganapathi, K Pittaluga, S Raffeld, M Jaffe, E AF Nicolae, Alina Ganapathi, Karthik Pittaluga, Stefania Raffeld, Mark Jaffe, Elaine TI Aggressive NK-Cell Leukemia/Lymphoma, EBV-Negative - A Report of 5 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1465 BP 368A EP 368A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202174 ER PT J AU Wang, HW Pittaluga, S Merino, M Jaffe, E AF Wang, Hao-Wei Pittaluga, Stefania Merino, Maria Jaffe, Elaine TI Primary Malignant Lymphomas of the Urinary Tract SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Wang, Hao-Wei; Pittaluga, Stefania; Merino, Maria; Jaffe, Elaine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1526 BP 383A EP 384A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202235 ER PT J AU Yousef, G Butz, H Szabo, P Mozes, R Rotondo, F Kovacs, K Patocs, A AF Yousef, George Butz, Henriett Szabo, Peter Mozes, Roy Rotondo, Fabio Kovacs, Kalman Patocs, Attila TI Integrative Bioinformatical Analysis of Clear Cell Renal Cell Carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 St Michaels Hosp, Toronto, ON M5B 1W8, Canada. NCI, NIH, Bethesda, MD 20892 USA. Hungarian Acad Sci, Budapest, Hungary. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1604 BP 403A EP 403A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202313 ER PT J AU Rosenberg, A Palmer, M Merlino, L Troost, J Gasim, A Bagnasco, SM Avila-Casado, C Johnstone, D Hodgin, J Conway, C Kopp, J Nast, C Barisoni, L Hewitt, S AF Rosenberg, Avi Palmer, Matthew Merlino, Lino Troost, Jonathan Gasim, Adil Bagnasco, Serena M. Avila-Casado, Carmen Johnstone, Duncan Hodgin, Jeffrey Conway, Catherine Kopp, Jeffrey Nast, Cynthia Barisoni, Laura Hewitt, Stephen TI The NEPTUNE Digital Pathology Protocol Increases Accurate Glomerular Number Assessment SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Miami, Miami, FL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Hlth Network, Toronto, ON, Canada. Temple Univ, Philadelphia, PA 19122 USA. Leica, Vista, CA USA. NIDDK, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, West Hollywood, CA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1639 BP 411A EP 412A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202348 ER PT J AU Ballester, L Wang, ZF Miettinen, M Rodriguez, F Raabe, E Nazarian, J Eberhart, C Warren, K Quezado, M AF Ballester, Leomar Wang, Zengfeng Miettinen, Markku Rodriguez, Fausto Raabe, Eric Nazarian, Javad Eberhart, Charles Warren, Katherine Quezado, Martha TI Overexpression of the Chromatin Remodeling Proteins ARID1A, BRG1 and SMARCD3 in Adult and Pediatric Gliomas SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Childrens Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1711 BP 428A EP 429A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202419 ER PT J AU Ghosh, A Li, A Brown, G Kebebew, E Merino, M AF Ghosh, Arunima Li, Ang Brown, Gregory Kebebew, Electron Merino, Maria TI Multifocal Pancreatic Neuroendocrine Tumors: Clonality and miRNA Profiling SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Ghosh, Arunima; Li, Ang; Brown, Gregory; Kebebew, Electron; Merino, Maria] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1771 BP 442A EP 442A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202479 ER PT J AU Rosenberg, A Pflicke, H Dreiling, J Wang, ZF Ylaya, K Hewitt, S Rudloff, U Miettinen, M AF Rosenberg, Avi Pflicke, Holger Dreiling, Jennifer Wang, Zeng-Feng Ylaya, Kris Hewitt, Stephen Rudloff, Udo Miettinen, Markku TI Elafin Expression in Gastrointestinal Neoplasia and Correlation With Sensitivity To PI3K/mTOR Inhibitor SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1791 BP 447A EP 447A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202499 ER PT J AU Schlitter, A Jang, KT Saka, B Choi, H Offerhaus, G Hruban, R Zen, Y Hong, SM Konzikiewitz, B Allgaeuer, M Kloppel, G Reid, M Esposito, I Adsay, V Basturk, O AF Schlitter, Anna Jang, Kee-Taek Saka, Burcu Choi, Hyejeong Offerhaus, G. Hruban, R. Zen, Yoh Hong, Seung-Mo Konzikiewitz, Bjorn Allgaeuer, Michael Kloppel, G. Reid, M. Esposito, Irene Adsay, Volkan Basturk, Olca TI Intraductal Tubulopapillary Neoplasms of the Bile Ducts: Further Immunohistochemical and Molecular Characterization SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 TUM, Munich, Germany. SMC, Seoul, South Korea. EU, Atlanta, GA USA. Univ Med Ctr, Utrecht, Netherlands. Johns Hopkins Univ, Baltimore, MD USA. KCH, London, England. Asan Med Ctr, Seoul, South Korea. NCI, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1795 BP 448A EP 448A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502202503 ER PT J AU Jawale, R Williams, K Yang, H Lee, M Otis, C Pentecost, B Arcaro, K AF Jawale, Rahul Williams, Kristin Yang, Howard Lee, Maxwell Otis, Christopher Pentecost, Brian Arcaro, Kathleen TI DNA Methylation in Endocrine Therapy Resistant Breast Cancer SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Baystate Med Ctr, Springfield, MA USA. UMass Amherst, Amherst, MA USA. Wadsworth Ctr, Albany, NY USA. NIH, Bethesda, MD 20892 USA. 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1837 BP 458A EP 459A PG 2 WC Pathology SC Pathology GA CB3BF UT WOS:000349502203034 ER PT J AU Killian, J Noyes, N Retnakumar, P Helman, L Killian, S Davis, S Bilke, S Su, J Smith, W Meltzer, P AF Killian, Jonathan Noyes, Natalia Retnakumar, Parvathy Helman, Lee Killian, Scott Davis, Sean Bilke, Sven Su, Joseph Smith, William Meltzer, Paul TI Cellular and Epiallelic Composition of Oral Fluid SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NIH, Bethesda, MD 20892 USA. Univ S Dakota, Vermillion, SD 57069 USA. Suburban Hosp, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 1839 BP 459A EP 459A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502203036 ER PT J AU Makhlouf, H Lubensky, I Altekruse, S Mehaffey, M Sachs, M Camalier, C Chuaqui, R Cozen, W Biswajit, D Hernandez, B Lih, CJ Lynch, C McGregor, P McShane, L Rohan, JP Walsh, W Williams, M Gillanders, E Mechanic, L Schully, S Carrick, D AF Makhlouf, Hala Lubensky, Irina Altekruse, Sean Mehaffey, Michele Sachs, Michael Camalier, Corinne Chuaqui, Rodrigo Cozen, Wendy Biswajit, Das Hernandez, Brenda Lih, Chih-Jian Lynch, Charles McGregor, Paul McShane, Lisa Rohan, JoyAnn Philips Walsh, William Williams, Mickey Gillanders, Elizabeth Mechanic, Leah Schully, Sheri Carrick, Danielle TI Effect of Storage Time of FFPE Ovarian Cancer Tissue on DNA Quality for Next Generation Sequencing SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Rockville, MD USA. Leidos, Frederick, MD USA. Univ So Calif, Los Angeles, CA USA. Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 2084 BP 519A EP 519A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502203280 ER PT J AU Miles, G Zhao, YM Levin, Y Shetty, J Tran, B Mitchell, S Oberholtzer, JC Levens, D AF Miles, George Zhao, Yongmei Levin, Yelena Shetty, Jyoti Tran, Bao Mitchell, Stephen Oberholtzer, J. Carl Levens, David TI Multiplex Tissue and Clinical Proteomics By Next-Generation Sequencing SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Frederick Natl Lab, Frederick, MD USA. Holy Cross Hosp, Silver Spring, MD USA. RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 2089 BP 520A EP 520A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502203285 ER PT J AU Rosenberg, A Armani, M Fetsch, P Xi, LQ Pham, TT Raffeld, M Chen, Y O'Flaherty, N Stussman, R Blackler, A Du, Q Hanson, J Roth, M Filie, A Rah, M Emmert-Buck, M Hipp, J Tangrea, M AF Rosenberg, Avi Armani Irm, Michael Fetsch, Patricia Xi, Liqiang Tina Thu Pham Raffeld, Mark Chen, Yun O'Flaherty, Neil Stussman, Rebecca Blackler, Adele Du, Qiang Hanson, Jeffrey Roth, Mark Filie, Armando Rah, Michael Emmert-Buck, Michael Hipp, Jason Tangrea, Michael TI A Do-It-Yourself, High-Throughput Microdissection System for Improving NGS Data SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Sch Med, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Sinai Hosp, Baltimore, MD 21215 USA. NR 0 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2015 VL 28 SU 2 MA 2099 BP 523A EP 523A PG 1 WC Pathology SC Pathology GA CB3BF UT WOS:000349502203295 ER PT J AU Davies, G Armstrong, N Bis, JC Bressler, J Chouraki, V Giddaluru, S Hofer, E Ibrahim-Verbaas, CA Kirin, M Lahti, J van der Lee, SJ Le Hellard, S Liu, T Marioni, RE Oldmeadow, C Postmus, I Smith, AV Smith, JA Thalamuthu, A Thomson, R Vitart, V Wang, J Yu, L Zgaga, L Zhao, W Boxall, R Harris, SE Hill, WD Liewald, DC Luciano, M Adams, H Ames, D Amin, N Amouyel, P Assareh, AA Au, R Becker, JT Beiser, A Berr, C Bertram, L Boerwinkle, E Buckley, BM Campbell, H Corley, J De Jager, PL Dufouil, C Eriksson, JG Espeseth, T Faul, JD Ford, I Gottesman, RF Griswold, ME Gudnason, V Harris, TB Heiss, G Hofman, A Holliday, EG Huffman, J Kardia, SLR Kochan, N Knopman, DS Kwok, JB Lambert, JC Lee, T Li, G Li, SC Loitfelder, M Lopez, OL Lundervold, AJ Lundqvist, A Mather, KA Mirza, SS Nyberg, L Oostra, BA Palotie, A Papenberg, G Pattie, A Petrovic, K Polasek, O Psaty, BM Redmond, P Reppermund, S Rotter, JI Schmidt, H Schuur, M Schofield, PW Scott, RJ Steen, VM Stott, DJ Van Swieten, JC Taylor, KD Trollor, J Trompet, S Uitterlinden, AG Weinstein, G Widen, E Windham, BG Jukema, JW Wright, AF Wright, MJ Yang, Q Amieva, H Attia, JR Bennett, DA Brodaty, H de Craen, AJM Hayward, C Ikram, MA Lindenberger, U Nilsson, LG Porteous, DJ Raikkonen, K Reinvang, I Rudan, I Sachdev, PS Schmidt, R Schofield, PR Srikanth, V Starr, JM Turner, ST Weir, DR Wilson, JF Van Duijn, C Launer, L Fitzpatrick, AL Seshadri, S Jr, THM Deary, IJ AF Davies, G. Armstrong, N. Bis, J. C. Bressler, J. Chouraki, V. Giddaluru, S. Hofer, E. Ibrahim-Verbaas, C. A. Kirin, M. Lahti, J. van der Lee, S. J. Le Hellard, S. Liu, T. Marioni, R. E. Oldmeadow, C. Postmus, I. Smith, A. V. Smith, J. A. Thalamuthu, A. Thomson, R. Vitart, V. Wang, J. Yu, L. Zgaga, L. Zhao, W. Boxall, R. Harris, S. E. Hill, W. D. Liewald, D. C. Luciano, M. Adams, H. Ames, D. Amin, N. Amouyel, P. Assareh, A. A. Au, R. Becker, J. T. Beiser, A. Berr, C. Bertram, L. Boerwinkle, E. Buckley, B. M. Campbell, H. Corley, J. De Jager, P. L. Dufouil, C. Eriksson, J. G. Espeseth, T. Faul, J. D. Ford, I. Gottesman, R. F. Griswold, M. E. Gudnason, V. Harris, T. B. Heiss, G. Hofman, A. Holliday, E. G. Huffman, J. Kardia, S. L. R. Kochan, N. Knopman, D. S. Kwok, J. B. Lambert, J-C Lee, T. Li, G. Li, S-C Loitfelder, M. Lopez, O. L. Lundervold, A. J. Lundqvist, A. Mather, K. A. Mirza, S. S. Nyberg, L. Oostra, B. A. Palotie, A. Papenberg, G. Pattie, A. Petrovic, K. Polasek, O. Psaty, B. M. Redmond, P. Reppermund, S. Rotter, J. I. Schmidt, H. Schuur, M. Schofield, P. W. Scott, R. J. Steen, V. M. Stott, D. J. Van Swieten, J. C. Taylor, K. D. Trollor, J. Trompet, S. Uitterlinden, A. G. Weinstein, G. Widen, E. Windham, B. G. Jukema, J. W. Wright, A. F. Wright, M. J. Yang, Q. Amieva, H. Attia, J. R. Bennett, D. A. Brodaty, H. de Craen, A. J. M. Hayward, C. Ikram, M. A. Lindenberger, U. Nilsson, L-G Porteous, D. J. Raikkonen, K. Reinvang, I. Rudan, I. Sachdev, P. S. Schmidt, R. Schofield, P. R. Srikanth, V. Starr, J. M. Turner, S. T. Weir, D. R. Wilson, J. F. Van Duijn, C. Launer, L. Fitzpatrick, A. L. Seshadri, S. Jr, T. H. Mosley Deary, I. J. CA Generation Scotland TI Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) SO MOLECULAR PSYCHIATRY LA English DT Article ID CPG-BINDING PROTEIN-2; ALZHEIMERS-DISEASE; HUMAN INTELLIGENCE; APOLIPOPROTEIN-E; OLD-AGE; SUSCEPTIBILITY LOCI; IDENTIFIES VARIANTS; TEST BATTERIES; TYPE-4 ALLELE; HUMAN HEIGHT AB General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C. C1 [Davies, G.; Marioni, R. E.; Harris, S. E.; Liewald, D. C.; Luciano, M.; Porteous, D. J.; Starr, J. M.; Deary, I. J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Davies, G.; Hill, W. D.; Luciano, M.; Corley, J.; Pattie, A.; Redmond, P.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Armstrong, N.] Univ Sydney, Sch Math & Stat, Sydney, NSW 2006, Australia. [Bis, J. C.; Li, G.; Psaty, B. M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Bressler, J.; Boerwinkle, E.] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Chouraki, V.; Amouyel, P.; Lambert, J-C] Inst Pasteur, Inserm UMR744, Unite Epidemiol & Sante Publ, F-59019 Lille, France. [Chouraki, V.; Au, R.; Beiser, A.; Weinstein, G.; Seshadri, S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Giddaluru, S.; Le Hellard, S.; Steen, V. M.] Univ Bergen, KG Jebsen Ctr Psychosis Res, Bergen, Norway. [Giddaluru, S.; Le Hellard, S.; Steen, V. M.] Univ Bergen, Norwegian Ctr Mental Disorders Res NORMENT, Dept Clin Sci, Bergen, Norway. [Giddaluru, S.; Le Hellard, S.; Steen, V. M.] Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Hofer, E.; Loitfelder, M.; Petrovic, K.; Schmidt, H.; Schmidt, R.] Med Univ Graz, Dept Neurol, Graz, Austria. [Hofer, E.] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Ibrahim-Verbaas, C. A.; Schuur, M.; Van Swieten, J. C.; Ikram, M. A.] Erasmus Univ, Dept Neurol, Med Ctr, Rotterdam, Netherlands. [Ibrahim-Verbaas, C. A.; van der Lee, S. J.; Amin, N.; Oostra, B. A.; Schuur, M.; Van Duijn, C.] Erasmus Univ, Genet Epidemiol Unit, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands. [Kirin, M.; Campbell, H.; Rudan, I.; Wilson, J. F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9JZ, Midlothian, Scotland. [Lahti, J.; Raikkonen, K.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Lahti, J.; Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Liu, T.; Li, S-C; Papenberg, G.; Lindenberger, U.] Max Planck Inst Human Dev, Berlin, Germany. [Liu, T.; Bertram, L.] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. [Marioni, R. E.; Boxall, R.; Harris, S. E.; Porteous, D. J.] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med,Western Gen Hosp, Edinburgh EH8 9JZ, Midlothian, Scotland. [Marioni, R. E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Oldmeadow, C.; Holliday, E. G.; Scott, R. J.; Attia, J. R.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia. [Oldmeadow, C.; Holliday, E. G.; Scott, R. J.; Attia, J. R.] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia. [Postmus, I.; Trompet, S.; de Craen, A. J. M.] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, Leiden, Netherlands. [Postmus, I.; de Craen, A. J. M.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Smith, A. V.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, A. V.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Smith, J. A.; Zhao, W.; Kardia, S. L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Thalamuthu, A.; Assareh, A. A.; Kochan, N.; Lee, T.; Mather, K. A.; Reppermund, S.; Trollor, J.; Brodaty, H.; Sachdev, P. S.] Univ New S Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia. [Thomson, R.; Srikanth, V.] Menzies Res Inst, Hobart, Tas, Australia. [Vitart, V.; Huffman, J.; Wright, A. F.; Hayward, C.] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH8 9JZ, Midlothian, Scotland. [Wang, J.; Au, R.; Beiser, A.; Weinstein, G.; Yang, Q.; Seshadri, S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Wang, J.; Yang, Q.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yu, L.; Bennett, D. A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Zgaga, L.] Univ Dublin Trinity Coll, Dept Publ Hlth & Primary Care, Dublin 2, Ireland. [Zgaga, L.] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Adams, H.; Hofman, A.; Mirza, S. S.; Uitterlinden, A. G.; Ikram, M. A.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Adams, H.; Amin, N.; Hofman, A.; Mirza, S. S.; Uitterlinden, A. G.; Ikram, M. A.; Van Duijn, C.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Ames, D.] Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia. [Ames, D.] Univ Melbourne, Acad Unit Psychiat Old Age, St Georges Hosp, Kew, Australia. [Becker, J. T.; Lopez, O. L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Becker, J. T.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Becker, J. T.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Berr, C.] INSERM, U106, Montpellier, France. [Berr, C.] Univ Montpellier I, Montpellier, France. [Bertram, L.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Fac Med, London, England. [Boerwinkle, E.] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med Prevent Human Dis, Houston, TX 77030 USA. [Boerwinkle, E.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Buckley, B. M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [De Jager, P. L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA. [De Jager, P. L.] Harvard Univ, Sch Med, Boston, MA USA. [De Jager, P. L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Dufouil, C.] INSERM, U708, Neuroepidemiol, Paris, France. [Dufouil, C.; Amieva, H.] Univ Bordeaux Segalen, INSERM, U897, Bordeaux, France. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Espeseth, T.] Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Norwegian Ctr Mental Disorders Res NORMENT, Div Mental Hlth & Addict, Oslo, Norway. [Espeseth, T.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Espeseth, T.; Reinvang, I.] Univ Oslo, Dept Psychol, Oslo, Norway. [Faul, J. D.; Weir, D. R.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Ford, I.] Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Porteous, D. J.; Generation Scotland] Univ Edinburgh, Generat Scotland, Ctr Genom & Expt Med, Inst Genet & Mol Med,Western Gen Hosp, Edinburgh EH8 9JZ, Midlothian, Scotland. [Gottesman, R. F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. [Griswold, M. E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Harris, T. B.; Launer, L.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Heiss, G.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Kochan, N.; Lee, T.; Sachdev, P. S.] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia. [Knopman, D. S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Kwok, J. B.] Neurosci Res Australia, Randwick, NSW, Australia. [Kwok, J. B.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Li, S-C] Tech Univ Dresden, D-01062 Dresden, Germany. [Lundervold, A. J.] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. [Lundervold, A. J.] Haraldsplass Deaconess Hosp, Kavli Res Ctr Aging & Dementia, Bergen, Norway. [Lundervold, A. J.] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, Bergen, Norway. [Lundqvist, A.; Nyberg, L.] Umea Univ, Umea Ctr Funct Brain Imaging UFBI, Umea, Sweden. [Nyberg, L.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Nyberg, L.] Umea Univ, Dept Integrat Med Biol, Umea, Sweden. [Palotie, A.] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, A.; Widen, E.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, A.] Univ Cent Hosp, Helsinki, Finland. [Papenberg, G.] Stockholm Univ, Aging Res Ctr, Karolinska Inst, S-10691 Stockholm, Sweden. [Polasek, O.] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Psaty, B. M.; Fitzpatrick, A. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, B. M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Unit, Seattle, WA USA. [Rotter, J. I.; Taylor, K. D.] Harbor UCLA Med Ctr, Inst Translat Genom, Los Angeles, CA USA. [Rotter, J. I.; Taylor, K. D.] Harbor UCLA Med Ctr, Populat Sci Los Angeles BioMed Res Inst, Los Angeles, CA USA. [Rotter, J. I.] Harbor UCLA Med Ctr, Div Genet Outcomes, Dept Pediat, Los Angeles, CA USA. [Schmidt, H.] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria. [Schofield, P. W.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Stott, D. J.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Taylor, K. D.] Harbor UCLA Med Ctr, Dept Pediat, Los Angeles, CA USA. [Trollor, J.] Univ New S Wales, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Sydney, NSW, Australia. [Trollor, J.] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Uitterlinden, A. G.] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands. [Windham, B. G.; Jr, T. H. Mosley] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Jukema, J. W.] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. W.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Wright, M. J.] QIMR Berghofer Med Res Inst, Neuroimaging Genet Grp, Brisbane, Qld, Australia. [Brodaty, H.] Univ New S Wales, Dementia Collaborat Res Ctr, Sydney, NSW, Australia. [Ikram, M. A.] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Nilsson, L-G] Karolinska Inst, ARC, Stockholm, Sweden. [Nilsson, L-G] Umea Univ, UFBI, Umea, Sweden. [Schofield, P. R.] Neurosci Res Australia, Sydney, NSW, Australia. [Schofield, P. R.] Univ New S Wales, Fac Med, Sydney, NSW, Australia. [Srikanth, V.] Monash Univ, Stroke & Ageing Res, Southern Clin Sch, Med, Melbourne, Vic 3004, Australia. [Starr, J. M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Turner, S. T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Fitzpatrick, A. L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. RP Davies, G (reprint author), Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. EM i.deary@ed.ac.uk RI Lambert, jean-charles/A-9553-2014; Smith, Albert/K-5150-2015; Nyberg, Lars/C-2514-2009; lambert, jean-charles/F-8787-2013; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Luciano, Michelle/F-7277-2010; Thomson, Russell/H-5653-2012; Li, Shu-Chen/K-7838-2012; Polasek, Ozren/B-6002-2011; Wright, Margaret/A-4560-2016; Bertram, Lars/K-3889-2015 OI Seshadri, Sudha/0000-0001-6135-2622; Zgaga, Lina/0000-0003-4089-9703; van Swieten, John /0000-0001-6278-6844; Sachdev, Perminder/0000-0002-9595-3220; Beiser, Alexa/0000-0001-8551-7778; Smith, Jennifer/0000-0002-3575-5468; Lahti, Jari/0000-0002-4310-5297; Lambert, jean-charles/0000-0003-0829-7817; Smith, Albert/0000-0003-1942-5845; Nyberg, Lars/0000-0002-3367-1746; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Luciano, Michelle/0000-0003-0935-7682; Thomson, Russell/0000-0003-4949-4120; Li, Shu-Chen/0000-0002-5520-5789; Chouraki, Vincent/0000-0002-4698-1794; Polasek, Ozren/0000-0002-5765-1862; Wright, Margaret/0000-0001-7133-4970; Bertram, Lars/0000-0002-0108-124X FU Zoll LifeCor FX Bruce M Psaty serves on a DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor). All other authors declare no conflict of interest. NR 84 TC 49 Z9 50 U1 6 U2 41 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 FEB PY 2015 VL 20 IS 2 BP 183 EP 192 DI 10.1038/mp.2014.188 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CB9XE UT WOS:000349986700007 PM 25644384 ER PT J AU Leng, Y Wang, Z Tsai, LK Leeds, P Fessler, EB Wang, J Chuang, DM AF Leng, Y. Wang, Z. Tsai, L-K Leeds, P. Fessler, E. B. Wang, J. Chuang, D-M TI FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers SO MOLECULAR PSYCHIATRY LA English DT Article DE FGF-21; GSK-3 inhibitor; HDAC inhibitor; lithium; neuroprotection; valproic acid ID C6 GLIOMA-CELLS; MEDIATED PHOSPHOINOSITIDE TURNOVER; INCREASES ENERGY-EXPENDITURE; CEREBELLAR GRANULE CELLS; BIPOLAR DISORDER; INSULIN SENSITIVITY; VALPROIC ACID; PHARMACOLOGICAL CHARACTERIZATION; NERVOUS-SYSTEM; CALCIUM INFLUX AB Fibroblast growth factor-21 (FGF-21) is a new member of the FGF super-family and an important endogenous regulator of glucose and lipid metabolism. It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studies from our laboratory demonstrated that aging primary neurons are more vulnerable to glutamate-induced excitotoxicity, and that co-treatment with the mood stabilizers lithium and valproic acid (VPA) induces synergistic neuroprotective effects. This study sought to identify molecule(s) involved in these synergistic effects. We found that FGF-21 mRNA was selectively and markedly elevated by co-treatment with lithium and VPA in primary rat brain neurons. FGF-21 protein levels were also robustly increased in neuronal lysates and culture medium following lithium-VPA co-treatment. Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF-21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. Together, our novel results suggest that FGF-21 is a key mediator of the effects of these mood stabilizers and a potential new therapeutic target for CNS disorders. C1 [Leng, Y.; Wang, Z.; Tsai, L-K; Leeds, P.; Fessler, E. B.; Wang, J.; Chuang, D-M] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov OI Tsai, Li-Kai/0000-0001-8420-6951 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). We thank the members of the Molecular Neurobiology Section, NIMH, NIH for their support, and Ioline Henter for critical reading and editing of the manuscript. NR 44 TC 11 Z9 11 U1 4 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 FEB PY 2015 VL 20 IS 2 BP 215 EP 223 DI 10.1038/mp.2013.192 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CB9XE UT WOS:000349986700011 PM 24468826 ER PT J AU Shaw, P Sharp, W Sudre, G Wharton, A Greenstein, D Raznahan, A Evans, A Chakravarty, MM Lerch, JP Rapoport, J AF Shaw, P. Sharp, W. Sudre, G. Wharton, A. Greenstein, D. Raznahan, A. Evans, A. Chakravarty, M. M. Lerch, J. P. Rapoport, J. TI Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE endophenotypes; genetics; neuroanatomy; obsessive-compulsive disorder; orbitofrontal cortex; striatum ID HUMAN CEREBRAL-CORTEX; DEFAULT-MODE NETWORK; UNAFFECTED RELATIVES; FUNCTIONAL CONNECTIVITY; EXECUTIVE DYSFUNCTIONS; BRAIN ACTIVATION; SHAPE DEFORMITY; VOLUME; THICKNESS; TWINS AB Endophentoypes, quantifiable traits lying on the causal chain between a clinical phenotype and etiology, can be used to accelerate genomic discovery in obsessive-compulsive disorder (OCD). Here we identify the neuroanatomic changes that are shared by 22 OCD adult and adolescent patients and 25 of their unaffected siblings who are at genetic risk for the disorder. Comparisons were made against 47 age and sex matched healthy controls. We defined the surface morphology of the striatum, globus pallidus and thalamus, and thickness of the cerebral cortex. Patients with OCD show significant surface expansion compared with healthy controls, following adjustment for multiple comparisons, in interconnected regions of the caudate, thalamus and right orbitofrontal cortex. Their unaffected siblings show similar, significant expansion, most marked in the ventromedial caudate bilaterally, the right pulvinar thalamic nucleus and the right orbitofrontal cortex. These regions define a network that has been consistently implicated in OCD. In addition, both patients with OCD and unaffected siblings showed similar increased thickness of the right precuneus, which receives rich input from the thalamic pulvinar nuclei and the left medial temporal cortex. Anatomic change within the orbitofrontostriatal and posterior brain circuitry thus emerges as a promising endophenotype for OCD. C1 [Shaw, P.; Sudre, G.; Wharton, A.] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Shaw, P.; Sharp, W.; Greenstein, D.; Raznahan, A.; Rapoport, J.] NIMH, Intramural Program, Bethesda, MD 20892 USA. [Evans, A.] McGill Univ, Neuroimaging Inst & Hosp, Brain Imaging Ctr, Montreal, PQ, Canada. [Chakravarty, M. M.] Ctr Addict & Mental Hlth, Res Imaging Ctr, Kimel Family Imaging Genet Res Lab, Toronto, ON, Canada. [Chakravarty, M. M.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Chakravarty, M. M.] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON, Canada. [Lerch, J. P.] Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON M5G 1X8, Canada. [Lerch, J. P.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU Intramural Program of the National Human Genome Research Institute; Intramural Program of the National Institute of Mental Health FX The study was funded by the Intramural Programs of the National Human Genome Research Institute and the National Institute of Mental Health. NR 65 TC 12 Z9 12 U1 0 U2 19 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 FEB PY 2015 VL 20 IS 2 BP 224 EP 231 DI 10.1038/mp.2014.3 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CB9XE UT WOS:000349986700012 PM 24514568 ER PT J AU Xu, P Stevens, ED French, AD Kovac, P AF Xu, Peng Stevens, Edwin D. French, Alfred D. Kovac, Pavol TI Synthesis and Molecular Structure of the 5-Methoxycarbonylpentyl alpha-Glycoside of the Upstream, Terminal Moiety of the O-Specific Polysaccharide of Vibrio cholerae O1, Serotype Inaba SO MOLECULES LA English DT Article ID CRYSTAL-STRUCTURE; THERMODYNAMIC CONTROL; OGAWA; HEXASACCHARIDE; ANTIGEN; UNIT; O-1; O/1 AB The trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed reaction of methyl 6-hydroxyhexanoate with 3-O-benzyl-4-(2,4-di-O-acetyl-3-deoxy-l-glycero-tetronamido)-4,6-dideoxy-2-O-levulinoyl-alpha-d-mannopyranosyl trichloroacetimidate followed by a two-step deprotection (hydrogenolysis over Pd/C catalyst and Zemplen deacylation, to simultaneously remove the acetyl and levulinoyl groups) gave 5-(methoxycarbonyl)pentyl 4-(3-deoxy-l-glycero-tetronamido)-4,6-dideoxy-alpha-d-mannopyranoside. The structure of the latter, for which crystals were obtained in the analytically pure state for the first time, followed from its NMR and high-resolution mass spectra and was confirmed by X-ray crystallography. The molecule has two approximately linear components; a line through the aglycon intersects a line through the mannosyl and tetronylamido groups at 120 degrees. The crystal packing separates the aglycon groups from the tetronylamido and mannosyl groups, with only C-H horizontal ellipsis O hydrogen bonding among the aglycon groups and N-H horizontal ellipsis O, O-H horizontal ellipsis O and C-H horizontal ellipsis O links among the tetronylamido and mannosyl groups. A carbonyl oxygen atom accepts the strongest O-H horizontal ellipsis O hydrogen bond and two strong C-H horizontal ellipsis O hydrogen bonds. The geometric properties were compared with those of related molecules. C1 [Xu, Peng; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. [Stevens, Edwin D.] Western Kentucky Univ, Dept Chem, Bowling Green, KY 42101 USA. [French, Alfred D.] USDA, So Reg Res Ctr, New Orleans, LA 70124 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM xup3@mail.nih.gov; Edwin.Stevens@wku.edu; Al.French@ars.usda.gov; kpn@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The crystallography was carried out at the University of New Orleans. NR 18 TC 0 Z9 0 U1 2 U2 3 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD FEB PY 2015 VL 20 IS 2 BP 2892 EP 2902 DI 10.3390/molecules20022892 PG 11 WC Chemistry, Organic SC Chemistry GA CD0GH UT WOS:000350748200066 PM 25679049 ER PT J AU Kenny, HA Lal-Nag, M White, EA Shen, M Chiang, CY Mitra, AK Zhang, YL Curtis, M Schryver, EM Bettis, S Jadhav, A Boxer, MB Li, ZY Ferrer, M Lengyel, E AF Kenny, Hilary A. Lal-Nag, Madhu White, Erin A. Shen, Min Chiang, Chun-Yi Mitra, Anirban K. Zhang, Yilin Curtis, Marion Schryver, Elizabeth M. Bettis, Sam Jadhav, Ajit Boxer, Matthew B. Li, Zhuyin Ferrer, Marc Lengyel, Ernst TI Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy SO NATURE COMMUNICATIONS LA English DT Article ID OVARIAN-CANCER METASTASIS; TUMOR MICROENVIRONMENT; MESOTHELIAL CELLS; DRUG DISCOVERY; SPHEROID MODEL; VITRO; FIBRONECTIN; FIBROBLASTS; PROGRESSION; INVASION AB The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial cells and extracellular matrix can be adapted into a reliable 384- and 1,536-multi-well HTS assay that reproduces the human ovarian cancer (OvCa) metastatic microenvironment. We validate the identified inhibitors in secondary in vitro and in vivo biological assays using three OvCa cell lines: HeyA8, SKOV3ip1 and Tyk-nu. The active compounds directly inhibit at least two of the three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that a complex three-dimensional culture of the tumour microenvironment can be adapted for quantitative HTS and may improve the disease relevance of assays used for drug screening. C1 [Kenny, Hilary A.; White, Erin A.; Chiang, Chun-Yi; Mitra, Anirban K.; Zhang, Yilin; Curtis, Marion; Schryver, Elizabeth M.; Lengyel, Ernst] Univ Chicago, Dept Obstet & Gynecol, Sect Gynecol Oncol, Chicago, IL 60637 USA. [Lal-Nag, Madhu; Shen, Min; Jadhav, Ajit; Boxer, Matthew B.; Li, Zhuyin; Ferrer, Marc] NIH, Div Preclin Innovat, NCATS, Rockville, MD 20850 USA. [Bettis, Sam] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Li, Zhuyin] Bristol Myers Squibb Co, Lead Discovery & Optimizat, Wallingford, CT 06492 USA. RP Kenny, HA (reprint author), Univ Chicago, Dept Obstet & Gynecol, Sect Gynecol Oncol, 5841 South Maryland Ave,MC2050, Chicago, IL 60637 USA. EM hkenny@uchicago.edu; elengyel@uchicago.edu FU charitable beneficiary of the Chicago Bears Football Club; National Institute of Neurological Disorders and Stroke (NINDS) [R21 NS075702]; National Cancer Institute [R01 CA111882]; National Institutes of Health (NIH) Common Fund Molecular Libraries and Imaging Program [U54 MH084681]; Bears Care FX We thank Dr A.F. Haney (the University of Chicago, Department of Obstetrics and Gynecology) for collecting all omental biopsies and G. Isenberg (the University of Chicago) for carefully editing the manuscript. We also thank the Cellular Screening Center core facility at the University of Chicago as well as the automation and compound management team at the National Center for Advancing Translational Sciences (NCATS) for their expert technical support. Finally, we thank all the patients, residents and attending physicians in the Department of Obstetrics and Gynecology at the University of Chicago for their commitment to collecting tissues for these experiments. This work was supported by Bears Care, the charitable beneficiary of the Chicago Bears Football Club, the National Institute of Neurological Disorders and Stroke (NINDS) R21 NS075702, the National Cancer Institute grant R01 CA111882 to E.L. and by the National Institutes of Health (NIH) Common Fund Molecular Libraries and Imaging Program Grant U54 MH084681 to NCATS. NR 35 TC 29 Z9 29 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6220 DI 10.1038/ncomms7220 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2UW UT WOS:000350201100029 PM 25653139 ER PT J AU Mishra, A Brown, AL Yao, XL Yang, ST Park, SJ Liu, CY Dagur, PK McCoy, JP Keeran, KJ Nugent, GZ Jeffries, KR Qu, X Yu, ZX Levine, SJ Chung, JH AF Mishra, Amarjit Brown, Alexandra L. Yao, Xianglan Yang, Shutong Park, Sung-Jun Liu, Chengyu Dagur, Pradeep K. McCoy, J. Philip Keeran, Karen J. Nugent, Gayle Z. Jeffries, Kenneth R. Qu, Xuan Yu, Zu-Xi Levine, Stewart J. Chung, Jay H. TI Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase SO NATURE COMMUNICATIONS LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; CATALYTIC SUBUNIT; T-CELLS; ANTIGEN PRESENTATION; OXIDATIVE STRESS; V(D)J RECOMBINATION; INHIBITOR NU7441; POTENTIAL ROLE; SCID MICE; IN-VIVO AB DNA-dependent protein kinase (DNA-PK) mediates double-stranded DNA break repair, V(D)J recombination and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cells in allergic asthma. Here we show that house dust mite induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstrate that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuates the induction of allergic sensitization and Th2 immunity via a mechanism that involves the impaired presentation of mite antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduces the manifestations of mite-induced airway disease. Collectively, these findings suggest that DNA-PK may be a potential target for treatment of allergic asthma. C1 [Mishra, Amarjit; Yao, Xianglan; Levine, Stewart J.] NHLBI, Lab Asthma & Lung Inflammat, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Brown, Alexandra L.; Yang, Shutong; Park, Sung-Jun; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Dagur, Pradeep K.; McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Nugent, Gayle Z.; Jeffries, Kenneth R.] NHLBI, Anim Surg & Resources Core Facil, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Qu, Xuan; Yu, Zu-Xi] NHLBI, Pathol Core Facil, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Lab Asthma & Lung Inflammat, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov; chungj@nhlbi.nih.gov RI MISHRA, AMARJIT/D-7504-2016 OI MISHRA, AMARJIT/0000-0002-3777-0338 FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX We thank Dalton Saunders for his assistance with mouse management. We also thank Dr Martha Vaughan and Dr Joel Moss for their helpful discussions. This study was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute. NR 63 TC 3 Z9 3 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6224 DI 10.1038/ncomms7224 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC2UW UT WOS:000350201100033 PM 25692509 ER PT J AU Mooshagian, E Keisler, A Zimmermann, T Schweickert, JM Wassermann, EM AF Mooshagian, Eric Keisler, Aysha Zimmermann, Trelawny Schweickert, Janell M. Wassermann, Eric M. TI Modulation of corticospinal excitability by reward depends on task framing SO NEUROPSYCHOLOGIA LA English DT Article DE Uncertainty; Expectation; Reward probability; Transcranial magnetic stimulation; Corticospinal excitability ID PRIMARY MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; DOPAMINE NEURONS; REACTION-TIME; MIDBRAIN DOPAMINE; IMPLICIT; UNCERTAINTY; PLASTICITY; SIGNALS; INFORMATION AB Findings from previous transcranial magnetic stimulation (TMS) experiments suggest that the primary motor cortex (M1) is sensitive to reward conditions in the environment. However, the nature of this influence on M1 activity is poorly understood. The dopamine neuron response to conditioned stimuli encodes reward probability and outcome uncertainty, or the extent to which the outcome of a situation is known. Reward uncertainty and probability are related: uncertainty is maximal when probability is 0.5 and minimal when probability is 0 or 1 (i.e., certain outcome). Previous TMS-reward studies did not examine these factors independently. Here, we used single-pulse TMS to measure corticospinal excitability in 40 individuals while they performed a simple computer task, making guesses to find or avoid a hidden target. The task stimuli implied three levels of reward probability and two levels of uncertainty. We found that reward probability level interacted with the trial search condition. That is, motor evoked potential (MEP) amplitude, a measure of corticospinal neuron excitability, increased with increasing reward probability when participants were instructed to "find" a target, but not when they were instructed to "avoid" a target. There was no effect of uncertainty on MEPs. Response times varied with the number of choices. A subset of participants also received paired-pulse stimulation to evaluate changes in short-intracortical inhibition (SICI). No effects of SICI were observed. Taken together, the results suggest that the reward-contingent modulation of M1 activity reflects reward probability or a related aspect of utility, not outcome uncertainty, and that this effect is sensitive to the conceptual framing of the task. Published by Elsevier Ltd. C1 [Mooshagian, Eric; Keisler, Aysha; Zimmermann, Trelawny; Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Mooshagian, Eric; Keisler, Aysha; Zimmermann, Trelawny] Uniformed Serv Univ Hlth Sci, Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Rockville, MD 20852 USA. [Schweickert, Janell M.] Wake Kendall Grp PLLC, Washington, DC 20015 USA. RP Wassermann, EM (reprint author), NINDS, Behav Neurol Unit, NIH, 10 CTR DR,MSC 1440, Bethesda, MD 20892 USA. EM wassermanne@ninds.nih.gov FU Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke; Center for Neuroscience and Regenerative Medicine via the Henry M. Jackson Foundation for the Advancement of Military Medicine FX Support for this work included intramural funding from the Clinical Neuroscience Program of the National Institute of Neurological Disorders and Stroke (EW) and funding from the Center for Neuroscience and Regenerative Medicine (AK, EM, EW, and TZ), via the Henry M. Jackson Foundation for the Advancement of Military Medicine. The authors have no conflicts of interest to report. The authors would like to thank Mr. Eric Emmons for his assistance with pilot data collection. NR 41 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD FEB PY 2015 VL 68 BP 31 EP 37 DI 10.1016/j.neuropsychologia.2014.12.021 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA CC1AS UT WOS:000350074000004 PM 25543022 ER PT J AU Martin, S Schmitt, SN Wolters, PL Abel, B Toledo-Tamula, MA Baldwin, A Wicksell, RK Merchant, M Widemann, B AF Martin, Staci Schmitt, Shawn Nelson Wolters, Pamela L. Abel, Brittany Toledo-Tamula, Mary Anne Baldwin, Andrea Wicksell, Rikard K. Merchant, Melinda Widemann, Brigitte TI Development and Validation of the English Pain Interference Index and Pain Interference Index-Parent Report SO PAIN MEDICINE LA English DT Article DE Pain Interference; Validation; NF1; Cancer; Children; Adolescents ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; PEDIATRIC PAIN; PLEXIFORM NEUROFIBROMAS; CANCER PAIN; CHILDREN; AGREEMENT; DISEASE; ADOLESCENTS; STRATEGIES AB ObjectiveMeasurement of pain interference in children is challenged by a lack of validated measures with a parent proxy report. This study investigated the psychometric properties of the Pain Interference Index (PII), a six-item questionnaire originally developed in Swedish, in chronically ill youth. MethodsWe adapted the PII for English-speaking participants and created a parallel parent proxy measure. Respondents indicate how much pain has interfered with the child's life in the past 2 weeks (0-6 scale); higher scores indicate more pain interference. Eligible participants included individuals 6-25 years with neurofibromatosis type 1 (NF1) and cancer. Internal consistency was assessed; validity was examined by correlating PII scores with existing measures of pain interference (Modified Brief Pain Inventory [MBPI]) and pain intensity (visual analogue scale [VAS]), and with measures of disease severity. ResultsAmong 60 participants (mean age 14.7 years, range 6-24) and their parents, PII internal consistency was 0.84 and 0.96, respectively. PII scores correlated with MBPI (r=0.81, P<0.0001) and VAS (r=0.55, P<0.0001) scores and differentiated between patients with mild vs moderate/severe NF1 disease severity (P<0.05). The PII-Parent was significantly correlated with the mothers' and fathers' VAS rating of the child's pain intensity (Ps<0.01). ConclusionsInternal consistency of the English PII is high; validity is supported by the PII's correlations with other measures of pain interference and pain intensity, and with disease severity in patients with NF1. Preliminary data indicate that the English PII is a reliable, valid, feasible pain interference measure for youth with NF1 and cancer. C1 [Martin, Staci; Wolters, Pamela L.; Abel, Brittany; Baldwin, Andrea; Merchant, Melinda; Widemann, Brigitte] NCI, NIH, Bethesda, MD 20892 USA. [Schmitt, Shawn Nelson] Uniformed Serv Univ Hlth Sci, Ettenhofer Lab Neurocognit Res, Bethesda, MD 20814 USA. [Toledo-Tamula, Mary Anne] Leidos Biomed Labs, Natl Lab Canc Res, Frederick, MD USA. [Wicksell, Rikard K.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Wicksell, Rikard K.] Karolinska Univ Hosp, Behav Med Pain Treatment Serv, Stockholm, Sweden. RP Martin, S (reprint author), NCI, Hlth Psychol & Neurobehav Res Grp, 9030 Old Georgetown Rd,107, Bethesda, MD 20892 USA. EM martins@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors are grateful to the patients and families who participated in this study. We also thank Amy Starosta, MA, Katherine Burns, PhD, and Ethan Eisen, M.Phil, for their assistance with data collection. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. In addition, this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 40 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD FEB PY 2015 VL 16 IS 2 BP 367 EP 373 DI 10.1111/pme.12620 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CB9UU UT WOS:000349979600021 PM 25377441 ER PT J AU Alvarez-Hernandez, G Murillo-Benitez, C Candia-Plata, MD Moro, M AF Alvarez-Hernandez, Gerardo Murillo-Benitez, Coral del Carmen Candia-Plata, Maria Moro, Manuel TI Clinical Profile and Predictors of Fatal Rocky Mountain Spotted Fever in Children from Sonora, Mexico SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE Rocky Mountain spotted fever; children; Mexico ID ACUTE-RENAL-FAILURE; UNITED-STATES; RISK-FACTORS; SOUTHEASTERN BRAZIL; SURVEILLANCE; MORTALITY; FEATURES AB Background: Rocky Mountain spotted fever (RMSF) is an increasingly important cause of preventable mortality in children in Sonora, Mexico. Although early treatment with tetracycline has shown to prevent fatal outcome, the disease remains a life-threatening condition, particularly for children. This study describes the clinical factors associated with pediatric mortality due to RMSF in Sonora, in order to guide healthcare practices. Methods: This is a retrospective analysis of 104 children consecutively hospitalized at the major pediatric hospital of Sonora, diagnosed with RMSF between January 2004 and December 2013. Descriptive statistics and multiple logistic regression were used to identify risk factors for fatal outcome. Results: The case fatality ratio in this cohort was 20.2%. Children were hospitalized after a median of 6 days from onset of symptoms including fever (100%), rash involving palms and soles (88.5%) and headache (79.8%); 90.4% of fatal cases had low platelet counts (<50,000/mu L) and 33.3% showed serum creatinine concentrations above the normal value. Acute kidney injury increased mortality, odds ratio (ORadj) = 4.84, 95% confidence interval (CI): 1.2-16.2, as well as delay in treatment (>= 5th day from onset) with doxycycline, ORadj = 2.62, 95% CI: 1.24-5.52 and hemorrhage, ORadj = 6.11, 95% CI: 1.89-19.69. Conclusions: RMSF is a public health problem in Sonora. Clinically, fatal cases differ from non-fatal cases in renal function and hemorrhagic manifestations, although these findings may occur too late for a timely intervention. First-line providers must be educated to harbor a timely suspicion of RMSF, and should provide empiric treatment with doxycycline when febrile patients first present for care. C1 [Alvarez-Hernandez, Gerardo; del Carmen Candia-Plata, Maria] Univ Sonora, Dept Med & Hlth Sci, Hermosillo 83000, Sonora, Mexico. [Murillo-Benitez, Coral] Inst Tecnol & Estudios Super Monterrey, Sch Med & Hlth Sci, Monterrey, Mexico. [Moro, Manuel] NIH, Div Comparat Med, Off Res Infrastruct Programs, Bethesda, MD 20892 USA. RP Alvarez-Hernandez, G (reprint author), Univ Sonora, Dept Med & Hlth Sci, Blvd Luis D Colosio SN, Hermosillo 83000, Sonora, Mexico. EM galvarez@guayacan.uson.mx FU Sonora State Children's Hospital of Mexico's Ministry of Public Health FX The authors thank the support of the Sonora State Children's Hospital of Mexico's Ministry of Public Health for the completion of this study. The authors also thank Dr. Jennifer McQuiston for the valuable comments made to this article. NR 29 TC 6 Z9 6 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2015 VL 34 IS 2 BP 125 EP 130 DI 10.1097/INF.0000000000000496 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CB8VE UT WOS:000349908800005 PM 25126856 ER PT J AU Rutstein, RM Samson, P Fenton, T Fletcher, CV Kiser, JJ Mofenson, LM Smith, E Graham, B Mathew, M Aldrovani, G AF Rutstein, Richard M. Samson, Pearl Fenton, Terry Fletcher, Courtney V. Kiser, Jennifer J. Mofenson, Lynne M. Smith, Elizabeth Graham, Bobbie Mathew, Marina Aldrovani, Grace CA PACTG 1020A Study Team TI Long-term Safety and Efficacy of Atazanavir-based Therapy in HIV-infected Infants, Children and Adolescents The Pediatric AIDS Clinical Trials Group Protocol 1020A SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE atazanavir; pediatric HIV; antiretroviral treatment ID ACTIVE ANTIRETROVIRAL THERAPY; TWICE-DAILY LOPINAVIR/RITONAVIR; ONCE-DAILY ATAZANAVIR/RITONAVIR; INCLUDING PROTEASE INHIBITORS; MULTIPLE VIROLOGICAL FAILURES; NAIVE HIV-1-INFECTED PATIENTS; MORTALITY-RATES; YOUNG-ADULTS; RITONAVIR; PHARMACOKINETICS AB Background: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. Methods: Antiretroviral-naive and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. Results: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA <= 400 cpm. At week 48, 69.5% of naive and 43.3% of experienced subjects had HIV RNA <= 400 cpm; median CD4 increase was 196.5 cells/mm(3). The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels >= 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. Conclusions: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels. C1 [Rutstein, Richard M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Samson, Pearl; Fenton, Terry] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Fletcher, Courtney V.] Univ Nebraska Med Ctr, Omaha, NE USA. [Kiser, Jennifer J.] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Mofenson, Lynne M.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Smith, Elizabeth] NICHD, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Graham, Bobbie] Frontier Sci Technol Res Fdn, Amherst, NY USA. [Mathew, Marina] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Aldrovani, Grace] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Rutstein, RM (reprint author), Childrens Hosp Philadelphia, Div Gen Pediat, Room 12NW60,Main Bldg,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Rutstein@email.chop.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group [1 U01 AI068616]; National Institute of Allergy and Infectious Diseases (NIAID); NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network - NICHD [N01-DK-9-001/HHSN267200800001C] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [AI068632]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). Protocol support also provided by Bristol-Myers Squibb. M Matthew is an employee of Bristol-Myers Squibb. The authors have no other funding or conflicts of interest to disclose. NR 31 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2015 VL 34 IS 2 BP 162 EP 167 DI 10.1097/INF.0000000000000538 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CB8VE UT WOS:000349908800012 PM 25232777 ER PT J AU Cournil, A Van de Perre, P Cames, C de Vincenzi, I Read, JS Luchters, S Meda, N Naidu, K Newell, ML Bork, K AF Cournil, Amandine Van de Perre, Philippe Cames, Cecile de Vincenzi, Isabelle Read, Jennifer S. Luchters, Stanley Meda, Nicolas Naidu, Kevi Newell, Marie-Louise Bork, Kirsten CA Kesho Bora Study Grp TI Early Infant Feeding Patterns and HIV-free Survival Findings from the Kesho-Bora Trial (Burkina Faso, Kenya, South Africa) SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE infant; HIV-free survival; prevention of mother-to-child transmission; breastfeeding; antiretroviral therapy; Africa ID TO-CHILD TRANSMISSION; RANDOMIZED CONTROLLED-TRIAL; PROPENSITY SCORE METHODS; INFECTED MOTHERS; ANTIRETROVIRAL THERAPY; UNINFECTED CHILDREN; BREAST-MILK; ZIDOVUDINE PROPHYLAXIS; CLINICAL-TRIAL; CELL-FREE AB Objective: To investigate the association between feeding patterns and HIV-free survival in children born to HIV-infected mothers and to clarify whether antiretroviral (ARV) prophylaxis modifies the association. Methods: From June 2005 to August 2008, HIV-infected pregnant women were counseled regarding infant feeding options, and randomly assigned to triple-ARV prophylaxis (triple ARV) until breastfeeding cessation (BFC) before age 6 months or antenatal zidovudine with single-dose nevirapine (short-course ARV). Eighteen-month HIV-free survival of infants HIV-negative at 2 weeks of age was assessed by feeding patterns (replacement feeding from birth, BFC <3 months, BFC >= 3 months). Results: Of the 753 infants alive and HIV-negative at 2 weeks, 28 acquired infection and 47 died by 18 months. Overall HIV-free survival at 18 months was 0.91 [95% confidence interval (CI): 0.88-0.93]. In the short-course ARV arm, HIV-free survival (0.88; CI: 0.84-0.91) did not differ by feeding patterns. In the triple ARV arm, overall HIV-free survival was 0.93 (CI: 0.90-0.95) and BFC <3 months was associated with lower HIV-free survival than BFC >= 3 months (adjusted hazard ratio: 0.36; CI: 0.15-0.83) and replacement feeding (adjusted hazard ratio: 0.20; CI: 0.04-0.94). In the triple ARV arm, 4 of 9 transmissions occurred after reported BFC (and 5 of 19 in the short-course arm), indicating that some women continued breastfeeding after interruption of ARV prophylaxis. Conclusions: In resource-constrained settings, early weaning has previously been associated with higher infant mortality. We show that, even with maternal triple-ARV prophylaxis during breastfeeding, early weaning remains associated with lower HIV-free survival, driven in particular by increased mortality. C1 [Cournil, Amandine; Cames, Cecile; Bork, Kirsten] UM1, IRD, UMI233, F-34394 Montpellier 5, France. [Van de Perre, Philippe] INSERM, Dept Bacteriol Virol, U1058, Montpellier, France. [Van de Perre, Philippe] Univ Montpellier, F-34059 Montpellier, France. [Van de Perre, Philippe] CHRU Montpellier, Montpellier, France. [de Vincenzi, Isabelle] WHO, Dept Reprod Hlth & Res, CH-1211 Geneva, Switzerland. [Read, Jennifer S.] NIH, Bethesda, MD 20892 USA. [Luchters, Stanley] ICRH, Mombasa, Kenya. [Luchters, Stanley] Univ Ghent, Int Ctr Reprod Hlth, B-9000 Ghent, Belgium. [Meda, Nicolas] Ctr Muraz, Bobo Dioulasso, Burkina Faso. [Naidu, Kevi] Univ KwaZulu Natal, Durban, South Africa. [Newell, Marie-Louise] Univ KwaZulu Natal, Africa Ctr Hlth & Populat Studies, Somkhele, South Africa. RP Cournil, A (reprint author), UM1, IRD, UMI233, BP 64501, F-34394 Montpellier 5, France. EM amandine.cournil@ird.fr RI Van de Perre, Philippe/B-9692-2008; OI Van de Perre, Philippe/0000-0002-3912-0427; Newell, Marie-Louise/0000-0002-1074-7699; Bork, Kirsten/0000-0002-5909-7332; Njagi, Ephantus/0000-0002-1484-0241 FU Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS); Department for International Development (DFID); European and Developing Countries Clinical Trials Partnership (EDCTP); Thrasher Research Fund; Belgian Directorate General for International Cooperation; GlaxoSmithKline Foundation; Centers for Disease Control and Prevention; Eunice Kennedy Shriver National Institute of Child Health and Human Development; UNDP/UNFPA/UNICEF/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction; Victorian Operational Infrastructure Support Program FX Financial support was provided by Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS), Department for International Development (DFID), European and Developing Countries Clinical Trials Partnership (EDCTP), Thrasher Research Fund, Belgian Directorate General for International Cooperation, GlaxoSmithKline Foundation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, UNDP/UNFPA/UNICEF/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction and the Victorian Operational Infrastructure Support Program. The authors have no other funding or conflicts of interest to disclose. NR 41 TC 3 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2015 VL 34 IS 2 BP 168 EP 174 DI 10.1097/INF.0000000000000512 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CB8VE UT WOS:000349908800013 PM 25741969 ER PT J AU Duarte, JO Cruz, FC Leao, RM Planeta, CS Crestani, CC AF Duarte, Josiane O. Cruz, Fabio C. Leao, Rodrigo M. Planeta, Cleopatra S. Crestani, Carlos C. TI Stress Vulnerability During Adolescence: Comparison of Chronic Stressors in Adolescent and Adult Rats SO PSYCHOSOMATIC MEDICINE LA English DT Article DE unpredictable stress; restraint; autonomic; baroreflex; vascular; glucocorticoids ID DIFFERENTIAL CARDIOVASCULAR-RESPONSES; CORTICOTROPIN-RELEASING FACTOR; NITRIC-OXIDE; REPEATED RESTRAINT; VENTRICULAR-ARRHYTHMIAS; ESSENTIAL-HYPERTENSION; VASCULAR REACTIVITY; BAROREFLEX FUNCTION; BRAIN-DEVELOPMENT; VARIABLE STRESS AB Objective This study investigated the physiological and somatic changes evoked by daily exposure to the same type of stressor (homotypic) or different aversive stressor stimuli (heterotypic) in adolescent and adult rats, with a focus on cardiovascular function. The long-term effects of stress exposure during adolescence were also investigated longitudinally. Methods Male Wistar rats were exposed to repeated restraint stress (RRS, homotypic) or chronic variable stress (CVS, heterotypic). Results Adrenal hypertrophy, thymus involution, and elevated plasma glucocorticoid were observed only in adolescent animals, whereas reduction in body weight was caused by both stress regimens in adults. CVS increased mean arterial pressure (adolescent: p = .001; adult: p = .005) and heart rate (HR; adolescent: p = .020; adult: p = .011) regardless of the age, whereas RRS increased blood pressure selectively in adults (p = .001). Rest tachycardia evoked by CVS was associated with increased cardiac sympathetic activity in adults, whereas a decreased cardiac parasympathetic activity was observed in adolescent animals. Changes in cardiovascular function and cardiac autonomic activity evoked by both CVS and RRS were followed by alterations in baroreflex activity and vascular reactivity to vasoconstrictor and vasodilator agents in adolescent adult animals. Except for the circulating glucocorticoid change, all alterations observed during adolescence were reversed in adulthood. Conclusions These findings suggest a stress vulnerability of adolescents to somatic and neuroendocrine effects regardless of stress regimen. Our results indicated an age-stress type-specific influence in stress-evoked cardiovascular/autonomic changes. Data suggest minimal consequences in adulthood of stress during adolescence. C1 [Duarte, Josiane O.; Planeta, Cleopatra S.; Crestani, Carlos C.] Univ Estadual Paulista UNESP, Pharmacol Lab, Sch Pharmaceut Sci, Araraquara, SP, Brazil. [Duarte, Josiane O.; Planeta, Cleopatra S.; Crestani, Carlos C.] Joint UFSCar UNESP Grad Program Physiol Sci, Sao Carlos, SP, Brazil. [Cruz, Fabio C.; Leao, Rodrigo M.] NIDA, Behav Neurosci Branch, Intramural Res Program, US Natl Inst Hlth,Dept Hlth & Human Serv, Baltimore, MD USA. RP Crestani, CC (reprint author), Sao Paulo State Univ UNESP, Pharmacol Lab, Dept Nat Act Principles & Toxicol, Sch Pharmaceut Sci, Rodovia Araraquara Jau Km 01 Campus Univ, BR-14801902 Araraquara, SP, Brazil. EM cccrestani@yahoo.com.br RI Crestani, Carlos/E-4161-2012 FU FAPESP [2012/14376-0, 2012/50549-6]; PADC-FCF UNESP FX This work was supported by FAPESP Grants 2012/14376-0 and 2012/50549-6 and PADC-FCF UNESP. C.S.P. is a CNPq research fellow. The authors declare no conflicts of interest. NR 60 TC 4 Z9 4 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD FEB-MAR PY 2015 VL 77 IS 2 BP 186 EP 199 DI 10.1097/PSY.0000000000000141 PG 14 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CC0UC UT WOS:000350051500009 PM 25659080 ER PT J AU Anthis, NJ Clore, GM AF Anthis, Nicholas J. Clore, G. Marius TI Visualizing transient dark states by NMR spectroscopy SO QUARTERLY REVIEWS OF BIOPHYSICS LA English DT Review ID PARAMAGNETIC RELAXATION ENHANCEMENT; NUCLEAR-MAGNETIC-RESONANCE; SITE-DIRECTED SPIN; EXCITED PROTEIN STATES; LONG-RANGE STRUCTURE; MOLECULAR-WEIGHT PROTEINS; NITROXIDE SIDE-CHAIN; MODEL-FREE APPROACH; X-RAY-SCATTERING; DIHYDROFOLATE-REDUCTASE CATALYSIS AB Myriad biological processes proceed through states that defy characterization by conventional atomic-resolution structural biological methods. The invisibility of these 'dark' states can arise from their transient nature, low equilibrium population, large molecular weight, and/or heterogeneity. Although they are invisible, these dark states underlie a range of processes, acting as encounter complexes between proteins and as intermediates in protein folding and aggregation. New methods have made these states accessible to high-resolution analysis by nuclear magnetic resonance (NMR) spectroscopy, as long as the dark state is in dynamic equilibrium with an NMR-visible species. These methods - paramagnetic NMR, relaxation dispersion, saturation transfer, lifetime line broadening, and hydrogen exchange - allow the exploration of otherwise invisible states in exchange with a visible species over a range of timescales, each taking advantage of some unique property of the dark state to amplify its effect on a particular NMR observable. In this review, we introduce these methods and explore two specific techniques - paramagnetic relaxation enhancement and dark state exchange saturation transfer - in greater detail. C1 [Anthis, Nicholas J.; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov FU Intramural Program of the NIH; NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank Nicolas Fawzi, Dennis Torchia, Vitali Tugarinov, Vincenzo Venditti and Jinfa Ying for useful discussions and other assistance. This work was supported by the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 369 TC 23 Z9 23 U1 11 U2 66 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-5835 EI 1469-8994 J9 Q REV BIOPHYS JI Q. Rev. Biophys. PD FEB PY 2015 VL 48 IS 1 BP 35 EP 116 DI 10.1017/S0033583514000122 PG 82 WC Biophysics SC Biophysics GA CC4ES UT WOS:000350304300002 PM 25710841 ER PT J AU Land, CE Kwon, D Hoffman, FO Moroz, B Drozdovitch, V Bouville, A Beck, H Luckyanov, N Weinstock, RM Simon, SL AF Land, Charles E. Kwon, Deukwoo Hoffman, F. Owen Moroz, Brian Drozdovitch, Vladimir Bouville, Andre Beck, Harold Luckyanov, Nicholas Weinstock, Robert M. Simon, Steven L. TI Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout SO RADIATION RESEARCH LA English DT Article ID NUCLEAR TEST-SITE; NEVADA TEST-SITE; WEAPONS TEST-SITE; LOCAL FALLOUT; RADIATION-EXPOSURE; KAZAKSTAN; TESTS; CANCER; COHORT; METHODOLOGY AB Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates''. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response. (C) 2015 by Radiation Research Society C1 [Land, Charles E.; Moroz, Brian; Drozdovitch, Vladimir; Bouville, Andre; Luckyanov, Nicholas; Simon, Steven L.] Natl Canc Inst, Bethesda, MD 20892 USA. [Kwon, Deukwoo] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Hoffman, F. Owen] Oak Ridge Ctr Risk Anal, Oak Ridge, TN USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU National Cancer Institute Intramural Research Program; National Institute of Allergy and Infectious Diseases [Y2-Al-5077]; National Cancer Institute, NIAID [Y2-Al-5077]; NCI [Y3-CO-5117] FX This work was supported by the National Cancer Institute Intramural Research Program and by the Intra-Agency agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement Y2-Al-5077 and NCI agreement Y3-CO-5117. The authors express appreciation to numerous colleagues who have, over the years, participated in discussions, workshops and various analyses related to dose estimation for radioactive fallout in Kazakhstan, in particular, Drs. Konstantin Gordeev (deceased), Sergey Shinkarev, Lynn Anspaugh, Boris Gusev, Zhanat Carr, Zhaxybay Zhumadilov, Masaharu Hoshi. In addition, the authors gratefully acknowledge the efforts of those whose work in risk analysis and uncertainty have preceded us and made our work easier, including Drs. Ethel Gilbert, Eduard Hofer, Don Pierce, Dale Preston, Dan Stram and Elisabeth Cardis. NR 42 TC 4 Z9 4 U1 1 U2 11 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2015 VL 183 IS 2 BP 159 EP 173 DI 10.1667/RR13794.1 PG 15 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA CC0KL UT WOS:000350024200003 PM 25574587 ER PT J AU Groffen, DAI Bosma, H Koster, A von Bonsdorff, MB Aspelund, T Eiriksdottir, G Penninx, BWJH Kempen, GIJM Kirschbaum, C Gudnason, V Harris, TB AF Groffen, Danielle A. I. Bosma, Hans Koster, Annemarie von Bonsdorff, Mikaela B. Aspelund, Thor Eiriksdottir, Gudny Penninx, Brenda W. J. H. Kempen, Gertrudis I. J. M. Kirschbaum, Clemens Gudnason, Vilmundur Harris, Tamara B. TI A blunted diurnal cortisol response in the lower educated does not explain educational differences in coronary heart disease: Findings from the AGES-Reykjavik Study SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Iceland; Educational attainment; Salivary cortisol; Coronary heart disease; Old age; Stress response ID OF-THE-LITERATURE; SALIVARY CORTISOL; SOCIOECONOMIC-STATUS; CARDIOVASCULAR-DISEASE; OLDER PERSONS; SOCIAL INEQUALITIES; ALLOSTATIC LOAD; WHITEHALL-II; RISK-FACTORS; STRESS AB Lower educational attainment generally is a strong predictor of coronary heart disease (CHD). The underlying mechanisms of this effect are, however, less clear. One hypothesis is that stress related to limitations imposed by lower socioeconomic status elicits changes in hypothalamic-pituitary-adrenal axis functioning, which, in turn, increases risk of CHD. In a large cohort study, we examined whether educational attainment was related to risk of fatal and non-fatal CHD and the extent to which salivary cortisol mediated this relation independent of potential confounders, including lifestyles. Data came from 3723 participants aged 66 through 96 from the Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Between 2002 and 2006, data were collected using questionnaires and examinations including morning and evening salivary samples. Hospital admission records and cause of death registries (ICD-9 and ICD-10 codes) were available until December 2009. Linear regression and Cox proportional hazards analyses were performed. Even after adjustment for potential confounders, including lifestyle, persons with lower educational attainment showed a blunted cortisol response and also greater risk of incident CHD. However, our data did not support the role of cortisol as a mediator in the association between education and CHD in an older sample (192). (C) 2014 Elsevier Ltd. All rights reserved. C1 [Groffen, Danielle A. I.; Bosma, Hans; Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, NL-6200 MD Maastricht, Netherlands. [von Bonsdorff, Mikaela B.] Univ Jyvaskyla, Dept Hlth Sci, Gerontol Res Ctr, Jyvaskyla, Finland. [Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor] Univ Iceland, Fac Med, Reykjavik, Iceland. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands. [Kempen, Gertrudis I. J. M.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Hlth Serv Res, NL-6200 MD Maastricht, Netherlands. [Kirschbaum, Clemens] Tech Univ Dresden, D-01062 Dresden, Germany. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Groffen, DAI (reprint author), Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, POB 616, NL-6200 MD Maastricht, Netherlands. EM D.Groffen@maastrichtuniversity.nl RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008; Kempen, Gertrudis/H-5978-2016; Bosma, Hans/A-6184-2013; Koster, Annemarie/E-7438-2010 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433; Kempen, Gertrudis/0000-0002-7053-2198; FU NIH [N01-AG-12100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and The Althingi (the Icelandic Parliament). NR 48 TC 2 Z9 2 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2015 VL 127 SI SI BP 143 EP 149 DI 10.1016/j.socscimed.2014.09.050 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CC1AZ UT WOS:000350074800016 PM 25308232 ER PT J AU Spittel, ML Riley, WT Kaplan, RM AF Spittel, Michael L. Riley, William T. Kaplan, Robert M. TI Educational attainment and life expectancy: A perspective from the NIH Office of Behavioral and Social Sciences Research SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE NIH; BSSR; Education and health; Program ID ADULT MORTALITY; UNITED-STATES; GRADIENT; HEALTH; RACE AB The NIH Office of Behavioral and Social Sciences Research (OBSSR) furthers the mission of the NIH by stimulating behavioral and social sciences research throughout NIH and integrating these areas of research more fully into the NIH health research enterprise, thereby improving our understanding, treatment, and prevention of disease. OBSSR accomplishes this mission through several strategic priorities: (1) supporting the next generation of basic behavioral and social sciences research, (2) facilitating interdisciplinary research, (3) promoting a multi-level systems perspective of health and behavior, and (4) encouraging a problem-focused perspective on population health. Published by Elsevier Ltd. C1 [Spittel, Michael L.; Riley, William T.] NIH, Off Behav & Social Sci Res, US Dept HHS, Bethesda, MD 20892 USA. [Kaplan, Robert M.] US Dept HHS, Agcy Healthcare Res & Qual, Washington, DC USA. RP Spittel, ML (reprint author), NIH, Off Behav & Social Sci Res, US Dept HHS, Bethesda, MD 20892 USA. EM Michael.Spittel@nih.gov NR 13 TC 1 Z9 1 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2015 VL 127 SI SI BP 203 EP 205 DI 10.1016/j.socscimed.2014.11.017 PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CC1AZ UT WOS:000350074800024 PM 25511259 ER PT J AU Liu, R Li, MY Li, ZD Hong, N Xu, HY Hong, YH AF Liu, Rong Li, Mingyou Li, Zhendong Hong, Ni Xu, Hongyan Hong, Yunhan TI Medaka Oct4 is Essential for Pluripotency in Blastula Formation and ES Cell Derivation SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE ES cell; Germ cell; Oct4; Pou2; Pluripotency ID EMBRYONIC STEM-CELLS; POU DOMAIN; TRANSCRIPTIONAL REGULATION; ORYZIAS-LATIPES; ADULT GONADS; GERM-CELLS; EXPRESSION; ZEBRAFISH; FISH; VERTEBRATE AB The origin and evolution of molecular mechanisms underlying cellular pluripotency is a fundamental question in stem cell biology. The transcription factor Oct4 or Pou5f1 identified in mouse features pluripotency expression and activity in the inner cell mass and embryonic stem (ES) cells. Pou2 identified in zebrafish is the non-mammalian homolog prototype of mouse Oct4. The genes oct4 and pou2 have reportedly evolved by pou5 gene duplication in the common ancestor of vertebrates. Unlike mouse oct4, however, zebrafish pou2 lacks pluripotency expression and activity. Whether the presence of pluripotency expression and activity is specific for mammalian Oct4 or common to the ancestor of vertebrate Oct4 and Pou2 proteins has remained to be determined. Here we report that Oloct4, the medaka oct4/pou2, is essential for early embryogenesis and pluripotency maintenance. Oloct4 exists as a single copy gene and is orthologous to pou2 by sequence and chromosome synteny. Oloct4 expression occurs in early embryos, germ stem cells and ES cells like mouse oct4 but also in the brain and tail bud like zebrafish pou2. Importantly, OlOct4 depletion caused blastula lethality or blockage. We show that Oloct4 depletion abolishes ES cell derivation from midblastula embryos. Thus, Oloct4 has pluripotency expression and is essential for early embryogenesis and pluripotency maintenance. Our results demonstrate the conservation of pluripotency expression and activity in vertebrate Oct4 and Pou2 proteins. The finding that Oloct4 combines the features of mouse oct4 and zebrafish pou2 in expression and function suggests that Oloct4 might represent the ancestral prototype of vertebrate oct4 and pou2 genes. C1 [Liu, Rong; Li, Mingyou; Li, Zhendong; Hong, Ni; Xu, Hongyan; Hong, Yunhan] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Li, Mingyou; Hong, Yunhan] Shanghai Ocean Univ, Coll Fisheries & Life Sci, Shanghai 201306, Peoples R China. [Hong, Ni] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Xu, Hongyan] Chinese Acad Fishery Sci, Key Lab Trop & Subtrop Fishery Resource Applicat, Minist Agr, Guangzhou 510380, Guangdong, Peoples R China. RP Hong, YH (reprint author), Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore. EM dbshyh@nus.edu.sg FU National Research Foundation Singapore [NRF-CRP7-2010-03] FX We thank J. Deng for fish breeding, Choy Mei Foong and Veronica Wong for laboratory management. This work was supported by the National Research Foundation Singapore (NRF-CRP7-2010-03). NR 52 TC 12 Z9 12 U1 1 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 EI 1558-6804 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD FEB PY 2015 VL 11 IS 1 BP 11 EP 23 DI 10.1007/s12015-014-9523-2 PG 13 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CB9NA UT WOS:000349957200002 PM 25142379 ER PT J AU Jha, BS Rao, M Malik, N AF Jha, Balendu Shekhar Rao, Mahendra Malik, Nasir TI Motor Neuron Differentiation from Pluripotent Stem Cells and Other Intermediate Proliferative Precursors that can be Discriminated by Lineage Specific Reporters SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Motor neuron; Motoneuron; Neural Stem Cell; Motor neuron progenitor; Stem cell differentiation; Neural differentiation; Neural induction; Motor neuron differentiation ID IN-VITRO DIFFERENTIATION; DIRECTED DIFFERENTIATION; SPINAL-CORD; CONVERSION; EFFICIENT; MOTONEURONS; PROGENITORS; GENERATION; DERIVATION; INDUCTION AB We have used a four stage protocol to generate spinal motor neurons (MNs) from human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs). These stages include the pluripotent stem cell (PSC) stage, neural stem cell (NSC) stage, OLIG2 expressing motor neuron precursor (MNP) stage, and HB9 expressing mature-MN stage. To optimize the differentiation protocol reporter lines marking the NSC and MNP stages were used. The NSC stage is a pro-proliferative precursor stage at which cells can be directed to differentiate to other neural types like cortical neurons also, in addition to MNs; thus, NSCs can be expanded and stored for future differentiation to different neural types thereby, shortening the differentiation interval as compared to the complete process of differentiation from ESCs or iPSCs. Additionally, we find that OLIG2 positive cells at the MNP stage can be cryopreserved and then recovered to continue the process of MN differentiation, thereby providing a highly stable and reproducible technique for bulk differentiation. MNPs were differentiated to MNs expressing the marker HB9 demonstrating that mature-MNs can be generated with this protocol. C1 [Jha, Balendu Shekhar; Rao, Mahendra; Malik, Nasir] NIH, Lab Stem Cell Biol, Bethesda, MD 20892 USA. RP Malik, N (reprint author), NIH, Lab Stem Cell Biol, Bldg 10, Bethesda, MD 20892 USA. EM malikn@mail.nih.gov OI Jha, Balendu Shekhar/0000-0002-6509-8171 FU NIH Common Fund, National Institutes of Health, Bethesda, USA FX The work in this manuscript was funded by the NIH Common Fund, National Institutes of Health, Bethesda, USA. The authors declare no potential conflicts of interest. NR 40 TC 4 Z9 4 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 EI 1558-6804 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD FEB PY 2015 VL 11 IS 1 BP 194 EP 204 DI 10.1007/s12015-014-9541-0 PG 11 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CB9NA UT WOS:000349957200016 PM 25091426 ER PT J AU Knudsen, TB Keller, DA Sander, M Carney, EW Doerrer, NG Eaton, DL Fitzpatrick, SC Hastings, KL Mendrick, DL Tice, RR Watkins, PB Whelan, M AF Knudsen, Thomas B. Keller, Douglas A. Sander, Miriam Carney, Edward W. Doerrer, Nancy G. Eaton, David L. Fitzpatrick, Suzanne Compton Hastings, Kenneth L. Mendrick, Donna L. Tice, Raymond R. Watkins, Paul B. Whelan, Maurice TI FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material DE in vitro; in silico; modeling; predictive toxicology; risk assessment ID CELL-DERIVED CARDIOMYOCYTES; ADVERSE OUTCOME PATHWAYS; RISK-ASSESSMENT; ENVIRONMENTAL CHEMICALS; CONCEPTUAL-FRAMEWORK; 21(ST) CENTURY; STEM-CELLS; 21ST-CENTURY; SYSTEMS; VISION AB FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. C1 [Knudsen, Thomas B.] US EPA, Res Triangle Pk, NC 27711 USA. [Keller, Douglas A.] Sanofi, Bridgewater, NJ 08807 USA. [Sander, Miriam] Page One Editorial Serv, Boulder, CO 80304 USA. [Carney, Edward W.] Dow Chem Co USA, Midland, MI 48674 USA. [Doerrer, Nancy G.] Hlth & Environm Sci Inst, Washington, DC 20005 USA. [Eaton, David L.] Univ Washington, Seattle, WA 98105 USA. [Fitzpatrick, Suzanne Compton; Mendrick, Donna L.] US FDA, Silver Spring, MD 20993 USA. [Hastings, Kenneth L.] Sanofi, Bethesda, MD 20814 USA. [Tice, Raymond R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Watkins, Paul B.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Watkins, Paul B.] Hamner Inst, Res Triangle Pk, NC 27709 USA. [Whelan, Maurice] European Commiss Joint Res Ctr, I-21027 Ispra, Italy. RP Keller, DA (reprint author), Sanofi, 55C 420A,55 Corp Dr, Bridgewater, NJ 08807 USA. EM douglas.keller@sanofi.com OI Keller, Douglas/0000-0002-6186-2881 NR 50 TC 17 Z9 17 U1 3 U2 39 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2015 VL 143 IS 2 BP 256 EP 267 DI 10.1093/toxsci/kfu234 PG 12 WC Toxicology SC Toxicology GA CC1LK UT WOS:000350102000004 PM 25628403 ER PT J AU Panch, SR Yau, YY Kang, EM De Ravin, SS Malech, HL Leitman, SF AF Panch, Sandhya R. Yau, Yu Ying Kang, Elizabeth M. De Ravin, Suk See Malech, Harry L. Leitman, Susan F. TI Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency SO TRANSFUSION LA English DT Article ID COLONY-STIMULATING FACTOR; BLOOD STEM-CELLS; TUMOR-NECROSIS-FACTOR; GENE-THERAPY; INTERFERON-GAMMA; MARROW; CYCLOPHOSPHAMIDE; PREDICTORS; MODULATION; EXPRESSION AB BackgroundGranulocyte-colony-stimulating factor (G-CSF)-mobilized autologous hematopoietic progenitor cells (HPCs) may be collected by apheresis of patients with chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) for use in gene therapy trials. CD34+ cell mobilization has not been well characterized in such patients. Study Design and MethodsWe retrospectively evaluated CD34+ cell mobilization and collection in 73 consecutive CGD and SCID patients and in 99 age-, weight-, and G-CSF dose-matched healthy allogeneic controls. ResultsIn subjects aged not more than 20 years, Day5 preapheresis circulating CD34+ counts were significantly lower in CGD and SCID patients than in controls; mean peak CD34+ cell counts were 58x10(6), 64x10(6), and 87x10(6)/L, respectively (p=0.01). The SCIDs had lower CD34+ collection efficiency than CGDs and controls; mean efficiencies were 40, 63, and 57%, respectively (p=0.003). In subjects aged more than 20 years, the CGDs had significantly lower CD34+ cell mobilization than controls; mean peak CD34+ cell counts were 41x10(6) and 113x10(6)/L, respectively (p<0.0001). In a multivariate analysis, lower erythrocyte sedimentation rate (ESR) at mobilization was significantly correlated with better CD34+ cell mobilization (p=0.007). In SCIDs, CD34 collection efficiency was positively correlated with higher red blood cell (RBC) indices (mean RBC volume, R-2=0.77; mean corpuscular hemoglobin [Hb], R-2=0.94; mean corpuscular Hb concentration, R-2=0.7; p<0.007) but not Hb. ConclusionsCGD and SCID populations are characterized by significantly less robust CD34+ HPC mobilization than healthy controls. The presence of active inflammation or infection as suggested by an elevated ESR may negatively impact mobilization. Among SCIDs, markedly reduced CD34 collection efficiencies were related to iron deficiency, wherein decreased RBC size and density may impair apheresis cell separation mechanics. C1 [Panch, Sandhya R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Yau, Yu Ying; Leitman, Susan F.] NIAID, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Kang, Elizabeth M.; De Ravin, Suk See; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Leitman, SF (reprint author), NIH, Blood Serv Sect, Dept Transfus Med, Bldg 10,Room 1C-711, Bethesda, MD 20854 USA. EM sleitman@nih.gov OI Malech, Harry/0000-0001-5874-5775 FU intramural research programs of the NIAID and the Clinical Center, NIH FX This work was supported by the intramural research programs of the NIAID and the Clinical Center, NIH. The authors are federal employees. There were no nonfederal sources of support. NR 33 TC 3 Z9 3 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2015 VL 55 IS 2 BP 265 EP 274 DI 10.1111/trf.12830 PG 10 WC Hematology SC Hematology GA CB7PX UT WOS:000349820900008 PM 25143186 ER PT J AU Bacot, SM Feldman, GM Yamada, KM Dhawan, S AF Bacot, Silvia M. Feldman, Gerald M. Yamada, Kenneth M. Dhawan, Subhash TI Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages SO VIROLOGY LA English DT Article DE Blood; HIV-1; Prion protein; Peripheral blood monocytes; Macrophages ID CREUTZFELDT-JAKOB-DISEASE; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; HIV-1 INFECTION; VARIANT CJD; TRANSMISSION; TRANSFUSION; ACTIVATION; LIPOCORTIN-1; EXPRESSION AB Transfusion of blood and blood products contaminated with the pathogenic form of prion protein Prp(sc), thought to be the causative agent of variant a Creutzfeldt-Jakob disease (vCJD), may result in serious consequences in recipients with a compromised immune system, for example, as seen in HIV-1 infection. In the present study, we demonstrate that treatment of peripheral blood monocyte-derived macrophages (MDM) with PrP106-126, a synthetic domain of PrPSC that has intrinsic functional activities related to the full-length protein, markedly increased their susceptibility to HIV-1 infection, induced cytokine secretion, and enhanced their migratory behavior in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). Live-cell imaging of MDM cultured in the presence of PrP106-126 showed large cell clusters indicative of cellular activation. Tyrosine kinase inhibitor STI-571, protein kinase C inhibitor K252B, and cyclin-dependent kinase inhibitor olomoucine attenuated PrP106-126-induced altered MDM functions. These findings delineate a previously undefined functional role of PrP106-126-mediated host cell response in promoting HIV-1 pathogenesis. Published by Elsevier Inc. C1 [Dhawan, Subhash] US FDA, Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Bethesda, MD USA. [Bacot, Silvia M.; Feldman, Gerald M.] US FDA, Ctr Drug Evaluat & Res, Div Monoclonal Antibodies, Bethesda, MD 20014 USA. [Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Dhawan, S (reprint author), US FDA, Mol Virol Lab, Ctr Biol Evaluat & Res, Viral Immunol Sect, 10903 New Hampshire Ave,Bldg 52-72,Room 4306, Silver Spring, MD 20993 USA. EM subhash.dhawan@fda.hhs.gov FU FDA intramural research program; NIDCR intramural research program FX We thank Dr. Viswanath Ragupathy, Dr. Xue Wang, Dr. David Asher, and Dr. Pedro Piccardo for critical review of the manuscript. This work was supported by FDA and NIDCR intramural research programs. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 25 TC 0 Z9 0 U1 1 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 FEB PY 2015 VL 476 BP 372 EP 376 DI 10.1016/j.virol.2014.11.032 PG 5 WC Virology SC Virology GA CB8MF UT WOS:000349883000043 PM 25589240 ER PT J AU Roux, A Muller, L Jackson, SN Baldwin, K Womack, V Pagiazitis, JG O'Rourke, JR Thanos, PK Balaban, C Schultz, JA Volkow, ND Woods, AS AF Roux, Aurelie Muller, Ludovic Jackson, Shelley N. Baldwin, Katherine Womack, Virginia Pagiazitis, John G. O'Rourke, Joseph R. Thanos, Panayotis K. Balaban, Carey Schultz, J. Albert Volkow, Nora D. Woods, Amina S. TI Chronic Ethanol Consumption Profoundly Alters Regional Brain Ceramide and Sphingomyelin Content in Rodents SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Ceramide; sphingomyelin; lipids; alcohol; mass spectrometry imaging; matrix-assisted laser desorption ionization; silver nanoparticles; matrix implanted laser desorption ionization ID NF-KAPPA-B; MASS-SPECTROMETRY; ALCOHOL-ABUSE; RAT-BRAIN; BIOLOGICAL SAMPLES; TISSUE-SECTIONS; GRAY-MATTER; NEURODEGENERATION; INVOLVEMENT; DRINKING AB Ceramides (CER) are involved in alcohol-induced neuroinflammation. In a mouse model of chronic alcohol exposure, 16 CER and 18 sphingomyelin (SM) concentrations from whole brain lipid extracts were measured using electrospray mass spectrometry. All 18 CER concentrations in alcohol exposed adults increased significantly (range: 25-607%); in juveniles, 6 CER decreased (range: -9 to -37%). In contrast, only three SM decreased in adult and one increased significantly in juvenile. Next, regional identification at SO m spatial resolution from coronal sections was obtained with matrix implanted laser desorption/ionization mass spectrometry imaging (MILDI-MSI) by implanting silver nanoparticulate matrices followed by focused laser desorption. Most of the CER and SM quantified in whole brain extracts were detected in MILDI images. Coronal sections from three brain levels show qualitative regional changes in CER-SM ion intensities, as a function of group and brain region, in cortex, striatum, accumbens, habenula, and hippocampus. Highly correlated changes in certain white matter CER-SM pairs occur in regions across all groups, including the hippocampus and the lateral (but not medial) cerebellar cortex of adult mice. Our data provide the first microscale MS evidence of regional lipid intensity variations induced by alcohol. C1 [Roux, Aurelie; Muller, Ludovic; Jackson, Shelley N.; Baldwin, Katherine; Womack, Virginia; Volkow, Nora D.; Woods, Amina S.] NIDA, Struct Biol Unit, IRP, NIH, Baltimore, MD 21224 USA. [Muller, Ludovic; Womack, Virginia; Balaban, Carey] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Schultz, J. Albert] Ionwerks Inc, Houston, TX 77002 USA. [Pagiazitis, John G.; O'Rourke, Joseph R.; Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Behav Neuropharmacol & Neuroimaging Lab, Stony Brook, NY 11790 USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, NIH; ARRA through NIDA phase II SBIR Grant [1RC3DA031431-01] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. lonwerks and the University of Pittsburgh gratefully acknowledge ARRA support through NIDA phase II SBIR Grant 1RC3DA031431-01. NR 66 TC 6 Z9 6 U1 2 U2 3 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 FEB PY 2015 VL 6 IS 2 BP 247 EP 259 DI 10.1021/cn500174c PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CB7NI UT WOS:000349813700007 PM 25387107 ER PT J AU Ko, SU Simonsick, EM Ferrucci, L AF Ko, Seung-uk Simonsick, Eleanor M. Ferrucci, Luigi TI Gait energetic efficiency in older adults with and without knee pain: results from the Baltimore Longitudinal Study of Aging SO AGE LA English DT Article DE Oxygen consumption; Knee pain; Energy efficiency in gait; Compensatory effort ID MECHANICAL WORK; WALKING; SPEED; COST AB With aging, customary gait patterns change and energetic efficiency declines, but the relationship between these alterations is not well understood. If gait characteristics that develop with aging explain part of the decline in energetic efficiency that occur in most aging individuals, then efforts to modify these characteristics could delay or prevent mobility limitation. This study characterizes gait patterns in older persons with and without knee pain and tests the hypothesis that changes in gait characteristics due to knee pain are associated with increased energetic cost of walking in older adults. Study participants were 364 men and 170 women aged 60 to 96 years enrolled in the Baltimore Longitudinal Study of Aging (BLSA), of whom 86 had prevalent knee pain. Gait patterns were assessed at participant self-selected usual pace in the gait laboratory, and the energetic cost of walking was assessed by indirect calorimetry during self-selected usual pace walking over 2.5 min in a tiled corridor using a portable equipment. Participants with knee pain were less energetically efficient than those without pain (oxygen consumption 0.97 vs. 0.88 ml/(10 m . 100 kg); p=0.002) and had slower gait speed and smaller range of motion (ROM) at the hip and knee joints (p<0.05, for all). Slower gait speed and lower knee ROM in participants with knee pain and longer double support time and higher ankle ROM in participants without knee pain were associated with lower energetic efficiency (p<0.05, for all). Slower gait speed and lower knee ROM were correlates of knee pain and were found to mediate the association between age and oxygen consumption. Although knee pain is associated with a higher energetic cost of walking, gait characteristics associated with energetic efficiency differ by pain status which suggests that compensatory strategies both in the presence and absence of pain may impact gait efficiency. C1 [Ko, Seung-uk] Chonnam Natl Univ, Dept Mech Engn, Yeosu 550749, South Korea. [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Ko, SU (reprint author), Chonnam Natl Univ, Dept Mech Engn, 50 Daehak Ro, Yeosu 550749, South Korea. EM seunguk.ko@gmail.com FU Intramural Research Program of the NIH; National Institute on Aging; Chonnam National University FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, and Chonnam National University. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. NR 13 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD FEB PY 2015 VL 37 IS 1 AR 15 DI 10.1007/s11357-015-9754-4 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CB3JR UT WOS:000349524600015 ER PT J AU Shimoyama, K Kagawa, S Ishida, M Watanabe, S Noma, K Takehara, K Tazawa, H Hashimoto, Y Tanabe, S Matsuoka, J Kobayashi, H Fujiwara, T AF Shimoyama, Kyoko Kagawa, Shunsuke Ishida, Michihiro Watanabe, Shinichiro Noma, Kazuhiro Takehara, Kiyoto Tazawa, Hiroshi Hashimoto, Yuuri Tanabe, Shunsuke Matsuoka, Junji Kobayashi, Hisataka Fujiwara, Toshiyoshi TI Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Photoimmunotherapy; HER2; Breast cancer; Adenovirus ID PHOTOCHEMICAL INTERNALIZATION PCI; TUMOR NECROSIS FACTOR; MONOCLONAL-ANTIBODY; GENE; TELOMERASE; RESISTANCE; THERAPY; HER2; AMPLIFICATION; CHEMOTHERAPY AB The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells. C1 [Shimoyama, Kyoko; Kagawa, Shunsuke; Ishida, Michihiro; Watanabe, Shinichiro; Noma, Kazuhiro; Takehara, Kiyoto; Tazawa, Hiroshi; Hashimoto, Yuuri; Tanabe, Shunsuke; Fujiwara, Toshiyoshi] Okayama Univ, Grad Sch Med Dent & Pharmacol Sci, Dept Surg Gastroenterol, Kita Ku, Okayama 7008558, Japan. [Tazawa, Hiroshi] Okayama Univ Hosp, Ctr Innovat Clin Med, Okayama, Japan. [Matsuoka, Junji] Okayama Univ Hosp, Dept Palliat Care, Okayama, Japan. [Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kagawa, S (reprint author), Okayama Univ, Grad Sch Med Dent & Pharmacol Sci, Dept Surg Gastroenterol, Kita Ku, 2-5-1 Shikata Cho, Okayama 7008558, Japan. EM skagawa@md.okayama-u.ac.jp RI TAZAWA, Hiroshi/B-2247-2011 OI TAZAWA, Hiroshi/0000-0003-4658-1050 FU Ministry of Education Culture, Sports, Science and Technology, Japan; Ministry of Health, Labor and Welfare, Japan FX We thank Tomoko Sueishi for her technical support. This study was supported by grants-in-aid from the Ministry of Education Culture, Sports, Science and Technology, Japan (Toshiyoshi Fujiwara, Hiroshi Tazawa, Shunsuke Tanabe, and Shunsuke Kagawa) and grants from the Ministry of Health, Labor and Welfare, Japan (Toshiyoshi Fujiwara). NR 36 TC 4 Z9 4 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2015 VL 149 IS 3 BP 597 EP 605 DI 10.1007/s10549-015-3265-y PG 9 WC Oncology SC Oncology GA CB6UC UT WOS:000349761200004 PM 25616354 ER PT J AU Ryan, BM Robles, AI McClary, AC Haznadar, M Bowman, ED Pine, SR Brown, D Khan, M Shiraishi, K Kohno, T Okayama, H Modali, R Yokota, J Harris, CC AF Ryan, Brd M. Robles, Ana I. McClary, Andrew C. Haznadar, Majda Bowman, Elise D. Pine, Sharon R. Brown, Derek Khan, Mohammed Shiraishi, Kouya Kohno, Takashi Okayama, Hirokazu Modali, Ramakrishna Yokota, Jun Harris, Curtis C. TI Identification of a Functional SNP in the 3 ' UTR of CXCR2 That Is Associated with Reduced Risk of Lung Cancer SO CANCER RESEARCH LA English DT Article ID MICRORNA BINDING-SITES; GENETIC-VARIATION; ALTERS SUSCEPTIBILITY; UNTRANSLATED REGION; TARGET SITES; INTERLEUKIN-8; SENESCENCE; POLYMORPHISMS; MECHANISM; PROMOTER AB Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT (vs). (CC) 0.56 (0.37-0.88); P = 0.008] and Japanese [ORTT (vs.) (CC)0.62 (0.38-1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3 ' UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer. (C) 2014 AACR. C1 [Ryan, Brd M.; Robles, Ana I.; McClary, Andrew C.; Haznadar, Majda; Bowman, Elise D.; Brown, Derek; Khan, Mohammed; Okayama, Hirokazu; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [McClary, Andrew C.] Stanford Univ Hosp & Clin, Dept Pathol, Stanford, CA USA. [Pine, Sharon R.] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Shiraishi, Kouya; Kohno, Takashi; Okayama, Hirokazu; Yokota, Jun] Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 104, Japan. [Modali, Ramakrishna] BioServe Ltd, Beltsville, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 3068,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU Intramural Program of the Centre for Cancer Research, NCI (Bethesda, MD); Ministry of Health, Labor, and Welfare of Japan; National Cancer Center Research and Development Fund [26-A-8] FX This work was supported by the Intramural Program of the Centre for Cancer Research, NCI (Bethesda, MD). This work was also supported in part by Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan for the 3rd term Comprehensive 10-year Strategy for Cancer Control, and by the National Cancer Center Research and Development Fund (26-A-8). NR 50 TC 13 Z9 14 U1 4 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2015 VL 75 IS 3 BP 566 EP 575 DI 10.1158/0008-5472.CAN-14-2101 PG 10 WC Oncology SC Oncology GA CB7XE UT WOS:000349841200010 PM 25480945 ER PT J AU Wohlfarth, A Scheidweiler, KB Castaneto, M Gandhi, AS Desrosiers, NA Klette, KL Martin, TM Huestis, MA AF Wohlfarth, Ariane Scheidweiler, Karl B. Castaneto, Marisol Gandhi, Adarsh S. Desrosiers, Nathalie A. Klette, Kevin L. Martin, Thomas M. Huestis, Marilyn A. TI Urinary prevalence, metabolite detection rates, temporal patterns and evaluation of suitable LC-MS/MS targets to document synthetic cannabinoid intake in US military urine specimens SO CLINICAL CHEMISTRY AND LABORATORY MEDICINE LA English DT Article DE liquid chromatography tandem mass spectrometry (LC-MS/MS); metabolites; qualitative confirmation; synthetic cannabinoids; urine ID RESOLUTION MASS-SPECTROMETRY; SIMULTANEOUS QUANTIFICATION; QUANTITATIVE MEASUREMENT; SMOKING MIXTURES; ILLEGAL PRODUCTS; JWH-018; IDENTIFICATION; DERIVATIVES; AM-2201; FUBINACA AB Background: Identifying synthetic cannabinoid designer drug abuse challenges toxicologists and drug testing programs. The best analytical approach for reliably documenting intake of emerging synthetic cannabinoids is unknown. Primarily metabolites are found in urine, but optimal metabolite targets remain unknown, and definitive identification is complicated by converging metabolic pathways. Methods: We screened 20,017 US military urine specimens collected from service members worldwide for synthetic cannabinoids between July 2011 and June 2012. We confirmed 1432 presumptive positive and 1069 presumptive negative specimens by qualitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis including 29 biomarkers for JWH-018, JWH-073, JWH-081, JWH-122, JWH-200, JWH-210, JWH-250, RCS-4, AM2201 and MAM2201. Specimen preparation included enzyme hydrolysis and acetonitrile precipitation prior to LC-MS/ MS analysis. We evaluated individual synthetic cannabinoid metabolite detection rates, prevalence, temporal patterns and suitable targets for analytical procedures. Results: Prevalence was 1.4% with 290 confirmed positive specimens, 92% JWH-018, 54% AM2201 and 39% JWH-122 metabolites. JWH-073, JWH-210 and JWH-250 also were identified in 37%, 4% and 8% of specimens, respectively. The United States Army Criminal Investigation Command seizure pattern for synthetic cannabinoid compounds matched our urine specimen results over the time frame of the study. Apart from one exception (AM2201), no parent compounds were observed. Conclusions: Hydroxyalkyl metabolites accounted for most confirmed positive tests, and in many cases, two metabolites were identified, increasing confidence in the results, and improving detection rates. These data also emphasize the need for new designer drug metabolism studies to provide relevant targets for synthetic cannabinoid identification. C1 [Scheidweiler, Karl B.; Castaneto, Marisol; Gandhi, Adarsh S.; Desrosiers, Nathalie A.; Klette, Kevin L.; Huestis, Marilyn A.] NIDA, NIH, IRP, Baltimore, MD 21224 USA. [Wohlfarth, Ariane; Scheidweiler, Karl B.; Castaneto, Marisol; Gandhi, Adarsh S.; Desrosiers, Nathalie A.] NIDA, Natl Inst Chem, Intramural Res Program, Baltimore, MD 21224 USA. [Wohlfarth, Ariane; Scheidweiler, Karl B.; Castaneto, Marisol; Gandhi, Adarsh S.; Desrosiers, Nathalie A.] NIDA, Natl Inst Drug Metab, Intramural Res Program, Baltimore, MD 21224 USA. [Castaneto, Marisol; Desrosiers, Nathalie A.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Klette, Kevin L.; Martin, Thomas M.] Off Secretary Def Personnel & Readiness, Drug Testing & Program Policy, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, NIH, IRP, 251 Bayview Blvd Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA-IRP); Department of Defense Counter Narcotics Program [Y3-DA-1116-01]; NIDA-IRP [Y3-DA-1116-01] FX This research was funded by the Intramural Research Program of the National Institute on Drug Abuse (NIDA-IRP) and by an Interagency Agreement (Y3-DA-1116-01) between Department of Defense Counter Narcotics Program and NIDA-IRP. NR 39 TC 8 Z9 9 U1 3 U2 20 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1434-6621 EI 1437-4331 J9 CLIN CHEM LAB MED JI Clin. Chem. Lab. Med. PD FEB PY 2015 VL 53 IS 3 BP 423 EP 434 DI 10.1515/cclm-2014-0612 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA CB3VY UT WOS:000349558500019 PM 25263309 ER PT J AU Drosten, C Muth, D Corman, VM Hussain, R Al Masri, M HajOmar, W Landt, O Assiri, A Eckerle, I Al Shangiti, A Al-Tawfig, JA Albarrak, A Zumla, A Rambaut, A Memish, ZA AF Drosten, Christian Muth, Doreen Corman, Victor M. Hussain, Raheela Al Masri, Malaki HajOmar, Waleed Landt, Olfert Assiri, Abdullah Eckerle, Isabella Al Shangiti, Ali Al-Tawfig, Jaffar A. Albarrak, Ali Zumla, Alimuddin Rambaut, Andrew Memish, Ziad A. TI An Observational, Laboratory-Based Study of Outbreaks of Middle East Respiratory Syndrome Coronavirus in Jeddah and Riyadh, Kingdom of Saudi Arabia, 2014 SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE MERS-coronavirus; outbreak; nosocomial transmission; virus isolation; transmission infection control ID MERS-CORONAVIRUS; INFECTION; EPIDEMIOLOGY AB Background. In spring 2014, a sudden rise in the number of notified Middle East respiratory syndrome coronavirus (MERS-CoV) infections occurred across Saudi Arabia with a focus in Jeddah. Hypotheses to explain the outbreak pattern include increased surveillance, increased zoonotic transmission, nosocomial transmission, and changes in viral transmissibility, as well as diagnostic laboratory artifacts. Methods. Diagnostic results from Jeddah Regional Laboratory were analyzed. Viruses from the Jeddah outbreak and viruses occurring during the same time in Riyadh, Al-Kharj, and Madinah were fully or partially sequenced. A set of 4 single-nucleotide polymorphisms distinctive to the Jeddah outbreak were determined from additional viruses. Viruses from Riyadh and Jeddah were isolated and studied in cell culture. Results. Up to 481 samples were received per day for reverse transcription polymerase chain reaction (RT-PCR) testing. A laboratory proficiency assessment suggested positive and negative results to be reliable. Forty-nine percent of 168 positive-testing samples during the Jeddah outbreak stemmed from King Fahd Hospital. All viruses from Jeddah were monophyletic and similar, whereas viruses from Riyadh were paraphyletic and diverse. A hospital-associated transmission cluster, to which cases in Indiana (United States) and the Netherlands belonged, was discovered in Riyadh. One Jeddah-type virus was found in Riyadh, with matching travel history to Jeddah. Virus isolates representing outbreaks in Jeddah and Riyadh were not different from MERS-CoV EMC/2012 in replication, escape of interferon response, or serum neutralization. Conclusions. Virus shedding and virus functions did not change significantly during the outbreak in Jeddah. These results suggest the outbreaks to have been caused by biologically unchanged viruses in connection with nosocomial transmission. C1 [Drosten, Christian; Muth, Doreen; Corman, Victor M.; Eckerle, Isabella] Univ Bonn, Med Ctr, Inst Virol, Hannover, Germany. [Drosten, Christian; Corman, Victor M.] German Ctr Infect Res, Hannover, Germany. [Hussain, Raheela] Minist Hlth, Jeddah Reg Lab, Riyadh, Saudi Arabia. [Al Masri, Malaki; Assiri, Abdullah; Zumla, Alimuddin; Memish, Ziad A.] Minist Hlth, Global Ctr Mass Gatherings Med, Riyadh, Saudi Arabia. [HajOmar, Waleed; Al Shangiti, Ali] Minist Hlth, Reg Lab, Riyadh, Saudi Arabia. [Landt, Olfert] Tib Molbiol, Berlin, Germany. [Al-Tawfig, Jaffar A.] Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia. [Al-Tawfig, Jaffar A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Albarrak, Ali] Prince Sultan Mil Med City, Riyadh, Saudi Arabia. [Zumla, Alimuddin] UCL, Div Infect & Immun, London WC1E 6BT, England. [Zumla, Alimuddin] Univ Coll London Hosp Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res Biomed Res Ctr, London, England. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ctr Infect Immun & Evolut, Edinburgh EH8 9YL, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Memish, Ziad A.] Al Faisal Univ, Riyadh, Saudi Arabia. RP Memish, ZA (reprint author), Al Faisal Univ, Altakhasusi Rd, Riyadh, Saudi Arabia. EM zmemish@yahoo.com OI Rambaut, Andrew/0000-0003-4337-3707; Zumla, Alimuddin/0000-0002-5111-5735; Corman, Victor Max/0000-0002-3605-0136 FU European Commission [223498]; ANTIGONE [278976]; German Research Council [01KIO701, DR 772/3-1]; European Commission; Ministry of Research (Germany); University College London Hospitals National Health Service Foundation Trust; National Institute of Health Research, Biomedical Research Centre, University College London Hospitals; European & Developing Countries Clinical Trials Partnership; European Commission Project RiD-RTI; European Commission under the project PREDEMICS [278433] FX C. D. acknowledges support from the European Commission (www.emperie.eu/emp/; contract number 223498) and ANTIGONE (contract number 278976), infrastructural support from the German Centre for Infection Research, the German Ministry for Research and Education, and the German Research Council (grant number 01KIO701 and DR 772/3-1). I. E., D. M., and V. M. C. acknowledge grant support from the European Commission, Ministry of Research (Germany), and German Research Council. A. Z. acknowledges support from the University College London Hospitals National Health Service Foundation Trust, the National Institute of Health Research, Biomedical Research Centre, University College London Hospitals, the European & Developing Countries Clinical Trials Partnership, and the European Commission Project RiD-RTI. A. R. acknowledges support by the European Commission under the project PREDEMICS (contract number 278433). NR 19 TC 53 Z9 54 U1 2 U2 23 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 FEB 1 PY 2015 VL 60 IS 3 BP 369 EP 377 DI 10.1093/cid/ciu812 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CB6UG UT WOS:000349761600015 PM 25323704 ER PT J AU Sun, KX Gao, Z Gui, P Wang, R Oguzman, I Xu, XC Vasanth, K Zhou, QF Shung, KK AF Sun, Kexu Gao, Zheng Gui, Ping Wang, Rui Oguzman, Ismail Xu, Xiaochen Vasanth, Karthik Zhou, Qifa Shung, K. Kirk TI A 180-V-pp Integrated Linear Amplifier for Ultrasonic Imaging Applications in a High-Voltage CMOS SOI Technology SO IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS II-EXPRESS BRIEFS LA English DT Article DE High voltage (HV); linear amplifier; second-order harmonic distortion (HD2); tissue harmonic imaging (THI); total harmonic distortion (THD); ultrasonic imaging; voltage swing AB This brief presents a monolithically integrated fully differential linear HV amplifier as the driver of an ultrasonic transducer. The linear amplifier is capable of transmitting HV arbitrary signals with a very low harmonic distortion, which is suitable for tissue harmonic imaging and other ultrasonic modes for enhanced imaging quality. The amplifier is designed and implemented using the 0.7-mu m CMOS silicon-on-insulator process with 120-V devices. The amplifier, when driving a load of 300 pF in parallel with 100 Omega, is capable of transmitting a sine-wave signal with a frequency of up to 4.4 MHz, a maximum signal swing of 180 V-pp, and a second-order harmonic distortion (HD2) of -56 dBc but only dissipating an average power of 62 mW with a 0.1% duty cycle. C1 [Sun, Kexu; Gui, Ping; Wang, Rui] So Methodist Univ, Lyle Sch Engn, Dept Elect Engn, Dallas, TX 75205 USA. [Gao, Zheng] So Methodist Univ, Dallas, TX 75205 USA. [Oguzman, Ismail; Xu, Xiaochen; Vasanth, Karthik] Texas Instruments Inc, Dallas, TX 75243 USA. [Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH, Ultrasound Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Sun, KX (reprint author), So Methodist Univ, Lyle Sch Engn, Dept Elect Engn, Dallas, TX 75205 USA. EM pgui@smu.edu FU Texas Instruments Incorporated; Semiconductor Research Corporation/Texas Analog Center of Excellence (TxACE) [1836.043] FX This work was supported in part by Texas Instruments Incorporated and in part by the Semiconductor Research Corporation/Texas Analog Center of Excellence (TxACE) under Project 1836.043. This brief was recommended by Associate Editor R. Rieger. NR 15 TC 1 Z9 1 U1 0 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1549-7747 EI 1558-3791 J9 IEEE T CIRCUITS-II JI IEEE Trans. Circuits Syst. II-Express Briefs PD FEB PY 2015 VL 62 IS 2 SI SI BP 149 EP 153 DI 10.1109/TCSII.2014.2387687 PG 5 WC Engineering, Electrical & Electronic SC Engineering GA CB5NR UT WOS:000349675000011 PM 25914609 ER PT J AU Nath, A AF Nath, Avindra TI Neuroinfectious Diseases A Crisis in Neurology and a Call for Action SO JAMA NEUROLOGY LA English DT Editorial Material ID ENCEPHALITIS; PREDICTORS C1 NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Room 7C-103,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU Intramural NIH HHS [, ZIA NS003130-06] NR 10 TC 2 Z9 2 U1 0 U2 3 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 FEB PY 2015 VL 72 IS 2 BP 143 EP 144 DI 10.1001/jamaneurol.2014.3442 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CB4SU UT WOS:000349619200002 PM 25485794 ER PT J AU Nash, RA Hutton, GJ Racke, MK Popat, U Devine, SM Griffith, LM Muraro, PA Openshaw, H Sayre, PH Stuve, O Arnold, DL Spychala, ME McConville, KC Harris, KM Phippard, D Georges, GE Wundes, A Kraft, GH Bowen, JD AF Nash, Richard A. Hutton, George J. Racke, Michael K. Popat, Uday Devine, Steven M. Griffith, Linda M. Muraro, Paolo A. Openshaw, Harry Sayre, Peter H. Stueve, Olaf Arnold, Douglas L. Spychala, Meagan E. McConville, Kaitlyn C. Harris, Kristina M. Phippard, Deborah Georges, George E. Wundes, Annette Kraft, George H. Bowen, James D. TI High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) A 3-Year Interim Report SO JAMA NEUROLOGY LA English DT Article ID DISEASE-ACTIVITY; OUTCOME MEASURE; WORKING PARTY; BLOOD; TRIAL; NATALIZUMAB; REPERTOIRE; GUIDELINES; EXPERIENCE AB IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34(+) selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4%(90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9%(90% CI, 73.7%-97.1%) and 86.3%(90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores. CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events. C1 [Nash, Richard A.] Colorado Blood Canc Inst, Denver, CO 80218 USA. [Hutton, George J.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Racke, Michael K.] Ohio State Univ, Dept Neurol & Neurosci, Columbus, OH 43210 USA. [Popat, Uday] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Div Canc Med, Houston, TX 77030 USA. [Devine, Steven M.] Ohio State Univ, Med Ctr, Dept Internal Med, Blood & Marrow Transplant Program,Div Hematol, Columbus, OH 43210 USA. [Griffith, Linda M.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Muraro, Paolo A.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, London, England. [Openshaw, Harry] City Hope Natl Med Ctr, Dept Neurol, Duarte, CA 91010 USA. [Sayre, Peter H.] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Sayre, Peter H.] Immune Tolerance Network, Clin Trials Grp, San Francisco, CA USA. [Stueve, Olaf] Univ Texas SW Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA. [Stueve, Olaf] Vet Affairs North Texas Hlth Care Syst, Neurol Sect, Dallas, TX USA. [Arnold, Douglas L.] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada. [Arnold, Douglas L.] NeuroRx, Montreal, PQ, Canada. [Spychala, Meagan E.; McConville, Kaitlyn C.] Rho Inc, Chapel Hill, NC USA. [Harris, Kristina M.; Phippard, Deborah] Immune Tolerance Network, San Francisco, CA USA. [Georges, George E.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Georges, George E.] Univ Washington, Med Ctr, Div Med Oncol, Seattle, WA 98195 USA. [Wundes, Annette] Univ Washington, Med Ctr, Dept Neurol, Seattle, WA 98195 USA. [Kraft, George H.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Bowen, James D.] Swedish Neurosci Inst, Seattle, WA USA. RP Nash, RA (reprint author), Colorado Blood Canc Inst, 1721 E 19th Ave,Stes 200 & 300, Denver, CO 80218 USA. EM richard.nash@healthonecares.com FU Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID), NIH; ITN [N01 AI015416]; DAIT-NIAID [HHSN272200800029C, HHSN272200900057C] FX This work was sponsored by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID), NIH, and was conducted by the ITN (grant N01 AI015416), and the DAIT-NIAID funded statistical and clinical coordinating centers (contracts HHSN272200800029C and HHSN272200900057C). Baxter Healthcare Corporation supplied the Isolex 300i Magnetic Cell Selection System machines, Disposable Sets, and CD34 Reagent Kits used for the HALT-MS clinical trial to DAIT, NIAID, without charge. NR 34 TC 35 Z9 35 U1 5 U2 21 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 FEB PY 2015 VL 72 IS 2 BP 159 EP 169 DI 10.1001/jamaneurol.2014.3780 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA CB4SU UT WOS:000349619200007 PM 25546364 ER PT J AU Schleider, JL Ginsburg, GS Keeton, CP Weisz, JR Birmaher, B Kendall, PC Piacentini, J Sherrill, J Walkup, JT AF Schleider, Jessica L. Ginsburg, Golda S. Keeton, Courtney P. Weisz, John R. Birmaher, Boris Kendall, Phillip C. Piacentini, John Sherrill, Joel Walkup, John T. TI Parental Psychopathology and Treatment Outcome for Anxious Youth: Roles of Family Functioning and Caregiver Strain SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE mediation; parental psychopathology; youth anxiety treatment; family functioning ID CHILDHOOD ANXIETY DISORDERS; ADOLESCENT PSYCHIATRIC-DISORDERS; MULTIPLE MEDIATOR MODELS; TREATMENT RESPONSE; FOLLOW-UP; CHILDREN; BURDEN; SCALE; PREDICTORS; CAMS AB Objective: Research has examined the effects of parental psychopathology, family functioning, and caregiver strain on treatment response in anxious youths. Although these variables have shown individual links to youth treatment response, theoretical models for their combined effects remain unexplored. This study tested the hypothesis that improvements in family functioning and reductions in caregiver strain explained the effects of parental psychopathology on youth treatment outcome in an anxiety treatment trial. Method: A multiple mediation technique was used to test the proposed model across independent evaluator (IE), parent, and youth informants in 488 youths, aged 7-17 years (50% female; mean age = 10.7) meeting Diagnostic and Statistical Manual of Mental Disorders criteria for social phobia, separation anxiety, and/or generalized anxiety disorder. Youths were randomized to receive 12 weeks of cognitive-behavioral treatment (Coping Cat), medication (sertraline), their combination, or a pill placebo. At pre- and posttreatment, parents completed self-report measures of global psychopathology symptoms, family functioning, and caregiver strain; parents, youths, and IEs rated youths' anxiety symptom severity. Results: Changes in family functioning and caregiver strain jointly explained relations between parental psychopathology and reductions in youth anxiety. Specifically, across IE and parent informants, families with higher pretreatment parental psychopathology showed more improvement in family functioning and caregiver strain, which in turn predicted greater youth anxiety reductions. Further, higher pretreatment parental psychopathology predicted greater caregiver strain reductions and, in turn, greater youth anxiety reductions, based on youths' reports of their own anxiety. Conclusions: Findings suggest that improvements in family functioning and reductions in caregiver strain can influence treatment outcomes for anxious youths, especially among youths with more distressed parents. C1 [Schleider, Jessica L.; Weisz, John R.] Harvard Univ, Cambridge, MA 02138 USA. [Ginsburg, Golda S.; Keeton, Courtney P.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Birmaher, Boris] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Birmaher, Boris] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Kendall, Phillip C.] Temple Univ, Philadelphia, PA 19122 USA. [Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Sherrill, Joel] NIMH, Bethesda, MD 20892 USA. [Walkup, John T.] Weill Cornell Med Coll, New York, NY USA. [Walkup, John T.] New York Presbyterian Hosp, New York, NY USA. RP Schleider, JL (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. EM jschleider@fas.harvard.edu FU National Institute of Mental Health (NIMH) [MH64089, MH64107, MH64003, MH63747, MH064092, MH64088]; Pfizer Pharmaceuticals FX This study was supported by National Institute of Mental Health (NIMH) Grants MH64089, MH64107, MH64003, MH63747, MH064092, and MH64088. Views expressed within this article represent those of the authors and are not intended to represent the position of NIMH, the National Institutes of Health, or the Department of Health and Human Services. Boris Birmaher receives book royalties from Random House, Inc., UpToDate, and Lippincott Williams & Wilkins. Phillip C. Kendall receives royalties for the sale of books and anxiety treatment materials. John Piacentini receives research support from Pfizer Pharmaceuticals. NR 74 TC 6 Z9 6 U1 6 U2 31 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 FEB PY 2015 VL 83 IS 1 BP 213 EP 224 DI 10.1037/a0037935 PG 12 WC Psychology, Clinical SC Psychology GA CB4PY UT WOS:000349611500019 PM 25222799 ER PT J AU Zablotsky, B Pringle, BA Colpe, LJ Kogan, MD Rice, C Blumberg, SJ AF Zablotsky, Benjamin Pringle, Beverly A. Colpe, Lisa J. Kogan, Michael D. Rice, Catherine Blumberg, Stephen J. TI Service and Treatment Use Among Children Diagnosed With Autism Spectrum Disorders SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE autism spectrum disorder; intellectual disability; national surveys ID PSYCHOTROPIC MEDICATION USE; INTELLECTUAL DISABILITY; CARE NEEDS; HEALTH; EXPENDITURES; PREVALENCE; ACCESS; EXPERIENCES; FAMILIES; SAMPLE AB Objective: Children diagnosed with autism spectrum disorder (ASD) require substantial support to address not only core ASD symptoms but also a range of co-occurring conditions. This study explores treatment and service use among children with ASD with and without intellectual disability (ID) and parents' perception of unmet needs from these treatments. Methods: Data were retrieved from a probability-based national sample of 2077 children diagnosed with ASD, ID, or both (ASD and ID). Weighted multivariate logistic regressions examined differences between diagnostic groups for current medication and service utilization with a subanalysis exploring differences among those with co-occurring psychiatric conditions. Additional modeling examined parents' perception of unmet needs. Results: Children diagnosed with ASD and ID were significantly more likely to be receiving current medication and services when compared with children with ID only or ASD only. Children with a co-occurring psychiatric diagnosis, from all 3 diagnostic groups, were more likely to be receiving a current medication, but not more likely to be receiving a current service when compared with children without a co-occurring psychiatric diagnosis. Children with ASD and a co-occurring psychiatric diagnosis were significantly more likely to have parents who reported unmet needs when compared with parents of children with ASD without a co-occurring psychiatric diagnosis. Conclusions: Children diagnosed with ASD and ID, especially those with a comorbid psychiatric condition, represent a vulnerable population with substantial rates of current service (98%) and medication (67%) usage, but despite these high rates, approximately 30% of parents report that their child's developmental needs are still not being met by their current treatment and services. C1 [Zablotsky, Benjamin; Blumberg, Stephen J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Pringle, Beverly A.] NIMH, Off Res Dispar & Global Mental Hlth, Bethesda, MD 20892 USA. [Colpe, Lisa J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Kogan, Michael D.] Maternal & Child Hlth Bur, Off Epidemiol & Res, Rockville, MD USA. [Rice, Catherine] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. RP Zablotsky, B (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 2118, Hyattsville, MD 20782 USA. EM bzablotsky@cdc.gov RI Rice, Catherine/D-6305-2016 FU Intramural CDC HHS [CC999999] NR 38 TC 6 Z9 6 U1 1 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB-MAR PY 2015 VL 36 IS 2 BP 98 EP 105 PG 8 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA CB2HO UT WOS:000349448000074 PM 25650952 ER PT J AU Barrett, AJ AF Barrett, Austin John TI Editorial: A new checkpoint in the path to GVHD? How bedside-to-bench stem cell transplant studies can inform human GVHD biology SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID VERSUS-HOST-DISEASE; RISK C1 [Barrett, Austin John] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), US NIH, Stem Cell Allotransplantat Sect, Hematol Branch, CRC, 3-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU Intramural NIH HHS NR 3 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2015 VL 97 IS 2 BP 213 EP 216 DI 10.1189/jlb.5CE0814-385 PG 4 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CB2GB UT WOS:000349443900002 PM 25649789 ER PT J AU Tarasenko, TN Gomez-Rodriguez, J McGuire, PJ AF Tarasenko, Tatyana N. Gomez-Rodriguez, Julio McGuire, Peter J. TI Impaired T cell function in argininosuccinate synthetase deficiency SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE immunity; arginine; metabolism; differentiation ID L-ARGININE; ADAPTIVE IMMUNITY; GENE-EXPRESSION; ZETA-CHAIN; AMINO-ACID; LYMPHOCYTES; METABOLISM; PROLIFERATION; CITRULLINE; LEUKEMIA AB ASS1 is a cytosolic enzyme that plays a role in the conversion of citrulline to arginine. In human and mouse tissues, ASS1 protein is found in several components of the immune system, including the thymus and T cells. However, the role of ASS1 in these tissues remains to be defined. Considerable attention has been focused recently on the role of metabolism in T cell differentiation and function. Based on the expression of ASS1 in the immune system, we hypothesized that ASS1 deficiency would result in T cell defects. To evaluate this question, we characterized immune function in hypomorphic fold/fold mice. Analysis of splenic T cells by flow cytometry showed a marked reduction in T cell numbers with normal expression of activation surface markers. Gene therapy correction of liver ASS1 to enhance survival resulted in a partial recovery of splenic T cells for characterization. In vitro and in vivo studies demonstrated the persistence of the ASS1 enzyme defect in T cells and abnormal T cell differentiation and function. Overall, our work suggests that ASS1 plays a role in T cell function, and deficiency produces primary immune dysfunction. In addition, these data suggest that patients with ASS1 deficiency (citrullinemia type I) may have T cell dysfunction. C1 [Tarasenko, Tatyana N.; Gomez-Rodriguez, Julio; McGuire, Peter J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, 49 Convent Dr,4A62, Bethesda, MD 20892 USA. EM Peter.mcguire@nih.gov FU U.S. National Institutes of Health, National Human Genome Research Institute (NHGRI); Physician Scientist Development Program at the NHGRI FX The intramural research program of the U.S. National Institutes of Health, National Human Genome Research Institute (NHGRI) supported all of the work herein. The authors thank Dr. Les Biesecker for his support and the support of the Physician Scientist Development Program at the NHGRI. The authors also thank Dr. Pamela Schwartzberg for her editorial insights during preparation of this manuscript. NR 32 TC 6 Z9 6 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2015 VL 97 IS 2 BP 273 EP 278 DI 10.1189/jlb.1AB0714-365R PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CB2GB UT WOS:000349443900008 PM 25492936 ER PT J AU Basu, S Hubbard, B Shevach, EM AF Basu, Samik Hubbard, Britany Shevach, Ethan M. TI Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE signal transduction; metabolism; lymphocyte; autoimmunity ID FOXP3 TARGET GENES; CUTTING EDGE; ACTIVATION; METABOLISM; PATHWAYS AB CD4(+)CD25(+)Foxp3(+)T(regs) have a diminished capacity to activate the PI3K/Akt pathway. Although blunted Akt activity is necessary to maintain T-reg function, the consequences of this altered signaling are unclear. Glut1 is a cell-surface receptor responsible for facilitating glucose transport across plasma membranes, whose expression is tightly coupled to costimulatory signals and Akt phosphorylation. Freshly isolated human T-regs were unable to up-regulate Glut1 in response to TCR and costimulatory signals compared with T-conv. Consequently, the ability of T-regs to use glucose was also reduced. Introduction of Foxp3 into T-conv inhibited Akt activation and Glut1 expression, indicating that Foxp3 can regulate Glut1. Finally, pharmacologic activation of Akt in T-regs can induce Glut1, overcoming the effects of Foxp3. Together, these results illustrate the molecular basis behind differential glucose metabolism in T-regs. C1 [Basu, Samik; Hubbard, Britany; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural Program of National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health; Cooperative Research and Development Agreement (CRADA); Boerhinger-Ingelheim FX This research was supported by the Intramural Program of National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health, and by a Cooperative Research and Development Agreement (CRADA) with Boerhinger-Ingelheim. The authors thank the NIAID Flow Cytometry Section, particularly Elina Stregvensky and Bishop Hague for all of their help in sorting our cells. The authors also thank the Department of Transfusion Medicine for providing the blood donors. NR 23 TC 11 Z9 11 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD FEB PY 2015 VL 97 IS 2 BP 279 EP 283 DI 10.1189/jlb.2AB0514-273RR PG 5 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA CB2GB UT WOS:000349443900009 PM 25492937 ER PT J AU Bigert, C Gustavsson, P Straif, K Pesch, B Bruning, T Kendzia, B Schuz, J Stucker, I Guida, F Bruske, I Wichmann, HE Pesatori, AC Landi, MT Caporaso, N Tse, LA Yu, ITS Siemiatycki, J Pintos, J Merletti, F Mirabelli, D Simonato, L Jockel, KH Ahrens, W Pohlabeln, H Tardon, A Zaridze, D Field, J 't Mannetje, A Pearce, N McLaughlin, J Demers, P Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Dumitru, RS Bencko, V Foretova, L Janout, V Boffetta, P Forastiere, F Bueno-de-Mesquita, B Peters, S Vermeulen, R Kromhout, H Olsson, AC AF Bigert, Carolina Gustavsson, Per Straif, Kurt Pesch, Beate Bruening, Thomas Kendzia, Benjamin Schuez, Joachim Stuecker, Isabelle Guida, Florence Brueske, Irene Wichmann, Heinz-Erich Pesatori, Angela C. Landi, Maria Teresa Caporaso, Neil Tse, Lap Ah Yu, Ignatius Tak-sun Siemiatycki, Jack Pintos, Javier Merletti, Franco Mirabelli, Dario Simonato, Lorenzo Joeckel, Karl-Heinz Ahrens, Wolfgang Pohlabeln, Hermann Tardon, Adonina Zaridze, David Field, John 't Mannetje, Andrea Pearce, Neil McLaughlin, John Demers, Paul Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Boffetta, Paolo Forastiere, Francesco Bueno-de-Mesquita, Bas Peters, Susan Vermeulen, Roel Kromhout, Hans Olsson, Ann C. TI Lung Cancer Risk Among Cooks When Accounting for Tobacco Smoking A Pooled Analysis of Case-Control Studies From Europe, Canada, New Zealand, and China SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID AROMATIC-HYDROCARBONS PAHS; DNA-REPAIR GENES; MUTAGENIC ALDEHYDES; PARTICULATE MATTER; OCCUPATIONAL-EXPOSURE; NONSMOKING WOMEN; CASE-REFERENT; POPULATION; MEN; MORTALITY AB Objectives: To investigate the risk of lung cancer among cooks, while controlling for smoking habits. Methods: We used data from the SYNERGY project including pooled information on lifetime work histories and smoking habits from 16 case-control studies conducted in Europe, Canada, New Zealand, and China. Results: Before adjustment for smoking, we observed an increased risk of lung cancer in male cooks, but not in female cooks. After adjusting, there was no increased risk and no significant exposure-response relationship. Nevertheless, subgroup analyses highlighted some possible excess risks of squamous cell carcinoma and small cell carcinoma in female cooks. Conclusions: There is evidence that lung cancer risks among cooks may be confounded by smoking. After adjustment, cooks did not experience an increased risk of lung cancer overall. The subgroup analyses showing some excess risks among female cooks require cautious interpretation. C1 [Bigert, Carolina; Gustavsson, Per] Karolinska Inst, Inst Environm Med, SE-11365 Stockholm, Sweden. [Straif, Kurt; Schuez, Joachim; Olsson, Ann C.] Int Agcy Res Canc, F-69372 Lyon, France. [Pesch, Beate; Bruening, Thomas; Kendzia, Benjamin] Ruhr Univ Bochum IPA, German Social Accid Insurance Inst, Inst Prevent & Occupat Med, Bochum, Germany. [Stuecker, Isabelle; Guida, Florence] Ctr Res Epidemiol & Populat Hlth CESP, INSERM, U1018, Environm Epidemiol Canc Team, F-94807 Villejuif, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France. [Brueske, Irene; Wichmann, Heinz-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol 1, Neuherberg, Germany. [Pesatori, Angela C.] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Landi, Maria Teresa; Caporaso, Neil] NCI, Bethesda, MD 20892 USA. [Tse, Lap Ah; Yu, Ignatius Tak-sun] Chinese Univ Hong Kong, Div Occupat & Environm Hlth, Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Siemiatycki, Jack; Pintos, Javier] Univ Montreal, Res Ctr, Univ Montreal Hosp Ctr, Montreal, PQ H3C 3J7, Canada. [Merletti, Franco; Mirabelli, Dario] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, I-10124 Turin, Italy. [Simonato, Lorenzo] Univ Padua, Dept Environm Med & Publ Hlth, I-35100 Padua, Italy. [Joeckel, Karl-Heinz] Univ Duisburg Essen, Inst Med Informat, Essen, Germany. [Ahrens, Wolfgang; Pohlabeln, Hermann] Bremen Inst Prevent Res & Social Med, Bremen, Germany. [Tardon, Adonina] Univ Oviedo, CIBERESP, Oviedo, Spain. [Zaridze, David] Russian Canc Res Ctr, Moscow, Russia. [Field, John] Univ Liverpool, Roy Castle Lung Canc Res Programme, Canc Res Ctr, Liverpool L69 3BX, Merseyside, England. ['t Mannetje, Andrea; Pearce, Neil] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [McLaughlin, John; Demers, Paul] Occupat Canc Res Ctr, Toronto, ON, Canada. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, CR-77147 Olomouc, Czech Republic. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Forastiere, Francesco] ASL RomaE, Dept Epidemiol, Rome, Italy. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm Protect RIVM, Bilthoven, Netherlands. [Peters, Susan; Vermeulen, Roel; Kromhout, Hans] Inst Risk Assessment Sci, Utrecht, Netherlands. [Peters, Susan] Univ Western Australia, Sch Populat Hlth, Perth, WA 6009, Australia. RP Bigert, C (reprint author), Karolinska Inst, Inst Environm Med, Solnavagen 4 10th Floor, SE-11365 Stockholm, Sweden. EM carolina.bigert@ki.se RI Yu, Ignatius Tak Sun/A-9936-2008; Szeszenia-Dabrowska, Neonila/F-7190-2010; Janout, Vladimir/M-5133-2014; Bruning, Thomas/G-8120-2015; Forastiere, Francesco/J-9067-2016; Vermeulen, Roel/F-8037-2011; OI pesatori, angela/0000-0002-0261-3252; Ahrens, Wolfgang/0000-0003-3777-570X; Bruning, Thomas/0000-0001-9560-5464; Forastiere, Francesco/0000-0002-9162-5684; Vermeulen, Roel/0000-0003-4082-8163; Field, John/0000-0003-3951-6365 FU AFA Insurance in Sweden; German Social Accident Insurance (DGUV); Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer; National Cancer Institute of Canada; Canadian Cancer Society; Cancer Care Ontario; French agency of health security (ANSES); Fondation de France; French National Research Agency (ANR); National Institute of Cancer (INCA); Fondation for Medical Research (FRM); French Institute for Public Health Surveillance (InVS); Health Ministry (DGS); Organization for the Research on Cancer (ARC); French Ministry; Federal Ministry of Education, Science, Research, and Technology; Federal Ministry of Science; Ministry of Labour and Social Affairs; European Commission's INCO-COPERNICUS program; Polish State Committee for Scientific Research grant; Roy Castle Foundation as part of the Liverpool Lung Project; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; Environmental Epidemiology Program of the Lombardy Region, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy; Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo; European Union Nuclear Fission Safety Program; Lazio Region; Dutch Ministry of Health, Welfare Sports; National Institute of Public Health & the Environment; Europe Against Cancer Program; Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias; Fondo de Investigacion Sanitaria (FIS); Ciber de Epidemiologia y Salud Publica (CIBERESP), Spain; Research Grants Council of the Hong Kong Special Administrative Region, China; Health Research Council of New Zealand; New Zealand Department of Labour, Lottery Health Research; Cancer Society of New Zealand; Swedish Council for Work Life Research; Swedish EPA FX This study was funded by the AFA Insurance in Sweden. The AFA Insurance is owned by Sweden's labor market parties: the Confederation of Swedish Enterprise, the Swedish Trade Union Confederation, and the Council for Negotiation and Co-operation. The SYNERGY project is funded by the German Social Accident Insurance (DGUV). The original studies were funded by a list of agencies including the Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and Cancer Care Ontario; the French agency of health security (ANSES), the Fondation de France, the French National Research Agency (ANR), the National Institute of Cancer (INCA), the Fondation for Medical Research (FRM), the French Institute for Public Health Surveillance (InVS), the Health Ministry (DGS), the Organization for the Research on Cancer (ARC), and the French Ministry of work, solidarity and public function (DGT). In Germany, the studies were funded by the Federal Ministry of Education, Science, Research, and Technology grant no. and the Federal Ministry of Science and the Ministry of Labour and Social Affairs. The INCO study was supported by a grant from the European Commission's INCO-COPERNICUS program, a grant from the Polish State Committee for Scientific Research grant and the Roy Castle Foundation as part of the Liverpool Lung Project. The EAGLE study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; the Environmental Epidemiology Program of the Lombardy Region, Italy; and the Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy. The TURIN study was supported by the Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo. The study in Rome was conducted with a partial support from the European Union Nuclear Fission Safety Program and from the Lazio Region. The MORGEN study was supported by the Dutch Ministry of Health, Welfare & Sports, National Institute of Public Health & the Environment, and the Europe Against Cancer Program. The CAPUA study was supported by the Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias, the Fondo de Investigacion Sanitaria (FIS), and the Ciber de Epidemiologia y Salud Publica (CIBERESP), Spain. The Hong Kong study was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China. The OCANZ study was funded by the Health Research Council of New Zealand, the New Zealand Department of Labour, Lottery Health Research, and by the Cancer Society of New Zealand. The Swedish study LUCAS was supported by the Swedish Council for Work Life Research and the Swedish EPA. NR 40 TC 1 Z9 1 U1 4 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD FEB PY 2015 VL 57 IS 2 BP 202 EP 209 DI 10.1097/JOM.0000000000000337 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CB2VO UT WOS:000349486700017 PM 25654522 ER PT J AU Chandler, JC Sutherland, MD Harton, MR Molins, CR Anderson, RV Heaslip, DG Bosio, CM Belisle, JT AF Chandler, Jeffrey C. Sutherland, Marjorie D. Harton, Marisa R. Molins, Claudia R. Anderson, Rebecca V. Heaslip, Darragh G. Bosio, Catharine M. Belisle, John T. TI Francisella tularensis LVS Surface and Membrane Proteins as Targets of Effective Post-Exposure Immunization for Tularemia SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Francisella tularensis; surface proteome; membrane proteome; adaptive immunity; antibodies ID CULTURE FILTRATE PROTEINS; LIVE VACCINE STRAIN; VIRULENT TYPE-A; PROTEOMIC ANALYSIS; ANTIBODY-RESPONSE; IMMUNOREACTIVE ANTIGENS; RESPIRATORY CHALLENGE; STATISTICAL-MODEL; MASS-SPECTROMETRY; ENRICHED FRACTION AB Francisella tularensis causes disease (tularemia) in a large number of mammals, including man. We previously demonstrated enhanced efficacy of conventional antibiotic therapy for tularemia by postexposure passive transfer of immune sera developed against a F. tularensis LVS membrane protein fraction (MPF). However, the protein composition of this immunogenic fraction was not defined. Proteomic approaches were applied to define the protein composition and identify the immunogens of MPF. MPF consisted of at least 299 proteins and 2-D Western blot analyses using sera from MPF-immunized and F. tularensis LVS-vaccinated mice coupled to liquid chromatography-tandem mass spectrometry identified 24 immunoreactive protein spots containing 45 proteins. A reverse vaccinology approach that applied labeling of F. tularensis LVS surface proteins and bioinformatics was used to reduce the complexity of potential target immunogens. Bioinformatics analyses of the immunoreactive proteins reduced the number of immunogen targets to 32. Direct surface labeling of F. tularensis LVS resulted in the identification of 31 surface proteins. However, only 13 of these were reactive with MPF and/or F. tularensis LVS immune sera. Collectively, this use of orthogonal proteomic approaches reduced the complexity of potential immunogens in MPF by 96% and allowed for prioritization of target immunogens for antibody-based immunotherapies against tularemia. C1 [Chandler, Jeffrey C.; Sutherland, Marjorie D.; Harton, Marisa R.; Heaslip, Darragh G.; Belisle, John T.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Rocky Mt Reg Ctr Excellence Biodef & Emerging Inf, Ft Collins, CO 80523 USA. [Molins, Claudia R.] Ctr Dis Control & Prevent, Div Vector Borne Dis, Ft Collins, CO 80521 USA. [Anderson, Rebecca V.; Bosio, Catharine M.] NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. RP Belisle, JT (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Rocky Mt Reg Ctr Excellence Biodef & Emerging Inf, Campus Delivery 0922, Ft Collins, CO 80523 USA. EM John.Belisle@colostate.edu RI Bosio, Catharine/D-7456-2015; Belisle, John/B-8944-2017 OI Belisle, John/0000-0002-2539-2798 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [U54 AI-065357] FX This research was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases grant: U54 AI-065357. NR 52 TC 1 Z9 1 U1 0 U2 6 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 FEB PY 2015 VL 14 IS 2 BP 664 EP 675 DI 10.1021/pr500628k PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CA9WV UT WOS:000349276400008 PM 25494920 ER PT J AU Luckenbaugh, DA Ameli, R Brutsche, NE Zarate, CA AF Luckenbaugh, David A. Ameli, Rezvan Brutsche, Nancy E. Zarate, Carlos A., Jr. TI Rating depression over brief time intervals with the Hamilton Depression Rating Scale: Standard vs. abbreviated scales SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Antidepressant; Bipolar disorder; Depression; HDRS; Ketamine; Ratings ID D-ASPARTATE ANTAGONIST; ADD-ON TRIAL; BIPOLAR DEPRESSION; REMISSION; ANTIDEPRESSANTS; SENSITIVITY; SUBSCALES; SEVERITY; PLACEBO; METAANALYSIS AB Although antidepressant trials typically use weekly ratings to examine changes in symptoms over six to 12 weeks, antidepressant treatments may improve symptoms more quickly. Thus, rating scales must be adapted to capture changes over shorter intervals. We examined the use of the 17-item Hamilton Depression Rating Scale (HDRS) to evaluate more rapid changes. Data were examined from 58 patients with major depressive disorder or bipolar disorder enrolled in double-blind, placebo-controlled, crossover studies who received a single infusion of ketamine (0.5 mg/kg) or placebo over 40 min then crossed over to the other condition. HDRS subscales, a single HDRS Depressed mood item, and a visual analogue scale were used at baseline, after a brief interval (230 min), and one week post-infusion. Effect sizes for the ketamine-placebo difference were moderate (d > 0.50), but one and two-item HDRS subscales had the smallest effects. Response rates on active drug were lowest for the complete HDRS (43%); the remaining scales had higher response rates to active drug, but the shortest subscales had higher response rates to placebo. Correlations between the changes from baseline to 230 min post-ketamine across scores were similar for most subscales (r = 0.82-0.97), but correlations using the single items were lower (r < 0.74). Overall, effect sizes for drug-placebo differences and correlations between changes were lower for one- and two-item measures. Response rates were lower with the full HDRS scale. The data suggest that, to best identify rapid antidepressant effects, a scale should have more than two items, but fewer items than a full scale. Published by Elsevier Ltd. C1 NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Dept Hlth & Human Serv, Bethesda, MD USA. RP Zarate, CA (reprint author), NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Clin Res Ctr, Bldg 10,10 Ctr Dr,Room 7-5342, Bethesda, MD 20892 USA. EM dave.luckenbaugh@nih.gov; rezvan.ameli@nih.gov; nancy.brutsche@nih.gov; zaratec@mail.nih.gov FU Intramural NIH HHS [ZIA MH002857-10, ZIA MH002927-05] NR 32 TC 3 Z9 3 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD FEB PY 2015 VL 61 BP 40 EP 45 DI 10.1016/j.jpsychires.2014.12.015 PG 6 WC Psychiatry SC Psychiatry GA CB6IP UT WOS:000349731000006 PM 25592045 ER PT J AU Liao, KP Playford, MP Frits, M Coblyn, JS Iannaccone, C Weinblatt, ME Shadick, NS Mehta, NN AF Liao, Katherine P. Playford, Martin P. Frits, Michelle Coblyn, Jonathan S. Iannaccone, Christine Weinblatt, Michael E. Shadick, Nancy S. Mehta, Nehal N. TI The Association Between Reduction in Inflammation and Changes in Lipoprotein Levels and HDL Cholesterol Efflux Capacity in Rheumatoid Arthritis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE inflammation; lipids; rheumatoid arthritis ID C-REACTIVE PROTEIN; INCIDENT CARDIOVASCULAR EVENTS; NECROSIS FACTOR THERAPY; MYOCARDIAL-INFARCTION; RESPONSE CRITERIA; LDL-CHOLESTEROL; EUROPEAN-LEAGUE; STATIN THERAPY; LIPID PROFILE; RISK-FACTORS AB Background-Potent anti-inflammatory rheumatoid arthritis (RA) treatments are associated with reduced cardiovascular risk as well as increases in low-density lipoprotein (LDL) cholesterol. This apparent paradox may be explained by favorable changes in other lipid measurements. The objective of this study was to determine the longitudinal association between changes in inflammation with advanced lipoprotein measurements and high-density lipoprotein (HDL) cholesterol efflux capacity. Methods and Results-We conducted this study in a longitudinal RA cohort from a large academic center, including subjects with high-sensitivity C-reactive protein (hs-CRP) reduction >= 10 mg/L at 2 time points 1 year apart. Subjects receiving statins during the study period or preceding 6 months were excluded. We compared total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B, and apolipoprotein A1 levels and HDL cholesterol efflux capacity at baseline and 1-year follow-up by using the paired t test. We also assessed the correlations between reductions in hs-CRP with percentage change in lipid parameters. We studied 90 RA subjects (mean age 57 years, 89% female), all of whom were receiving disease-modifying antirheumatic drugs. We observed a 7.2% increase in LDL cholesterol levels (P= 0.02) and improvement in efflux capacity by 5.7% (P= 0.002) between baseline and follow-up, with a median hs-CRP reduction of 23.5 mg/L. We observed significant correlations between reductions in hs-CRP with increases in apolipoprotein A1 (r= 0.27, P= 0.01) and HDL cholesterol efflux capacity (r= 0.24, P= 0.02). Conclusion-Among RA subjects experiencing reductions in hs-CRP, we observed increased LDL cholesterol levels and concomitant improvements in HDL cholesterol efflux capacity. These findings provide further insight into lipid modulation and the beneficial effect of reduction in inflammation on lipids in vivo. C1 [Liao, Katherine P.; Frits, Michelle; Coblyn, Jonathan S.; Iannaccone, Christine; Weinblatt, Michael E.; Shadick, Nancy S.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Playford, Martin P.; Mehta, Nehal N.] NIH, Heart Blood & Lung Inst, Bethesda, MD 20892 USA. RP Liao, KP (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St,PBB B3, Boston, MA 02115 USA. EM kliao@partners.org FU National Institutes of Health (NIH) [K08 AR060257]; Harold and Duval Bowen Fund; Division of Intramural Research at the NIH [HL-Z-0000] FX Dr Liao is supported by National Institutes of Health (NIH) grant K08 AR060257 and the Harold and Duval Bowen Fund. Dr Mehta is funded by grant HL-Z-0000 from the Division of Intramural Research at the NIH. NR 48 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2015 VL 4 IS 2 AR e001588 DI 10.1161/JAHA.114.001588 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CB5LG UT WOS:000349668000017 ER PT J AU Hart, PC Mao, M de Abreu, ALP Ansenberger-Fricano, K Ekoue, DN Ganini, D Kajdacsy-Balla, A Diamond, AM Minshall, RD Consolaro, MEL Santos, JH Bonini, MG AF Hart, Peter C. Mao, Mao de Abreu, Andre Luelsdorf P. Ansenberger-Fricano, Kristine Ekoue, Dede N. Ganini, Douglas Kajdacsy-Balla, Andre Diamond, Alan M. Minshall, Richard D. Consolaro, Marcia E. L. Santos, Janine H. Bonini, Marcelo G. TI MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer SO NATURE COMMUNICATIONS LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; ACTIVATED PROTEIN-KINASE; HYPOXIA-INDUCIBLE FACTOR; CELL-CYCLE PROGRESSION; BREAST-CANCER; EPITHELIAL-CELLS; PROSTATE-CANCER; INHIBIT APOPTOSIS; INITIATING CELLS; OXIDATIVE STRESS AB Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism. C1 [Hart, Peter C.; Mao, Mao; de Abreu, Andre Luelsdorf P.; Ansenberger-Fricano, Kristine; Bonini, Marcelo G.] Univ Illinois, Dept Med, Chicago, IL 60612 USA. [Hart, Peter C.; Ekoue, Dede N.; Kajdacsy-Balla, Andre; Diamond, Alan M.; Bonini, Marcelo G.] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Mao, Mao; de Abreu, Andre Luelsdorf P.; Ansenberger-Fricano, Kristine; Minshall, Richard D.; Bonini, Marcelo G.] Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. [de Abreu, Andre Luelsdorf P.; Consolaro, Marcia E. L.] Univ Estadual Maringa, BR-87020900 Maringa, Parana, Brazil. [Ganini, Douglas] NIEHS, Free Radical Metabolite Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Minshall, Richard D.] Univ Illinois, Dept Anesthesiol, Chicago, IL 60612 USA. [Santos, Janine H.] Univ Med & Dent New Jersey, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. RP Bonini, MG (reprint author), Univ Illinois, Dept Med, 909 South Wolcott Ave,COMRB 1131, Chicago, IL 60612 USA. EM mbonini@uic.edu RI Mao, Mao/E-3783-2013; Consolaro, Marcia/I-4932-2014; OI Mao, Mao/0000-0003-1524-8853; Consolaro, Marcia/0000-0001-9102-4865; Hart, Peter/0000-0003-1843-9102 FU US Department of Defense (ARO) [61758-LS]; NCRR/NIH [S10RR027848]; NIH [HL072742, P01 HL60678]; CAPES-Coordenacao de Aperfeicoamento Pessoal, Ministerio da Ciencia e Tecnologia/Brazil [RO1 CA101053, A109/2013]; [1R21CA182103-01] FX We are indebted to Drs Larry W. Oberley (in memoriam) and Frederick Domann (University of Iowa) for the generous gift of cell lines stably overexpressing MnSOD, Dr Kevin P. Claffey (University of Connecticut) for the generous gift of MCF-7-AMPKa1 -/- cells, Dr Kevin Struhl (Harvard University) for the gift of the MCF10A lines expressing v-Src under ER induction, Patricia Mavrogianis, Andrew Hall and Emily Ionetz at the Research Histology Core at the University of Illinois at Chicago for providing histology services, Dr Soumen Bera, Emmanuel Ansong, Paula Green, Alyssa Master and M. Saqib Baig for technical assistance, and for funding provided by the US Department of Defense (ARO no. 61758-LS) to M.G.B, the NCRR/NIH (S10RR027848) to M.G.B., 1R21CA182103-01 to A.M.D. and M.G.B. K.A.-F. and P.C.H. were supported by NIH T32 (HL072742). We also acknowledge gifts from RO1 CA101053 to A.M.D., NIH P01 HL60678 to R.D.M., CAPES-Coordenacao de Aperfeicoamento Pessoal, Ministerio da Ciencia e Tecnologia/Brazil-A109/2013 to M.G.B. and M.E.L.C. NR 70 TC 29 Z9 29 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2015 VL 6 AR 6053 DI 10.1038/ncomms7053 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CC0OO UT WOS:000350035500001 PM 25651975 ER PT J AU Radke, AK Zlebnik, NE Carroll, ME AF Radke, Anna K. Zlebnik, Natalie E. Carroll, Marilyn E. TI Cocaine withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Rat; Motivation; Sweet preference; Selective breeding; Withdrawal ID OPIATE WITHDRAWAL; NUCLEUS-ACCUMBENS; SUCROSE SOLUTION; TASTE; ABSTINENCE; SCHEDULE; ESCALATION; PREFERENCE; ADDICTION; NICOTINE AB Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al., 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30 mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to greater drug vulnerability in the HiS line. Published by Elsevier Inc. C1 [Radke, Anna K.; Zlebnik, Natalie E.; Carroll, Marilyn E.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. RP Radke, AK (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM anna.radke@nih.gov FU NIDA [K05 DA015267, R01 DA003240, P20 DA024196] FX This work was funded by NIDA grants K05 DA015267, R01 DA003240, and P20 DA024196 (MEC). NR 43 TC 3 Z9 3 U1 4 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 FEB PY 2015 VL 129 BP 51 EP 55 DI 10.1016/j.pbb.2014.11.022 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA CB4HD UT WOS:000349587900008 PM 25482327 ER PT J AU Patel, N Grillon, C Pavletic, N Rosen, D Pine, DS Ernst, M AF Patel, Nilam Grillon, Christian Pavletic, Nevia Rosen, Dana Pine, Daniel S. Ernst, Monique TI Oxytocin and vasopressin modulate risk-taking SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Neuropeptides; Motivated behavior; Social stress; Sex; Risk-valence ID MEDIAL PREFRONTAL CORTEX; GENDER-DIFFERENCES; DECISION-MAKING; HUMANS; BEHAVIOR; ANXIETY; STRESS; BRAIN; CIRCUITRY; WOMEN AB The modulation of risk-taking is critical for adaptive and optimal behavior. This study examined how oxytocin (OT) and arginine vasopressin (AVP) influence risk-taking in function of three parameters: sex, risk-valence, and social context. Twenty-nine healthy adults (14 males) completed a risk-taking task, the Stunt task, both in a social-stress (evaluation by unfamiliar peers) and non-social context, in three separate drug treatment sessions. During each session, one of three drugs, OT, AVP, or placebo (PLC), was administered intra-nasally. OT and AVP relative to PLC reduced betting-rate (risk-averse effect). This risk-averse effect was further qualified: AVP reduced risk-taking in the positive risk-valence (high win-probability), and regardless of social context or sex. In contrast, OT reduced risk-taking in the negative risk-valence (low win-probability), and only in the social-stress context and men. The reduction in risk-taking might serve a role in defensive behavior. These findings extend the role of these neuromodulators to behaviors beyond the social realm. How the behavioral modulation of risk-taking maps onto the function of the neural targets of OT and AVP may be the next step in this line of research. Published by Elsevier Inc. C1 [Patel, Nilam] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Patel, Nilam; Grillon, Christian; Pavletic, Nevia; Rosen, Dana; Pine, Daniel S.; Ernst, Monique] NIMH, NIH, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM emstm@mail.nih.gov FU National Institute of Mental Health [MH002798] FX This study was funded by the Intramural Research Program of the National Institute of Mental Health (Grant number MH002798). Dr. Pine has received compensation for activities related to teaching, editing, and clinical care that pose no conflicts of interest. The authors declare no conflict of interest. NR 35 TC 7 Z9 7 U1 1 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB PY 2015 VL 139 BP 254 EP 260 DI 10.1016/j.physbeh.2014.11.018 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA CB4BY UT WOS:000349574400035 PM 25446228 ER PT J AU Vega-Sanchez, R Arenas-Hernandez, M Vazquez-Perez, JA Moreno-Valencia, Y Gomez-Lopez, N AF Vega-Sanchez, R. Arenas-Hernandez, M. Vazquez-Perez, J. A. Moreno-Valencia, Y. Gomez-Lopez, N. TI Evaluation of reference genes for expression studies in leukocytes from term human pregnancy SO PLACENTA LA English DT Article DE Pregnancy; Labor; Leukocytes; Housekeeping genes; Stability; geNorm ID 18S RIBOSOMAL-RNA; REAL-TIME PCR; HOUSEKEEPING GENES; SELECTION; VALIDATION; STABILITY; TISSUES; LABOR AB Introduction: Human labor is considered an inflammatory process modulated by systemic and local leukocytes that infiltrate into the maternal fetal interface. The putative roles of these leukocytes are currently being studied with gene expression assays. Such assays are normalized by the expression of housekeeping genes. However, expression of housekeeping genes may vary depending on the cell type and/or the experimental conditions. The aim of this study was to analyze the expression stability of several housekeeping genes in leukocytes from term human pregnancies, considering both anatomical origin and presence of labor. Methods: We analyzed the gene expression of ACTB, B2M, GAPDH, GUSB, PGK1, RN18S1, TBP and UBC in leukocytes from maternal peripheral blood, placental blood and choriodecidua in women delivering at term with or without the presence of labor through real-time qPCR. Then we used geNorm to evaluate expression stability and pairwise variation. Results: The expression of all tested genes showed to be stable independent of the anatomical compartment and the absence or presence of labor. However, PGK1, GUSB and TBP showed to be the most stable and RN18S1 the least stable. Pairwise variation analyses showed that only two genes are needed for normalization yet the inclusion of a third improves its accuracy. Discussion: PGK1, GUSB and TBP are the most adequate reference genes for gene expression normalization in leukocytes from term pregnancies, regardless of their anatomical origin (maternal peripheral blood, placental blood or choriodecidua) or the presence or absence of labor. Our study is the first report on housekeeping gene stability in leukocytes from healthy pregnant women. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Vega-Sanchez, R.] Inst Nacl Perinatol, Dept Nutr & Bioprogramming, Mexico City 11000, DF, Mexico. [Arenas-Hernandez, M.; Gomez-Lopez, N.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Arenas-Hernandez, M.] Inst Politecn Nacl, Natl Sch Biol Sci, Mexico City, DF, Mexico. [Vazquez-Perez, J. A.; Moreno-Valencia, Y.] Inst Nacl Enfermedades Resp, Dept Virol & Mycol Res, Mexico City 14080, DF, Mexico. [Gomez-Lopez, N.] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Perinatol Res Branch,NICHD,NIH,Sch Med, Detroit, MI 48201 USA. RP Vega-Sanchez, R (reprint author), Inst Nacl Perinatol, Dept Nutr & Bioprogramming, Montes Urales 800, Mexico City 11000, DF, Mexico. EM r.vega@inper.mx; marenash@med.wayne.edu; joevazpe@gmail.com; yazmin258@gmail.com; ngomezlo@med.wayne.edu RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU CONACYT, Mexico [SALUD-2010-01-141144]; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD/NIH) FX This study was supported by grant SALUD-2010-01-141144 from CONACYT, Mexico. N.G-L is funded by Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD/NIH). NR 20 TC 2 Z9 2 U1 0 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD FEB PY 2015 VL 36 IS 2 BP 240 EP 245 DI 10.1016/j.placenta.2014.11.010 PG 6 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA CB4FH UT WOS:000349583100020 PM 25484264 ER PT J AU Green, M Covington, S Taranto, S Wolfe, C Bell, W Biggins, SW Conti, D DeStefano, GD Dominguez, E Ennis, D Gross, T Klassen-Fischer, M Kotton, C LaPointe-Rudow, D Law, Y Ludrosky, K Menegus, M Morris, MI Nalesnik, MA Pavlakis, M Pruett, T Sifri, C Kaul, D AF Green, Michael Covington, Shandie Taranto, Sarah Wolfe, Cameron Bell, Walter Biggins, Scott W. Conti, David DeStefano, G. David Dominguez, Edward Ennis, Donna Gross, Thomas Klassen-Fischer, Mary Kotton, Camille LaPointe-Rudow, Dianne Law, Yuk Ludrosky, Kristen Menegus, Marilyn Morris, Michele I. Nalesnik, Michael A. Pavlakis, Martha Pruett, Timothy Sifri, Costi Kaul, Daniel TI Donor-Derived Transmission Events in 2013: A Report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee SO TRANSPLANTATION LA English DT Article AB Background. The Organ Procurement Transplant Network Disease Transmission Advisory Committee (DTAC), a multidisciplinary committee, evaluates potential donor-derived transmission events (PDDTE), including infections andmalignancies, to assess for donor transmitted events. Methods. Reports of unexpected PDDTE to Organ Procurement Transplant Network in 2013 were fully reviewed by DTAC. A standardized algorithm was used to assess each PDDTE from a given donor and to classify each individual recipient from that donor. Results. Of 443 total PDDTE submitted, 159 were triaged and not sent out to the full DTAC. Of 284 fully evaluated reports, 32 (11.3%) resulted in a proven/probable (P/P) transmission of infection, malignancy or other conditions to 42 recipients. Of 204 infection events, 24 were classified as P/P affecting 30 recipients, with four deaths. Bacteria were the most frequently reported type of infection, accounting for 99 reports but only 12 recipients from 11 donors experienced P/P transmission. There were 65 donors reported with potential malignancy events and 5 were classified as P/P transmissions with 8 affected recipients and 2 deaths. Additionally, there were 16 noninfection, nonmalignancy reports resulting in 3 P/P transmissions to 4 recipients and 1 death. Conclusions. There was a 43% increase in the number of PDDTE reported and reviewed in 2013 over 2012. However, the percent with P/P transmission remains low, affecting recipients from 32 donors especially when compared with the more than 14,000 donors recovered annually in the United States. The continued use of the new standard algorithm and triaging process will enhance the reproducibility of DTAC assessments and allow more robust analysis of our aggregate DTAC experience. C1 [Green, Michael] Univ Pittsburgh, Med Ctr, Div Pediat Infect Dis, Pittsburgh, PA USA. [Covington, Shandie; Taranto, Sarah] United Network Organ Sharing, Richmond, VA USA. [Wolfe, Cameron] Duke Univ, Med Ctr, Div Transplant Infect Dis, Durham, NC USA. [Bell, Walter] Univ Alabama Birmingham, Div Anat Pathol, Birmingham, AL USA. [Biggins, Scott W.] Univ Colorado, Div Gastroenterol, Aurora, CO USA. [Conti, David] Albany Med Coll, Dept Transplant Surg, Albany, NY 12208 USA. [DeStefano, G. David] Lifesharing, San Diego, CA USA. [Dominguez, Edward] Methodist Dallas Med Ctr, Div Infect Dis, Dallas, TX USA. [Ennis, Donna] Indiana Univ Hosp, Indianapolis, IN 46202 USA. [Gross, Thomas] NCI, Ctr Global Hlth, Rockville, MD USA. [Klassen-Fischer, Mary] Joint Pathol Ctr, Silver Spring, MD USA. [Kotton, Camille] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [LaPointe-Rudow, Dianne] Mt Sinai Med Ctr, New York, NY 10029 USA. [Law, Yuk] Seattle Childrens Hosp, Div Cardiac Transplant, Seattle, WA USA. [Ludrosky, Kristen] Cleveland Clin, Cleveland, OH 44106 USA. [Menegus, Marilyn] Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Morris, Michele I.] Univ Miami Hosp, Div Internal Med, Miami, FL USA. [Nalesnik, Michael A.] Univ Pittsburgh, Med Ctr, Div Transplant Pathol, Pittsburgh, PA USA. [Pavlakis, Martha] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Pruett, Timothy] Univ Minnesota, Med Ctr, Div Transplantat, Minneapolis, MN 55455 USA. [Sifri, Costi] Univ Virginia Hlth Syst, Div Infect Dis, Charlottesville, VA USA. [Kaul, Daniel] Univ Michigan, Med Ctr, Div Infect Dis, Ann Arbor, MI USA. RP Green, M (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. EM Michael.green@chp.edu FU Health Resources and Services Administration [234-2005-370011C] FX This analysis of DTAC data was supported wholly or in part by Health Resources and Services Administration contract 234-2005-370011C. NR 2 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD FEB PY 2015 VL 99 IS 2 BP 282 EP 287 DI 10.1097/TP.0000000000000584 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA CB2YH UT WOS:000349493900016 PM 25594557 ER PT J AU Bai, P Nagy, L Fodor, T Liaudet, L Pacher, P AF Bai, Peter Nagy, Lille Fodor, Tamas Liaudet, Lucas Pacher, Pal TI Poly(ADP-ribose) polymerases as modulators of mitochondrial activity SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review DE poly(ADP-ribose) polymerase; NAD(+); AMP activated kinase; Sirtuin; hypoxia-inducible factor; nuclear respiratory factor ID INDUCIBLE FACTOR-I; OXIDATIVE STRESS; SKELETAL-MUSCLE; NITRIC-OXIDE; CELL-DEATH; GLYCOHYDROLASE PARG; PARP-1; ACTIVATION; INHIBITION; SIRT1 AB Mitochondria are essential in cellular stress responses. Mitochondrial output to environmental stress is a major factor in metabolic adaptation and is regulated by a complex network of energy and nutrient sensing proteins. Activation of poly(ADP-ribose) polymerases (PARPs) has been known to impair mitochondrial function; however, our view of PARP-mediated mitochondrial dysfunction and injury has only recently fundamentally evolved. In this review, we examine our current understanding of PARP-elicited mitochondria! damage, PARP-mediated signal transduction pathways, transcription factors that interact with PARPs and govern mitochondrial biogenesis, as well as mitochondrial diseases that are mediated by PARPs. With PARP activation emerging as a common underlying mechanism in numerous pathologies, a better understanding the role of various PARPs in mitochondrial regulation may help open new therapeutic avenues. C1 [Bai, Peter] Univ Debrecen, Res Ctr Mol Med, H-4012 Debrecen, Hungary. [Bai, Peter; Nagy, Lille; Fodor, Tamas] MTA DE Lendulet Lab, Cellular Metab Res Grp, Debrecen, Hungary. [Bai, Peter; Nagy, Lille; Fodor, Tamas] Univ Debrecen, Dept Med Chem, H-4012 Debrecen, Hungary. [Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. [Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Burn Ctr, Lausanne, Switzerland. [Pacher, Pal] NIAAA, Lab Physiol Studies, Sect Oxidat Stress & Tissue Injury, NIH,DICBR, Bethesda, MD USA. RP Bai, P (reprint author), Univ Debrecen, Res Ctr Mol Med, H-4012 Debrecen, Hungary. EM baip@med.unideb.hu RI Pacher, Pal/B-6378-2008; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Bolyai; Momentum fellowship of the Hungarian Academy of Sciences; OTKA [K108308, K105872, TAMOP-4.2.2.A-11/1/KONV-2012-0025]; Intramural Research Program of NIH/NIAAA FX We would like to apologize to all the authors whose relevant work was not cited due to the space limitations of this review. This work was supported by Bolyai and the Momentum fellowship of the Hungarian Academy of Sciences, by grants from OTKA (K108308, K105872), TAMOP-4.2.2.A-11/1/KONV-2012-0025 to P.B., and by the Intramural Research Program of NIH/NIAAA to P.P. NR 87 TC 23 Z9 23 U1 1 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD FEB PY 2015 VL 26 IS 2 BP 75 EP 83 DI 10.1016/j.tem.2014.11.003 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CB6HZ UT WOS:000349729400003 PM 25497347 ER PT J AU Dineley, KT Pandya, AA Yakel, JL AF Dineley, Kelly T. Pandya, Anshul A. Yakel, Jerrel L. TI Nicotinic ACh receptors as therapeutic targets in CNS disorders SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE alpha 7 receptor; alpha 4 beta 2 receptor; nAChR; cys-loop receptor ID POSITIVE ALLOSTERIC MODULATOR; BETA-AMYLOID PEPTIDE; ALZHEIMERS ASSOCIATION WORKGROUPS; AUTISM SPECTRUM DISORDERS; HIPPOCAMPAL SYNAPTIC PLASTICITY; MILD COGNITIVE IMPAIRMENT; PLACEBO-CONTROLLED TRIAL; BASAL FOREBRAIN NEURONS; CENTRAL-NERVOUS-SYSTEM; PROOF-OF-CONCEPT AB The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the alpha 7 and alpha 4 beta 2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain. C1 [Dineley, Kelly T.] Univ Texas Med Branch, Mitchell Ctr Neurodegenerat Dis, Dept Neurol, Galveston, TX 77555 USA. [Pandya, Anshul A.] Univ Alaska Fairbanks, Coll Rural & Community Dev, Dept Biosci, Kotzebue, AK 99752 USA. [Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, DHHS, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU Intramural Research Program, NIEHS/NIH; Independent Investigator Research Grant from the Alzheimer's Association FX This work was supported by the Intramural Research Program, NIEHS/NIH to J.L.Y. and A.A.P., a kind gift to K.T.D. from J&W Mohn, and an Independent Investigator Research Grant from the Alzheimer's Association to K.T.D. NR 192 TC 64 Z9 64 U1 11 U2 55 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 FEB PY 2015 VL 36 IS 2 BP 96 EP 108 DI 10.1016/j.tips.2014.12.002 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CB6HT UT WOS:000349728800005 PM 25639674 ER PT J AU Brunoni, AR Baeken, C Machado-Vieira, R Gattaz, WF Vanderhasselt, MA AF Brunoni, Andre R. Baeken, Chris Machado-Vieira, Rodrigo Gattaz, Wagner F. Vanderhasselt, Marie-Anne TI BDNF blood levels after non-invasive brain stimulation interventions in major depressive disorder: A systematic review and meta-analysis SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE non-invasive brain stimulation; brain-derived neurotrophic factor; meta-analysis; major depressive disorder; neurotrophic factors ID TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT DEPRESSION; NEUROTROPHIC FACTOR; ELECTROCONVULSIVE-THERAPY; SYNAPTIC PLASTICITY; HEALTHY-VOLUNTEERS; PREFRONTAL CORTEX; SERUM-LEVELS; DOUBLE-BLIND; RTMS AB Objectives. To evaluate whether the antidepressant effects of novel non-invasive brain stimulation (NIBS) therapies are associated with neurotrophic effects, indexed by peripheral brain-derived neurotrophic factor (BDNF) levels. Methods. Systematic review and meta-analysis. We included trials published in PubMed/Medline from the first date available to June 2014 measuring BDNF blood levels before and after repetitive transcranial magnetic stimulation or transcranial direct current stimulation in depression. Results. Eight datasets (n = 259) were included. These studies enrolled mostly treatment-resistant depression patients, who received daily stimulation sessions on the left dorsolateral prefrontal cortex. BDNF did not increase after NIBS (Hedges' g = 0.03, 95% CI = -0.21 to 0.27), even when examining each intervention separately. Meta-regressions did not identify the influence of any clinical and demographic predictors on the outcome. Finally, Begg's funnel plot did not suggest publication bias and results were robust according to sensitivity analysis. Conclusions. Peripheral BDNF levels do not increase after NIBS in depression. Such biomarker might, therefore, not be suitable to index NIBS antidepressant response. Further trials are needed, particularly exploring non-medicated populations, performing subsequent BDNF assessments in a larger timeframe and employing more intensive NIBS treatment protocols. C1 [Brunoni, Andre R.; Machado-Vieira, Rodrigo; Gattaz, Wagner F.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM27, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Univ Hosp, Interdisciplinary Ctr Appl Neuromodulat & Clin CI, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Univ Hosp, Epidemiol Res Ctr, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, SIN, Sao Paulo, Brazil. [Baeken, Chris] Univ Ghent, Dept Psychiat & Med Psychol, B-9000 Ghent, Belgium. [Baeken, Chris] Univ Hosp UZBrussel, Dept Psychiat, Brussels, Belgium. [Machado-Vieira, Rodrigo] NIMH, NIH, Intramural Res Program, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Vanderhasselt, Marie-Anne] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. RP Brunoni, AR (reprint author), Dept & Inst Psychiatry, R Dr Ovidio Pires Campos 785,2nd floor, Sao Paulo, Brazil. EM Brunoni@usp.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Russowsky Brunoni, Andre/0000-0002-6310-3571 FU Brain & Behavior Research Foundation (NARSAD) [YI 2013]; Sao Paulo Research State Foundation [FAPESP 2012/20911-5]; National Council for Scientific and Technological Development (CNPq) [455157/2013-8]; AssociacaoBeneficenteAlzira Denise Hertzog da Silva (ABADHS); Ghent University Multidisciplinary Research Partnership "The integrative neuroscience of behavioral control" FX MAV (FWO08/PDO/168) is a postdoctoral research fellow of the Research Foundation Flanders (FWO). ARB receives Young Investigator grants from the Brain & Behavior Research Foundation (NARSAD, YI 2013), Sao Paulo Research State Foundation (FAPESP 2012/20911-5) and the National Council for Scientific and Technological Development (CNPq, 455157/2013-8). "The Laboratory of Neurosciences receives financial support from the AssociacaoBeneficenteAlzira Denise Hertzog da Silva (ABADHS)". This work was also supported by the Ghent University Multidisciplinary Research Partnership "The integrative neuroscience of behavioral control". The authors have no conflicts of interest to disclose. NR 41 TC 5 Z9 5 U1 2 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD FEB PY 2015 VL 16 IS 2 BP 114 EP 122 DI 10.3109/15622975.2014.958101 PG 9 WC Psychiatry SC Psychiatry GA CB5LZ UT WOS:000349670200005 PM 25264290 ER PT J AU Lountos, GT Cherry, S Tropea, JE Waugh, DS AF Lountos, George T. Cherry, Scott Tropea, Joseph E. Waugh, David S. TI Structural analysis of human dual-specificity phosphatase 22 complexed with a phosphotyrosine-like substrate SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE dual-specificity phosphatase 22; 4-nitrophenyl phosphate ID PROTEIN-TYROSINE PHOSPHATASES; JSP-1 INHIBITORS; RHODANINE DERIVATIVES; CRYSTAL-STRUCTURE; CATALYTIC ROLE; TARGETS; CRYSTALLOGRAPHY; VHR; PROBABILITIES; RECOGNITION AB 4-Nitrophenyl phosphate (p-nitrophenyl phosphate, pNPP) is widely used as a small molecule phosphotyrosine-like substrate in activity assays for protein tyrosine phosphatases. It is a colorless substrate that upon hydrolysis is converted to a yellow 4-nitrophenolate ion that can be monitored by absorbance at 405 nm. Therefore, the pNPP assay has been widely adopted as a quick and simple method to assess phosphatase activity and is also commonly used in assays to screen for inhibitors. Here, the first crystal structure is presented of a dual-specificity phosphatase, human dual-specificity phosphatase 22 (DUSP22), in complex with pNPP. The structure illuminates the molecular basis for substrate binding and may also facilitate the structure-assisted development of DUSP22 inhibitors. C1 [Lountos, George T.] Leidos Biomedical Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Lountos, George T.; Cherry, Scott; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM waughd@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX 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. 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. We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCI at Frederick for use of the LC/ESMS instrument. X-ray diffraction data were collected on the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-BM of the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract No. W-31-109-Eng-38. NR 47 TC 1 Z9 1 U1 1 U2 8 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD FEB PY 2015 VL 71 BP 199 EP 205 DI 10.1107/S2053230X15000217 PN 2 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CB0YN UT WOS:000349353700015 PM 25664796 ER PT J AU Kuzmina, Z Gounden, V Curtis, L Avila, D Taylor, T Baruffaldi, J Cowen, EW Naik, HB Hasni, SA Mays, JW Mitchell, S Baird, K Steinberg, SM Pavletic, SZ AF Kuzmina, Zoya Gounden, Verena Curtis, Lauren Avila, Daniele Taylor, Tiffani Baruffaldi, Judy Cowen, Edward W. Naik, Haley B. Hasni, Sarfaraz A. Mays, Jacqueline W. Mitchell, Sandra Baird, Kristin Steinberg, Seth M. Pavletic, Steven Z. TI Clinical significance of autoantibodies in a large cohort of patients with chronic graft-versus-host disease defined by NIH criteria SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGEN; BONE-MARROW TRANSPLANTATION; REFRACTORY CHRONIC GVHD; B-CELL; RITUXIMAB; SEVERITY; BAFF; MULTICENTER; CORRELATE AB There is an unmet need for identifying new clinical biomarkers in chronic Graft-versus-Host-disease (cGVHD) suitable for diagnosis and disease monitoring. Circulating autoantibodies represent an ongoing immune response and suggest a pathogenic role for B cells in cGVHD. Autoantibodies could be useful markers of cGVHD disease activity, severity, or organ specificity; however, their clinical utility is not established. The focus of this study was to determine the incidence and associations of a broad array of clinical autoantibodies with cGVHD manifestations in a large patient cohort characterized by NIH criteria. A panel of 21 circulating antibodies commonly used in clinical medicine was tested in 280 cGVHD patients (70% severe) enrolled in a cross-sectional prospective natural history study. Median cGVHD duration was two years. Patients with circulating autoantibodies (62%) had significantly higher levels of IgM (P<0.0001), IgG (P<0.0001), and IgA (P=0.001), elevated uric acid (P=0.008) and total protein (P=0.0004), and higher numbers of CD3+ (P=0.002), CD4+ (P=0.001), CD8+ (P=0.023) T cells, and CD19+ B cells (P<0.0001). Multiple antibodies were detected in 35% of patients. Prior rituximab therapy (n=66) was associated with reduced presence of autoantibodies (48 vs. 66% P=0.01). Only oral cGVHD was significantly associated with presence of autoantibodies in this study (P=0.028). No significant associations were found between cGVHD activity and severity, and presence of autoantibodies. Circulating autoantibodies are common in patients with advanced cGVHD. Their presence is associated with better quantitative immunologic reconstitution but does not have utility as a clinical biomarker of cGVHD. Am. J. Hematol. 90:114-119, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Kuzmina, Zoya; Curtis, Lauren; Avila, Daniele; Taylor, Tiffani; Baruffaldi, Judy; Pavletic, Steven Z.] NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kuzmina, Zoya] Evangel Hosp, Dept Internal Med, Vienna, Austria. [Gounden, Verena] NCI, Dept Lab Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.; Naik, Haley B.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Hasni, Sarfaraz A.] NIAMSD, NCI, NIH, Bethesda, MD USA. [Mays, Jacqueline W.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Mitchell, Sandra] NIH, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD USA. RP Kuzmina, Z (reprint author), NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Zoya.Kuzmina@gmail.com NR 46 TC 3 Z9 5 U1 0 U2 4 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 FEB PY 2015 VL 90 IS 2 BP 114 EP 119 DI 10.1002/ajh.23885 PG 6 WC Hematology SC Hematology GA CA4AL UT WOS:000348846600011 PM 25363867 ER PT J AU Keppler-Noreuil, KM Rios, JJ Parker, VER Semple, RK Lindhurst, MJ Sapp, JC Alomari, A Ezaki, M Dobyns, W Biesecker, LG AF Keppler-Noreuil, Kim M. Rios, Jonathan J. Parker, Victoria E. R. Semple, Robert K. Lindhurst, Marjorie J. Sapp, Julie C. Alomari, Ahmad Ezaki, Marybeth Dobyns, William Biesecker, Leslie G. TI PIK3CA-Related Overgrowth Spectrum (PROS): Diagnostic and Testing Eligibility Criteria, Differential Diagnosis, and Evaluation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE somatic mosaicism; PIK3CA gene; fibroadipose overgrowth; segmental overgrowth; macrodactyly; CLOVES syndrome; PIK3CA-Related Overgrowth Spectrum (PROS) ID ACTIVATING MUTATIONS; PROTEUS-SYNDROME; CLOVES SYNDROME; MEGALENCEPHALY SYNDROMES; EPIDERMAL-NEVI; PIK3CA CAUSE; GENE; MALFORMATIONS; AKT3 AB Somatic activating mutations in the phosphatidylinositol-3-kinase/AKT/mTOR pathway underlie heterogeneous segmental overgrowth phenotypes. Because of the extreme differences among patients, we sought to characterize the phenotypic spectrum associated with different genotypes and mutation burdens, including a better understanding of associated complications and natural history. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Fibroadipose hyperplasia or Overgrowth (FAO), Hemihyperplasia Multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly, Fibroadipose Infiltrating Lipomatosis, and the related megalencephaly syndromes, Megalencephaly-Capillary Malformation (MCAP or M-CM) and Dysplastic Megalencephaly (DMEG). A workshop was convened at the National Institutes of Health (NIH) to discuss and develop a consensus document regarding diagnosis and treatment of patients with PIK3CA-associated somatic overgrowth disorders. Participants in the workshop included a group of researchers from several institutions who have been studying these disorders and have published their findings, as well as representatives from patient-advocacy and support groups. The umbrella term of PIK3CA-Related Overgrowth Spectrum (PROS) was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions. Key clinical diagnostic features and criteria for testing were proposed, and testing approaches summarized. Preliminary recommendations for a uniform approach to assessment of overgrowth and molecular diagnostic testing were determined. Future areas to address include the surgical management of overgrowth tissue and vascular anomalies, the optimal approach to thrombosis risk, and the testing of potential pharmacologic therapies. (c) 2014 Wiley Periodicals, Inc. C1 [Keppler-Noreuil, Kim M.; Lindhurst, Marjorie J.; Sapp, Julie C.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rios, Jonathan J.] Univ Texas SW Med Ctr Dallas, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Eugene McDermott Ctr Human Growth & Dev, Texas Scottish Rite Hosp Children,Dept Pediat, Dallas, TX 75390 USA. [Rios, Jonathan J.; Ezaki, Marybeth] Univ Texas SW Med Ctr Dallas, Dept Orthopaed Surg, Dallas, TX 75390 USA. [Parker, Victoria E. R.; Semple, Robert K.] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Cambridge, MA USA. [Alomari, Ahmad] Boston Childrens Hosp, Div Vasc & Intervent Radiol, Boston, MA USA. [Alomari, Ahmad] Harvard Univ, Sch Med, Boston, MA USA. [Dobyns, William] Univ Washington, Seattle, WA 98195 USA. RP Keppler-Noreuil, KM (reprint author), NHGRI, NIH, 49 Convent,4A83, Bethesda, MD 20892 USA. EM kim.keppler-noreuil@nih.gov OI Semple, Robert/0000-0001-6539-3069; Dobyns, William/0000-0002-7681-2844 FU National Human Genome Research Institute; UK: Wellcome Trust, Clinical Research Training Fellowship, UK national Institute for Health Research (NIHR) Cambridge Biomedical Research Centre FX Grant sponsors: National Human Genome Research Institute; UK: Wellcome Trust, Clinical Research Training Fellowship, UK national Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. NR 35 TC 35 Z9 35 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2015 VL 167 IS 2 BP 287 EP 295 DI 10.1002/ajmg.a.36836 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CA3ZJ UT WOS:000348843600006 PM 25557259 ER PT J AU Kuhn, JH Durrwald, R Bao, YM Briese, T Carbone, K Clawson, AN deRisi, JL Garten, W Jahrling, PB Kolodziejek, J Rubbenstroth, D Schwemmle, M Stenglein, M Tomonaga, K Weissenbock, H Nowotny, N AF Kuhn, Jens H. Duerrwald, Ralf Bao, Yiming Briese, Thomas Carbone, Kathryn Clawson, Anna N. deRisi, Joseph L. Garten, Wolfgang Jahrling, Peter B. Kolodziejek, Jolanta Rubbenstroth, Dennis Schwemmle, Martin Stenglein, Mark Tomonaga, Keizo Weissenboeck, Herbert Nowotny, Norbert TI Taxonomic reorganization of the family Bornaviridae SO ARCHIVES OF VIROLOGY LA English DT Article ID BORNA-DISEASE-VIRUS; PROVENTRICULAR DILATATION DISEASE; STRAND RNA VIRUS; AVIAN BORNAVIRUS; STANDARDIZED NOMENCLATURE; PSITTACINE BIRDS; SPECIES LEVEL; IDENTIFICATION; VARIANTS; GENOTYPE AB Knowledge of bornaviruses has expanded considerably during the last decade. A possible reservoir of mammalian Borna disease virus has been identified, divergent bornaviruses have been detected in birds and reptiles, and endogenous bornavirus-like elements have been discovered in the genomes of vertebrates of several species. Previous sequence comparisons and alignments have indicated that the members of the current family Bornaviridae are phylogenetically diverse and are not adequately classified in the existing bornavirus taxonomy supported by the International Committee on Taxonomy of Viruses (ICTV). We provide an update of these analyses and describe their implications for taxonomy. We propose retaining the family name Bornaviridae and the genus Bornavirus but reorganizing species classification. PAirwise Sequence Comparison (PASC) of bornavirus genomes and Basic Local Alignment Search Tool (BLAST) comparison of genomic and protein sequences, in combination with other already published phylogenetic analyses and known biological characteristics of bornaviruses, indicate that this genus should include at least five species: Mammalian 1 bornavirus (classical Borna disease virus and divergent Borna disease virus isolate No/98), Psittaciform 1 bornavirus (avian/psittacine bornaviruses 1, 2, 3, 4, 7), Passeriform 1 bornavirus (avian/canary bornaviruses C1, C2, C3, LS), Passeriform 2 bornavirus (estrildid finch bornavirus EF), and Waterbird 1 bornavirus (avian bornavirus 062(CG)). This classification is also in line with biological characteristics of these viruses and their vertebrate hosts. A snake bornavirus, proposed to be named Loveridge's garter snake virus 1, should be classified as a member of an additional species (Elapid 1 bornavirus), unassigned to a genus, in the family Bornaviridae. Avian bornaviruses 5, 6, MALL, and another "reptile bornavirus" ("Gaboon viper virus") should stay unclassified until further information becomes available. Finally, we propose new virus names and abbreviations when necessary to achieve clear differentiation and unique identification. C1 [Kuhn, Jens H.; Clawson, Anna N.; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, Ft Detrick, MD 20884 USA. [Duerrwald, Ralf] IDT Biol GmbH, Dessau Rosslau, Germany. [Bao, Yiming] NIH, Informat Engn Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Briese, Thomas] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY USA. [Carbone, Kathryn] NIH, Bethesda, MD 20892 USA. [deRisi, Joseph L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [deRisi, Joseph L.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [deRisi, Joseph L.] Univ Calif San Francisco, Dept Microbiol, San Francisco, CA 94143 USA. [Garten, Wolfgang] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [Kolodziejek, Jolanta; Nowotny, Norbert] Univ Vet Med Vienna, Dept Pathobiol, Viral Zoonoses Emerging & Vector Borne Infect Grp, Inst Virol, A-1210 Vienna, Austria. [Rubbenstroth, Dennis; Schwemmle, Martin] Univ Med Ctr Freiburg, Inst Virol, Freiburg, Germany. [Stenglein, Mark] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Tomonaga, Keizo] Kyoto Univ, Inst Virus Res, Kyoto 606, Japan. [Weissenboeck, Herbert] Univ Vet Med Vienna, Dept Pathobiol, Inst Pathol & Forens Vet Med, A-1210 Vienna, Austria. [Nowotny, Norbert] Sultan Qaboos Univ, Dept Microbiol & Immunol, Coll Med & Hlth Sci, Muscat, Oman. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, B-8200 Res Plaza, Ft Detrick, MD 20884 USA. EM kuhnjens@mail.nih.gov; Norbert.Nowotny@vetmeduni.ac.at RI Stenglein, Mark/E-3541-2017; OI Stenglein, Mark/0000-0002-0993-813X; Kuhn, Jens H./0000-0002-7800-6045 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [HHSN272200700016I]; National Institutes of Health, National Library of Medicine FX We would like to thank Laura Bollinger and Jiro Wada of the IRF-Frederick for critically editing the manuscript and creating/editing figures. JHK performed this work as an employee of Tunnell Government Services, Inc., and ANC, as the owner of Logos Consulting, Inc., both subcontractors to Battelle Memorial Institute under its prime contract with the National Institutes of Health/National Institute of Allergy and Infectious Diseases, under Contract No. HHSN272200700016I. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (YB). NR 65 TC 22 Z9 23 U1 2 U2 25 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 FEB PY 2015 VL 160 IS 2 BP 621 EP 632 DI 10.1007/s00705-014-2276-z PG 12 WC Virology SC Virology GA CB2CE UT WOS:000349433500042 PM 25449305 ER PT J AU Maslak, E Zabielski, P Kochan, K Kus, K Jasztal, A Sitek, B Proniewski, B Wojcik, T Gula, K Kij, A Walczak, M Baranska, M Chabowski, A Holland, RJ Saavedra, JE Keefer, LK Chlopicki, S AF Maslak, Edyta Zabielski, Piotr Kochan, Kamila Kus, Kamil Jasztal, Agnieszka Sitek, Barbara Proniewski, Bartosz Wojcik, Tomasz Gula, Katarzyna Kij, Agnieszka Walczak, Maria Baranska, Malgorzata Chabowski, Adrian Holland, Ryan J. Saavedra, Joseph E. Keefer, Larry K. Chlopicki, Stefan TI The liver-selective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Nitric oxide; Hepatoprotection; Liver steatosis; Glucose tolerance; Fatty acid metabolism ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; CONTROLLED-TRIAL; IN-VIVO; NONALCOHOLIC STEATOHEPATITIS; MITOCHONDRIAL BIOGENESIS; HEPATIC MICROCIRCULATION; INDUCED HEPATOTOXICITY; INSULIN-RESISTANCE; L-ARGININE AB Background and purpose: There is an unmet medical need for novel NAFLD treatments. Here we have examined the effects of liver-selective NO donor (V-PYRRO/NO) as compared with metformin on hepatic steatosis and glucose tolerance in mice fed high fat diet. Material and methods: Effects of V-PYRRO/NO (5 mg kg(-1)) or metformin (616 mg kg(-1)) were examined in C57BL/6J mice fed high fat diet (HF, 60 kcal% fat). Quantitative determination of steatosis, liver fatty acid composition and western blot analysis of selected proteins involved in mitochondrial biogenesis, fatty acid de nova synthesis and oxidation, triacylglycerols and cholesterol transport from the liver were performed. Liver NO and nitrate concentration and blood biochemistry were also analyzed. Results: V-PYRRO/NO and metformin reduced liver steatosis with simultaneous reduction of total liver triacylglycerols, diacylglycerols and ceramides fraction and reversed HF-induced decrease in UFA/SFA ratio. V-PYRRO/NO substantially improved postprandial glucose tolerance, while the effect of metformin was modest and more pronounced on HOMA IR index. The anti-steatotic mechanism of V-PYRRO/NO was dependent on NO release, differed from that of metformin and involved improved glucose tolerance and inhibition of de novo fatty acid synthesis by Akt activation and ACC phosphorylation. In turn, major mechanism of metformin action involved increased expression of proteins implicated in mitochondrial biogenesis and metabolism (PGC-1 alpha, PPAR alpha, COX IV, cytochrome c, HADHSC). Conclusions: V-PYRRO/NO acts as a liver-specific NO donor prodrug affording pronounced anti-steatotic effects and may represent an efficient, mechanistically novel approach to prevent liver steatosis and insulin resistance. (C) 2015 Elsevier Inc. All rights reserved. C1 [Maslak, Edyta; Kochan, Kamila; Kus, Kamil; Jasztal, Agnieszka; Sitek, Barbara; Proniewski, Bartosz; Wojcik, Tomasz; Gula, Katarzyna; Kij, Agnieszka; Walczak, Maria; Baranska, Malgorzata; Chlopicki, Stefan] Jagiellonian Univ, Jagiellonian Ctr Expt Therapeut, PL-30348 Krakow, Poland. [Chlopicki, Stefan] Jagiellonian Univ, Coll Med, Chair Pharmacol, Dept Expt Pharmacol, PL-31531 Krakow, Poland. [Zabielski, Piotr; Chabowski, Adrian] Med Univ Bialystok, Dept Physiol, PL-15222 Bialystok, Poland. [Kus, Kamil; Walczak, Maria] Jagiellonian Univ, Coll Med, Dept Pharmacokinet & Phys Pharm, PL-30688 Krakow, Poland. [Kochan, Kamila; Baranska, Malgorzata] Jagiellonian Univ, Fac Chem, PL-30060 Krakow, Poland. [Holland, Ryan J.; Keefer, Larry K.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Saavedra, Joseph E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Chlopicki, S (reprint author), Jagiellonian Univ, Jagiellonian Ctr Expt Therapeut, Bobrzynskiego 14, PL-30348 Krakow, Poland. EM edyta.maslak@jcet.eu; piotrz@umb.edu.pl; kochan@chemia.uj.edu.pl; kamil.kus@jcet.eu; agnieszka.jasztal@jcet.eu; barbara.sitek@jcet.eu; bartosz.proniewski@jcet.eu; tomasz.wojcik@jcet.eu; katarzyna.gula@jcet.eu; agnieszka.kij@jcet.eu; maria.walczak@jcet.eu; baranska@chemia.uj.edu.pl; adrian@umb.edu.pl; hollandrj@mail.nih.gov; saavedjo@mail.nih.gov; keeferl@mail.nih.gov; stefan.chlopicki@jcet.eu RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU European Union [POIG.01.01.02-00-069/09]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by European Union from the resources of the European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, No. POIG.01.01.02-00-069/09), and partially by federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN26120080001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 57 TC 4 Z9 4 U1 2 U2 13 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 FEB 1 PY 2015 VL 93 IS 3 BP 389 EP 400 DI 10.1016/j.bcp.2014.12.004 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CB2AP UT WOS:000349429400014 PM 25534988 ER PT J AU Leijnse, JNAL Hallett, M Sonneveld, GJ AF Leijnse, J. N. A. L. Hallett, M. Sonneveld, G. J. TI A multifactorial conceptual model of peripheral neuromusculoskeletal predisposing factors in task-specific focal hand dystonia in musicians: etiologic and therapeutic implications SO BIOLOGICAL CYBERNETICS LA English DT Article DE Hand; Biomechanics; Control; Focal dystonia; Overuse; Musicians ID FLEXOR DIGITORUM PROFUNDUS; MEASURING FORCE TRANSFERS; MULTI-FINGER TASKS; WRITERS CRAMP; ANATOMICAL RESTRICTIONS; TRIGGERING FACTORS; OVERUSE SYNDROME; MOTOR CORTEX; DEEP FLEXORS; BRAIN AB A model is presented showing how peripheral factors may cause a process of movement adaptation that leads to task-specific focal hand dystonia in musicians (FHDM). To acquire a playing technique, the hand must find effective and physiologically sustainable movements within a complex set of functional demands and anatomic, ergonomic, and physiological constraints. In doing so, individually discriminating constraints may become effective, such as limited anatomic independence of finger muscles/tendons, limited joint ranges of motion, or (subclinical) neuromusculoskeletal defects. These factors may, depending on the instrument-specific playing requirements, compromise or exclude functional playing movements. The controller (i.e., the brain) then needs to develop alternative motions to execute the task, which is called compensation. We hypothesize that, if this compensation process does not converge to physiologically sustainable muscle activation patterns that satisfy all constraints, compensation could increase indefinitely under the pressure of practice. Dystonic symptoms would become manifest when overcompensation occurs, resulting in motor patterns that fail in proper task execution. The model presented in this paper only concerns the compensatory processes preceding such overcompensations and does not aim to explain the nature of the dystonic motions themselves. While the model considers normal learning processes in the development of compensations, neurological predispositions could facilitate developing overcompensations or further abnormal motor programs. The model predicts that if peripheral factors are involved, FHDM symptoms would be preceded by long-term gradual changes in playing movements, which could be validated by prospective studies. Furthermore, the model implies that treatment success might be enhanced by addressing the conflict between peripheral factors and playing tasks before decompensating/retraining the affected movements. C1 [Leijnse, J. N. A. L.] Univ Libre Bruxelles, Fac Sci Appl, Dept Bio Electro & Mech Syst BEAMS, B-1050 Brussels, Belgium. [Leijnse, J. N. A. L.] Univ Libre Bruxelles, Erasme Univ Hosp, Dept Orthoped & Traumatol, B-1050 Brussels, Belgium. [Hallett, M.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Sonneveld, G. J.] Bethesda Hosp, Hoogeveen, Netherlands. RP Leijnse, JNAL (reprint author), Univ Libre Bruxelles, Fac Sci Appl, Dept Bio Electro & Mech Syst BEAMS, Av Fr Roosevelt 50, B-1050 Brussels, Belgium. EM jleijn@yahoo.com FU Dystonia Medical Research Foundation, Chicago, IL; University of Louisville (IRIG-MRG grant), Louisville, KY, USA; Universite Libre de Bruxelles, Brussels, Belgium; NINDS Intramural Program FX The authors thank J. E. Bonte, MD, J. C. Van der Meulen, MD, PhD, J. M. F. Landsmeer, MD, PhD, C. W. Spoor, PhD, J. C. Snijders, PhD, A. B. M. Rietveld, MD, A. Gupta, MD, N. Campbell-Kyureghyan, PhD, P. M. Quesada, PhD, W. P. Hnat, PhD, G. Prater, PhD, P. Mathys, PhD, A. Delchambre, PhD, and F. Schuind, MD, PhD, for their support. This paper is part of the study 'Anatomical variations predisposing to focal dystonia in the musicians' hand', supported by the Dystonia Medical Research Foundation, Chicago, IL (http://www.dystonia-foundation.org), the University of Louisville (IRIG-MRG grant), Louisville, KY, USA, and the Universite Libre de Bruxelles, Brussels, Belgium. Dr. Hallett is supported by the NINDS Intramural Program. NR 83 TC 4 Z9 4 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-1200 EI 1432-0770 J9 BIOL CYBERN JI Biol. Cybern. PD FEB PY 2015 VL 109 IS 1 BP 109 EP 123 DI 10.1007/s00422-014-0631-5 PG 15 WC Computer Science, Cybernetics; Neurosciences SC Computer Science; Neurosciences & Neurology GA CB1RN UT WOS:000349405800008 PM 25323627 ER PT J AU Ali, SA Steinberg, SM Mossoba, M Rimando, J Rowley, S Donato, ML Camphausen, K Sigal, G Hakim, F Gress, R Halverson, D Fowler, D AF Ali, Syed Abbas Steinberg, Seth M. Mossoba, Miriam Rimando, Joseph Rowley, Scott Donato, Michele L. Camphausen, Kevin Sigal, George Hakim, Fran Gress, Ronald Halverson, David Fowler, Daniel TI Plasma IL-7 and IL-15 Levels Vary Greatly after Low-Intensity Conditioning and May be Associated with Clinical Outcome in Recipients of High-Dose Sirolimus GVHD Prophylaxis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Ali, Syed Abbas] NCI, Expt Transplant & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Rockville, MD USA. [Mossoba, Miriam] NCI, ETIB, Bethesda, MD 20892 USA. [Rimando, Joseph] NIH, Med Res Scholars Program, Bethesda, MD 20892 USA. [Rowley, Scott] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sigal, George] Meso Scale Diagnost, Gaithersburg, MD USA. [Hakim, Fran; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Halverson, David] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 378 BP S266 EP S267 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000380 ER PT J AU Anandi, P Duhavin, N Jain, NA Chokshi, PD Anand, A Le, RQ Ito, S Barrett, AJ Battiwalla, M AF Anandi, Prathima Duhavin, Neil Jain, Natasha A. Chokshi, Puja D. Anand, Ankit Le, Robert Q. Ito, Sawa Barrett, A. John Battiwalla, Minoo TI Blood Stream Infection Is Frequent during Conditioning but Does Not Impact Allogeneic Transplant Outcomes in the Modern Era SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Anandi, Prathima; Duhavin, Neil; Jain, Natasha A.; Chokshi, Puja D.; Anand, Ankit; Le, Robert Q.; Ito, Sawa; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 380 BP S268 EP S268 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000382 ER PT J AU Anandi, P Jain, NA Wu, C Tian, X Pophali, PA Koklanaris, E Dunavin, N Ito, S Le, RQ Savani, BN Barrett, AJ Battiwalla, M AF Anandi, Prathima Jain, Natasha A. Wu, Colin Tian, Xin Pophali, Priyanka A. Koklanaris, Eleftheria Dunavin, Neil Ito, Sawa Le, Robert Q. Savani, Bipin N. Barrett, A. John Battiwalla, Minoo TI Bone Mineral Density (BMD) Improves in Survivors in Their Second Decade Post-Allogeneic Stem Cell Transplantation and Is Influenced By Body Mass Index (BMI) and Age SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Anandi, Prathima; Jain, Natasha A.; Pophali, Priyanka A.; Koklanaris, Eleftheria; Dunavin, Neil; Ito, Sawa; Le, Robert Q.; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Colin; Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. RI Pophali, Priyanka/P-8646-2016 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 213 BP S171 EP S171 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000218 ER PT J AU Buxbaum, NP Farthing, DE Boehrer, AC Kapoor, V Castro, E Bouladoux, NJ Swan, G Telford, W Eckhaus, M Belkaid, Y Bosselut, R Gress, R AF Buxbaum, Nataliya Prokopenko Farthing, Donald Eugene Boehrer, Andrea Carpenter Kapoor, Veena Castro, Ehydel Bouladoux, Nicolas Jean Swan, Gregory Telford, William Eckhaus, Michael Belkaid, Yasmine Bosselut, Remy Gress, Ronald TI T Regulatory Cell Kinetics Are Altered in a Target Organ of Chronic GVHD, Resulting in a Low T Regulatory to T Effector Memory Cell Ratio SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Buxbaum, Nataliya Prokopenko; Farthing, Donald Eugene; Kapoor, Veena; Telford, William] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Boehrer, Andrea Carpenter; Bosselut, Remy] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Castro, Ehydel; Swan, Gregory] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas Jean; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael] NCI, Diagnost & Res Serv Branch, NIH, Bethesda, MD 20892 USA. [Gress, Ronald] NCI, Co Senior Expt Transplantat & Immunol Branch, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 474 BP S327 EP S328 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000476 ER PT J AU Chakrabarty, JH Nguyen, CT Havlicek, JP Vesely, SK Lindenberg, L Adler, S Blacklock-Schuver, BAJ Kurdziel, K Lin, F Avila, D Selby, GB Mann, J Hsu, J Chai, A Epstein, RB Duong, NQT Li, SB Krauss, T Hopps, S Pham, T Bollard, CM Choyke, P Gress, R Williams, KM AF Chakrabarty, Jennifer Holter Nguyen, Chuong T. Havlicek, Joseph P. Vesely, Sara K. Lindenberg, Liza Adler, Steve Blacklock-Schuver, Bazetta A. J. Kurdziel, Karen Lin, Frank Avila, Daniele Selby, George B. Mann, Jennifer Hsu, Jennifer Chai, Amy Epstein, Robert B. Duong, Ngoc Quyen T. Li, Shibo Krauss, Teresa Hopps, Sarah Pham, Tom Bollard, Catherine M. Choyke, Peter Gress, Ronald Williams, Kirsten M. TI Novel Imaging Analysis of the Marrow Compartment after Myeloablative HSCT Reveals the Kinetics and Degree of Myeloablation and Cell Recovery SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Chakrabarty, Jennifer Holter] Univ Oklahoma, Peggy & Charles Stephenson Canc Ctr, Oklahoma City, OK USA. [Nguyen, Chuong T.] Univ Oklahoma, Co First Sch Elect & Comp Engn, Norman, OK 73019 USA. [Havlicek, Joseph P.] Univ Oklahoma, Sch Elect & Comp Engn, Norman, OK 73019 USA. [Vesely, Sara K.] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK USA. [Lindenberg, Liza; Adler, Steve; Kurdziel, Karen; Choyke, Peter] NIH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Blacklock-Schuver, Bazetta A. J.; Avila, Daniele; Mann, Jennifer; Hsu, Jennifer; Chai, Amy] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Lin, Frank] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. [Selby, George B.; Epstein, Robert B.; Duong, Ngoc Quyen T.; Li, Shibo; Krauss, Teresa; Pham, Tom] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK USA. [Hopps, Sarah] Univ Oklahoma, Oklahoma City, OK USA. [Bollard, Catherine M.] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA. [Gress, Ronald] NCI, Co Senior Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Williams, Kirsten M.] NCI, CNMC, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 462 BP S319 EP S320 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000464 ER PT J AU Chang, K Merideth, M Stratton, P AF Chang, Katherine Merideth, Melissa Stratton, Pamela TI Women's Health and Hormonal Treatment Options for Therapeutic Amenorrhea and Contraception during the Peri-Transplant Period SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Chang, Katherine] Northwestern, Obstet & Gynecol, Chicago, IL USA. [Merideth, Melissa] Natl Human Genome Inst, Bethesda, MD USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 FEB PY 2015 VL 21 IS 2 SU 1 MA 236 BP S183 EP S183 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000240 ER PT J AU Chokshi, PD Anandi, P Jain, NA Dunavin, N Le, RQ Ito, S Barrett, AJ Battiwalla, M AF Chokshi, Puja D. Anandi, Prathima Jain, Natasha A. Dunavin, Neil Le, Robert Q. Ito, Sawa Barrett, A. John Battiwalla, Minoo TI Minor ABO Incompatibility Does Not Impact Non-Relapse Mortality in T-Cell Depleted HLA-Matched Sibling Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Chokshi, Puja D.; Anandi, Prathima; Jain, Natasha A.; Dunavin, Neil; Le, Robert Q.; Ito, Sawa; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 391 BP S276 EP S277 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000393 ER PT J AU Curtis, LM Cantilena, C Yau, YY Chinn, T Hsu, J Pirsl, F Baruffaldi, JL Hakim, F Fowler, D Gress, R Pavletic, SZ AF Curtis, Lauren M. Cantilena, Cathy Yau, Yu Ying Chinn, Tracey Hsu, Jennifer Pirsl, Filip Baruffaldi, Judy L. Hakim, Fran Fowler, Daniel Gress, Ronald Pavletic, Steven Z. TI Leukapheresis Safely and Effectively Yields Lymphocyte Populations Sufficient for Chronic Gvhd Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Curtis, Lauren M.] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Curtis, Lauren M.; Chinn, Tracey; Hsu, Jennifer; Pirsl, Filip; Baruffaldi, Judy L.; Hakim, Fran; Fowler, Daniel; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cantilena, Cathy; Yau, Yu Ying] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Gress, Ronald] NCI, Co Senior Expt Transplantat & Immunol Branch, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 476 BP S328 EP S329 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000478 ER PT J AU Curtis, LM Datiles, MB Steinberg, SM Bishop, RJ Cowen, EW Mays, J Pirsl, F Baruffaldi, JL Hsu, J Mitchell, SA Pavletic, SZ AF Curtis, Lauren M. Datiles, Manuel B., III Steinberg, Seth M. Bishop, Rachel J. Cowen, Edward W. Mays, Jacqueline Pirsl, Filip Baruffaldi, Judy L. Hsu, Jennifer Mitchell, Sandra A. Pavletic, Steven Z. TI Predictive Models Using NIH Criteria and Clinical Characteristics Define Diagnosis, Disease Activity and Risk Factors for Chronic Ocular Graft-Versus Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Curtis, Lauren M.; Pirsl, Filip; Baruffaldi, Judy L.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Datiles, Manuel B., III; Bishop, Rachel J.] NEI, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Mays, Jacqueline] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Hsu, Jennifer] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 475 BP S328 EP S328 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000477 ER PT J AU Halverson, D Mossoba, M Hansen, B Schuver, BB Steinberg, SM Hakim, F Ali, SA Kurlander, R Gea-Banacloche, J Hickstein, D Pavletic, SZ Khuu, H Stroncek, DF Bishop, MR Gress, R Fowler, D AF Halverson, David Mossoba, Miriam Hansen, Brenna Schuver, Bazetta Blacklock Steinberg, Seth M. Hakim, Fran Ali, Syed Abbas Kurlander, Roger Gea-Banacloche, Juan Hickstein, Dennis Pavletic, Steven Z. Khuu, Hanh Stroncek, David F. Bishop, Michael R. Gress, Ronald Fowler, Daniel TI Pilot Clinical Trial of Lymphocyte-Selective Pentostatin Plus Cyclophosphamide Conditioning, High Dose Sirolimus and Pre-Emptive DLI with Rapamycin-Resistant Donor CD4+T Cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Halverson, David; Hansen, Brenna; Schuver, Bazetta Blacklock; Gea-Banacloche, Juan; Hickstein, Dennis] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Mossoba, Miriam] NCI, ETIB, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hakim, Fran; Pavletic, Steven Z.; Fowler, Daniel] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Ali, Syed Abbas] NCI, Expt Transplantat & Immunol Branch, NIH, Little Rock, AR USA. [Kurlander, Roger] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Khuu, Hanh] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Stroncek, David F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Chicago, IL 60637 USA. [Gress, Ronald] NCI, Expt Transplantat & Immunol Branch, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 409 BP S286 EP S288 PG 3 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000411 ER PT J AU Hanley, PJ Melenhorst, J Nikiforow, S Scheinberg, P Cruz, R Krance, RA Leung, K Martinez, C Heslop, HE Rooney, CM Barrett, AJ Shpall, EJ Bollard, CM AF Hanley, Patrick J. Melenhorst, Jan Nikiforow, Sarah Scheinberg, Phillip Cruz, Russell Krance, Robert A. Leung, Kathryn Martinez, Caridad Heslop, Helen E. Rooney, Cliona M. Barrett, A. John Shpall, Elizabeth J. Bollard, Catherine M. TI CMVpp65-Specific T Cells Generated from Naive T Cell Populations Recognize Atypical but Not Canonical Epitopes and May Be Protective In Vivo SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Hanley, Patrick J.] Childrens Natl Med Ctr, CETI, Washington, DC 20010 USA. [Melenhorst, Jan] NHLBI, NIH, Bethesda, MD 20892 USA. [Nikiforow, Sarah] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Scheinberg, Phillip] Hosp Beneficencia Portuguesa Sao Paulo, Antonio Ermirio de Moraes Oncol Ctr, Sao Paulo, Brazil. [Cruz, Russell] Childrens Natl Med Ctr, Sheikh Zayad Inst, Washington, DC 20010 USA. [Krance, Robert A.] Houston Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX USA. [Krance, Robert A.] Texas Childrens Hosp, Houston, TX 77030 USA. [Leung, Kathryn; Martinez, Caridad] Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Heslop, Helen E.; Rooney, Cliona M.] Houston Methodist Hosp, Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX USA. [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bollard, Catherine M.] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 33 BP S51 EP S52 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000038 ER PT J AU Heimall, J Logan, BR Cowan, MJ Notarangelo, LD Griffith, LM Puck, J Parikh, S O'Reilly, RJ Pai, SY Hanson, IC Martinez, C Pulsipher, MA Kapoor, N Goldman, F Kletzel, M Filipovich, L Cuvellier, G Thakar, M Burroughs, L Knudsen, A Connelly, JA Quigg, TC Smith, AR Sullivan, K Loechelt, BJ Gillio, AP Haddad, E Kohn, DB Fleisher, T Shearer, W Dvorak, CC Buckley, RH AF Heimall, Jennifer Logan, Brent R. Cowan, Morton J. Notarangelo, Luigi D. Griffith, Linda M. Puck, Jennifer Parikh, Suhag O'Reilly, Richard J. Pai, Sung-Yun Hanson, Imelda C. Martinez, Caridad Pulsipher, Michael A. Kapoor, Neena Goldman, Frederick Kletzel, Morris Filipovich, Lisa Cuvellier, Geoff Thakar, Monica Burroughs, Lauri Knudsen, Alan Connelly, James A. Quigg, Troy C. Smith, Angela R. Sullivan, Kathleen Loechelt, Brett J. Gillio, Alfred P. Haddad, Elie Kohn, Donald B. Fleisher, Thomas Shearer, William Dvorak, Christopher C. Buckley, Rebecca H. TI Early Hematopoietic Cell Transplant (HCT) Outcomes of Children with Severe Combined Immunodeficiency Disease (SCID): The First Seventy Four Patients of the Primary Immune Deficiency Treatment Consortium (PIDTC) Prospective Study 6901 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Heimall, Jennifer] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Cowan, Morton J.; Puck, Jennifer] UCSF Benioff Childrens Hosp, Pediat Allergy Immunol & Blood & Marrow Transplan, San Francisco, CA USA. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Primary Immunodeficiencies, Boston, MA USA. [Griffith, Linda M.] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Parikh, Suhag] Duke Univ, Med Ctr, Pediat BMT Program, Durham, NC USA. [O'Reilly, Richard J.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Pai, Sung-Yun] Boston Childrens Hosp, Boston, MA USA. [Hanson, Imelda C.; Shearer, William] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Martinez, Caridad] Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Pulsipher, Michael A.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Kapoor, Neena] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90027 USA. [Goldman, Frederick] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Kletzel, Morris] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Filipovich, Lisa] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Cuvellier, Geoff] CC Manitoba, Winnipeg, MB, Canada. [Thakar, Monica] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Burroughs, Lauri] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Knudsen, Alan] St Louis Univ, St Louis, MO 63103 USA. [Connelly, James A.] Univ Michigan, Pediat Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Quigg, Troy C.] Texas Transplant Inst, San Antonio, TX USA. [Smith, Angela R.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Sullivan, Kathleen] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Loechelt, Brett J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gillio, Alfred P.] Hackensack Univ, Med Ctr, Inst Pediat Canc & Blood Disorders, Hackensack, NJ USA. [Haddad, Elie] Ste Justine Hosp, Montreal, PQ, Canada. [Kohn, Donald B.] Univ Calif Los Angeles, Div Hematol Oncol, Mattel Childrens Hosp, Los Angeles, CA USA. [Fleisher, Thomas] NIH, Lab Host Def, Bethesda, MD 20892 USA. [Dvorak, Christopher C.] Univ San Francisco, San Francisco, CA 94117 USA. [Buckley, Rebecca H.] Duke Univ, Med Ctr, Durham, NC USA. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 NR 0 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 413 BP S289 EP S291 PG 3 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000415 ER PT J AU Jain, NA Chen, MY Shanbhag, S Anandi, P Lu, K Pophali, PA Dunavin, N Ito, S Koklanaris, E Hourigan, CS Barrett, AJ Battiwalla, M AF Jain, Natasha A. Chen, Marcus Y. Shanbhag, Sujata Anandi, Prathima Lu, Kit Pophali, Priyanka A. Dunavin, Neil Ito, Sawa Koklanaris, Eleftheria Hourigan, Christopher S. Barrett, A. John Battiwalla, Minoo TI Cardiac CT Imaging Is a Feasible Screening Strategy for Coronary Artery Disease (CAD) in Long Term Allogeneic Stem Cell Transplant (Allo-SCT) Survivors SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Jain, Natasha A.; Anandi, Prathima; Lu, Kit; Pophali, Priyanka A.; Dunavin, Neil; Ito, Sawa; Koklanaris, Eleftheria; Hourigan, Christopher S.; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Marcus Y.; Shanbhag, Sujata] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RI Pophali, Priyanka/P-8646-2016 NR 0 TC 0 Z9 0 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 FEB PY 2015 VL 21 IS 2 SU 1 MA 60 BP S73 EP S73 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000065 ER PT J AU Kekre, N Mak, K Stopsack, K Ishii, K Binder, M Branvall, E Cutler, CS AF Kekre, Natasha Mak, Kimberley Stopsack, Konrad Ishii, Kazusa Binder, Moritz Branvall, Elsa Cutler, Corey S. TI Impact of HLA-Mismatch in Unrelated Donor Hematopoietic Stem Cell Transplantation: A Comprehensive Meta-Analysis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Kekre, Natasha; Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mak, Kimberley] Harvard Radiat Oncol Program, Boston, MA USA. [Stopsack, Konrad; Binder, Moritz] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ishii, Kazusa] NIH, Bethesda, MD 20892 USA. [Branvall, Elsa] Karolinska Univ Hosp, Stockholm, Sweden. RI Binder, Moritz/D-3279-2016 OI Binder, Moritz/0000-0001-9014-9658 NR 0 TC 0 Z9 0 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 FEB PY 2015 VL 21 IS 2 SU 1 MA 52 BP S66 EP S67 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000057 ER PT J AU Kohn, DB Shaw, KL Sokolic, R Carbonaro, DA Davila, A Barman, P Garabedian, E Silvin, C De Oliveira, S Shah, AJ Moore, TB Hershfield, M Thrasher, A Gaspar, HR Candotti, F AF Kohn, Donald B. Shaw, Kit L. Sokolic, Robert Carbonaro, Denise A. Davila, Alejandar Barman, Provaboti Garabedian, Elizabeth Silvin, Christopher De Oliveira, Satiro Shah, Ami J. Moore, Theodore B. Hershfield, Michael Thrasher, Adrian Gaspar, H. Robert Candotti, Fabio TI Autologous Transplant/Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Kohn, Donald B.; Shaw, Kit L.; Carbonaro, Denise A.; Davila, Alejandar; Barman, Provaboti; Shah, Ami J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Sokolic, Robert] NHGRI, Bethesda, MD 20892 USA. [Garabedian, Elizabeth; Silvin, Christopher] Natl Genome Res Inst, NIH, Bethesda, MD USA. [De Oliveira, Satiro; Moore, Theodore B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hershfield, Michael] Duke Univ, Sch Med, Durham, NC USA. [Thrasher, Adrian; Gaspar, H. Robert] UCL, Inst Child Hlth, London, England. [Candotti, Fabio] NHGRI, NIH, Bethesda, MD 20892 USA. RI De Oliveira, Satiro/D-8860-2014 OI De Oliveira, Satiro/0000-0002-8181-7316 NR 0 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 100 BP S102 EP S102 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000105 ER PT J AU Palmer, J Chai, XY Martin, PJ Pidala, J Lazaryan, A Arora, M Cutler, CS Pavletic, SZ Pusic, I Jagasia, MH Inamoto, Y Flowers, MED Vogelsang, G Lee, SJ AF Palmer, Jeanne Chai, Xiaoyu Martin, Paul J. Pidala, Joseph Lazaryan, Aleksandr Arora, Mukta Cutler, Corey S. Pavletic, Steven Z. Pusic, Iskra Jagasia, Madan H. Inamoto, Yoshihiro Flowers, Mary E. D. Vogelsang, Georgia Lee, Stephanie J. TI Physician-Reported CR+PR at 6 Months Predicts Subsequent Survival in Patients with Chronic GVHD SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Palmer, Jeanne] Mayo Clin, Div Hematol Oncol, Phoenix, AZ USA. [Chai, Xiaoyu; Martin, Paul J.; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Pidala, Joseph] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Lazaryan, Aleksandr; Arora, Mukta] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Cutler, Corey S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Pusic, Iskra] Washington Univ, Med Ctr, St Louis, MO USA. [Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Stem Cell Transplantat Div, Tokyo, Japan. [Vogelsang, Georgia] Johns Hopkins Med Ctr, Lutherville Timonium, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 43 BP S59 EP S60 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000048 ER PT J AU Pirsl, F Curtis, LM Steinberg, SM Katic, M Dobbin, M Hsu, J Avila, D Taylor, T Baruffaldi, JL Barsony, J Pavletic, SZ AF Pirsl, Filip Curtis, Lauren M. Steinberg, Seth M. Katic, Masenjka Dobbin, Marnie Hsu, Jennifer Avila, Daniele Taylor, Tiffani Baruffaldi, Judy L. Barsony, Julianna Pavletic, Steven Z. TI High Incidence of Osteoporosis in a Natural History Cohort of Patients with Moderate to Severe Chronic Graft-Versus-Host Disease and Risk Factor Analysis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Pirsl, Filip; Curtis, Lauren M.; Katic, Masenjka; Taylor, Tiffani; Baruffaldi, Judy L.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Curtis, Lauren M.] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Dobbin, Marnie] NIH, Dept Clin Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Hsu, Jennifer; Avila, Daniele] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Barsony, Julianna] Georgetown Univ, Div Endocrinol & Metab, Washington, DC 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 67 BP S77 EP S77 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000072 ER PT J AU Pulsipher, MA Logan, BR Kiefer, DM Chitphakdithai, P Switzer, GE Riches, ML Rizzo, JD Anderlini, P Leitman, SF Varni, JW Kobusingye, H Besser, RM Miller, JP Drexler, RJ King, RJ Horowitz, MM Confer, DL AF Pulsipher, Michael A. Logan, Brent R. Kiefer, Deidre M. Chitphakdithai, Pintip Switzer, Galen E. Riches, Marcie L. Rizzo, J. Douglas Anderlini, Paolo Leitman, Susan F. Varni, James W. Kobusingye, Hati Besser, RaeAnne M. Miller, John P. Drexler, Rebecca J. King, Roberta J. Horowitz, Mary M. Confer, Dennis L. TI Related PBSC Donors Experience Higher Levels of Pain and Donation-Related Symptoms and Less Complete Rates of Recovery Compared to Unrelated Donors: Primary Analysis of the Related Donor Safety Study (RDSafe) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Logan, Brent R.; Rizzo, J. Douglas; Horowitz, Mary M.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Kiefer, Deidre M.; Chitphakdithai, Pintip; Kobusingye, Hati; Besser, RaeAnne M.; Drexler, Rebecca J.; Confer, Dennis L.] Ctr Int Blood & Marrow Transplant Res, Natl Marrow Donor Program, Minneapolis, MN USA. [Switzer, Galen E.] Univ Pittsburgh, Pittsburgh, PA USA. [Riches, Marcie L.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Leitman, Susan F.] NHLBI, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. [Varni, James W.] Texas A&M Univ, College Stn, TX USA. [Miller, John P.] Dept Donor Med Serv, Natl Marrow Donor Program, Minneapolis, MN USA. [King, Roberta J.] CIBMTR, Natl Marrow Donor Program, Minneapolis, MN USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 20 BP S41 EP S42 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000025 ER PT J AU Pulsipher, MA Logan, BR Kiefer, DM Chitphakdithai, P Pedersen, TL Stroncek, DF Williams, EP O'Donnell, PV Majhail, NS Confer, DL Shaw, BE AF Pulsipher, Michael A. Logan, Brent R. Kiefer, Deidre M. Chitphakdithai, Pintip Pedersen, Tanya L. Stroncek, David F. Williams, Eric P. O'Donnell, Paul V. Majhail, Navneet S. Confer, Dennis L. Shaw, Bronwen E. TI The Effect of Race, Socioeconomic Status, and Collection Center Size on Bone Marrow (BM) and Peripheral Blood Stem Cell (PBSC) Donor Experiences at National Marrow Donor Program (NMDP) Collection Centers SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Logan, Brent R.; Shaw, Bronwen E.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Kiefer, Deidre M.] Ctr Int Blood & Marrow Transplant Res, Natl Marrow Donor Program, Minneapolis, MN USA. [Chitphakdithai, Pintip; Confer, Dennis L.] CIBMTR, Natl Marrow Donor Program, Minneapolis, MN USA. [Pedersen, Tanya L.] Allina Hlth, Minneapolis, MN USA. [Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Williams, Eric P.] Natl Marrow Donor Program, Dept Bioinformat Res, Minneapolis, MN USA. [O'Donnell, Paul V.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Majhail, Navneet S.] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. NR 0 TC 1 Z9 1 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 19 BP S40 EP S41 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000024 ER PT J AU Purev, E Gormley, N Ramos, C Reger, R Tian, X Cho, E Reda, D Chen, C Suffredini, AF Childs, RW AF Purev, Enkhtsetseg Gormley, Nicole Ramos, Catalina Reger, Robert Tian, Xin Cho, Elena Reda, Debra Chen, Clara Suffredini, Anthony F. Childs, Richard W. TI Inhaled Cyclosporine Solution for the Treatment of Bronchiolitis Obliterans Following Hematopoietic Stem Cell Transplantation (HSCT) or Lung Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Purev, Enkhtsetseg; Gormley, Nicole; Ramos, Catalina; Reger, Robert; Cho, Elena; Childs, Richard W.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Reda, Debra; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Chen, Clara] NIH, Dept Radiol & Imaging Sci, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 505 BP S347 EP S348 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000506 ER PT J AU Ritzau, N Aker, D AF Ritzau, Nicole Aker, Diane TI Eliminating Cross Contamination from Intravenous Cyclosporine and Tacrolimus and Accurate Blood Sampling SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Ritzau, Nicole; Aker, Diane] NIH, Ctr Clin, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 442 BP S306 EP S306 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000444 ER PT J AU Scrivani, C Merideth, M Pulanic, TK Pavletic, SZ Childs, RW Hsieh, M Stratton, P AF Scrivani, Claire Merideth, Melissa Pulanic, Tajana Klepac Pavletic, Steven Z. Childs, Richard W. Hsieh, Matthew Stratton, Pamela TI Early Diagnosis of Labial Fusion Enables Medical Treatment in an Office Setting SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Scrivani, Claire] NHLBI, NIH, Bethesda, MD 20892 USA. [Merideth, Melissa] Natl Human Genome Inst, Bethesda, MD USA. [Pulanic, Tajana Klepac] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Childs, Richard W.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Hsieh, Matthew] NIH, Bethesda, MD 20892 USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 FEB PY 2015 VL 21 IS 2 SU 1 MA 237 BP S184 EP S184 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000241 ER PT J AU Shah, NN Yates, B Delbrook, C Lee, DW Fleisher, T Rampertaap, S Lemberg, K Sabatino, M Stroncek, DE Zhang, H Fry, TJ Mackall, CL AF Shah, Nirali N. Yates, Bonnie Delbrook, Cindy Lee, Daniel W. Fleisher, Thomas Rampertaap, Shakuntala Lemberg, Kimberly Sabatino, Marianna Stroncek, David E. Zhang, Hua Fry, Terry J. Mackall, Crystal L. TI Ex Vivo T Cell Depleted HLA-Matched PBSCT with Post-Transplant Activated Donor-Derived NK Cell Infusions for High-Risk Acute Lymphoblastic Leukemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT BMT Tandem Meetings CY FEB 11-15, 2015 CL San Diego, CA C1 [Shah, Nirali N.; Yates, Bonnie; Delbrook, Cindy; Lee, Daniel W.; Zhang, Hua; Fry, Terry J.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Fleisher, Thomas; Rampertaap, Shakuntala; Lemberg, Kimberly] NCI, Dept Lab Med, NIH, Bethesda, MD 20892 USA. [Sabatino, Marianna; Stroncek, David E.] NIH, Dept Transfus Med, 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2015 VL 21 IS 2 SU 1 MA 446 BP S309 EP S309 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CA0UZ UT WOS:000348633000448 ER PT J AU Hinkle, SN Laughon, SK Catov, JM Olsen, J Bech, BH AF Hinkle, S. N. Laughon, S. K. Catov, J. M. Olsen, J. Bech, B. H. TI First trimester coffee and tea intake and risk of gestational diabetes mellitus: a study within a national birth cohort SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Caffeine; coffee; gestational diabetes; pregnancy; tea ID UTERINE ARTERY DOPPLER; INTRAUTERINE GROWTH RESTRICTION; EARLY-ONSET PREECLAMPSIA; ANGIOGENIC FACTORS; NULLIPAROUS WOMEN; 1ST-TRIMESTER PREDICTION; PRETERM PREECLAMPSIA; BIOCHEMICAL MARKERS; EARLY-PREGNANCY; PREVENTION AB Objective Coffee and tea consumption is associated with a decreased type 2 diabetes risk in non-pregnant adults. We examined the relation between first trimester coffee and tea consumption and gestational diabetes mellitus (GDM) risk. Design Population-based cohort study. Setting Denmark 1996-2002. Population Non-diabetic women with singleton pregnancies in the Danish National Birth Cohort (n = 71 239). Methods Estimated adjusted relative risks (RR) and 95% confidence intervals (95% CI) for the association between first trimester coffee and tea or estimated total caffeine and GDM. Main outcome measures GDM ascertained from the National Hospital Discharge Register or maternal interview. Results Coffee or tea intake was reported in 81.2% (n = 57 882) and 1.3% (n = 912) of pregnancies were complicated by GDM. Among non-consumers, 1.5% of pregnancies were complicated by GDM. Among coffee drinkers, GDM was highest among women who drank = 8 cups/day (1.8%) with no significant difference across intake levels (P = 0.10). Among tea drinkers, there was no difference in GDM across intake levels (1.2%; P = 0.98). After adjustment for age, socio-occupational status, parity, pre-pregnancy body mass index, smoking, and cola, there was suggestion of a protective, but non-significant association with increasing coffee (RR = 8 versus 0 cups/day = 0.89 [95% CI 0.64-1.25]) and tea (RR = 8 versus 0 cups/day = 0.77 [95% CI 0.55-1.08]). Results were similar by smoking status, except a non-significant 1.45-fold increased risk with = 8 coffee cups/day for non-smokers. There was a non-significant reduced GDM risk with increasing total caffeine. Conclusions Our results suggest that moderate first trimester coffee and tea intake were not associated with GDM increased risk and possibly may have a protective effect. C1 [Hinkle, S. N.; Laughon, S. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Catov, J. M.] Univ Pittsburgh, Dept Obstet, Pittsburgh, PA USA. [Catov, J. M.] Univ Pittsburgh, Dept Gynecol, Pittsburgh, PA USA. [Catov, J. M.] Univ Pittsburgh, Dept Reprod Serv, Pittsburgh, PA USA. [Catov, J. M.] Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. [Olsen, J.; Bech, B. H.] Aarhus Univ, Inst Publ Hlth, Dept Epidemiol, Aarhus, Denmark. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM laughonsk@mail.nih.gov RI Olsen, Jorn/F-8801-2015; Hinkle, Stefanie/F-8253-2013; Bech, Bodil Hammer/B-9646-2016; OI Olsen, Jorn/0000-0001-7462-5140; Hinkle, Stefanie/0000-0003-4312-708X; Grantz, Katherine/0000-0003-0276-8534 FU Danish National Research Foundation; Pharmacy Foundation; Egmont Foundation; March of Dimes Birth Defects Foundation; Augustinus Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is provided by the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation and the Augustinus Foundation. This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 40 TC 4 Z9 4 U1 2 U2 38 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 FEB PY 2015 VL 122 IS 3 BP 420 EP 428 DI 10.1111/1471-0528.12930 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CA4HZ UT WOS:000348866600033 PM 24947484 ER PT J AU Jain, NA Ito, S Tian, X Kurlander, R Battiwalla, M Lu, K Savani, BN Malkovska, V Rezvani, K Le, Q Shenoy, A Hourigan, CS Keyvanfar, K Koklanaris, E Superata, J Muranski, P Barrett, AJ Yong, ASM AF Jain, N. A. Ito, S. Tian, X. Kurlander, R. Battiwalla, M. Lu, K. Savani, B. N. Malkovska, V. Rezvani, K. Le, Q. Shenoy, A. Hourigan, C. S. Keyvanfar, K. Koklanaris, E. Superata, J. Muranski, P. Barrett, A. J. Yong, A. S. M. TI Clinical and biological predictors of outcome following relapse of CML post-allo-SCT SO BONE MARROW TRANSPLANTATION LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; RESIDUAL DISEASE DETECTION; POLYMERASE-CHAIN-REACTION; BCR-ABL TRANSCRIPTS; MOLECULAR REMISSION; ALLOGENEIC TRANSPLANTATION AB Although there are now fewer allo-SCTs performed for CML, leukemic relapse post transplant remains a persistent problem. To better define clinical and biological parameters determining postrelapse outcome, we studied 59 patients with CML relapsing after HLA-identical sibling allo-SCT between 1993 and 2008. Eighteen (30.5%) were transplanted in advanced phase and 41 (69.5%) in chronic phase. With a median follow-up from relapse of 7.9 years, 5-year post relapse survival (PRS) was 62%. Multivariate analysis found disease status at transplant, time to diagnosis of relapse from transplant and pretransplant tyrosine kinase inhibitor (TKI) use as significant factors associated with PRS. Analysis of BCR-ABL transcript expression in the hematopoietic progenitor compartment was performed in 36 patients (22 relapsed, 8 non-relapsed and 6 TKI alone controls). Patients with BCR-ABL expression in their early hematopoietic stem cell compartment (Lineage CD34(+)CD38 CD90(+)) had worse survival irrespective of the disease status. We conclude that disease status remains the strongest clinical prognostic factor for PRS in CML following allo-SCT. The persistence of BCR-ABL expression in the progenitor cell compartment in some patients after SCT emphasizes the need to target CML-leukemia stem cells. C1 [Jain, N. A.; Ito, S.; Battiwalla, M.; Lu, K.; Savani, B. N.; Rezvani, K.; Le, Q.; Shenoy, A.; Hourigan, C. S.; Keyvanfar, K.; Koklanaris, E.; Superata, J.; Muranski, P.; Barrett, A. J.; Yong, A. S. M.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tian, X.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Kurlander, R.] NIH, Dept Lab Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Malkovska, V.] Medstar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. RP Ito, S (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr 10 CRC 5-3581, Bethesda, MD 20892 USA. EM itos2@nhlbi.nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural Research Program of the National Institutes of Health at the National Heart, Lung, and Blood Institute FX This paper is dedicated to the memory of John Michael Goldman who inspired us with his insightful observations on the definition and nature of cure of CML. We thank N Hensel, S Miner, M Franco Colon and F Chinian (Hematology Branch, NHLBI, NIH, USA) for their technical support. We also thank all patients who participated in this study. This research was supported by the Intramural Research Program of the National Institutes of Health at the National Heart, Lung, and Blood Institute. NR 37 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2015 VL 50 IS 2 BP 189 EP 196 DI 10.1038/bmt.2014.249 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CB1QM UT WOS:000349402900006 PM 25387087 ER PT J AU Roberto, A Castagna, L Gandolfi, S Zanon, V Bramanti, S Sarina, B Crocchiolo, R Todisco, E Carlo-Stella, C Tentorio, P Timofeeva, I Santoro, A Della Bella, S Roederer, M Mavilio, D Lugli, E AF Roberto, A. Castagna, L. Gandolfi, S. Zanon, V. Bramanti, S. Sarina, B. Crocchiolo, R. Todisco, E. Carlo-Stella, C. Tentorio, P. Timofeeva, I. Santoro, A. Della Bella, S. Roederer, M. Mavilio, D. Lugli, E. TI B-cell reconstitution recapitulates B-cell lymphopoiesis following haploidentical BM transplantation and post-transplant CY SO BONE MARROW TRANSPLANTATION LA English DT Letter ID IDENTIFICATION C1 [Roberto, A.; Zanon, V.; Tentorio, P.; Della Bella, S.; Mavilio, D.; Lugli, E.] Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Rozzano, Italy. [Castagna, L.; Gandolfi, S.; Bramanti, S.; Sarina, B.; Crocchiolo, R.; Todisco, E.; Carlo-Stella, C.; Timofeeva, I.; Santoro, A.] Humanitas Clin & Res Ctr, Humanitas Canc Ctr, Hematol & Bone Marrow Transplant Unit, Rozzano, Italy. [Della Bella, S.; Mavilio, D.] Univ Milan, Dept Med Biotechnol & Translat Med BioMeTra, Milan, Italy. [Roederer, M.] NIAID, Vaccine Res Ctr, ImmunoTechnol Sect, NIH, Bethesda, MD 20892 USA. RP Roberto, A (reprint author), Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Rozzano, Italy. EM domenico.mavilio@humanitas.it; enrico.lugli@humanitasresearch.it OI Mavilio, Domenico/0000-0001-6147-0952; Castagna, Luca/0000-0002-6239-7387; Della Bella, Silvia/0000-0003-0818-5049; Roberto, Alessandra/0000-0001-6615-0026; Carlo-Stella, Carmelo/0000-0003-3144-0124 FU Intramural NIH HHS NR 9 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2015 VL 50 IS 2 BP 317 EP 319 DI 10.1038/bmt.2014.266 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CB1QM UT WOS:000349402900031 PM 25419693 ER PT J AU Cid, J Lozano, M Ziman, A West, KA O'Brien, KL Murphy, MF Wendel, S Vazquez, A Ortin, X Hervig, TA Delaney, M Flegel, WA Yazer, MH AF Cid, Joan Lozano, Miguel Ziman, Alyssa West, Kamille A. O'Brien, Kerry L. Murphy, Michael F. Wendel, Silvano Vazquez, Alejandro Ortin, Xavier Hervig, Tor A. Delaney, Meghan Flegel, Willy A. Yazer, Mark H. CA Biomedical Excellence Safer TI Low frequency of anti-D alloimmunization following D plus platelet transfusion: the Anti-D Alloimmunization after D-incompatible Platelet Transfusions (ADAPT) study SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE platelet transfusion; D compatibility; anti-D alloantibodies; alloimmunization; RhIG ID RED-BLOOD-CELLS; D-GAMMA-GLOBULIN; TRANSPLANT RECIPIENTS; HEMATOLOGIC DISEASES; ONCOLOGY PATIENTS; RHD IMMUNIZATION; ABSENCE; DONORS; ALLOANTIBODIES; PREVENTION AB The reported frequency of D alloimmunization in D- recipients after transfusion of D+ platelets varies. This study was designed to determine the frequency of D alloimmunization, previously reported to be an average of 5 +/- 2%. A primary anti-D immune response was defined as the detection of anti-D28d following the first D+ platelet transfusion. Data were collected on 485 D- recipients of D+ platelets in 11 centres between 2010 and 2012. Their median age was 60 (range 2-100) years. Diagnoses included: haematological (203/485, 42%), oncological (64/485, 13%) and other diseases (218/485, 45%). Only 7/485 (144%; 95% CI 058-297%) recipients had a primary anti-D response after a median serological follow-up of 77d (range: 28-2111). There were no statistically significant differences between the primary anti-D formers and the other patients, in terms of gender, age, receipt of immunosuppressive therapy, proportion of patients with haematological/oncological diseases, transfusion of whole blood-derived or apheresis platelets or both, and total number of transfused platelet products. This is the largest study with the longest follow-up of D alloimmunization following D+ platelet transfusion. The low frequency of D alloimmunization should be considered when deciding whether to administer Rh Immune Globulin to D- males and D- females without childbearing potential after transfusion of D+ platelets. C1 [Cid, Joan; Lozano, Miguel] UB, Hosp Clin, Dept Haemotherapy & Haemostasis, IDIBAPS, Barcelona, Spain. [Cid, Joan; West, Kamille A.; Flegel, Willy A.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Ziman, Alyssa] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Div Transfus Med, Los Angeles, CA 90095 USA. [O'Brien, Kerry L.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Murphy, Michael F.] Oxford Univ Hosp & NHS Blood & Transplant, Oxford, England. [Wendel, Silvano] Hosp Sirio Libanes Blood Bank, Sao Paulo, Brazil. [Vazquez, Alejandro] Hosp Univ Puerta de Hierro, Dept Blood Transfus, Majadahonda, Spain. [Ortin, Xavier] Hosp Verge de la Cinta, Dept Haematol, Tortosa, Spain. [Hervig, Tor A.] Univ Bergen, Dept Clin Sci, Haukeland Univ Hosp, Bergen, Norway. [Delaney, Meghan] Univ Washington, Dept Lab Med, Puget Sound Blood Ctr, Seattle, WA 98195 USA. [Yazer, Mark H.] Univ Pittsburgh, Dept Pathol, Inst Transfus Med, Pittsburgh, PA USA. RP Cid, J (reprint author), Hosp Clin Barcelona, Serv Hemoterapia & Hemostasia, C Villarroel 170, E-08036 Barcelona, Spain. EM jcid@clinic.ub.es RI Cid, Joan/F-7778-2016 OI Cid, Joan/0000-0001-5445-4508 FU Sociedad Espanola de Transfusion Sanguinea y Terapia Celular; NIH Clinical Center FX The authors would like to thank: Gloria Carbasse, from Department of Haemotherapy and Haemostasis, Hospital Clinic, Barcelona, SPAIN; Kulvara Anuruckparadorn, from UCLA Division of Transfusion Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; Sherry L Sheldon, from Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Julie Staves, from Oxford University Hospitals and NHS Blood & Transplant, Oxford, UK; Arlete Lazar, from Hospital Sirio Libanes Blood Bank, Sao Paulo, Brazil; Jose L. Bueno, from Hospital Universitario Puerta de Hierro, Majadahonda, Spain; Jorunn Vadheim, Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Norway; Megan Keane, from Department of Pathology, University of Pittsburgh and the Institute for Transfusion Medicine, Pittsburgh, PA. This research was supported in part by a sabbatical leave and a research grant from the 'Sociedad Espanola de Transfusion Sanguinea y Terapia Celular' for Joan Cid and by the Intramural Research Program of the NIH Clinical Center. NR 38 TC 9 Z9 9 U1 1 U2 4 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 FEB PY 2015 VL 168 IS 4 BP 598 EP 603 DI 10.1111/bjh.13158 PG 6 WC Hematology SC Hematology GA CA8GZ UT WOS:000349157200019 PM 25283094 ER PT J AU Zablotska, LB Nadyrov, EA Rozhko, AV Gong, Z Polyanskaya, ON McConnell, RJ O'Kane, P Brenner, AV Little, MP Ostroumova, E Bouville, A Drozdovitch, V Minenko, V Demidchik, Y Nerovnya, A Yauseyenka, V Savasteeva, I Nikonovich, S Mabuchi, K Hatch, M AF Zablotska, Lydia B. Nadyrov, Eldar A. Rozhko, Alexander V. Gong, Zhihong Polyanskaya, Olga N. McConnell, Robert J. O'Kane, Patrick Brenner, Alina V. Little, Mark P. Ostroumova, Evgenia Bouville, Andre Drozdovitch, Vladimir Minenko, Viktor Demidchik, Yuri Nerovnya, Alexander Yauseyenka, Vassilina Savasteeva, Irina Nikonovich, Sergey Mabuchi, Kiyohiko Hatch, Maureen TI Analysis of Thyroid Malignant Pathologic Findings Identified During 3 Rounds of Screening (1997-2008) of a Cohort of Children and Adolescents from Belarus Exposed to Radioiodines After the Chernobyl Accident SO CANCER LA English DT Article DE thyroid cancer; pathology; morphology; thyroid neoplasms; Chernobyl nuclear accident; papillary carcinoma; radiation; latency ID CANCER RISK; RADIATION; CHILDHOOD; CARCINOMA; DISEASES; UKRAINE; I-131 AB BACKGROUND: Recent studies of children and adolescents who were exposed to radioactive iodine-131 (I-131) after the 1986 Chernobyl nuclear accident in Ukraine exhibited a significant dose-related increase in the risk of thyroid cancer, but the association of radiation doses with tumor histologic and morphologic features is not clear. METHODS: A cohort of 11,664 individuals in Belarus who were aged <= 18 years at the time of the accident underwent 3 cycles of thyroid screening during 1997 to 2008. I-131 thyroid doses were estimated from individual thyroid activity measurements taken within 2 months after the accident and from dosimetric questionnaire data. Demographic, clinical, and tumor pathologic characteristics of the patients with thyroid cancer were analyzed using 1-way analysis of variance, chi-square tests or Fisher exact tests, and logistic regression. RESULTS: In total, 158 thyroid cancers were identified as a result of screening. The majority of patients had T1a and T1b tumors (93.7%), with many positive regional lymph nodes (N1; 60.6%) but few distant metastases (M1; <1%). Higher I-131 doses were associated with higher frequency of solid and diffuse sclerosing variants of thyroid cancer (P<.01) and histologic features of cancer aggressiveness, such as lymphatic vessel invasion, intrathyroidal infiltration, and multifocality (all P<.03). Latency was not correlated with radiation dose. Fifty-two patients with self-reported thyroid cancers which were diagnosed before 1997 were younger at the time of the accident and had a higher percentage of solid variant cancers compared with patients who had screening-detected thyroid cancers (all P<.0001). CONCLUSIONS: I-131 thyroid radiation doses were associated with a significantly greater frequency of solid and diffuse sclerosing variants of thyroid cancer and various features of tumor aggressiveness. (C) 2014 American Cancer Society. C1 [Zablotska, Lydia B.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Nadyrov, Eldar A.; Rozhko, Alexander V.; Polyanskaya, Olga N.; Yauseyenka, Vassilina; Savasteeva, Irina; Nikonovich, Sergey] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [Gong, Zhihong] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [McConnell, Robert J.] Columbia Univ, Thyroid Ctr, New York, NY USA. [O'Kane, Patrick] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Brenner, Alina V.; Little, Mark P.; Ostroumova, Evgenia; Bouville, Andre; Drozdovitch, Vladimir; Mabuchi, Kiyohiko; Hatch, Maureen] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Minenko, Viktor] Res Inst Nucl Problems, Minsk, Byelarus. [Demidchik, Yuri; Nerovnya, Alexander] Belarusian Med Acad Postgrad Educ, Minsk, Byelarus. RP Zablotska, LB (reprint author), 3333 Calif St,Suite 280, San Francisco, CA 94118 USA. EM Lydia.Zablotska@ucsf.edu OI Little, Mark/0000-0003-0980-7567 FU National Cancer Institute [CA132918, NO1-CP-21178]; National Cancer Institute (Intramural Research Program, Division of Cancer Epidemiology and Genetics) FX Funding for this study was provided by the National Cancer Institute (grant CA132918 to L.B.Z.; contract NO1-CP-21178 to L.B.Z., Z.G., R.J.M. and P.O; and the Intramural Research Program, Division of Cancer Epidemiology and Genetics to A.V.B., M.P.L., E.O., A.B., V.D., K.M., and M.H.). NR 35 TC 7 Z9 7 U1 1 U2 5 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 FEB 1 PY 2015 VL 121 IS 3 BP 457 EP 466 DI 10.1002/cncr.29073 PG 10 WC Oncology SC Oncology GA CB1NP UT WOS:000349394900020 PM 25351557 ER PT J AU Chen, W Wang, JB Abnet, CC Dawsey, SM Fan, JH Yin, LY Yin, J Taylor, PR Qiao, YL Freedman, ND AF Chen, Wen Wang, Jian-Bing Abnet, Christian C. Dawsey, Sanford M. Fan, Jin-Hu Yin, Liang-Yu Yin, Jian Taylor, Philip R. Qiao, You-Lin Freedman, Neal D. TI Association between C-Reactive Protein, Incident Liver Cancer, and Chronic Liver Disease Mortality in the Linxian Nutrition Intervention Trials: A Nested Case-Control Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; OVARIAN-CANCER; RISK; INFLAMMATION; PROGNOSIS; CIRRHOSIS; SUPPLEMENTATION; MONOCYTES; CHINA AB Background: C-reactive protein (CRP) is a marker of systemic inflammation that has been associated with the incidence and prognosis for a number of different cancers. Recent data suggest that CRP may be a prognostic factor for liver cancer and cirrhosis. However, few long-term studies are available. Methods: We prospectively examined associations between serum CRP and subsequent risk of liver cancer incidence or chronic liver disease mortality in a nested case-control study performed in the Linxian Nutrition Intervention Trials cohort. Baseline serum CRP was measured for 220 incident liver cancer cases, 276 participants who died of chronic liver disease, and 1,018 age-, sex-, and trial-matched controls. Unconditional logistical regression models were used to estimate ORs and 95% confidence intervals (CI). Results: Compared with the lowest quartile, subjects in the fourth quartile of serum CRP had a higher risk of liver cancer incidence (OR, 1.63; 95% CI, 1.06-2.51), with a significant P-trend across quartiles (P = 0.01). The association with liver cancer was only significant among men (Q4 vs. Q1; OR, 2.00; 1.10-3.62), but not among women (Q4 vs. Q1; OR, 1.15; 0.60-2.22). For chronic liver disease deaths, the corresponding risk estimate in men and women was 2.95 (1.90-4.57), with amonotonic trend (P < 0.001). Conclusions: Higher serum CRP concentrations at baseline were associated with subsequent incidence of liver cancer and death from chronic liver disease. Impact: Our findings suggest that levels of systemic inflammation may serve as a long-term marker of liver cancer and liver disease. (C) 2015 AACR. C1 [Chen, Wen; Wang, Jian-Bing; Fan, Jin-Hu; Yin, Jian; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Dept Canc Epidemiol, Beijing 100730, Peoples R China. [Chen, Wen; Wang, Jian-Bing; Fan, Jin-Hu; Yin, Jian; Qiao, You-Lin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Wang, Jian-Bing; Abnet, Christian C.; Dawsey, Sanford M.; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Wang, Jian-Bing] Zhejiang Univ, Sch Publ Hlth, Dept Epidemiol & Hlth Stat, Hangzhou 310003, Zhejiang, Peoples R China. [Yin, Liang-Yu] Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing, Peoples R China. [Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Freedman, ND (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,MSC 9768, Rockville, MD 20850 USA. EM qiaoy@cicams.ac.cn; freedmanne@mail.nih.gov RI Freedman, Neal/B-9741-2015; Abnet, Christian/C-4111-2015; Qiao, You-Lin/B-4139-2012 OI Freedman, Neal/0000-0003-0074-1098; Abnet, Christian/0000-0002-3008-7843; Qiao, You-Lin/0000-0001-6380-0871 FU National Cancer Institute [N01-SC-91030, N01-RC-47701]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; NIH; Cancer Institute, Chinese Academy of Medical Sciences FX This work was supported in part by National Cancer Institute contracts (N01-SC-91030 and N01-RC-47701) to the Cancer Institute, Chinese Academy of Medical Sciences; in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, the NIH; and in part by the Cancer Institute, Chinese Academy of Medical Sciences. NR 34 TC 2 Z9 2 U1 0 U2 5 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 FEB PY 2015 VL 24 IS 2 BP 386 EP 392 DI 10.1158/1055-9965.EPI-14-1038 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CB1XY UT WOS:000349422500009 PM 25613115 ER PT J AU Casbas-Hernandez, P Sun, XZ Roman-Perez, E D'Arcy, M Sandhu, R Hishida, A McNaughton, KK Yang, XHR Makowski, L Sherman, ME Figueroa, JD Troester, MA AF Casbas-Hernandez, Patricia Sun, Xuezheng Roman-Perez, Erick D'Arcy, Monica Sandhu, Rupninder Hishida, Asahi McNaughton, Kirk K. Yang, Xiaohong R. Makowski, Liza Sherman, Mark E. Figueroa, Jonine D. Troester, Melissa A. TI Tumor Intrinsic Subtype Is Reflected in Cancer-Adjacent Tissue SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CARCINOMA-IN-SITU; ESTROGEN-RECEPTOR EXPRESSION; BREAST-CONSERVING THERAPY; STROMAL-CELL-INTERACTIONS; 20-YEAR FOLLOW-UP; GENE-EXPRESSION; MOLECULAR CHARACTERIZATION; LOCAL RECURRENCE; MAMMARY-GLAND; RISK-FACTORS AB Introduction: Overall survival of early-stage breast cancer patients is similar for those who undergo breast-conserving therapy (BCT) and mastectomy; however, 10% to 15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with breast cancer subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk. Methods: We utilized two independent datasets to study gene expression data in cancer-adjacent tissue from invasive breast cancer patients. Complementary in vitro cocultures were used to study cell-cell communication between fibroblasts and specific breast cancer subtypes. Results: Our results suggest that intrinsic tumor subtypes are reflected in histologically normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple-negative (Claudin-low or basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. Although such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, although triple-negative breast cancers are associated with upregulated immune response genes, luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues. Conclusions: Specific characteristics of breast cancers are reflected in the surrounding histologically normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences. Impact: Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk. (C)2014 AACR. C1 [Casbas-Hernandez, Patricia; Troester, Melissa A.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Sun, Xuezheng; Roman-Perez, Erick; D'Arcy, Monica; Troester, Melissa A.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Sandhu, Rupninder; Hishida, Asahi; Makowski, Liza; Troester, Melissa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [McNaughton, Kirk K.] Univ N Carolina, Sch Med, Dept Physiol, Chapel Hill, NC 27599 USA. [Yang, Xiaohong R.; Sherman, Mark E.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Makowski, Liza] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. RP Troester, MA (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM troester@unc.edu RI Hishida, Asahi/C-4888-2016; OI Hishida, Asahi/0000-0002-4867-0201; Makowski, Liza/0000-0002-5337-8037 FU Avon Foundation; University Cancer Research Fund; National Cancer Institute [R01CA-138255]; NCI/National Institutes of Environmental Health Sciences (NIEHS) Breast Cancer; Environment Research Program (BCERP) [U01-ES-019472]; SPORE Grant [P50-CA-058223]; Howard Hughes Medical Institute Fellowship; National Cancer Institute Intramural funds FX X.R. Yang, M.E. Sherman, and J.D. Figueroa received NCI intramural funds. M.A. Troester received funds from the Avon Foundation, the University Cancer Research Fund, the National Cancer Institute (R01CA-138255), the NCI/National Institutes of Environmental Health Sciences (NIEHS) Breast Cancer and the Environment Research Program (BCERP; U01-ES-019472), and a SPORE Grant (P50-CA-058223). P. Casbas-Hernandez was supported by a Howard Hughes Medical Institute Fellowship. The Polish Breast Cancer Study was supported by the National Cancer Institute Intramural funds. NR 49 TC 12 Z9 12 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 FEB PY 2015 VL 24 IS 2 BP 406 EP 414 DI 10.1158/1055-9965.EPI-14-0934 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CB1XY UT WOS:000349422500012 PM 25465802 ER PT J AU Marks, JR Anderson, KS Engstrom, P Godwin, AK Esserman, LJ Longton, G Iversen, ES Mathew, A Patriotis, C Pepe, MS AF Marks, Jeffrey R. Anderson, Karen S. Engstrom, Paul Godwin, Andrew K. Esserman, Laura J. Longton, Gary Iversen, Edwin S. Mathew, Anu Patriotis, Christos Pepe, Margaret S. TI Construction and Analysis of the NCI-EDRN Breast Cancer Reference Set for Circulating Markers of Disease SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ADHESION MOLECULES; BIOMARKERS; POPULATION; MORTALITY; HEALTHY; PROTEIN; AGE AB Background: Many circulating biomarkers have been reported for the diagnosis of breast cancer, but few, if any, have undergone rigorous credentialing using prospective cohorts and blinded evaluation. Methods: The NCI Early Detection Research Network (EDRN) has created a prospective, multicenter collection of plasma and serum samples from 832 subjects designed to evaluate circulating biomarkers for the detection and diagnosis of breast cancer. These samples are available to investigators who wish to evaluate their biomarkers using a set of blinded samples. The breast cancer reference set is composed of blood samples collected using a standard operating procedure at four U.S. medical centers from 2008 to 2010 from women undergoing either tissue diagnosis for breast cancer or routine screening mammography. The reference set contains samples from women with incident invasive cancer (n = 190), carcinoma in situ (n = 55), benign pathology with atypia (n = 63), benign disease with no atypia (n = 231), and women with no evidence of breast disease by screening mammography (BIRADS 1 or 2, n = 276). Using a subset of plasma samples (n = 505) from the reference set, we analyzed 90 proteins by multiplexed immunoassays for their potential utility as diagnostic markers. Results: We found that none of these markers is useful for distinguishing cancer from benign controls. However, elevated CA-125 does appear to be a candidate marker for estrogen receptor-negative cancers. Conclusions: Markers that can distinguish benign breast conditions from invasive cancer have not yet been found. Impact: Availability of prospectively collected samples should improve future validation efforts. (C)2014 AACR. C1 [Marks, Jeffrey R.] Duke Univ, Dept Surg, Durham, NC 27710 USA. [Anderson, Karen S.] Arizona State Univ, Biodesign Inst, Ctr Personalized Diagnost, Tempe, AZ USA. [Engstrom, Paul] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Esserman, Laura J.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Longton, Gary; Pepe, Margaret S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Mathew, Anu] Meso Scale Diagnost LLC, Rockville, MD USA. [Patriotis, Christos] NCI, NIH, Bethesda, MD 20892 USA. RP Marks, JR (reprint author), Duke Univ, Med Ctr, Box 3873, Durham, NC 27710 USA. EM marks003@mc.duke.edu FU NCI Early Detection Research Network [U01 CA117374, U01 CA113916, UO1 CA084955, UO1 CA111234, U24 CA086368] FX This work was supported by the NCI Early Detection Research Network (U01 CA117374 to K.S. Anderson; U01 CA113916 to P. Engstrom and A.K. Godwin; UO1 CA084955 to J.R. Marks; UO1 CA111234 to L.J. Esserman; and U24 CA086368 to M.S. Pepe). NR 20 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2015 VL 24 IS 2 BP 435 EP 441 DI 10.1158/1055-9965.EPI-14-1178 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CB1XY UT WOS:000349422500015 PM 25471344 ER PT J AU Goldszmid, RS Dzutsev, A Viaud, S Zitvogel, L Restifo, NP Trinchieri, G AF Goldszmid, Romina S. Dzutsev, Amiran Viaud, Sophie Zitvogel, Laurence Restifo, Nicholas P. Trinchieri, Giorgio TI Microbiota Modulation of Myeloid Cells in Cancer Therapy SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID RECURRENT CLOSTRIDIUM-DIFFICILE; INFLAMMATORY BOWEL DISEASES; CD8(+) T-CELLS; GUT MICROBIOTA; TUMOR MICROENVIRONMENT; INTESTINAL MICROBIOTA; COMMENSAL MICROBIOTA; IMMUNITY; RESPONSES; INFECTION AB Myeloid cells represent a major component of the tumor microenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy. (C) 2015 AACR. C1 [Goldszmid, Romina S.; Dzutsev, Amiran; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dzutsev, Amiran] Leidos Biomed Res Inc, Bethesda, MD USA. [Viaud, Sophie; Zitvogel, Laurence] Inst Gustave Roussy, Inst Natl Sante & Rech Med, Villejuif, France. [Viaud, Sophie; Zitvogel, Laurence] Univ Paris 11, Le Kremlin Bicetre, France. [Restifo, Nicholas P.] NCI, Surg Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Trinchieri, G (reprint author), NCI, NIH, Bldg 37,Room 4146, Bethesda, MD 20892 USA. EM rgoldszmid@mail.nih.gov; trinchig@mail.nih.gov FU intramural research program of the NCI; Institut National du Cancer (INCa); la Ligue contre le cancer (LIGUE labellisee); SIRIC Socrate; LABEX; PACRI Onco-Immunology FX The work of R.S. Goldszmid, A. Dzutsev, N.P. Restifo, and G. Trinchieri was supported by the intramural research program of the NCI. The work of S. Viaud and L. Zitvogel was supported by Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee), SIRIC Socrate, LABEX, and PACRI Onco-Immunology. NR 72 TC 7 Z9 9 U1 4 U2 12 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 FEB PY 2015 VL 3 IS 2 BP 103 EP 109 DI 10.1158/2326-6066.CIR-14-0225 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA CB1XZ UT WOS:000349422600002 PM 25660553 ER PT J AU Yang, H Cong, WN Yoon, JS Egan, JM AF Yang, Hyekyung Cong, Wei-na Yoon, Jeong Seon Egan, Josephine M. TI Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds SO CANCER MEDICINE LA English DT Article DE Basal-cell carcinoma; sonic hedgehog; taste buds; taste perception; Vismodegib ID BASAL-CELL CARCINOMA; SWEET TASTE; PAPILLA DEVELOPMENT; ALPHA-GUSTDUCIN; DOSE-ESCALATION; NEVUS SYNDROME; UMAMI TASTE; III CELLS; PHASE-I; PATHWAY AB Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30mg/kg vismodegib for 15weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase C2- and -gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds. C1 [Yang, Hyekyung; Cong, Wei-na; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Yoon, Jeong Seon] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, Lab Clin Invest, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 47 TC 9 Z9 9 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD FEB PY 2015 VL 4 IS 2 BP 245 EP 252 DI 10.1002/cam4.350 PG 8 WC Oncology SC Oncology GA CB0IS UT WOS:000349309800008 PM 25354792 ER PT J AU Kaplan, RM Sun, QK Ries, AL AF Kaplan, Robert M. Sun, Qiankun Ries, Andrew L. TI Quality of Well-being Outcomes in the National Emphysema Treatment Trial SO CHEST LA English DT Article ID VOLUME-REDUCTION SURGERY; OBSTRUCTIVE PULMONARY-DISEASE; OF-LIFE; LUNG-VOLUME; COST-EFFECTIVENESS; MAJOR DEPRESSION; RANDOMIZED-TRIAL; CYSTIC-FIBROSIS; SCALE; TRANSPLANTATION AB BACKGROUND: Surgical and medical treatments for emphysema may affect both quality and quantity of life. The purpose of this article is to report outcomes from the National Emphysema Treatment Trial ( NETT) using an index that combines quality and quantity of life. METHODS: This was a prospective randomized clinical trial. Following pulmonary rehabilitation, 1,218 patients with severe emphysema were randomly assigned to maximal medical therapy or to lung volume reduction surgery (LVRS). A generic quality-of-life measure, known as the Quality of Well-being Scale (QWB), was administered at baseline and again at 6, 12, 24, 36, 48, 60, and 72 months following treatment assignment. RESULTS: At baseline, QWB scores were comparable for the Medical and LVRS groups. For both groups, scores significantly improved following the rehabilitation program. The QWB scores before death for patients in the LVRS group improved up to the year 2 visit, whereas scores for the Medical group dropped significantly following the baseline visit. Imputing zeros ( 0) for death, QWB scores decreased significantly for both groups. With or without scoring death as 0, the LVRS group achieved better outcomes, and the significant differences were maintained until the sixth year. Over 6 years of follow-up, LVRS produced an average of 0.30 quality-adjusted life years (QALYs), or the equivalent of about 3.6 months of well life. CONCLUSIONS: Compared with maximal medical therapy alone, patients undergoing maximal medical therapy plus LVRS experienced improved health-related quality of life and gained more QALYs. C1 [Kaplan, Robert M.; Sun, Qiankun] NIH, Bethesda, MD 20892 USA. [Ries, Andrew L.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ries, Andrew L.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP Kaplan, RM (reprint author), Agcy Healthcare Res & Qual, 540 Gaither Rd, Rockville, MD 20850 USA. EM robert.kaplan@ahrq.hhs.gov FU National Heart, Lung, and Blood Institute [N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01-HR76119]; Center for Medicare and Medicaid Services; Agency for Healthcare Research and Quality FX This study was supported by contracts with the National Heart, Lung, and Blood Institute [Grants N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01-HR76119], the Center for Medicare and Medicaid Services (formerly the Health Care Financing Administration), and the Agency for Healthcare Research and Quality. NR 30 TC 1 Z9 1 U1 0 U2 4 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2015 VL 147 IS 2 BP 377 EP 387 DI 10.1378/chest.14-0528 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CB1YF UT WOS:000349423200018 PM 25340383 ER PT J AU Emoto, C Fukuda, T Mizuno, T Schniedewind, B Christians, U Adams, DM Widemann, BC Fisher, MJ Perentesis, J Weiss, B Vinks, AA AF Emoto, C. Fukuda, T. Mizuno, T. Schniedewind, B. Christians, U. Adams, D. M. Widemann, B. C. Fisher, M. J. Perentesis, J. Weiss, B. Vinks, A. A. TI AGE-DEPENDENT CHANGES IN CYP3A METABOLIC CAPACITY DETERMINE SIROLIMUS CLEARANCE IN PEDIATRIC PATIENTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Emoto, C.; Fukuda, T.; Mizuno, T.; Vinks, A. A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Schniedewind, B.; Christians, U.] Univ Colorado, Aurora, CO USA. [Adams, D. M.; Perentesis, J.; Weiss, B.] Cincinnati Childrens Hosp Med Ctr, Div Oncol, Can & Blood Dis Inst, Cincinnati, OH 45229 USA. [Widemann, B. C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fisher, M. J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. RI Mizuno, Tomoyuki/G-6101-2012 OI Mizuno, Tomoyuki/0000-0002-8471-9826 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PII-108 BP S92 EP S93 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500286 ER PT J AU Goey, AK Sissung, TM Peer, CJ Ehrlich, S Balasubramaniam, S Bryla, C Bates, SE Figg, WD AF Goey, A. K. Sissung, T. M. Peer, C. J. Ehrlich, S. Balasubramaniam, S. Bryla, C. Bates, S. E. Figg, W. D. TI EFFECTS OF UGT1A1 GENETIC VARIANTS ON PHARMACOKINETICS AND TOXICITIES OF BELINOSTAT ADMINSTERED BY CONTINUOUS INFUSION IN COMBINATION WITH CISPLATIN AND ETOPOSIDE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Goey, A. K.; Sissung, T. M.; Peer, C. J.; Ehrlich, S.; Balasubramaniam, S.; Bryla, C.; Bates, S. E.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-021 BP S27 EP S27 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500074 ER PT J AU McCann, DJ AF McCann, D. J. TI WHAT IS THE IMPACT OF "PROFESSIONAL SUBJECTS" ON MEDICATION EFFICACY TRIALS? SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [McCann, D. J.] NIDA, 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-008 BP S22 EP S23 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500061 ER PT J AU Oni-Orisan, A Edin, ML Lee, J Stouffer, GA Zeldin, DC Lee, CR AF Oni-Orisan, A. Edin, M. L. Lee, J. Stouffer, G. A. Zeldin, D. C. Lee, C. R. TI CHARACTERIZATION OF THE RELATIONSHIP BETWEEN BIOMARKERS OF CYTOCHROME P450-MEDIATED EICOSANOID METABOLISM AND CORONARY ARTERY DISEASE SEVERITY IN HUMANS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Oni-Orisan, A.; Lee, J.; Lee, C. R.] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC USA. [Edin, M. L.; Zeldin, D. C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Stouffer, G. A.] UNC Sch Med, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA OIII-4 BP S103 EP S104 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500315 ER PT J AU Oni-Orisan, A Edin, ML Lee, J Stouffer, GA Zeldin, DC Lee, CR AF Oni-Orisan, A. Edin, M. L. Lee, J. Stouffer, G. A. Zeldin, D. C. Lee, C. R. TI CHARACTERIZATION OF THE RELATIONSHIP BETWEEN BIOMARKERS OF CYTOCHROME P450-MEDIATED EICOSANOID METABOLISM AND CORONARY ARTERY DISEASE SEVERITY IN HUMANS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Oni-Orisan, A.; Lee, J.; Lee, C. R.] UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Edin, M. L.; Zeldin, D. C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Stouffer, G. A.] UNC Sch Med, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PT-07 BP S13 EP S13 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500034 ER PT J AU Peer, CJ Goey, A Sissung, TM Ehrlich, S Bryla, C Bates, SE Figg, WD AF Peer, C. J. Goey, A. Sissung, T. M. Ehrlich, S. Bryla, C. Bates, S. E. Figg, W. D. TI A POPULATION PHARMACOKINETIC MODEL FOR OPTIMIZED BELINOSTAT DOSING BY CONTINUOUS INFUSION BASED ON UGT1A1 GENOTYPE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Peer, C. J.; Goey, A.; Sissung, T. M.; Ehrlich, S.; Bryla, C.; Bates, S. E.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-089 BP S47 EP S47 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500142 ER PT J AU Sissung, TM Peer, CJ Schrump, DS Figg, WD AF Sissung, T. M. Peer, C. J. Schrump, D. S. Figg, W. D. TI PHARMACOGENOMICS OF MITHRAMYCIN-INDUCED HEPTATO-TOXICITY. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Sissung, T. M.; Peer, C. J.; Schrump, D. S.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PII-019 BP S65 EP S65 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500197 ER PT J AU Vatsalya, V Gowin, JL Schwandt, ML Momenan, R Heilig, M Bardett, SE Ramchandani, VA AF Vatsalya, V. Gowin, J. L. Schwandt, M. L. Momenan, R. Heilig, M. Bardett, S. E. Ramchandani, V. A. TI EFFECTS OF VARENICLINE IN HUMAN LABORATORY MODELS FOR SCREENING OFPHARMACOTHERAPEUTICS FOR ALCOHOL USE DISORDER. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Vatsalya, V.; Gowin, J. L.; Schwandt, M. L.; Momenan, R.; Heilig, M.; Ramchandani, V. A.] NIAAA, Bethesda, MD USA. [Bardett, S. E.] Queensland Univ Technol, Brisbane, Qld 4001, Australia. 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PI-003 BP S21 EP S21 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500056 ER PT J AU Yang, H Ramalingam, S Kummar, S Harvey, R Ivy, P Beumer, J AF Yang, H. Ramalingam, S. Kummar, S. Harvey, R. Ivy, P. Beumer, J. TI POPULATION PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF VORINOSTAT IN PATIENTS WITH ADVANCED SOLID TUMORS WITH VARYING DEGREES OF HEPATIC FUNCTION. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 03-07, 2015 CL New Orleans, LA SP Amer Soc Clin Pharmacol & Therapeut C1 [Yang, H.; Beumer, J.] Univ Pittsburgh, Pittsburgh, PA USA. [Ramalingam, S.; Harvey, R.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Kummar, S.] NIH, Clin Ctr Maryland, Bethesda, MD 20892 USA. [Ivy, P.] NIH, Invest Drug Branch, Pittsburgh, PA 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2015 VL 97 SU 1 MA PII-029 BP S67 EP S68 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CA2HW UT WOS:000348730500207 ER PT J AU Veleri, S Lazar, CH Chang, B Sieving, PA Banin, E Swaroop, A AF Veleri, Shobi Lazar, Csilla H. Chang, Bo Sieving, Paul A. Banin, Eyal Swaroop, Anand TI Biology and therapy of inherited retinal degenerative disease: insights from mouse models SO DISEASE MODELS & MECHANISMS LA English DT Review DE Mouse mutants; Photoreceptor; Retinal development; Retinal disease ID LEBER CONGENITAL AMAUROSIS; BARDET-BIEDL-SYNDROME; DOMINANT RETINITIS-PIGMENTOSA; STATIONARY NIGHT BLINDNESS; CONE-ROD DYSTROPHY; NUCLEAR RECEPTOR NR2E3; HEREDITARY OPTIC NEUROPATHY; LINKED JUVENILE RETINOSCHISIS; NUCLEOTIDE-GATED CHANNEL; EMBRYONIC STEM-CELLS AB Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. C1 [Veleri, Shobi; Lazar, Csilla H.; Banin, Eyal; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Lazar, Csilla H.] Univ Babes Bolyai, Mol Biol Ctr, Interdisciplinary Res Inst Bionano Sci, Cluj Napoca 400271, Romania. [Chang, Bo] Jackson Lab, Bar Harbor, ME 04609 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Banin, Eyal] Hadassah Hebrew Univ Med Ctr, Dept Ophthalmol, Ctr Retinal & Macular Degenerat, IL-91120 Jerusalem, Israel. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health FX This work is supported by the intramural research program of the National Eye Institute, National Institutes of Health. NR 303 TC 27 Z9 27 U1 2 U2 23 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD FEB PY 2015 VL 8 IS 2 BP 109 EP 129 DI 10.1242/dmm.017913 PG 21 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CB0SL UT WOS:000349337200002 PM 25650393 ER PT J AU Sue, M Martucci, V Frey, F Lenders, JWM Timmers, HJ Peczkowska, M Prejbisz, A Swantje, B Bornstein, SR Arlt, W Fassnacht, M Beuschlein, F Robledo, M Pacak, K Eisenhofer, G AF Sue, Mariko Martucci, Victoria Frey, Florina Lenders, Jacques W. M. Timmers, Henri J. Peczkowska, Mariola Prejbisz, Aleksander Swantje, Brede Bornstein, Stefan R. Arlt, Wiebke Fassnacht, Martin Beuschlein, Felix Robledo, Mercedes Pacak, Karel Eisenhofer, Graeme TI Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID NON-SYNDROMIC PHEOCHROMOCYTOMA; GERMLINE MUTATIONS; NECK PARAGANGLIOMA; CLINICAL-PRACTICE; GENE; HEAD AB Objective: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype-phenotype features of metastatic PPGLs according to underlying gene mutations. Design and methods: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42 +/- 16 years (range 9-86 years) at diagnosis of metastatic PPGLs with and without adrenaline production. Results: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36-41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours. Conclusion: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations. C1 [Sue, Mariko; Bornstein, Stefan R.; Eisenhofer, Graeme] Tech Univ Dresden, Fac Med, Dept Med 3, D-01307 Dresden, Germany. [Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Frey, Florina; Eisenhofer, Graeme] Tech Univ Dresden, Fac Med, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany. [Lenders, Jacques W. M.; Timmers, Henri J.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Peczkowska, Mariola; Prejbisz, Aleksander] Inst Cardiol, Dept Hypertens, PL-04628 Warsaw, Poland. [Swantje, Brede] Univ Lubeck, Dept Neuroendocrinol, D-23562 Lubeck, Germany. [Arlt, Wiebke] Univ Birmingham, Inst Biomed Res, Sch Clin & Expt Med, Ctr Endocrinol Diabet & Metab, Birmingham B15 2TT, W Midlands, England. [Fassnacht, Martin] Univ Wurzburg, Univ Hosp, D-97080 Wurzburg, Germany. [Fassnacht, Martin] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, D-97080 Wurzburg, Germany. [Beuschlein, Felix] Klinikum Univ Munchen, Med Klin & Poliklin 4, Endocrine Res Unit, D-80336 Munich, Germany. [Robledo, Mercedes] Hereditary Endocrine Canc Grp, Spanish Natl Canc Res Ctr Med CNIO, Madrid 28029, Spain. RP Sue, M (reprint author), Tech Univ Dresden, Fac Med, Dept Med 3, Fetscherstr 74, D-01307 Dresden, Germany. EM Mariko.Sue@uniklinikum-dresden.de RI Arlt, Wiebke/B-6310-2009; Lenders, J.W.M./L-4487-2015 OI Arlt, Wiebke/0000-0001-5106-9719; FU Deutsche Forschungsgemeinschaft [EI855/1/1]; Polish Ministry of Science and Higher Education [N N402 386038]; European Union Seventh Framework Programme (FP7) [259735] FX This study was supported by the Deutsche Forschungsgemeinschaft (EI855/1/1), the Polish Ministry of Science and Higher Education (N N402 386038), and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 259735 (ENS@T-Cancer). NR 22 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 2015 VL 172 IS 2 DI 10.1530/EJE-14-0756 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CB2LD UT WOS:000349458000005 ER PT J AU Li, Q Wojciechowski, R Simpson, CL Hysi, PG Verhoeven, VJM Ikram, MK Hohn, R Vitart, V Hewitt, AW Oexle, K Makela, KM MacGregor, S Pirastu, M Fan, Q Cheng, CY St Pourcain, B McMahon, G Kemp, JP Northstone, K Rahi, JS Cumberland, PM Martin, NG Sanfilippo, PG Lu, Y Wang, YX Hayward, C Polasek, O Campbell, H Bencic, G Wright, AF Wedenoja, J Zeller, T Schillert, A Mirshahi, A Lackner, K Yip, SP Yap, MKH Ried, JS Gieger, C Murgia, F Wilson, JF Fleck, B Yazar, S Vingerling, JR Hofman, A Uitterlinden, A Rivadeneira, F Amin, N Karssen, L Oostra, BA Zhou, X Teo, YY Tai, ES Vithana, E Barathi, V Zheng, YF Siantar, RG Neelam, K Shin, YC Lam, J Yonova-Doing, E Venturini, C Hosseini, SM Wong, HS Lehtimaki, T Kahonen, M Raitakari, O Timpson, NJ Evans, DM Khor, CC Aung, T Young, TL Mitchell, P Klein, B van Duijn, CM Meitinger, T Jonas, JB Baird, PN Mackey, DA Wong, TY Saw, SM Parssinen, O Stambolian, D Hammond, CJ Klaver, CCW Williams, C Paterson, AD Bailey-Wilson, JE Guggenheim, JA AF Li, Qing Wojciechowski, Robert Simpson, Claire L. Hysi, Pirro G. Verhoeven, Virginie J. M. Ikram, Mohammad Kamran Hoehn, Rene Vitart, Veronique Hewitt, Alex W. Oexle, Konrad Makela, Kari-Matti MacGregor, Stuart Pirastu, Mario Fan, Qiao Cheng, Ching-Yu St Pourcain, Beat McMahon, George Kemp, John P. Northstone, Kate Rahi, Jugnoo S. Cumberland, Phillippa M. Martin, Nicholas G. Sanfilippo, Paul G. Lu, Yi Wang, Ya Xing Hayward, Caroline Polasek, Ozren Campbell, Harry Bencic, Goran Wright, Alan F. Wedenoja, Juho Zeller, Tanja Schillert, Arne Mirshahi, Alireza Lackner, Karl Yip, Shea Ping Yap, Maurice K. H. Ried, Janina S. Gieger, Christian Murgia, Federico Wilson, James F. Fleck, Brian Yazar, Seyhan Vingerling, Johannes R. Hofman, Albert Uitterlinden, Andre Rivadeneira, Fernando Amin, Najaf Karssen, Lennart Oostra, Ben A. Zhou, Xin Teo, Yik-Ying Tai, E. Shyong Vithana, Eranga Barathi, Veluchamy Zheng, Yingfeng Siantar, Rosalynn Grace Neelam, Kumari Shin, Youchan Lam, Janice Yonova-Doing, Ekaterina Venturini, Cristina Hosseini, S. Mohsen Wong, Hoi-Suen Lehtimaki, Terho Kahonen, Mika Raitakari, Olli Timpson, Nicholas J. Evans, David M. Khor, Chiea-Chuen Aung, Tin Young, Terri L. Mitchell, Paul Klein, Barbara van Duijn, Cornelia M. Meitinger, Thomas Jonas, Jost B. Baird, Paul N. Mackey, David A. Wong, Tien Yin Saw, Seang-Mei Parssinen, Olavi Stambolian, Dwight Hammond, Christopher J. Klaver, Caroline C. W. Williams, Cathy Paterson, Andrew D. Bailey-Wilson, Joan E. Guggenheim, Jeremy A. CA CREAM Consortium TI Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium SO HUMAN GENETICS LA English DT Article ID EXPERIMENTALLY-INDUCED MYOPIA; OPEN-ANGLE GLAUCOMA; BLUE MOUNTAINS EYE; CORNEAL ASTIGMATISM; SUSCEPTIBILITY LOCI; NONCODING RNAS; MAJOR LOCUS; POPULATION; AGE; DISEASE AB To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged < 25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged < 25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors. C1 [Li, Qing; Wojciechowski, Robert; Simpson, Claire L.; Bailey-Wilson, Joan E.] NHGRI, NIH, Baltimore, MD 21224 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Hysi, Pirro G.; Yonova-Doing, Ekaterina; Venturini, Cristina; Hammond, Christopher J.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Verhoeven, Virginie J. M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Verhoeven, Virginie J. M.; Hofman, Albert; Uitterlinden, Andre; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart; van Duijn, Cornelia M.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, Mohammad Kamran; Cheng, Ching-Yu; Vithana, Eranga; Barathi, Veluchamy; Zheng, Yingfeng; Siantar, Rosalynn Grace; Neelam, Kumari; Shin, Youchan; Lam, Janice; Aung, Tin; Wong, Tien Yin; Saw, Seang-Mei] Singapore Eye Res Inst, Singapore, Singapore. [Ikram, Mohammad Kamran; Cheng, Ching-Yu; Vithana, Eranga; Barathi, Veluchamy; Khor, Chiea-Chuen; Wong, Tien Yin; Saw, Seang-Mei] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 117595, Singapore. [Ikram, Mohammad Kamran; Cheng, Ching-Yu; Wong, Tien Yin] Duke NUS Grad Med Sch, Off Clin Sci, Singapore, Singapore. [Hoehn, Rene; Mirshahi, Alireza] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Hoehn, Rene] Klin Pallas, Olten, Switzerland. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hewitt, Alex W.; Baird, Paul N.; Mackey, David A.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Hewitt, Alex W.; Sanfilippo, Paul G.; Yazar, Seyhan; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Oexle, Konrad; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-80290 Munich, Germany. [Makela, Kari-Matti; Lehtimaki, Terho] Tampere Univ Hosp, Dept Clin Chem, Tampere 33520, Finland. [Makela, Kari-Matti; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere 33520, Finland. [MacGregor, Stuart; Lu, Yi] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Pirastu, Mario; Murgia, Federico] CNR, Inst Populat Genet, I-07040 Sassari, Italy. [Fan, Qiao; Zhou, Xin; Teo, Yik-Ying; Tai, E. Shyong; Saw, Seang-Mei] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [St Pourcain, Beat; McMahon, George; Kemp, John P.; Timpson, Nicholas J.; Evans, David M.] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol BS8 2BN, Avon, England. [St Pourcain, Beat; McMahon, George; Kemp, John P.; Northstone, Kate; Timpson, Nicholas J.; Evans, David M.; Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Rahi, Jugnoo S.; Cumberland, Phillippa M.] UCL Inst Child Hlth, Ctr Epidemiol & Biostat, London, England. [Rahi, Jugnoo S.; Venturini, Cristina] UCL, Inst Ophthalmol, London, England. [Rahi, Jugnoo S.; Cumberland, Phillippa M.] UCL Inst Child Hlth, Ulverscroft Vis Res Grp, London, England. [Martin, Nicholas G.] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia. [Wang, Ya Xing] Capital Univ Med Sci, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Polasek, Ozren] Univ Split, Fac Med, Split, Croatia. [Campbell, Harry; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Bencic, Goran] Sisters Mercy Univ Hosp, Dept Ophthalmol, Zagreb, Croatia. [Wedenoja, Juho] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland. [Wedenoja, Juho] Univ Helsinki, Cent Hosp, Dept Ophthalmol, Helsinki, Finland. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Schillert, Arne] Med Univ Lubeck, Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, D-23538 Lubeck, Germany. [Schillert, Arne] DZHK German Ctr Cardiovasc Res, Lubeck, Germany. [Mirshahi, Alireza] Dardenne Eye Hosp, Bonn, Germany. [Lackner, Karl] Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, Mainz, Germany. [Yip, Shea Ping] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Yip, Shea Ping; Yap, Maurice K. H.; Guggenheim, Jeremy A.] Hong Kong Polytech Univ, Sch Optometry, Ctr Myopia Res, Kowloon, Hong Kong, Peoples R China. [Ried, Janina S.; Gieger, Christian] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh EH3 9HA, Midlothian, Scotland. [Hofman, Albert; Uitterlinden, Andre; Rivadeneira, Fernando] Netherlands Genom Initiat, Netherlands Consortium Hlth Ageing, The Hague, Netherlands. [Uitterlinden, Andre; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Hlth Syst, Singapore, Singapore. [Tai, E. Shyong; Barathi, Veluchamy; Young, Terri L.; Saw, Seang-Mei] Duke Natl Univ Singapore Grad Med Sch, Singapore, Singapore. [Vithana, Eranga] Duke NUS Grad Med Sch, NBD Program, Singapore, Singapore. [Hosseini, S. Mohsen; Wong, Hoi-Suen; Paterson, Andrew D.] Hosp Sick Children Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 0A4, Canada. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Tampere 33521, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20041, Finland. [Evans, David M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. [Khor, Chiea-Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Young, Terri L.] Duke Univ, Sch Med, Duke Eye Ctr, Durham, NC USA. [Mitchell, Paul] Univ Sydney, Sydney, NSW 2006, Australia. [Mitchell, Paul] Western Sydney Local Hlth Network, Sydney, NSW, Australia. [Mitchell, Paul] Westmead Millennium Inst, Westmead, NSW, Australia. [Klein, Barbara] Univ Wisconsin Madison, Madison, WI 53726 USA. [Jonas, Jost B.] Capital Med Univ, Beijing Ophthalmol & Visual Sci Key Lab, Beijing Tongren Hosp, Beijing Inst Ophthalmol,Beijing Tongren Eye Ctr, Beijing, Peoples R China. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Parssinen, Olavi] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. [Parssinen, Olavi] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla, Finland. [Parssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla, Finland. [Stambolian, Dwight] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Hammond, Christopher J.] Kings Coll London, Dept Ophthalmol, London, England. [Paterson, Andrew D.] Univ Toronto, Dala Lanna Sch Publ Hlth, Toronto, ON, Canada. RP Guggenheim, JA (reprint author), Hong Kong Polytech Univ, Sch Optometry, Ctr Myopia Res, Kowloon, Hong Kong, Peoples R China. EM jeremy.guggenheim@polyu.edu.hk RI wang, YA XING/K-9671-2016; Mackey, David/H-5340-2014; Northstone, Kate/A-8165-2011; Paterson, Andrew/A-4088-2011; Hewitt, Alex/D-1936-2013; Yap, Maurice/K-4927-2016; Delcourt, Cecile/I-2627-2013; Macgregor, Stuart/C-6442-2009; DeAngelis, e/J-7863-2015; Mitchell, Paul/P-1498-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Biino, Ginevra/B-5334-2013; Rivadeneira, Fernando/O-5385-2015; Yip, Shea Ping/A-1185-2016; OI wang, YA XING/0000-0003-2749-7793; Mackey, David/0000-0001-7914-4709; Northstone, Kate/0000-0002-0602-1983; Simpson, Claire/0000-0003-2244-7690; Yazar, Seyhan/0000-0003-0994-6196; Wojciechowski, Robert/0000-0002-9593-4652; Bailey-Wilson, Joan/0000-0002-9153-2920; Baird, Paul/0000-0002-1305-3502; Hosseini, Mohsen/0000-0003-3626-9928; Gieger, Christian/0000-0001-6986-9554; Luben, Robert/0000-0002-5088-6343; Rantanen, Taina/0000-0002-1604-1945; Gharahkhani, Puya/0000-0002-4203-5952; Hohn, Rene /0000-0003-2870-1469; St Pourcain, Beate/0000-0002-4680-3517; Khor, Chiea Chuen/0000-0002-1128-4729; Hammond, Christopher/0000-0002-3227-2620; Paterson, Andrew/0000-0002-9169-118X; Hewitt, Alex/0000-0002-5123-5999; Yap, Maurice/0000-0003-4687-4101; Delcourt, Cecile/0000-0002-2099-0481; Macgregor, Stuart/0000-0001-6731-8142; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Biino, Ginevra/0000-0002-9936-946X; Rivadeneira, Fernando/0000-0001-9435-9441; Yip, Shea Ping/0000-0002-2170-8185; Kemp, John/0000-0002-9105-2249; Ikram, Mohammad Kamran/0000-0003-0173-9571; Evans, David/0000-0003-0663-4621; Tai, E Shyong/0000-0003-2929-8966; Karssen, Lennart C./0000-0002-1959-342X FU Chief Scientist Office [CZB/4/438, CZB/4/710]; Department of Health [CDF-2009-02-35, SRF/01/010]; Intramural NIH HHS [Z99 EY999999]; Medical Research Council [MC_PC_15018, MC_PC_U127561128, MC_UU_12013/3, MC_UU_12013/4]; NEI NIH HHS [K08 EY022943, P30 EY001583, R01 EY014685, R01 EY024233]; Wellcome Trust [102215] NR 93 TC 3 Z9 3 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD FEB PY 2015 VL 134 IS 2 BP 131 EP 146 DI 10.1007/s00439-014-1500-y PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AZ3TM UT WOS:000348149500001 PM 25367360 ER PT J AU Carvajal-Carmona, LG O'Mara, TA Painter, JN Lose, FA Dennis, J Michailidou, K Tyrer, JP Ahmed, S Ferguson, K Healey, CS Pooley, K Beesley, J Cheng, T Jones, A Howarth, K Martin, L Gorman, M Hodgson, S Wentzensen, N Fasching, PA Hein, A Beckmann, MW Renner, SP Dork, T Hillemanns, P Durst, M Runnebaum, I Lambrechts, D Coenegrachts, L Schrauwen, S Amant, F Winterhoff, B Dowdy, SC Goode, EL Teoman, A Salvesen, HB Trovik, J Njolstad, TS Werner, HMJ Scott, RJ Ashton, K Proietto, T Otton, G Wersall, O Mints, M Tham, E Hall, P Czene, K Liu, JJ Li, JM Hopper, JL Southey, MC Ekici, AB Ruebner, M Johnson, N Peto, J Burwinkel, B Marme, F Brenner, H Dieffenbach, AK Meindl, A Brauch, H Lindblom, A Depreeuw, J Moisse, M Chang-Claude, J Rudolph, A Couch, FJ Olson, JE Giles, GG Bruinsma, F Cunningham, JM Fridley, BL Borresen-Dale, AL Kristensen, VN Cox, A Swerdlow, AJ Orr, N Bolla, MK Wang, Q Weber, RP Chen, ZH Shah, M Pharoah, PDP Dunning, AM Tomlinson, I Easton, DF Spurdle, AB Thompson, DJ AF Carvajal-Carmona, Luis G. O'Mara, Tracy A. Painter, Jodie N. Lose, Felicity A. Dennis, Joe Michailidou, Kyriaki Tyrer, Jonathan P. Ahmed, Shahana Ferguson, Kaltin Healey, Catherine S. Pooley, Karen Beesley, Jonathan Cheng, Timothy Jones, Angela Howarth, Kimberley Martin, Lynn Gorman, Maggie Hodgson, Shirley Wentzensen, Nicholas Fasching, Peter A. Hein, Alexander Beckmann, Matthias W. Renner, Stefan P. Doerk, Thilo Hillemanns, Peter Duerst, Matthias Runnebaum, Ingo Lambrechts, Diether Coenegrachts, Lieve Schrauwen, Stefanie Amant, Frederic Winterhoff, Boris Dowdy, Sean C. Goode, Ellen L. Teoman, Attila Salvesen, Helga B. Trovik, Jone Njolstad, Tormund S. Werner, Henrica M. J. Scott, Rodney J. Ashton, Katie Proietto, Tony Otton, Geoffrey Wersaell, Ofra Mints, Miriam Tham, Emma Hall, Per Czene, Kamila Liu, Jianjun Li, Jingmei Hopper, John L. Southey, Melissa C. Ekici, Arif B. Ruebner, Matthias Johnson, Nichola Peto, Julian Burwinkel, Barbara Marme, Frederik Brenner, Hermann Dieffenbach, Aida K. Meindl, Alfons Brauch, Hiltrud Lindblom, Annika Depreeuw, Jeroen Moisse, Matthieu Chang-Claude, Jenny Rudolph, Anja Couch, Fergus J. Olson, Janet E. Giles, Graham G. Bruinsma, Fiona Cunningham, Julie M. Fridley, Brooke L. Borresen-Dale, Anne-Lise Kristensen, Vessela N. Cox, Angela Swerdlow, Anthony J. Orr, Nicholas Bolla, Manjeet K. Wang, Qin Weber, Rachel Palmieri Chen, Zhihua Shah, Mitul Pharoah, Paul D. P. Dunning, Alison M. Tomlinson, Ian Easton, Douglas F. Spurdle, Amanda B. Thompson, Deborah J. CA NSECG ANECS RENDOCAS AOCS GENICA Network TI Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; BREAST-CANCER; OVARIAN-CANCER; FUNCTIONAL VARIATION; TELOMERE LENGTH; COMMON VARIANT; EXPRESSION; GENE AB Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 x 10(-6) to P = 7.7 x 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 x 10(-18), CLPTM1L P = 1.5 x 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. C1 [Carvajal-Carmona, Luis G.] Univ Calif Davis, Sch Med, Genome Ctr, Davis, CA 95616 USA. [Carvajal-Carmona, Luis G.] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. [O'Mara, Tracy A.; Painter, Jodie N.; Lose, Felicity A.; Ferguson, Kaltin; Beesley, Jonathan; Spurdle, Amanda B.; ANECS] QIMR Berghofer Med Res Inst, Australian Ovarian Canc Study AOCS, Australian Natl Endometrial Canc Study Grp ANECS, Brisbane, Qld, Australia. [Dennis, Joe; Michailidou, Kyriaki; Pooley, Karen; Bolla, Manjeet K.; Wang, Qin; Easton, Douglas F.; Thompson, Deborah J.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Tyrer, Jonathan P.; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Cheng, Timothy; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Tomlinson, Ian; NSECG] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hodgson, Shirley] St Georges Hosp Med Sch, Dept Clin Genet, London, England. [Wentzensen, Nicholas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Renner, Stefan P.; Ekici, Arif B.; Ruebner, Matthias] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Duerst, Matthias; Runnebaum, Ingo] Univ Jena, Jena Univ Hosp, Dept Gynaecol, Jena, Germany. [Lambrechts, Diether; Depreeuw, Jeroen; Moisse, Matthieu] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether; Depreeuw, Jeroen; Moisse, Matthieu] Katholieke Univ Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium. [Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium. [Amant, Frederic] Univ Hosp Leuven, Div Gynaecol Oncol, Leuven, Belgium. [Winterhoff, Boris; Dowdy, Sean C.; Teoman, Attila] Mayo Clin, Dept Obstet & Gynecol, Div Gynecol Oncol, Rochester, MN USA. [Goode, Ellen L.; Olson, Janet E.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Salvesen, Helga B.; Trovik, Jone; Njolstad, Tormund S.; Werner, Henrica M. J.] Univ Bergen, Dept Clin Sci, Ctr Cancerbiomarkers, Bergen, Norway. [Salvesen, Helga B.; Trovik, Jone; Njolstad, Tormund S.; Werner, Henrica M. J.] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. [Scott, Rodney J.; Ashton, Katie] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia. [Scott, Rodney J.] John Hunter Hosp, Hunter Area Pathol Serv, Newcastle, NSW, Australia. [Scott, Rodney J.; Ashton, Katie] Univ Newcastle, Sch Biomed Sci & Pharm, Ctr Informat Based Med, Newcastle, NSW 2300, Australia. [Ashton, Katie] Univ Newcastle, Sch Biomed Sci & Pharm, Discipline Med Genet, Newcastle, NSW 2300, Australia. [Proietto, Tony; Otton, Geoffrey] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia. [Wersaell, Ofra; Mints, Miriam] Karolinska Inst, Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Tham, Emma; Lindblom, Annika; RENDOCAS] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Liu, Jianjun; Li, Jingmei] Genome Inst Singapore, Singapore, Singapore. [Hopper, John L.; Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic, Australia. [AOCS] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Peto, Julian] London Sch Hyg & Trop Med, London WC1, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Gynecol & Obstet, Heidelberg, Germany. [Burwinkel, Barbara; Brenner, Hermann; Dieffenbach, Aida K.] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K.] German Canc Consortium DKTK, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Dept Obstet & Gynecol, Div Tumor Genet, D-80290 Munich, Germany. [Brauch, Hiltrud] Univ Tubingen, Dr Margarete Fischer Bosch Inst Clin Pharmacol St, Tubingen, Germany. Univ Med Ctr Hamburg Eppendorf, Inst Occupat Med & Maritime Med, Hamburg, Germany. Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Univ Bonn, Inst Pathol, Fac Med, Bonn, Germany. Ruhr Univ Bochum IPA, German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [GENICA Network] Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Rudolph, Anja] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Rudolph, Anja] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Couch, Fergus J.; Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, Fergus J.; Cunningham, Julie M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.; Bruinsma, Fiona] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Norwegian Radium Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Fac Med, Oslo, Norway. [Kristensen, Vessela N.] Akershus Univ Hosp, Dept Clin Mol Oncol, Div Med, Ahus, Norway. [Cox, Angela] Univ Sheffield, Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Swerdlow, Anthony J.] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Swerdlow, Anthony J.; Orr, Nicholas] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Weber, Rachel Palmieri] Duke Univ, Sch Med, Dept Community & Family Med, Durham, NC USA. [Chen, Zhihua] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33682 USA. RP Hopper, JL (reprint author), Univ Calif Davis, Sch Med, Genome Ctr, Davis, CA 95616 USA. EM lgcarvajal@ucdavis.edu; djt25@medschl.cam.ac.uk RI Hein, Alexander/F-6999-2010; Fridley, Brooke/D-8315-2015; Li, Jingmei/I-2904-2012; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Brenner, Hermann/B-4627-2017; salvesen, Helga/C-1187-2017; Cheng, Timothy/D-8747-2017; Spurdle, Amanda/A-4978-2011; O'Mara, Tracy/M-7508-2016; Renner, Stefan/F-1158-2014 OI Dunning, Alison Margaret/0000-0001-6651-7166; Cox, Angela/0000-0002-5138-1099; Moisse, Matthieu/0000-0001-8880-9311; Njolstad, Tormund/0000-0003-4024-3819; Giles, Graham/0000-0003-4946-9099; Hein, Alexander/0000-0003-2601-3398; Fridley, Brooke/0000-0001-7739-7956; Li, Jingmei/0000-0001-8587-7511; Bowtell, David/0000-0001-9089-7525; Brenner, Hermann/0000-0002-6129-1572; salvesen, Helga/0000-0002-4438-8831; Spurdle, Amanda/0000-0003-1337-7897; Lose, Felicity/0000-0001-8337-3547; Czene, Kamila/0000-0002-3233-5695; O'Mara, Tracy/0000-0002-5436-3232; Renner, Stefan/0000-0003-2057-1268 FU NHMRC [1031333]; University of California Davis; V Foundation for Cancer Research; National Institute On Aging [P30AG043097]; National Cancer Institute of the National Institutes of Health [K12CA138464]; National Health and Medical Research Council (NHMRC); Joseph Mitchell Trust; Cancer Research UK; Oxford Comprehensive Biomedical Research Centre; Dr. Mildred Scheel Stiftung of the Deutsche Krebshilfe (German Cancer Aid); European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C490/A10124, C1287/A12014]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; NCI [CA 15083]; National Health and Medical Research Council of Australia [339435]; Cancer Council Queensland [4196615]; Cancer Council Tasmania [403031, 457636]; National Health and Medical Research Council [1031333]; Oxford Comprehensive Biomedical Research Centre [075491/Z/04]; University of Erlangen; Verelst Foundation for endometrial cancer; National Cancer Institute of United States Public Health Service [R01 CA122443, P30 CA15083, P50 CA136393, RO1 CA 092585, R01 CA90899, R01 CA64277]; GAME-ON the NCI Cancer Post-GWAS Initiative [U19 CA148112]; Fred C and Katherine B Andersen Foundation; Mayo Foundation; Smith family; Helse Vest Grant; University of Bergen; Melzer Foundation; Norwegian Cancer Society (Harald Andersens legat); Research Council of Norway; Haukeland University Hospital; Stockholm County Council [20110222, 20110483, 20110141, DF 07015]; Karolinska Institutet [20110222, 20110483, 20110141, DF 07015]; Swedish Labor Market Insurance [100069]; Swedish Cancer Society [11 0439]; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Ovarian Cancer Research Fund [PPD/RPCI.07]; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge FX The authors thank the many individuals who participated in this study and the numerous institutions and their staff who have supported recruitment, detailed in full in the Supplementary Notes. Fine-mapping analysis was supported by NHMRC Project Grant (ID#1031333) to ABS, DFE and AMD. LGC-C receives funding from the University of California Davis, The V Foundation for Cancer Research, and The National Institute On Aging (award number P30AG043097) and The National Cancer Institute (award number K12CA138464) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ABS is supported by the National Health and Medical Research Council (NHMRC) Fellowship scheme. D. F. E. is a Principal Research Fellow of Cancer Research UK. A. M. D. is supported by the Joseph Mitchell Trust. I. T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. P. A. F. was partly funded by the Dr. Mildred Scheel Stiftung of the Deutsche Krebshilfe (German Cancer Aid). FA is senior clinical researcher for the Research Fund Flanders (F.W.O.). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under Grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. NCI CA 15083 (Mayo Clinic CCSG) supported the genotyping carried out by the Genotyping Core laboratory. ANECS recruitment was supported by Project Grants from the National Health and Medical Research Council of Australia (ID#339435), The Cancer Council Queensland (ID#4196615) and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme Grant from Cancer Research UK (C490/A10124). Case genotyping was supported by the National Health and Medical Research Council (ID#1031333). NSECG was supported principally by Cancer Research UK and by funds from the Oxford Comprehensive Biomedical Research Centre, with core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford provided by Grant 075491/Z/04. The Bavarian Endometrial Cancer Study (BECS) was partly funded by the ELAN fund of the University of Erlangen. The Leuven Endometrium Study (LES) was supported by the Verelst Foundation for endometrial cancer. The Mayo Endometrial Cancer Study (MECS) and Mayo controls (MAY) were supported by Grants from the National Cancer Institute of United States Public Health Service (R01 CA122443, P30 CA15083, P50 CA136393, and GAME-ON the NCI Cancer Post-GWAS Initiative U19 CA148112), the Fred C and Katherine B Andersen Foundation, the Mayo Foundation, and the Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith. MoMaTEC received financial support from a Helse Vest Grant, the University of Bergen, Melzer Foundation, The Norwegian Cancer Society (Harald Andersens legat), The Research Council of Norway and Haukeland University Hospital.; The Newcastle Endometrial Cancer Study (NECS) acknowledges contributions from the University of Newcastle, The NBN Children's Cancer Research Group, Ms Jennie Thomas and the Hunter Medical Research Institute. RENDOCAS was supported through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (numbers: 20110222, 20110483, 20110141 and DF 07015), The Swedish Labor Market Insurance (number 100069) and The Swedish Cancer Society (number 11 0439). The Cancer Hormone Replacement Epidemiology in Sweden Study (CAHRES, formerly called The Singapore and Swedish Breast/Endometrial Cancer Study; SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The Shanghai Endometrial Cancer Genetic Study (SECGS) was supported by Grants from the National Cancer Institute of United States Public Health Service (RO1 CA 092585 and R01 CA90899, R01 CA64277). The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK (C1287/A10118, C1287/A12014). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07), and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Additional funding for individual control groups is detailed in the Supplementary Text. NR 63 TC 11 Z9 11 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD FEB PY 2015 VL 134 IS 2 BP 231 EP 245 DI 10.1007/s00439-014-1515-4 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AZ3TM UT WOS:000348149500010 PM 25487306 ER PT J AU Rivera, MM Soza, A Jazwinski, A Mi, LJ Kleiner, DE Zhao, XC Zuber, C Brust, D Hsu, E Simpson, J Hoofnagle, JH Heller, T AF Rivera, Maria M. Soza, Alejandro Jazwinski, Alison Mi, Lijun Kleiner, David E. Zhao, Xiongce Zuber, Charma Brust, Douglas Hsu, Emory Simpson, Jennifer Hoofnagle, Jay H. Heller, Theo TI HIV Through the Looking Glass: Insights Derived From Hepatitis B SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE co-infection; HBV; HIV; immune ID VIRUS-INFECTION; HOMOSEXUAL-MEN; CORE ANTIGEN; MICROBIAL TRANSLOCATION; MORTALITY; PROGRESSION; HEPATOCYTE; PREVALENCE; THERAPY; PATIENT AB Background:Although higher levels of hepatitis B virus (HBV) replication in HIV-HBV co-infection may relate to liver disease progression, this has not been completely elucidated. We used expression of hepatitis B core antigen (HBcAg) in liver biopsies from HIV-HBV co-infected and HBV mono-infected patients as a marker for HBV replication, and related these findings to clinical and histological parameters.Methods:Data from 244 HBV patients were compared with 34 HIV-HBV patients. Liver biopsies were scored for inflammation, fibrosis, HBcAg, and hepatitis B surface antigen. Univariate and multivariate analyses were performed.Results:HBcAg, but not hepatitis B surface antigen, staining was stronger in HIV co-infected than in HBV mono-infected. Co-infected and HBV mono-infected had similar alanine aminotransferase, inflammatory and fibrosis scores, and hepatitis B e antigen status. HBcAg staining correlated with HIV after correcting for HBV DNA and hepatitis B e antigen. CD4 counts and HIV RNA level did not correlate with intensity of HBcAg staining. HBV DNA levels were higher in HIV co-infected and correlated with HBcAg staining.Conclusions:By looking at HBcAg as a reflection of HBV replication in HIV-HBV co-infected with controlled HIV, our findings suggest that these patients may have subtle immune function defects, which could lead to adverse liver disease outcomes. C1 [Rivera, Maria M.; Jazwinski, Alison; Mi, Lijun; Zhao, Xiongce; Hsu, Emory; Simpson, Jennifer; Hoofnagle, Jay H.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Soza, Alejandro] Pontificia Univ Catolica Chile, NIH, Bethesda, MD USA. [Kleiner, David E.] NCI, NIH, Bethesda, MD 20892 USA. [Zuber, Charma] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Brust, Douglas] NIAID, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr MSC 1800,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM theoh@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [Z01 DK054514-02 LDB]; National Cancer Institute; Clinical Center, National Institutes of Health, Bethesda, MD FX Supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases (Z01 DK054514-02 LDB), National Cancer Institute, and the Clinical Center, National Institutes of Health, Bethesda, MD. NR 21 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD FEB 1 PY 2015 VL 68 IS 2 BP 123 EP 127 DI 10.1097/QAI.0000000000000415 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AZ8IF UT WOS:000348458200006 PM 25590267 ER PT J AU Kahana, SY Fernandez, MI Wilson, PA Bauermeister, JA Lee, S Wilson, CM Hightow-Weidman, LB AF Kahana, Shoshana Y. Fernandez, Maria Isabel Wilson, Patrick A. Bauermeister, Jose A. Lee, Sonia Wilson, Craig M. Hightow-Weidman, Lisa B. TI Rates and Correlates of Antiretroviral Therapy Use and Virologic Suppression Among Perinatally and Behaviorally HIV-Infected Youth Linked to Care in the United States SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; youth; antiretroviral therapy; viral suppression ID SEXUALLY-TRANSMITTED INFECTIONS; YOUNG-ADULTS; ACQUIRED HIV; POSITIVE ADOLESCENTS; DRUG-RESISTANCE; SCREENING-TEST; VIRAL LOAD; HEALTH; DISPARITIES; ADHERENCE AB Objective:To measure rates of antiretroviral therapy (ART) use and virologic suppression among perinatally HIV-infected youth (PIY) and behaviorally HIV-infected youth (BIY) linked to care in the United States and examine the effects of demographic, biomedical, and psychosocial factors on those rates.Methods:Between 2009 and 2012, 649 PIY and 1547 BIY in 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions sites completed cross-sectional surveys through audio computer-assisted self-interviews. Viral load data were collected from chart abstraction or blood draw.Results:Overall 82.4% of PIY and 49.1% of BIY reported current ART use. Only 37.0% of PIY and 27.1% of BIY were virologically suppressed. Virologic suppression rates did not vary as a function of time since HIV diagnosis in either group. Consistent HIV care and no current substance abuse were significant correlates of ART use among PIY. These variables and non-African American race were some factors associated with virologic suppression for PIY [odds ratios (ORs) P < 0.05]. Among BIY, older age, heterosexuals, employment, and education were significantly related to ART use (ORs: P < 0.05); suppression was related to ART use 6 months, 90% ART adherence, and consistent HIV care (ORs: P < 0.05). Nearly 75% (n = 498) of nonsuppressed youth reported unprotected sex in the past 3 months.Conclusions:There are continued challenges with successfully treating youth even once diagnosed and linked to HIV care. Strategies targeting barriers to ART access, use, and virologic suppression are needed to optimize the impact of the Treatment as Prevention paradigm among PIY and BIY. C1 [Kahana, Shoshana Y.] NIDA, Div Epidemiol, Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Fernandez, Maria Isabel] Nova SE Univ, Coll Osteopath Med, Dept Prevent Med, Ft Lauderdale, FL 33314 USA. [Fernandez, Maria Isabel] Nova SE Univ, Coll Osteopath Med, Dept Publ Hlth Program, Ft Lauderdale, FL 33314 USA. [Wilson, Patrick A.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY USA. [Bauermeister, Jose A.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Lee, Sonia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Pediat Infect Dis Branch, NIH, Bethesda, MD USA. [Wilson, Craig M.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Hightow-Weidman, Lisa B.] Univ N Carolina, Div Infect Dis, Dept Med, Chapel Hill, NC USA. RP Kahana, SY (reprint author), NIDA, Div Epidemiol, Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. EM kahanas@mail.nih.gov OI Bauermeister, Jose/0000-0002-9276-2306 FU Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD 040533, U01 HD 040474]; National Institute on Drug Abuse; National Institute on Mental Health FX Supported by The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health [U01 HD 040533 and U01 HD 040474] through the National Institute of Child Health and Human Development (B. Kapogiannis and S.L.), with supplemental funding from the National Institutes on Drug Abuse (K. Davenny and S.Y.K.) and Mental Health (P. Brouwers, S. Allison). S.Y.K. and S.L. are NIDA and NICHD Program Scientists, respectively, with the ATN. NR 51 TC 13 Z9 13 U1 2 U2 6 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 FEB 1 PY 2015 VL 68 IS 2 BP 169 EP 177 DI 10.1097/QAI.0000000000000408 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AZ8IF UT WOS:000348458200013 PM 25590270 ER PT J AU Olfson, M King, M Schoenbaum, M AF Olfson, Mark King, Marissa Schoenbaum, Michael TI Benzodiazepine Use in the United States SO JAMA PSYCHIATRY LA English DT Article ID INAPPROPRIATE MEDICATION USE; ELIMINATION HALF-LIFE; LONG-TERM USE; OLDER-ADULTS; ANXIETY DISORDERS; PERSISTENT INSOMNIA; BEHAVIORAL-THERAPY; GENERAL-POPULATION; CONSENSUS PANEL; NATIONAL-SURVEY AB IMPORTANCE Although concern exists regarding the rate of benzodiazepine use, especially long-term use by older adults, little information is available concerning patterns of benzodiazepine use in the United States. OBJECTIVE To describe benzodiazepine prescription patterns in the United States focusing on patient age and duration of use. DESIGN, SETTING, AND PARTICIPANTS A retrospective descriptive analysis of benzodiazepine prescriptions was performed with the 2008 LifeLink LRx Longitudinal Prescription database (IMS Health Inc), which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population. MAIN OUTCOMES AND MEASURES The percentage of adults filling 1 or more benzodiazepine prescriptions during the study year by sex and age group (18-35 years, 36-50 years, 51-64 years, and 65-80 years) and among individuals receiving benzodiazepines, the corresponding percentages with long-term (>= 120 days) benzodiazepine use, prescription of a long-acting benzodiazepine, and benzodiazepine prescriptions from a psychiatrist. RESULTS In 2008, approximately 5.2% of US adults aged 18 to 80 years used benzodiazepines. The percentage who used benzodiazepines increased with age from 2.6% (18-35 years) to 5.4%(36-50 years) to 7.4%(51-64 years) to 8.7%(65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term increased with age from 14.7%(18-35 years) to 31.4% (65-80 years), while the proportion that received a benzodiazepine prescription from a psychiatrist decreased with age from 15.0%(18-35 years) to 5.7%(65-80 years). In all age groups, roughly one-quarter of individuals receiving benzodiazepine involved long-acting benzodiazepine use. CONCLUSIONS AND RELEVANCE Despite cautions concerning risks associated with long-term benzodiazepine use, especially in older patients, long-term benzodiazepine use remains common in this age group. More vigorous clinical interventions supporting judicious benzodiazepine use may be needed to decrease rates of long-term benzodiazepine use in older adults. C1 [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [King, Marissa] Yale Univ, Sch Management, New Haven, CT USA. [Schoenbaum, Michael] NIMH, Off Director, NIH, Bethesda, MD 20892 USA. RP Olfson, M (reprint author), Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@.columbia.edu FU National Institutes of Health; Agency for Healthcare Research and Quality [U19HSO2112]; New York State Psychiatric Institute FX This research was funded by contracts from the National Institutes of Health to Yale University (King) and Columbia University (Olfson), grant U19HSO2112 from the Agency for Healthcare Research and Quality (Olfson), and the New York State Psychiatric Institute (Olfson). NR 79 TC 67 Z9 67 U1 4 U2 25 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 FEB PY 2015 VL 72 IS 2 BP 136 EP 142 DI 10.1001/jamapsychiatry.2014.1763 PG 7 WC Psychiatry SC Psychiatry GA CB2JH UT WOS:000349452800009 PM 25517224 ER PT J AU Fernandez-Boyanapalli, RF Frasch, SC Thomas, SM Malcolm, KC Nicks, M Harbeck, RJ Jakubzick, CV Nemenoff, R Henson, PM Holland, SM Bratton, DL AF Fernandez-Boyanapalli, Ruby F. Frasch, S. Courtney Thomas, Stacey M. Malcolm, Kenneth C. Nicks, Michael Harbeck, Ronald J. Jakubzick, Claudia V. Nemenoff, Raphael Henson, Peter M. Holland, Steven M. Bratton, Donna L. TI Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Chronic granulomatous disease; phagocytes; mitochondria; oxidants; thioglitazones ID ACTIVATED-RECEPTOR-GAMMA; REACTIVE OXYGEN; PPAR-GAMMA; NADPH OXIDASE; SUPEROXIDE-PRODUCTION; INSULIN-RESISTANCE; HUMAN NEUTROPHILS; CELL-DEATH; INFLAMMATION; MACROPHAGES AB Background: Deficient production of reactive oxygen species (ROS) by the phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase in patients with chronic granulomatous disease (CGD) results in susceptibility to certain pathogens secondary to impaired oxidative killing and mobilization of other phagocyte defenses. Peroxisome proliferator-activated receptor (PPAR) gamma agonists, including pioglitazone, approved for type 2 diabetes therapy alter cellular metabolism and can heighten ROS production. It was hypothesized that pioglitazone treatment of gp91(phox-/-) mice, a murine model of human CGD, would enhance phagocyte oxidant production and killing of Staphylococcus aureus, a significant pathogen in patients with this disorder. Objectives: We sought to determine whether pioglitazone treatment of gp91(phox-/-) mice enhanced phagocyte oxidant production and host defense. Methods: Wild-type and gp91(phox-/-) mice were treated with the PPAR gamma agonist pioglitazone, and phagocyte ROS and killing of Staphylococcus aureus were investigated. Results: As demonstrated by 3 different ROS-sensing probes, short-term treatment of gp91(phox-/-) mice with pioglitazone enhanced stimulated ROS production in neutrophils and monocytes from blood and neutrophils and inflammatory macrophages recruited to tissues. Mitochondria were identified as the source of ROS. Findings were replicated in human monocytes from patients with CGD after ex vivo pioglitazone treatment. Importantly, although mitochondrial (mt) ROS were deficient in gp91(phox-/-) phagocytes, their restoration with treatment significantly enabled killing of Staphylococcus aureus both ex vivo and in vivo. Conclusions: Together, the data support the hypothesis that signaling from the NADPH oxidase under normal circumstances governs phagocyte mtROS production and that such signaling is lacking in the absence of a functioning phagocyte oxidase. PPAR gamma agonism appears to bypass the need for the NADPH oxidase for enhanced mtROS production and partially restores host defense in CGD. C1 [Fernandez-Boyanapalli, Ruby F.; Frasch, S. Courtney; Thomas, Stacey M.; Nicks, Michael; Harbeck, Ronald J.; Jakubzick, Claudia V.; Henson, Peter M.; Bratton, Donna L.] Natl Jewish Med & Res Ctr, Dept Pediat, Denver, CO 80206 USA. [Malcolm, Kenneth C.; Harbeck, Ronald J.; Henson, Peter M.] Natl Jewish Med & Res Ctr, Dept Med, Denver, CO USA. [Harbeck, Ronald J.; Henson, Peter M.] Natl Jewish Med & Res Ctr, Dept Immunol, Denver, CO USA. [Nemenoff, Raphael] Univ Denver, Dept Med, Div Renal Dis & Hypertens, Denver, CO 80208 USA. [Holland, Steven M.] NIAID, Labs Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bratton, DL (reprint author), Natl Jewish Med & Res Ctr, Dept Pediat, Rm A540,1400 Jackson St, Denver, CO 80206 USA. EM brattond@njhealth.org OI Thomas, Stacey/0000-0002-5666-4311 FU National Institutes of Health [AI058228, AI110408, HL34303]; Chronic Granulomatous Disorder Society (United Kingdom) [J4G/10/03] FX This investigation was entirely funded by National Institutes of Health grants AI058228, AI110408, and HL34303 and the Chronic Granulomatous Disorder Society (United Kingdom, J4G/10/03). NR 69 TC 5 Z9 5 U1 0 U2 3 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 FEB PY 2015 VL 135 IS 2 BP 517 EP U323 DI 10.1016/j.jaci.2014.10.034 PG 23 WC Allergy; Immunology SC Allergy; Immunology GA CB1FL UT WOS:000349372300026 PM 25498313 ER PT J AU Czifra, G Szollosi, A Nagy, Z Boros, M Juhasz, I Kiss, A Erdodi, F Szabo, T Kovacs, I Torok, M Kovacs, L Blumberg, PM Biro, T AF Czifra, Gabriella Szoellosi, Attila Nagy, Zsuzsanna Boros, Miklos Juhasz, Istvan Kiss, Andrea Erdodi, Ferenc Szabo, Tamas Kovacs, Ilona Toeroek, Miklos Kovacs, Laszlo Blumberg, Peter M. Biro, Tamas TI Protein kinase C delta promotes proliferation and induces malignant transformation in skeletal muscle SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE Skeletal muscle; C2C12 myoblasts; rhabdomyosarcoma; protein kinase C; nPKC delta; PKC isoenzymes; recombinant overexpression; proliferation; differentiation; tumourigenesis ID GROWTH-FACTOR; IGF-I; RHABDOMYOSARCOMA CELLS; GLUCOSE-TRANSPORT; SATELLITE CELLS; NIH 3T3-CELLS; DIFFERENTIATION; EXPRESSION; MYOBLASTS; ISOFORMS AB In this paper, we investigated the isoform-specific roles of certain protein kinase C (PKC) isoforms in the regulation of skeletal muscle growth. Here, we provide the first intriguing functional evidence that nPKC (originally described as an inhibitor of proliferation in various cells types) is a key player in promoting both in vitro and in vivo skeletal muscle growth. Recombinant overexpression of a constitutively active nPKC in C2C12 myoblast increased proliferation and inhibited differentiation. Conversely, overexpression of kinase-negative mutant of nPKC (DN-nPKC) markedly inhibited cell growth. Moreover, overexpression of nPKC also stimulated in vivo tumour growth and induced malignant transformation in immunodeficient (SCID) mice whereas that of DN-nPKC suppressed tumour formation. The role of nPKC in the formation of rhabdomyosarcoma was also investigated where recombinant overexpression of nPKC in human rhabdomyosarcoma RD cells also increased cell proliferation and enhanced tumour formation in mouse xenografts. The other isoforms investigated (PKC, , epsilon) exerted only minor (mostly growth-inhibitory) effects in skeletal muscle cells. Collectively, our data introduce nPKC as a novel growth-promoting molecule in skeletal muscles and invite further trials to exploit its therapeutic potential in the treatment of skeletal muscle malignancies. C1 [Czifra, Gabriella; Szoellosi, Attila; Nagy, Zsuzsanna; Boros, Miklos; Kovacs, Laszlo; Biro, Tamas] Univ Debrecen, Dept Physiol, DE MTA Lendulet Cellular Physiol Res Grp, Med Fac,Res Ctr Mol Med, H-4032 Debrecen, Hungary. [Juhasz, Istvan] Univ Debrecen, Fac Med, Dept Dermatol, Res Ctr Mol Med, H-4012 Debrecen, Hungary. [Kiss, Andrea; Erdodi, Ferenc] Univ Debrecen, Dept Med Chem, Fac Med, Res Ctr Mol Med, H-4032 Debrecen, Hungary. [Szabo, Tamas] Univ Debrecen, Dept Pediat, Fac Med, Res Ctr Mol Med, H-4032 Debrecen, Hungary. [Kovacs, Ilona; Toeroek, Miklos] Gyula Kenezy Hosp, Dept Pathol, Debrecen, Hungary. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Czifra, G (reprint author), Univ Debrecen, Dept Physiol, Nagyerdei Krt 98 POB 22, H-4032 Debrecen, Hungary. EM czifrag@gmail.com FU Hungarian research grants "Lendulet" [LP2011-003/2014, TAMOP-4.2.2.A-11/1/KONV-2012-0025, TAMOP-4.2.2.A-11/1/KONV-2012-0045]; University of Debrecen [RH/885/2013]; [TAMOP-4.2.2./B-10/1-2010-0024] FX This work was supported by Hungarian research grants "Lendulet" LP2011-003/2014, TAMOP-4.2.2.A-11/1/KONV-2012-0025 and TAMOP-4.2.2.A-11/1/KONV-2012-0045 as well as by the University of Debrecen (RH/885/2013). ZN is a recipient of the TAMOP-4.2.2./B-10/1-2010-0024 Predoctoral Research Scholarship. The technical assistance of Ms. Ibolya Varga and Janos Vincze is gratefully appreciated. NR 51 TC 0 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1582-4934 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD FEB PY 2015 VL 19 IS 2 BP 396 EP 407 DI 10.1111/jcmm.12452 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CA7NQ UT WOS:000349104500011 PM 25283340 ER PT J AU Chang, KK Frankovich, J Cooperstock, M Cunningham, MW Latimer, ME Murphy, TK Pasternack, M Thienemann, M Williams, K Walter, J Swedo, SE AF Chang, Kiki Frankovich, Jennifer Cooperstock, Michael Cunningham, Madeleine W. Latimer, M. Elizabeth Murphy, Tanya K. Pasternack, Mark Thienemann, Margo Williams, Kyle Walter, Jolan Swedo, Susan E. CA PANS Collaborative Consortium TI Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID MYCOPLASMA-PNEUMONIAE INFECTION; OBSESSIVE-COMPULSIVE DISORDER; STREPTOCOCCAL INFECTIONS; SYDENHAMS CHOREA; ANTINUCLEAR ANTIBODIES; TOURETTES-SYNDROME; CHILDREN; DISEASE; PANDAS; PATHOGENESIS AB On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS. C1 [Chang, Kiki] Stanford Univ, Sch Med, Pediat Bipolar Disorders Program, Stanford, CA 94305 USA. [Frankovich, Jennifer] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Cooperstock, Michael] Univ Missouri, Sch Med, Div Infect Dis & Rheumatol, Columbia, MO USA. [Cunningham, Madeleine W.] Univ Oklahoma, Coll Med, Norman, OK 73019 USA. [Latimer, M. Elizabeth] Latimer Neurol Ctr, Bethesda, MD USA. [Murphy, Tanya K.] Univ S Florida, St Petersburg, FL 33701 USA. [Pasternack, Mark] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thienemann, Margo] Stanford Univ, Sch Med, Adjunct Clin Fac, Stanford, CA 94305 USA. [Williams, Kyle] Massachusetts Gen Hosp, Behav & Immunol Clin OCD, Boston, MA 02114 USA. [Williams, Kyle] Massachusetts Gen Hosp, Related Disorders Program, Boston, MA 02114 USA. [Walter, Jolan] Massachusetts Gen Hosp, Pediat Immunodeficiency Program, Boston, MA 02114 USA. [Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, Rockville, MD 20857 USA. RP Chang, KK (reprint author), Stanford Univ, Sch Med, Div Child & Adolescent Psychiat, 401 Quarry Rd, Stanford, CA 94305 USA. EM kchang88@stanford.edu RI Murphy, Tanya/J-7079-2013 FU GlaxoSmithKline; Merck FX Dr. Chang is an unpaid consultant for GlaxoSmithKline, Lilly, and Bristol-Myers Squibb. He is on the DSMB for Sunovion. In the past two years he has received research support from GlaxoSmithKline and Merck. Dr. Walter is on the Advisory Board of Baxter regarding IGHy, a new formulation of subcutaneous immunoglobulin. NR 48 TC 13 Z9 13 U1 6 U2 16 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2015 VL 25 IS 1 SI SI BP 3 EP 13 DI 10.1089/cap.2014.0084 PG 11 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CB4RF UT WOS:000349614900002 PM 25325534 ER PT J AU Swedo, SE Seidlitz, J Kovacevic, M Latimer, ME Hommer, R Lougee, L Grant, P AF Swedo, Susan E. Seidlitz, Jakob Kovacevic, Miro Latimer, M. Elizabeth Hommer, Rebecca Lougee, Lorraine Grant, Paul TI Clinical Presentation of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections in Research and Community Settings SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; TOURETTES-SYNDROME; SYDENHAMS CHOREA; PLASMA-EXCHANGE; CHILDHOOD; PANDAS; EXACERBATIONS; PROPHYLAXIS; PENICILLIN; TICS AB Background: The first cases of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) were described>15 years ago. Since that time, the literature has been divided between studies that successfully demonstrate an etiologic relationship between Group A streptococcal (GAS) infections and childhood-onset obsessive-compulsive disorder (OCD), and those that fail to find an association. One possible explanation for the conflicting reports is that the diagnostic criteria proposed for PANDAS are not specific enough to describe a unique and homogeneous cohort of patients. To evaluate the validity of the PANDAS criteria, we compared clinical characteristics of PANDAS patients identified in two community practices with a sample of children meeting full research criteria for PANDAS. Methods: A systematic review of clinical records was used to identify the presence or absence of selected symptoms in children evaluated for PANDAS by physicians in Hinsdale, Illinois (n=52) and Bethesda, Maryland (n=40). Results were compared against data from participants in National Institute of Mental Health (NIMH) research investigations of PANDAS (n=48). Results: As described in the original PANDAS cohort, males outnumbered females (95:45) by similar to 2:1, and symptoms began in early childhood (7.3 +/- 2.7 years). Clinical presentations were remarkably similar across sites, with all children reporting acute onset of OCD symptoms and multiple comorbidities, including separation anxiety (86-92%), school issues (75-81%), sleep disruptions (71%), tics (60-65%), urinary symptoms (42-81%), and others. Twenty of the community cases (22%) failed to meet PANDAS criteria because of an absence of documentation of GAS infections. Conclusions: The diagnostic criteria for PANDAS can be used by clinicians to accurately identify patients with common clinical features and shared etiology of symptoms. Although difficulties in documenting an association between GAS infection and symptom onset/exacerbations may preclude a diagnosis of PANDAS in some children with acute-onset OCD, they do appear to meet criteria for pediatric acute-onset neuropsychiatric syndrome (PANS). C1 [Swedo, Susan E.; Seidlitz, Jakob; Hommer, Rebecca; Lougee, Lorraine; Grant, Paul] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Kovacevic, Miro] Loyola Univ, Sch Med, Dept Pediat, Hinsdale, IL USA. [Latimer, M. Elizabeth] Georgetown Univ, Sch Med, Washington, DC USA. RP Swedo, SE (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM swedos@mail.nih.gov FU Intramural Research Program of the NIMH [11-M-0058 (NCT01281969), 13-M-0028 (NCT01778504)] FX Funding: The research was supported (in part) by the Intramural Research Program of the NIMH, including protocols 11-M-0058 (NCT01281969) and 13-M-0028 (NCT01778504). NR 20 TC 5 Z9 5 U1 5 U2 17 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2015 VL 25 IS 1 SI SI BP 26 EP 30 DI 10.1089/cap.2014.0073 PG 5 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CB4RF UT WOS:000349614900004 PM 25695941 ER PT J AU Toufexis, MD Hommer, R Gerardi, DM Grant, P Rothschild, L D'Souza, P Williams, K Leckman, J Swedo, SE Murphy, TK AF Toufexis, Megan D. Hommer, Rebecca Gerardi, Diana M. Grant, Paul Rothschild, Leah D'Souza, Precilla Williams, Kyle Leckman, James Swedo, Susan E. Murphy, Tanya K. TI Disordered Eating and Food Restrictions in Children with PANDAS/PANS SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; MYCOPLASMA-PNEUMONIAE INFECTION; ANOREXIA-NERVOSA; NEUROPSYCHIATRIC DISORDERS; STREPTOCOCCAL INFECTIONS; CLINICAL DESCRIPTION; TOURETTES-SYNDROME; BULIMIA-NERVOSA; ADOLESCENTS; CHILDHOOD AB Objective: Sudden onset clinically significant eating restrictions are a defining feature of the clinical presentation of some of the cases of pediatric acute-onset neuropsychiatric syndrome (PANS). Restrictions in food intake are typically fueled by contamination fears; fears of choking, vomiting, or swallowing; and/or sensory issues, such as texture, taste, or olfactory concerns. However, body image distortions may also be present. We investigate the clinical presentation of PANS disordered eating and compare it with that of other eating disorders. Methods: We describe 29 patients who met diagnostic criteria for PANS. Most also exhibited evidence that the symptoms might be sequelae of infections with Group A streptococcal bacteria (the pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections [PANDAS] subgroup of PANS). Results: The clinical presentations are remarkable for a male predominance (2:1 M:F), young age of the affected children (mean=9 years; range 5-12 years), acuity of symptom onset, and comorbid neuropsychiatric symptoms. Conclusions: The food refusal associated with PANS is compared with symptoms listed for the new Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) diagnosis of avoidant/restrictive food intake disorder (ARFID). Treatment implications are discussed, as well as directions for further research. C1 [Toufexis, Megan D.; Gerardi, Diana M.; Murphy, Tanya K.] Univ S Florida, Dept Pediat, Rothman Ctr, Div Pediat Neuropsychiat, St Petersburg, FL 33701 USA. [Hommer, Rebecca; Grant, Paul; Rothschild, Leah; D'Souza, Precilla; Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. [Williams, Kyle] Massachusetts Gen Hosp, Pediat Neuropsychiat & Immunol Clin, Boston, MA 02114 USA. [Williams, Kyle] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Leckman, James] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Murphy, Tanya K.] Univ S Florida, Dept Psychiat, Tampa, FL USA. RP Toufexis, MD (reprint author), USF Dept Pediat, Rothman Ctr Pediat Neuropsychiat, 880 6th St South,Suite 460,Box 7523, St Petersburg, FL 33701 USA. EM mtoufexi@health.usf.edu RI Murphy, Tanya/J-7079-2013 FU Intramural Research Program of the NIMH [11-M-0058 (NCT01281969)] FX This research was supported (in part) by the Intramural Research Program of the NIMH, including protocol 11-M-0058 (NCT01281969). NR 50 TC 3 Z9 3 U1 3 U2 13 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2015 VL 25 IS 1 SI SI BP 48 EP 56 DI 10.1089/cap.2014.0063 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CB4RF UT WOS:000349614900007 PM 25329522 ER PT J AU Kovacevic, M Grant, P Swedo, SE AF Kovacevic, Miro Grant, Paul Swedo, Susan E. TI Use of Intravenous Immunoglobulin in the Treatment of Twelve Youths with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; PLASMA-EXCHANGE; SYDENHAM CHOREA; CHILDHOOD; PANDAS AB This is a case series describing 12 youths treated with intravenous immunoglobulin (IVIG) for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). Although it is a clinically based series, the case reports provide new information about the short-term benefits of IVIG therapy, and are the first descriptions of long-term outcome for PANDAS patients. C1 [Kovacevic, Miro] Loyola Univ, Sch Med, Maywood, IL 60153 USA. [Grant, Paul; Swedo, Susan E.] NIMH, PDN Branch, Bethesda, MD 20892 USA. RP Swedo, SE (reprint author), NIMH, PDN Branch, 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM swedos@mail.nih.gov NR 15 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 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2015 VL 25 IS 1 SI SI BP 65 EP 69 DI 10.1089/cap.2014.0067 PG 5 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CB4RF UT WOS:000349614900009 PM 25658609 ER PT J AU Latimer, ME L'Etoile, N Seidlitz, J Swedo, SE AF Latimer, M. Elizabeth L'Etoile, Nathan Seidlitz, Jakob Swedo, Susan E. TI Therapeutic Plasma Apheresis as a Treatment for 35 Severely Ill Children and Adolescents with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; SYDENHAMS CHOREA; INTRAVENOUS IMMUNOGLOBULIN; CHILDHOOD; EXCHANGE; PANDAS; PLASMAPHERESIS; MODEL AB Background: Because of its reported similarities to Sydenham chorea, therapeutic plasma apheresis (TPA) has been proposed as a potential treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). To date, support for the use of TPA has been limited to a few anecdotal reports and a small placebo-controlled trial demonstrating dramatic symptom improvements at 1 month and 1 year follow-up. To evaluate the safety and efficacy of TPA further, we undertook a retrospective review of all PANDAS patients treated with TPA at Georgetown University Hospital between August 2009 and October 2013. Methods: Forty patients were identified, and sufficient information was available from medical records and telephone interview for 35 cases (88%). All 35 (23 boys; 12 girls) met diagnostic criteria for PANDAS (Swedo et al. 1998) and had severe symptoms. The TPA procedures were performed at Georgetown University Hospital using a protocol that processes a total of 4.5 blood volumes over 3-5 days (three treatments of 1.5 volumes each). Overall symptom improvements at 6 months post-TPA and long-term follow-up were estimated by parents, who also rated changes in individual symptoms to provide information about patterns of improvement. Results: All patients were reported to have received at least some benefit from TPA, with average improvement of 65% at 6 months post-TPA and 78% at longer-term follow-up. A decrease in the number of reported symptoms also occurred, with particular improvements in obsessive-compulsive disorder (OCD), anxiety, tics, and somatic symptoms, including dysgraphia, sleep difficulties, and urinary urgency or frequency. Contrary to expectations, preceding duration of illness was not correlated with degree of improvement following TPA, suggesting that acuity of illness is not a factor affecting response. Only two adverse events were reported: both involved reopening of the site where the central line had been placed and resolved immediately following application of pressure and re-dressing of the puncture site. Conclusions: Therapeutic plasma apheresis is an invasive medical intervention that should be reserved for treatment of children and adolescents who are severely affected by PANDAS. In such patients, it appears to be a safe, well-tolerated, and beneficial treatment option. C1 [Latimer, M. Elizabeth] Georgetown Univ, Sch Med, Washington, DC USA. [Seidlitz, Jakob; Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. RP Swedo, SE (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM swedos@mail.nih.gov NR 23 TC 4 Z9 4 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2015 VL 25 IS 1 SI SI BP 70 EP 75 DI 10.1089/cap.2014.0080 PG 6 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA CB4RF UT WOS:000349614900010 PM 25658452 ER PT J AU Wiener, L Viola, A Wilfond, BS Wendler, D Grady, C AF Wiener, Lori Viola, Adrienne Wilfond, Benjamin S. Wendler, David Grady, Christine TI Contrasting Views of Risk Perception and Influence of Financial Compensation Between Adolescent Research Participants and Their Parents SO JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS LA English DT Article DE teens; payment; decision-making; health status; assent; medical; psychiatric ID MEDICAL DECISION-MAKING; BIOMEDICAL-RESEARCH; CLINICAL-TRIALS; CHILDREN; CONSENT; PAYMENT; PERSPECTIVES; ATTITUDES; BENEFITS; ASSENT AB U.S. regulations governing pediatric research do not specify the assent process. To identify best practices, it is important to examine parents' and adolescents' views. The present study focuses on parents' and adolescents' views regarding possible research risks and the influence of financial compensation on their willingness to accept research procedures. Interviews were conducted with 177 adolescents participating in clinical research for a medical or psychiatric illness, or as healthy volunteers, and a parent. Significant discordance was found between how bothered the teen would feel from research-related side effects and procedures compared with parental report. Most teens were willing to accept non-beneficial procedures without compensation. Payment had significantly greater influence on healthy volunteers and their parents compared with those with a medical or psychiatric illness. Discordance between adolescent and parental views about risks recommends obtaining direct input from adolescents during the assent process. Modest payments should not raise concerns of undue inducement, especially in teens with pre-existing conditions. C1 [Wiener, Lori; Viola, Adrienne] NCI, Bethesda, MD 20892 USA. [Viola, Adrienne] Yale Univ, New Haven, CT USA. [Wilfond, Benjamin S.] Seattle Childrens Res Inst, Seattle, WA USA. [Wendler, David; Grady, Christine] NIH, Unit Vulnerable Populat, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cgrady@mail.nih.gov FU Intramural Program of the National Cancer Institute, Center for Cancer Research; National Institutes of Health (NIH) Clinical Center; NIH Program Evaluation Funds FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the Intramural Program of the National Cancer Institute, Center for Cancer Research, the National Institutes of Health (NIH) Clinical Center, and the NIH Program Evaluation Funds. This funding supported the design and conduct of the study; the collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript. NR 35 TC 0 Z9 0 U1 2 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1556-2646 EI 1556-2654 J9 J EMPIR RES HUM RES JI J. Empir. Res. Hum. Res. Ethics PD FEB PY 2015 VL 10 IS 1 BP 49 EP 58 DI 10.1177/1556264614563249 PG 10 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA CB4TH UT WOS:000349620600006 PM 25742666 ER PT J AU Narayan, V Ravindra, KC Liao, C Kaushal, N Carlson, BA Prabhu, KS AF Narayan, Vivek Ravindra, Kodihalli C. Liao, Chang Kaushal, Naveen Carlson, Bradley A. Prabhu, K. Sandeep TI Epigenetic regulation of inflammatory gene expression in macrophages by selenium SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Selenium; p300; Epigenetic regulation; Inflammatory gene expression; Cyclopentenone prostaglandins; Selenoproteins ID PROSTATE-CANCER CELLS; KETO ACID METABOLITES; FACTOR-KAPPA-B; HISTONE ACETYLTRANSFERASE; TRANSCRIPTIONAL ACTIVITY; ORGANOSELENIUM COMPOUNDS; UP-REGULATION; ACETYLATION; ACTIVATION; P300 AB Acetylation of histone and non-histone proteins by histone acetyltransferases plays a pivotal role in the expression of proinflammatory genes. Given the importance of dietary selenium in mitigating inflammation, we hypothesized that selenium supplementation may regulate inflammatory gene expression at the epigenetic level. The effect of selenium towards histone acetylation was examined in both in vitro and in vivo models of inflammation by chromatin immunoprecipitation assays and immunoblotting. Our results indicated that selenium supplementation, as selenite, decreased acetylation of histone H4 at K12 and K16 in COX-2 and TNF alpha promoters, and of the p65 subunit of the redox sensitive transcription factor NF kappa B in primary and immortalized macrophages. On the other hand, selenomethionine had a much weaker effect. Selenite treatment of HIV-1-infected human monocytes also significantly decreased the acetylation of H4 at K12 and K16 on the HIV-1 promoter, supporting the down-regulation of proviral expression by selenium. A similar decrease in histone acetylation was also seen in the colonic extracts of mice treated with dextran sodium sulfate that correlated well with the levels of selenium in the diet. Bone-marrow-derived macrophages from Trsp(fl/fl)Cre(LysM) mice that lack expression of selenoproteins in macrophages confirmed the important role of selenoproteins in the inhibition of histone H4 acetylation. Our studies suggest that the ability of selenoproteins to skew the metabolism of arachidonic acid contributes, in part, to their ability to inhibit histone acetylation. In summary, our studies suggest a new role for selenoproteins in the epigenetic modulation of proinflammatory genes. (C) 2015 Elsevier Inc. All rights reserved. C1 [Narayan, Vivek; Ravindra, Kodihalli C.; Liao, Chang; Kaushal, Naveen; Prabhu, K. Sandeep] Penn State Univ, Ctr Mol Immunol & Infect Dis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Carlson, Bradley A.] NCI, Mol Biol Selenium Sect, Mouse Canc Genet Program, NIH, Bethesda, MD 20892 USA. RP Prabhu, KS (reprint author), Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM ksprabhu@psu.edu FU National Institutes of Health PHS grants [DK 077152, CA 162665] FX National Institutes of Health PHS grants DK 077152 and CA 162665. NR 37 TC 8 Z9 8 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD FEB PY 2015 VL 26 IS 2 BP 138 EP 145 DI 10.1016/j.jnutbio.2014.09.009 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA CB4DL UT WOS:000349578300005 PM 25458528 ER PT J AU Felisiak-Golabek, A Wasag, B Coates, T Lasota, JP Miettinen, M AF Felisiak-Golabek, Anna Wasag, Bartosz Coates, Tiffany Lasota, Jerzy P. Miettinen, Markku TI Frequency and Clinicopathologic Profile of PIK3CA Mutant GISTs SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Med Univ, Gdansk, Poland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 54 BP 17A EP 17A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948000055 ER PT J AU Hsi, A Brown, G Lee, CC Schaffer, A AF Hsi, Andy Brown, Gregory Lee, Chyi-Chia Schaffer, Andras TI Expression of Master Regulators of Mature T-Cell Differentiation FOXP3, T-Bet, and GATA-3 in Cutaneous Adult T-Cell Leukemia/Lymphoma By Immunohistochemistry SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Washington Univ, Sch Med, St Louis, MO USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 471 BP 121A EP 121A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948000471 ER PT J AU Giubellino, A Li, A Lara-Otero, K Linehan, M Merino, M AF Giubellino, Alessio Li, Ang Lara-Otero, Karlena Linehan, Marston Merino, Maria TI MicroRNA Profiling of Morphologically Heterogeneous Clear Renal Cell Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Giubellino, Alessio; Li, Ang; Lara-Otero, Karlena; Linehan, Marston; Merino, Maria] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 886 BP 223A EP 223A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948001393 ER PT J AU Merino, M Ghosh, A Schmidt, L Linehan, M AF Merino, Maria Ghosh, Arunima Schmidt, Laura Linehan, Marston TI Clonal Analysis of Multi-Focal Tumors in Patients With Birt-Hogg-Dube Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Frederick Natl Lab, Frederick, MD USA. NR 0 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 975 BP 245A EP 245A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948001482 ER PT J AU Moreno, V Metwali, A Linehan, WM Merino, M AF Moreno, Vanessa Metwali, Adam Linehan, W. Marston Merino, Maria TI New and Old Testicular Lesions Associated With VHL Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Moreno, Vanessa; Metwali, Adam; Linehan, W. Marston; Merino, Maria] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 979 BP 246A EP 246A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948001486 ER PT J AU Yan, WS Young, D Song, YJ Chen, YM Katta, S Ravindranath, L Lee, J Srinivasan, A Cullen, J Kagan, J Srivastava, S Dobi, A Rosner, I McLeod, D Sesterhenn, I Srivastava, S Petrovics, G AF Yan, Wusheng Young, Denise Song, Yingjie Chen, Yongmei Katta, Shilpa Ravindranath, Lakshmi Lee, Jocelyn Srinivasan, Alagarsamy Cullen, Jennifer Kagan, Jacob Srivastava, Sudhir Dobi, Albert Rosner, Inger McLeod, David Sesterhenn, Isabell Srivastava, Shiv Petrovics, Gyotgy TI Optimization of Nanostring Platform for Evaluation of Prostate Cancer Biomarkers and Therapeutic Targes in FFPE Specimens SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Uniformed Serv Univ Hlth Sci, Rockville, MD USA. NCI, Rockville, MD USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. Joint Pathol Ctr, Silver Spring, MD USA. NR 0 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1070 BP 268A EP 269A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002089 ER PT J AU Yang, ZM Li, A Pinto, P Merino, M AF Yang, Zhiming Li, Ang Pinto, Peter Merino, Maria TI microRNA Profiling of Prostate Cancer in Young and Older Man, One or Two Diseases? SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Yang, Zhiming; Li, Ang; Pinto, Peter; Merino, Maria] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1072 BP 269A EP 269A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002091 ER PT J AU Zheng, XY Mao, Y Huang, W Kamalakaran, S Yang, Y Linehan, WM Merino, MJ Zhong, MH Dimitrova, N Fallon, J AF Zheng, Xiaoyong Mao, Yong Huang, Weihua Kamalakaran, Sitharthan Yang, Youfeng Linehan, W. Marston Merino, Maria J. Zhong, Minghao Dimitrova, Nevenka Fallon, John TI Detecting Additional Chromosomal Translocations in TFE3 Translocation Renal Cell RCC By RNA-Seq SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 New York Med Coll, Westchester Med Ctr, Valhalla, NY 10595 USA. Philips Res North Amer, Briarcliff Manor, NY USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1080 BP 271A EP 271A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002099 ER PT J AU Gong, SY Townsley, D Hsu, A Arthur, D Giri, N Alter, B Hickstein, D Young, N Braylan, R Holland, S Calvo, K AF Gong, Shunyou Townsley, Danielle Hsu, Amy Arthur, Diane Giri, Neelam Alter, Blanche Hickstein, Dennis Young, Neal Braylan, Raul Holland, Steven Calvo, Katherine TI Atypical Myelofibrosis in Patients Harboring Germline GATA2 Mutations SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Gong, Shunyou; Townsley, Danielle; Hsu, Amy; Arthur, Diane; Giri, Neelam; Alter, Blanche; Hickstein, Dennis; Young, Neal; Braylan, Raul; Holland, Steven; Calvo, Katherine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1384 BP 346A EP 346A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002402 ER PT J AU Gong, SY Dumitriu, B Young, N Maric, I AF Gong, Shunyou Dumitriu, Bogdan Young, Neal Maric, Irina TI Evaluation of Phospho-STAT3 Immunohistochemical Stain in Diagnosis of Marrow Involvement By Large Granular Lymphocytic Leukemia SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NHLBI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1385 BP 346A EP 346A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002403 ER PT J AU King, R Dao, L McPhail, E Jaffe, E Said, J Swerdlow, S Sidhu, J Hsi, E Karikehalli, S Jiang, LY Gibson, S Ondrejka, S Nicolae, A Macon, W Castellar, EP Feldman, AL AF King, Rebecca Dao, Linda McPhail, Ellen Jaffe, Elaine Said, Jonathan Swerdlow, Steven Sidhu, Jagmohan Hsi, Eric Karikehalli, Shrideyi Jiang, Liuyan Gibson, Sarah Ondrejka, Sarah Nicolae, Alina Macon, William Castellar, Edgardo Parrilla Feldman, Andrew L. TI Morphology of ALK-Negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. United Hlth Serv Hopsitals, Binghamton, NY USA. Cleveland Clin, Cleveland, OH 44106 USA. Centrex Clin Labs, Utica, NY USA. Univ Washington, Seattle, WA 98195 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1416 BP 355A EP 355A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002434 ER PT J AU Nicolae, A Ganapathi, K Pittaluga, S Raffeld, M Jaffe, E AF Nicolae, Alina Ganapathi, Karthik Pittaluga, Stefania Raffeld, Mark Jaffe, Elaine TI Aggressive NK-Cell Leukemia/Lymphoma, EBV-Negative - A Report of 5 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. NR 0 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1465 BP 368A EP 368A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948002483 ER PT J AU Wang, HW Pittaluga, S Merino, M Jaffe, E AF Wang, Hao-Wei Pittaluga, Stefania Merino, Maria Jaffe, Elaine TI Primary Malignant Lymphomas of the Urinary Tract SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Wang, Hao-Wei; Pittaluga, Stefania; Merino, Maria; Jaffe, Elaine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1526 BP 383A EP 384A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003027 ER PT J AU Yousef, G Butz, H Szabo, P Mozes, R Rotondo, F Kovacs, K Patocs, A AF Yousef, George Butz, Henriett Szabo, Peter Mozes, Roy Rotondo, Fabio Kovacs, Kalman Patocs, Attila TI Integrative Bioinformatical Analysis of Clear Cell Renal Cell Carcinoma SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 St Michaels Hosp, Toronto, ON M5B 1W8, Canada. NCI, NIH, Bethesda, MD 20892 USA. Hungarian Acad Sci, Budapest, Hungary. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1604 BP 403A EP 403A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003105 ER PT J AU Rosenberg, A Palmer, M Merlino, L Troost, J Gasim, A Bagnasco, SM Avila-Casado, C Johnstone, D Hodgin, J Conway, C Kopp, J Nast, C Barisoni, L Hewitt, S AF Rosenberg, Avi Palmer, Matthew Merlino, Lino Troost, Jonathan Gasim, Adil Bagnasco, Serena M. Avila-Casado, Carmen Johnstone, Duncan Hodgin, Jeffrey Conway, Catherine Kopp, Jeffrey Nast, Cynthia Barisoni, Laura Hewitt, Stephen TI The NEPTUNE Digital Pathology Protocol Increases Accurate Glomerular Number Assessment SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Miami, Miami, FL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Hlth Network, Toronto, ON, Canada. Temple Univ, Philadelphia, PA 19122 USA. Leica, Vista, CA USA. NIDDK, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, West Hollywood, CA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1639 BP 411A EP 412A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003140 ER PT J AU Ballester, L Wang, Z Miettinen, M Rodriguez, F Raabe, E Nazarian, J Eberhart, C Warren, K Quezado, M AF Ballester, Leomar Wang, Zengfeng Miettinen, Markku Rodriguez, Fausto Raabe, Eric Nazarian, Javad Eberhart, Charles Warren, Katherine Quezado, Martha TI Overexpression of the Chromatin Remodeling Proteins ARID1A, BRG1 and SMARCD3 in Adult and Pediatric Gliomas SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Childrens Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1711 BP 428A EP 429A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003211 ER PT J AU Ghosh, A Li, A Brown, G Kebebew, E Merino, M AF Ghosh, Arunima Li, Ang Brown, Gregory Kebebew, Electron Merino, Maria TI Multifocal Pancreatic Neuroendocrine Tumors: Clonality and miRNA Profiling SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 [Ghosh, Arunima; Li, Ang; Brown, Gregory; Kebebew, Electron; Merino, Maria] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1771 BP 442A EP 442A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003271 ER PT J AU Rosenberg, A Pflicke, H Dreiling, J Wang, ZF Ylaya, K Hewitt, S Rudloff, U Miettinen, M AF Rosenberg, Avi Pflicke, Holger Dreiling, Jennifer Wang, Zeng-Feng Ylaya, Kris Hewitt, Stephen Rudloff, Udo Miettinen, Markku TI Elafin Expression in Gastrointestinal Neoplasia and Correlation With Sensitivity To PI3K/mTOR Inhibitor SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Univ, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1791 BP 447A EP 447A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003291 ER PT J AU Schlitter, A Jang, KT Saka, B Choi, H Offerhaus, G Hruban, R Zen, Y Hong, SM Konukiewitz, B Allgaeuer, M Kloppel, G Reid, M Esposito, I Adsay, V Basturk, O AF Schlitter, Anna Jang, Kee-Taek Saka, Burcu Choi, Hyejeong Offerhaus, G. Hruban, R. Zen, Yoh Hong, Seung-Mo Konukiewitz, Bjorn Allgaeuer, Michael Kloppel, G. Reid, M. Esposito, Irene Adsay, Volkan Basturk, Olca TI Intraductal Tubulopapillary Neoplasms of the Bile Ducts: Further Immunohistochemical and Molecular Characterization SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 TUM, Munich, Germany. SMC, Seoul, South Korea. EU, Atlanta, GA USA. Univ Med Ctr, Utrecht, Netherlands. Johns Hopkins Univ, Baltimore, MD USA. KCH, London, England. Asan Med Ctr, Seoul, South Korea. NCI, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1795 BP 448A EP 448A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003295 ER PT J AU Jawale, R Williams, K Yang, H Lee, M Otis, C Pentecost, B Arcaro, K AF Jawale, Rahul Williams, Kristin Yang, Howard Lee, Maxwell Otis, Christopher Pentecost, Brian Arcaro, Kathleen TI DNA Methylation in Endocrine Therapy Resistant Breast Cancer SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Baystate Med Ctr, Springfield, MA USA. UMass Amherst, Amherst, MA USA. Wadsworth Ctr, Albany, NY USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1837 BP 458A EP 459A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003337 ER PT J AU Killian, J Noyes, N Retnakumar, P Helman, L Killian, S Davis, S Bilke, S Su, J Smith, W Meltzer, P AF Killian, Jonathan Noyes, Natalia Retnakumar, Parvathy Helman, Lee Killian, Scott Davis, Sean Bilke, Sven Su, Joseph Smith, William Meltzer, Paul TI Cellular and Epiallelic Composition of Oral Fluid SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Univ S Dakota, Vermillion, SD 57069 USA. Suburban Hosp, Bethesda, MD USA. 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 1839 BP 459A EP 459A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003339 ER PT J AU Makhlouf, H Lubensky, I Altekruse, S Mehaffey, M Sachs, M Camalier, C Chuaqui, R Cozen, W Biswajit, D Hernandez, B Lih, CJ Lynch, C McGregor, P McShane, L Rohan, JP Walsh, W Williams, M Gillanders, E Mechanic, L Schully, S Carrick, D AF Makhlouf, Hala Lubensky, Irina Altekruse, Sean Mehaffey, Michele Sachs, Michael Camalier, Corinne Chuaqui, Rodrigo Cozen, Wendy Biswajit, Das Hernandez, Brenda Lih, Chih-Jian Lynch, Charles McGregor, Paul McShane, Lisa Rohan, JoyAnn Philips Walsh, William Williams, Mickey Gillanders, Elizabeth Mechanic, Leah Schully, Sheri Carrick, Danielle TI Effect of Storage Time of FFPE Ovarian Cancer Tissue on DNA Quality for Next Generation Sequencing SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Rockville, MD USA. Leidos, Frederick, MD USA. Univ So Calif, Los Angeles, CA USA. Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 2084 BP 519A EP 519A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003583 ER PT J AU Miles, G Zhao, YM Levin, Y Shetty, J Tran, B Mitchell, S Oberholtzer, JC Levens, D AF Miles, George Zhao, Yongmei Levin, Yelena Shetty, Jyoti Tran, Bao Mitchell, Stephen Oberholtzer, J. Carl Levens, David TI Multiplex Tissue and Clinical Proteomics By Next-Generation Sequencing SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Frederick Natl Lab, Frederick, MD USA. Holy Cross Hosp, Silver Spring, MD USA. NR 0 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 2089 BP 520A EP 520A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003588 ER PT J AU Rosenberg, A Armani, M Fetsch, P Xi, LQ Pham, TT Raffeld, M Chen, Y O'Flaherty, N Stussman, R Blackler, A Du, Q Hanson, J Roth, M Filie, A Roh, M Emmert-Buck, M Hipp, J Tangrea, M AF Rosenberg, Avi ArmaniIrm, Michael M Fetsch, Patricia Xi, Liqiang Tina Thu Pham Raffeld, Mark Chen, Yun O'Flaherty, Neil Stussman, Rebecca Blackler, Adele Du, Qiang Hanson, Jeffrey Roth, Mark Filie, Armando Roh, Michael Emmert-Buck, Michael Hipp, Jason Tangrea, Michael TI A Do-It-Yourself, High-Throughput Microdissection System for Improving NGS Data SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 21-27, 2015 CL Boston, MA SP US & Canadian Acad Pathol C1 Johns Hopkins Sch Med, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Sinai Hosp, Baltimore, MD 21215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2015 VL 95 SU 1 MA 2099 BP 523A EP 523A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA CA5KT UT WOS:000348948003598 ER PT J AU Mani, R Mao, Y Frissora, FW Chiang, CL Wang, J Zhao, Y Wu, Y Yu, B Yan, R Mo, X Yu, L Flynn, J Jones, J Andritsos, L Baskar, S Rader, C Phelps, MA Chen, CS Lee, RJ Byrd, JC Lee, LJ Muthusamy, N AF Mani, R. Mao, Y. Frissora, F. W. Chiang, C-L Wang, J. Zhao, Y. Wu, Y. Yu, B. Yan, R. Mo, X. Yu, L. Flynn, J. Jones, J. Andritsos, L. Baskar, S. Rader, C. Phelps, M. A. Chen, C-S Lee, R. J. Byrd, J. C. Lee, L. J. Muthusamy, N. TI Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia SO LEUKEMIA LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; KINASE-C; HEPATOCELLULAR-CARCINOMA; ABERRANT METHYLATION; MYELOGENOUS LEUKEMIA; PRECLINICAL ACTIVITY; DOWN-REGULATION; LYMPHOMA-CELLS; SHP-1; FTY720 AB Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen-targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A (PP2A), phosphorylation and nuclear translocation of SHP1(S591) and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S-mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects, we developed an OSU-2S-targeted delivery of immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic (Tg) mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1 + malignancies including mantle cell lymphoma and acute lymphoblastic leukemia. C1 [Mani, R.; Frissora, F. W.; Chiang, C-L; Flynn, J.; Jones, J.; Andritsos, L.; Byrd, J. C.; Muthusamy, N.] Ohio State Univ, Coll Med, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Mani, R.; Mao, Y.; Frissora, F. W.; Chiang, C-L; Wang, J.; Yu, B.; Phelps, M. A.; Chen, C-S; Lee, R. J.; Byrd, J. C.; Muthusamy, N.] Ohio State Univ, Comprehens Canc Ctr, Columbus, OH 43210 USA. [Mani, R.; Chen, C-S; Byrd, J. C.; Muthusamy, N.] Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. [Mao, Y.; Zhao, Y.; Phelps, M. A.; Lee, R. J.] Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA. [Mao, Y.; Wu, Y.; Yu, B.; Lee, R. J.; Lee, L. J.] Ohio State Univ, Ctr Affordable Nanoengn Polymer Biomed Devices, Columbus, OH 43210 USA. [Yan, R.; Chen, C-S; Byrd, J. C.] Ohio State Univ, Coll Pharm, Div Med Chem, Columbus, OH 43210 USA. [Mo, X.; Yu, L.] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Baskar, S.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rader, C.] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA. [Rader, C.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. [Lee, L. J.] Ohio State Univ, Dept Chem & Biomol Engn, Columbus, OH 43210 USA. RP Muthusamy, N (reprint author), Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med Mol Virol Immunol & Med Genet &, Div Hematol,OSUCCC, 455E,410,West 12th Ave, Columbus, OH 43210 USA. EM raj.muthusamy@osumc.edu RI Mani, Rajeswaran/Q-2762-2015; Jones, Jeffrey/E-3321-2011; Chiang, Chi-Ling/O-3038-2016 OI Chiang, Chi-Ling/0000-0002-0275-9673 FU Leukemia & Lymphoma Society Specialized Center of Research (SCOR) in leukemia [LLS 7004-11, NCI-P50-CA140158]; Harry Mangurian Foundation; D Warren Brown Foundation; Robert J Anthony Fund; NSF [NSEC EEC-0914790] FX We are thankful to the patients who supported this research by providing their blood. This work was funded by Leukemia & Lymphoma Society Specialized Center of Research (SCOR) in leukemia grant LLS 7004-11, NCI-P50-CA140158, Harry Mangurian Foundation, D Warren Brown Foundation, Robert J Anthony Fund and NSF grant NSEC EEC-0914790. NR 52 TC 13 Z9 13 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD FEB PY 2015 VL 29 IS 2 BP 346 EP 355 DI 10.1038/leu.2014.199 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA CB2GL UT WOS:000349445000011 PM 24947019 ER PT J AU Suryani, S Bracken, LS Harvey, RC Sia, KCS Carol, H Chen, IM Evans, K Dietrich, PA Roberts, KG Kurmasheva, RT Billups, CA Mullighan, CG Willman, CL Loh, ML Hunger, SP Houghton, PJ Smith, MA Lock, RB AF Suryani, Santi Bracken, Lauryn S. Harvey, Richard C. Sia, Keith C. S. Carol, Hernan Chen, I-Ming Evans, Kathryn Dietrich, Philipp A. Roberts, Kathryn G. Kurmasheva, Raushan T. Billups, Catherine A. Mullighan, Charles G. Willman, Cheryl L. Loh, Mignon L. Hunger, Stephen P. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Evaluation of the In Vitro and In Vivo Efficacy of the JAK Inhibitor AZD1480 against JAK-Mutated Acute Lymphoblastic Leukemia SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PRECLINICAL TESTING PROGRAM; CELL-CYCLE PROGRESSION; B-PROGENITOR; XENOGRAFT MODELS; BREAST-CANCER; SOLID TUMORS; PHASE-I; CRLF2; PATHWAY; KINASE AB Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAKmutated ALL. (C) 2014 AACR. C1 [Suryani, Santi; Bracken, Lauryn S.; Sia, Keith C. S.; Carol, Hernan; Evans, Kathryn; Dietrich, Philipp A.; Lock, Richard B.] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia Med Res, Sydney, NSW 2031, Australia. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Evans, Kathryn; Mullighan, Charles G.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Ctr Childhood Canc, Columbus, OH USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Loh, Mignon L.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Hunger, Stephen P.] Univ Colorado Denver, Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Univ Colorado Denver, Childrens Hosp Colorado, Aurora, CO USA. [Smith, Malcolm A.] NCI, CTEP, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia Med Res, POB 81, Sydney, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Lock, Richard/G-4253-2013; OI Harvey, Richard/0000-0002-4904-9767; Mullighan, Charles/0000-0002-1871-1850 FU National Cancer Institute [NOI-CM-42216, NOI-CM-91001-03, CA98543, CA98413, CA114766]; Leukaemia Foundation of Australia; Cure Cancer Australia Foundation; Cancer Institute NSW; National Health and Medical Research Council FX This research was funded by grants from the National Cancer Institute including NOI-CM-42216 and NOI-CM-91001-03 (to P. J. Houghton), CA98543 (COG Chair's grant), CA98413 (COG Statistical Center) and CA114766 (COG Specimen Banking; to S. P. Hunger). S. Suryani is supported by Postdoctoral Fellowships from the Leukaemia Foundation of Australia and the Cure Cancer Australia Foundation, and an Early Career Fellowship from the Cancer Institute NSW. S. P. Hunger is the Ergen Family Chair in Pediatric Cancer. R. B. Lock is supported by a Fellowship from the National Health and Medical Research Council. NR 39 TC 7 Z9 7 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2015 VL 14 IS 2 BP 364 EP 374 DI 10.1158/1535-7163.MCT-14-0647 PG 11 WC Oncology SC Oncology GA CB3OV UT WOS:000349538700005 PM 25504635 ER PT J AU Weiss, K Gonzalez, AN Lopez, G Pedoeim, L Groden, C Sidransky, E AF Weiss, Karin Gonzalez, Ashley N. Lopez, Grisel Pedoeim, Leah Groden, Catherine Sidransky, Ellen TI The clinical management of type 2 Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Gaucher disease; Acute neuronopathic; Lysosomal storage disorder; Hydrops fetalis; Congenital ichthyosis; Palliative care ID ENZYME REPLACEMENT THERAPY; STEM-CELL TRANSPLANTATION; DIAGNOSTIC IMPLICATIONS; INTERMEDIATE PHENOTYPE; MUTANT ALLELES; FABRY DISEASE; GLUCOCEREBROSIDASE; MUTATION; SEIZURES; GENOTYPE AB Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease. Published by Elsevier Inc. C1 [Weiss, Karin; Gonzalez, Ashley N.; Lopez, Grisel; Pedoeim, Leah; Groden, Catherine; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, NIH, Room 1E623,35 Convent Dr, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [ZIA MH*00002-08] NR 85 TC 10 Z9 10 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 BP 110 EP 122 DI 10.1016/j.ymgme.2014.11.008 PG 13 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100296 PM 25435509 ER PT J AU Borger, DK Aflaki, E Moaven, N Lopez, G Chae, JJ Maniwang, E Sidransky, E AF Borger, Daniel K. Aflaki, Elma Moaven, Nima Lopez, Grisel Chae, Jae Jin Maniwang, Emerson Sidransky, Ellen TI Impaired autophagy leads to inflammasome activation and a heightened inflammatory profile of macrophages in Gaucher disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Borger, Daniel K.; Aflaki, Elma; Moaven, Nima; Lopez, Grisel; Chae, Jae Jin; Maniwang, Emerson; Sidransky, Ellen] NIH, Bethesda, MD 20892 USA. NR 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 33 BP S24 EP S24 DI 10.1016/j.ymgme.2014.12.035 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100033 ER PT J AU Choi, EY Baker, E Kaler, SG AF Choi, Eun-Young Baker, Eva Kaler, Stephen G. TI Choroid plexus-directed viral gene therapy for alpha-mannosidosis, a prototypical lysosomal disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Choi, Eun-Young; Kaler, Stephen G.] NICHD, NIH, Bethesda, MD USA. [Baker, Eva] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 50 BP S31 EP S31 DI 10.1016/j.ymgme.2014.12.052 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100050 ER PT J AU Dai, S Dulcey, AE Swaroop, M Marugan, J Mckew, J Zheng, W AF Dai, Sheng Dulcey, Andres E. Swaroop, Manju Marugan, Juan Mckew, John Zheng, Wei TI Rapid kinetics of beta-cyclodextrin entering and exiting cells: Implication of its mechanism on reduction of cholesterol accumulation in Niemann-Pick disease type C cells SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Dai, Sheng; Dulcey, Andres E.; Swaroop, Manju; Marugan, Juan; Mckew, John; Zheng, Wei] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 59 BP S35 EP S35 DI 10.1016/j.ymgme.2014.12.061 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100059 ER PT J AU Gonzalez, AN Trivedi, NS Berhe, B Tayebi, N Sidransky, E AF Gonzalez, Ashley N. Trivedi, Niraj S. Berhe, Bahafta Tayebi, Nahid Sidransky, Ellen TI Modeling the association between Gaucher disease and Parkinson disease using in vivo mouse models SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Gonzalez, Ashley N.; Trivedi, Niraj S.; Berhe, Bahafta; Tayebi, Nahid; Sidransky, Ellen] NIH, Bethesda, MD 20892 USA. NR 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 93 BP S48 EP S49 DI 10.1016/j.ymgme.2014.12.095 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100092 ER PT J AU Kim, J Cintron, D Groden, C Wiggs, E Davis, J Mistry, P Pastores, G Zimran, A Goker-Alpan, O Sidransky, E Lopez, G AF Kim, Jenny Cintron, Dahima Groden, Catherine Wiggs, Edythe Davis, Joie Mistry, Pramod Pastores, Gregory Zimran, Ari Goker-Alpan, Ozlem Sidransky, Ellen Lopez, Grisel TI Gaucher disease and Parldnsonism: Clinical course and prognosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Kim, Jenny; Groden, Catherine; Wiggs, Edythe; Davis, Joie; Sidransky, Ellen; Lopez, Grisel] NIH, Bethesda, MD 20892 USA. [Cintron, Dahima] Univ Puerto Rico, San Juan, PR 00936 USA. [Mistry, Pramod] Yale Univ, Sch Med, New Haven, CT USA. [Pastores, Gregory] Mater Misericordiae Univ Hosp, Natl Ctr Inherited Metab Disorders, Dublin, Ireland. [Zimran, Ari] Shaare Zedek Med Ctr, Gaucher Clin, Jerusalem, Israel. [Goker-Alpan, Ozlem] O&O Alpan LLC, Lysosomal Disorders Res & Treatment Unit, Fairfax, VA USA. NR 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 127 BP S62 EP S62 DI 10.1016/j.ymgme.2014.12.130 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100126 ER PT J AU Li, LS Lim, JA Raben, N AF Li, Lishu Lim, Jeong-A Raben, Nina TI Two masters of lysosomal and autophagosomal biogenesis, TFEB and TFE3, and their potential therapeutic value in Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Li, Lishu; Lim, Jeong-A; Raben, Nina] NIAMS, NIH, Bethesda, MD USA. RI Li, Lishu /J-3191-2015 NR 0 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 152 BP S72 EP S72 DI 10.1016/j.ymgme.2014.12.155 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100151 ER PT J AU Long, Y Xu, M Shi, ZD Swaroop, M Xu, BY Dai, S Mckew, J Zheng, W AF Long, Yan Xu, Miao Shi, Zhen-Dan Swaroop, Manju Xu, Biying Dai, Sheng McKew, John Zheng, Wei TI Cellular distribution and mechanism of delta-tocopherol on reduction of lysosomal cholesterol accumulation in cells with Niemann-Pick disease type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Long, Yan; Xu, Miao; Swaroop, Manju; Dai, Sheng; McKew, John; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Shi, Zhen-Dan; Xu, Biying] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 158 BP S75 EP S75 DI 10.1016/j.ymgme.2014.12.161 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100157 ER PT J AU Nguyen, M Westbroek, W Burnett, R Fujiwara, H Sidhu, R Berhe, B Tayebi, N Aflaki, E Ory, D Sidransky, E AF Nguyen, Matthew Westbroek, Wendy Burnett, Robert Fujiwara, Hideji Sidhu, Rohini Berhe, Bahafta Tayebi, Nahid Aflaki, Elma Ory, Daniel Sidransky, Ellen TI Development of a novel neuronal cell model for investigating the link between glucocerebrosidase and Parkinson disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Nguyen, Matthew; Westbroek, Wendy; Burnett, Robert; Berhe, Bahafta; Tayebi, Nahid; Aflaki, Elma; Sidransky, Ellen] NIH, Bethesda, MD 20892 USA. [Fujiwara, Hideji; Sidhu, Rohini; Ory, Daniel] Washington Univ, St Louis, MO USA. RI Sidhu, Rohini/G-3547-2012 NR 0 TC 0 Z9 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 190 BP S87 EP S87 DI 10.1016/j.ymgme.2014.12.193 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100189 ER PT J AU Schiffmann, R Swift, C Wang, X Brady, RO Ries, M AF Schiffmann, Raphael Swift, Caren Wang, Xuan Brady, Roscoe O. Ries, Markus TI A prospective 10 year study of individualized, intensified enzyme replacement therapy in advanced Fabry disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 11th Annual WORLD Symposium of the Lysosomal-Disease-Network CY FEB 09-13, 2015 CL Orlando, FL SP Lysosomal Dis Network C1 [Schiffmann, Raphael; Swift, Caren; Wang, Xuan] Baylor Res Inst, Dallas, TX USA. [Brady, Roscoe O.] NINDS, Bethesda, MD 20892 USA. [Ries, Markus] Univ Heidelberg Hosp, Heidelberg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2015 VL 114 IS 2 MA 229 BP S103 EP S103 DI 10.1016/j.ymgme.2014.12.232 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CA5UK UT WOS:000348973100228 ER PT J AU Samuel, M Rodriguez-Oroz, M Antonini, A Brotchie, JM Chaudhuri, KR Brown, RG Galpern, WR Nirenberg, MJ Okun, MS Lang, AE AF Samuel, Michael Rodriguez-Oroz, Maria Antonini, Angelo Brotchie, Jonathan M. Chaudhuri, Kallol Ray Brown, Richard G. Galpern, Wendy R. Nirenberg, Melissa J. Okun, Michael S. Lang, Anthony E. TI Management of Impulse Control Disorders in Parkinson's Disease: Controversies and Future Approaches SO MOVEMENT DISORDERS LA English DT Review DE Parkinson's; Impulse control; Management; Dopamine Agonist Withdrawal; Deep Brain Stimulation; Clinical Trials ID DEEP-BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS STIMULATION; AGONIST WITHDRAWAL SYNDROME; DOPAMINE DYSREGULATION SYNDROME; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-LESIONED MACAQUE MODEL; COGNITIVE-BEHAVIORAL THERAPY; REACTION-TIME-TASK; COMPULSIVE BEHAVIORS; RECEPTOR ANTAGONIST; INDUCED DYSKINESIA AB Impulse control disorders in Parkinson's disease are a group of impulsive behaviors most often associated with dopaminergic treatment. Presently, there is a lack of high quality evidence available to guide their management. This manuscript reviews current management strategies, before concentrating on the concept of dopamine agonist withdrawal syndrome and its implications for the management of impulse control disorders. Further, we focus on controversies, including the role of more recently available anti-parkinsonian drugs, and potential future approaches involving routes of drug delivery, nonpharmacological treatments (such as cognitive behavioral therapy and deep brain stimulation), and other as yet experimental strategies. (c) 2015 International Parkinson and Movement Disorder Society C1 [Samuel, Michael; Chaudhuri, Kallol Ray] Kings Hlth Partners, Kings Coll Hosp, Natl Parkinson Fdn Int Ctr Excellence, Dept Neurol, London, England. [Rodriguez-Oroz, Maria] Univ Hosp Donostia, Dept Neurol, San Sebastian, Spain. [Rodriguez-Oroz, Maria] BioDonostia Res Inst, Neurosci Unit, San Sebastian, Spain. [Rodriguez-Oroz, Maria] Ikerbasque, Basque Fdn Sci, E-48011 Bilbao, Spain. [Rodriguez-Oroz, Maria] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Antonini, Angelo] Fdn Osped San Camillo IRCCS, Parkinson Unit, Venice, Italy. [Brotchie, Jonathan M.] Toronto Western Hosp, Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. [Chaudhuri, Kallol Ray] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, London SE5 8AF, England. [Brown, Richard G.] Kings Coll London, Inst Psychiat, Dept Psychol PO77, London SE5 8AF, England. [Galpern, Wendy R.] NINDS, NIH, Bethesda, MD 20892 USA. [Nirenberg, Melissa J.] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA. [Okun, Michael S.] UF Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32607 USA. [Lang, Anthony E.] Toronto Western Hosp, Morton & Gloria Movement Disorders Clin, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada. RP Samuel, M (reprint author), Kings Hlth Partners, Kings Coll Hosp, Natl Parkinson Fdn Int Ctr Excellence, Dept Neurol, London, England. EM m.samuel@nhs.net RI Brown, Richard/A-9599-2010; OI Brown, Richard/0000-0001-9021-0172; Ray Chaudhuri, K/0000-0003-2815-0505 FU Movement Disorders Society (USA); National Institute of Health (USA) [U13NS080495]; Parkinson's Disease Foundation (USA); Parkinson's UK; Parkinson's Disease Society (Canada); AbbVie Ltd; UCB; St Jude Medical Limited FX The ICD meeting in Boston October 25-26, 2012 was sponsored by the Movement Disorders Society (USA), and received financial support from the Movement Disorders Society (USA), National Institute of Health (USA, U13NS080495), Parkinson's Disease Foundation (USA), Parkinson's UK, Parkinson's Disease Society (Canada), AbbVie Ltd, UCB, and St Jude Medical Limited. NR 95 TC 16 Z9 17 U1 4 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2015 VL 30 IS 2 BP 150 EP 159 DI 10.1002/mds.26099 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CB0IZ UT WOS:000349310600004 PM 25607799 ER PT J AU Hallett, M Obeso, J AF Hallett, Mark Obeso, Jose TI Where Does Chorea Come From? Cortical Excitability Findings Challenge Classic Pathophysiological Concepts SO MOVEMENT DISORDERS LA English DT Editorial Material ID BASAL GANGLIA DISORDERS; PARKINSONS-DISEASE; HUNTINGTONS-DISEASE; MOVEMENT-DISORDERS; PRIMATE MODELS; STIMULATION C1 [Hallett, Mark] NINDS, Bethesda, MD 20892 USA. [Obeso, Jose] Hosp Madrid, CINAC, Madrid, Spain. [Obeso, Jose] CEU San Pablo Univ, Madrid, Spain. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D37,10 Ctr Dr, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU Intramural NIH HHS NR 16 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2015 VL 30 IS 2 BP 169 EP 170 DI 10.1002/mds.26109 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CB0IZ UT WOS:000349310600007 PM 25546440 ER PT J AU Singleton, A AF Singleton, Andrew TI X-Linked Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Editorial Material C1 NIA, Bethesda, MD 20892 USA. RP Singleton, A (reprint author), NIA, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009 NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2015 VL 30 IS 2 BP 196 EP 196 DI 10.1002/mds.26131 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CB0IZ UT WOS:000349310600011 PM 25641059 ER PT J AU Johnson, JO Stevanin, G van de Leemput, J Hernandez, DG Arepalli, S Forlani, S Zonozi, R Gibbs, JR Brice, A Durr, A Singleton, AB AF Johnson, Janel O. Stevanin, Giovanni van de Leemput, Joyce Hernandez, Dena G. Arepalli, Sampath Forlani, Sylvie Zonozi, Reza Gibbs, J. Raphael Brice, Alexis Durr, Alexandra Singleton, Andrew B. TI A 7.5-Mb Duplication at Chromosome 11q21-11q22.3 Is Associated With a Novel Spastic Ataxia Syndrome SO MOVEMENT DISORDERS LA English DT Article DE whole-genome genotyping; genomic duplications; spinocerebellar ataxia; structural variation; SCA39 ID COPY NUMBER VARIATION; SPINOCEREBELLAR ATAXIA; DISEASE AB BackgroundThe autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally important genes. Structural variation has recently been shown to underlie spinocerebellar ataxia types 15 and 20. MethodsWe applied single-nucleotide polymorphism (SNP) genotyping to determine whether structural variation causes spinocerebellar ataxia in a family from France. ResultsWe identified an approximately 7.5-megabasepair duplication on chromosome 11q21-11q22.3 that segregates with disease. This duplication contains an estimated 44 genes. Duplications at this locus were not found in control individuals. ConclusionsWe have identified a new spastic ataxia syndrome caused by a genomic duplication, which we have denoted as spinocerebellar ataxia type 39. Finding additional families with this phenotype will be important to identify the genetic lesion underlying disease. (c) 2014 International Parkinson and Movement Disorder Society C1 [Johnson, Janel O.; van de Leemput, Joyce; Hernandez, Dena G.; Arepalli, Sampath; Zonozi, Reza; Gibbs, J. Raphael; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Johnson, Janel O.; van de Leemput, Joyce; Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Johnson, Janel O.; van de Leemput, Joyce; Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Inst Neurol, Reta Lila Weston Inst Neurol Studies, London, England. [Stevanin, Giovanni; Forlani, Sylvie; Brice, Alexis; Durr, Alexandra] INSERM, U1127, Paris, France. [Stevanin, Giovanni; Forlani, Sylvie; Brice, Alexis; Durr, Alexandra] Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, UMR S1127, Paris, France. [Stevanin, Giovanni; Forlani, Sylvie; Brice, Alexis; Durr, Alexandra] CNRS, UMR7225, Paris, France. [Stevanin, Giovanni] Ecole Prat Hautes Etud, Paris, France. RP Singleton, AB (reprint author), 9000 Rockville Pike Bldg 35 Rm1A1000, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Stevanin, Giovanni/E-5038-2016; OI Stevanin, Giovanni/0000-0001-9368-8657 FU National Institute on Aging, National Institutes of Health, Department of Health and Human Services; European Union; Verum foundation; association Connaitre les Syndromes cerebelleux (France); Programme Hospitalier de Recherche Clinique FX This study was supported by the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, in part by the European Union (to the The NEUROMICS Consortium Network), the Verum foundation, the association Connaitre les Syndromes cerebelleux (France) and the Programme Hospitalier de Recherche Clinique (to A.D.) NR 15 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2015 VL 30 IS 2 BP 262 EP 266 DI 10.1002/mds.26059 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CB0IZ UT WOS:000349310600022 PM 25545641 ER PT J AU Catalfamo, M Mawle, A Verthelyi, D AF Catalfamo, Marta Mawle, Alison Verthelyi, Daniela TI Immunology careers at the NIH, FDA and CDC: different paths that focus on advancing public health SO NATURE IMMUNOLOGY LA English DT Article C1 [Catalfamo, Marta] NIAID, Immunoregulat Lab, US NIH, Bethesda, MD 20892 USA. [Mawle, Alison] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Off Biotechnol Prod, Div Therapeut Prot, Silver Spring, MD USA. RP Catalfamo, M (reprint author), NIAID, Immunoregulat Lab, US NIH, Bldg 10, Bethesda, MD 20892 USA. EM catalfam@mail.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2015 VL 16 IS 2 BP 129 EP 132 PG 4 WC Immunology SC Immunology GA AZ3QZ UT WOS:000348143100001 PM 25594454 ER PT J AU Huang, YF Guo, LY Qiu, J Chen, X Hu-Li, J Siebenlist, U Williamson, PR Urban, JF Paul, WE AF Huang, Yuefeng Guo, Liying Qiu, Jin Chen, Xi Hu-Li, Jane Siebenlist, Ulrich Williamson, Peter R. Urban, Joseph F. Paul, William E. TI IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential 'inflammatory' type 2 innate lymphoid cells SO NATURE IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA3; LUNG INFLAMMATION; IMMUNITY; T(H)2; HOMEOSTASIS; POPULATION; INFECTION; ELICITS; IL-25; FATE AB Innate lymphoid cells (ILCs) are lymphocyte-like cells that lack T cell or B cell antigen receptors and mediate protective and repair functions through cytokine secretion. Among these, type 2 ILCs (ILC2 cells) are able to produce type 2 cytokines. We report the existence of an inflammatory ILC2 (iILC2) population responsive to interleukin 25 (IL-25) that complemented IL-33-responsive natural ILC2 (nILC2) cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo and contributed to the expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing ability and provided partial protection against Candida albicans. We propose that iILC2 cells are transient progenitors of ILCs mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi. C1 [Huang, Yuefeng; Guo, Liying; Chen, Xi; Hu-Li, Jane; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Qiu, Jin; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Urban, Joseph F.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov OI Urban, Joseph/0000-0002-1590-8869 FU NIAID Division of Intramural Research (US National Institutes of Health) FX We thank J. Zhu for critical reading of the manuscript; J. Edwards for assistance in the preparation of sorter-purified cells; L. Feigenbaum of the SAIC Laboratory Animal Sciences Program for injection of the recombinant bacterial artificial chromosome into oocytes, transfer into pseudopregnant females and screening of pups; C. Dong (MD Anderson Cancer Center) for IL-17F-RFP reporter mice; A. McKenzie (MRC Laboratory of Molecular Biology, Cambridge) for Il1rl1-/- mice; and members of Laboratory of Immunology at NIAID for discussions. Supported by the NIAID Division of Intramural Research (US National Institutes of Health). NR 29 TC 64 Z9 65 U1 4 U2 17 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 FEB PY 2015 VL 16 IS 2 BP 161 EP + DI 10.1038/ni.3078 PG 10 WC Immunology SC Immunology GA AZ3QZ UT WOS:000348143100008 PM 25531830 ER PT J AU Yu, F Sharma, S Edwards, J Feigenbaum, L Zhu, JF AF Yu, Fang Sharma, Suveena Edwards, Julie Feigenbaum, Lionel Zhu, Jinfang TI Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance SO NATURE IMMUNOLOGY LA English DT Article ID ROR-GAMMA-T; FACTOR FOXP3; HELPER-CELLS; IN-VIVO; DIFFERENTIATION; INFLAMMATION; ACTIVATION; RESPONSES; PROGRAM; SUPPRESSION AB Regulatory T cells (T-reg cells) can express the transcription factors T-bet and GATA-3, but the function of this expression and whether such cells represent stable subsets is still unknown. By using various reporter tools, we found that the expression of T-bet and GATA-3 in T-reg cells was dynamically influenced by the cytokine environment. T-reg cell-specific deletion of the gene encoding either T-bet (Tbx21) or GATA-3 (Gata3) alone did not result in loss of T-reg cell function; however, mice with combined deficiency in both genes in T-reg cells developed severe autoimmune-like diseases. Loss of T-reg cell function correlated with upregulation of expression of the transcription factor ROR gamma t and reduced expression of the transcription factor Foxp3. Thus, in the steady state, activated T-reg cells transiently upregulated either T-bet or GATA-3 to maintain T cell homeostasis. C1 [Yu, Fang; Sharma, Suveena; Edwards, Julie; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Frederick, MD 21701 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU Division of Intramural Research of the NIAID (US National Institutes of Health) FX We thank J.D. Engel (University of Michigan) for GATA-3-GFP reporter mice on the C57BL/6 background; S. Reiner (University of Columbia) for Tbx21fl/fl mice; A. Rudensky (Memorial Sloan Kettering Cancer Center) for Foxp3-IRES-YFP-Cre mice; D. Jankovic (National Institute of Allergy and Infectious Diseases (NIAID)) for Stat1-/- mice; E. Shevach, Y. Belkaid and W. Paul for critical reading of the manuscript and discussions; A. Thornton for discussions; L. Guo for the help with enzyme-linked immunosorbent assay experiments; N. Cereb and S.Y. Yang (Histogenetics) and S. Reiner (Columbia University) for constructing and providing Tbx21fl/fl mice; and the flow cytometry core facility of the NIAID for cell sorting. Supported by the Division of Intramural Research of the NIAID (US National Institutes of Health). NR 46 TC 36 Z9 37 U1 5 U2 14 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 FEB PY 2015 VL 16 IS 2 BP 197 EP + DI 10.1038/ni.3053 PG 12 WC Immunology SC Immunology GA AZ3QZ UT WOS:000348143100012 PM 25501630 ER PT J AU Dalton, HJ Garcia-Filion, P Holubkov, R Moler, FW Shanley, T Heidemann, S Meert, K Berg, RA Berger, J Carcillo, J Newth, C Harrison, R Doctor, A Rycus, P Dean, JM Jenkins, T Nicholson, C AF Dalton, Heidi J. Garcia-Filion, Pamela Holubkov, Richard Moler, Frank W. Shanley, Thomas Heidemann, Sabrina Meert, Kathleen Berg, Robert A. Berger, John Carcillo, Joseph Newth, Christopher Harrison, Richard Doctor, Allan Rycus, Peter Dean, J. Michael Jenkins, Tammara Nicholson, Carol CA Eunice Kennedy Shriver Natl Inst TI Association of Bleeding and Thrombosis With Outcome in Extracorporeal Life Support SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE bleeding; cardiopulmonary bypass; complications; extracorporeal life support; extracorporeal membrane oxygenation; thrombosis ID CONGENITAL DIAPHRAGMATIC-HERNIA; MEMBRANE-OXYGENATION; CARDIOPULMONARY-RESUSCITATION; ORGANIZATION REGISTRY; CARDIAC-ARREST; ECMO; CHILDREN; SURVIVAL; FAILURE; ANTICOAGULATION AB Objective: Changes in technology and increased reports of successful extracorporeal life support use in patient populations, such as influenza, cardiac arrest, and adults, are leading to expansion of extracorporeal life support. Major limitations to extracorporeal life support expansion remain bleeding and thrombosis. These complications are the most frequent causes of death and morbidity. As a pilot project to provide baseline data for a detailed evaluation of bleeding and thrombosis in the current era, extracorporeal life support patients were analyzed from eight centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Study Design: Retrospective analysis of patients (< 19 yr) reported to the Extracorporeal Life Support Organization registry from eight Collaborative Pediatric Critical Care Research Network centers between 2005 and 2011. Setting: Tertiary children's hospitals within the Collaborative Pediatric Critical Care Research Network. Subjects: The study cohort consisted of 2,036 patients (13% with congenital diaphragmatic hernia). Interventions: None. Main Results: In the cohort of patients without congenital diaphragmatic hernia (n = 1,773), bleeding occurred in 38% of patients, whereas thrombosis was noted in 31%. Bleeding and thrombosis were associated with a decreased survival by 40% (relative risk, 0.59; 95% CI, 0.53-0.66) and 33% (odds ratio, 0.67; 95% CI, 0.60-0.74). Longer duration of extracorporeal life support and use of venoarterial cannulation were also associated with increased risk of bleeding and/or thrombotic complications and lower survival. The most common bleeding events included surgical site bleeding (17%; n = 306), cannulation site bleeding (14%; n = 256), and intracranial hemorrhage (11%; n = 192). Common thrombotic events were clots in the circuit (15%; n = 274) and the oxygenator (12%; n = 212) and hemolysis (plasma-free hemoglobin > 50 mg/dL) (10%; n = 177). Among patients with congenital diaphragmatic hernia, bleeding and thrombosis occurred in, respectively, 45% (n = 118) and 60% (n = 159), Bleeding events were associated with reduced survival (relative risk, 0.62; 95% CI, 0.46-0.86) although thrombotic events were not (relative risk, 0.92; 95% CI, 0.67-1.26). Conclusions: Bleeding and thrombosis remain common complications in patients undergoing extracorporeal life support. Further research to reduce or eliminate bleeding and thrombosis is indicated to help improve patient outcome. C1 [Dalton, Heidi J.] Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ 85006 USA. [Dalton, Heidi J.] Univ Arizona, Coll Med Phoenix, Phoenix, AZ USA. [Garcia-Filion, Pamela] Phoenix Childrens Hosp, Phoenix, AZ USA. [Holubkov, Richard; Dean, J. Michael] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Moler, Frank W.; Shanley, Thomas] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Heidemann, Sabrina; Meert, Kathleen] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Berg, Robert A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Berger, John] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Crit Care & Anesthesia, Pittsburgh, PA 15213 USA. [Newth, Christopher] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Harrison, Richard] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Pediat, St Louis Childrens Hosp, St Louis, MO 63110 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Biochem, St Louis Childrens Hosp, St Louis, MO 63110 USA. [Rycus, Peter] Extracorporeal Life Support Org, Ann Arbor, MI USA. [Jenkins, Tammara; Nicholson, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Trauma & Crit Illness Branch, NIH, Bethesda, MD USA. RP Dalton, HJ (reprint author), Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ 85006 USA. EM heidi.dalton26@gmail.com OI Doctor, Allan/0000-0002-6096-6400 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, U01HD049934]; National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, U01HD049934]; NICHD; NIH; NIH CPCCRN; NICHD CPCCRN; NICHD/NIH; Collaborative Pediatric Critical Care Research Network; CPCCRN FX Supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services: U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, and U01HD049934.; Dr. Dalton received royalties from the Rogers Textbook of Critical Care Medicine and received support for article research from the National Institutes of Health (NIH). Her institution received grant support: this work was supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Department of Health and Human Services: U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, and U01HD049934 (centers who participated in this project were those in the Collaborative Pediatric Critical Care Research Network); consulted for rEVO Biologics; and lectured for rEVO Biologics. Dr. Garcia-Filion's institution received grant support from the NICHD (paid under the grant for the Collaborative Pediatric Critical Care Research Network [CPCCRN]). Dr. Holubkov served as a board member for Pfizer Inc. (Data Safety Monitoring Board), consulted for St. Jude Medical Inc. (biostatistical consultation), and received support for article research from the NIH. Dr. Holubkov and his institution received grant support from the NIH CPCCRN (coordinating center funding for CPCCRN). Dr. Moler received support for article research from the NIH. Dr. Shanley consulted for Case Western Res University (EAB Member), received royalties from Springer (Springer for text book editing), received support for travel from SPR (secretary-treasurer for SPR), and received support for article research from the NIH. His institution received grant support from the NIH (CPCCRN funding and NIH grants) and received support for travel from the NIH (CPCCRN Funding). Dr. Heidemann received support for article research from the NIH. Her institution received grant support and support for travel. Dr. Meert received support for article research from the NIH. Her institution received grant support from the NIH. Dr. Berg received support for article research from the NIH. His institution received grant support (This study was funded by the NICHD CPCCRN grant. Dr. Berg is a PI on the grant) and received support for travel (travel to CPCCRN meetings to discuss this study funded by NICHD CPCCRN grant). Dr. Berger received support for article research from NIH. His institution received grant support from the NICHD/NIH. Dr. Carcillo received support for article research from the NIH. His institution received grant support and support for travel. Dr. Newth received support for article research from the NIH. His institution received grant support from the NICHD and the Collaborative Pediatric Critical Care Research Network. Dr. Harrison received support for article research from the NIH. His institution received grant support and support for travel from the NIH and CPCCRN. Dr. Dean received support for article research from the NIH. His institution received grant support from the NIH. Dr. Jenkins received support for article research from the NIH and disclosed government work. Dr. Nicholson received support for article search from the NIH and disclosed government work. Dr. Rycus disclosed that he does not have any potential conflicts of interest. NR 31 TC 10 Z9 10 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD FEB PY 2015 VL 16 IS 2 BP 167 EP 174 DI 10.1097/PCC.0000000000000317 PG 8 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA CB1KZ UT WOS:000349387600016 PM 25647124 ER PT J AU Remy, KE Chertow, DS AF Remy, Kenneth E. Chertow, Daniel S. TI A Place at the Table for Children in the Ebola Virus Disease Discussion SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Editorial Material DE Ebola virus; hypovolemic shock; pediatric critical care; sepsis ID WEST-AFRICA; SURVIVAL C1 [Remy, Kenneth E.; Chertow, Daniel S.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Remy, KE (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. OI Remy, Kenneth/0000-0001-5222-9884 NR 17 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD FEB PY 2015 VL 16 IS 2 BP 184 EP 185 DI 10.1097/PCC.0000000000000368 PG 2 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA CB1KZ UT WOS:000349387600018 PM 25647125 ER PT J AU Kumar, A Baycin-Hizal, D Shiloach, J Bowen, MA Betenbaugh, MJ AF Kumar, Amit Baycin-Hizal, Deniz Shiloach, Joseph Bowen, Michael A. Betenbaugh, Michael J. TI Coupling enrichment methods with proteomics for understanding and treating disease SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE Biomarker discovery; Drug target discovery; Exosomes; Membrane proteomics; mAb discovery ID N-LINKED GLYCOPROTEINS; TANDEM MASS-SPECTROMETRY; REVEAL DIFFERENTIAL EXPRESSION; PLASMA-MEMBRANE PROTEOMICS; PROTEIN REFERENCE DATABASE; COLORECTAL-CANCER CELLS; TUMOR-DERIVED EXOSOMES; QUANTITATIVE PROTEOMICS; EXTRACELLULAR VESICLES; CEREBROSPINAL-FLUID AB Owing to recent advances in proteomics analytical methods and bioinformatics capabilities there is a growing trend toward using these capabilities for the development of drugs to treat human disease, including target and drug evaluation, understanding mechanisms of drug action, and biomarker discovery. Currently, the genetic sequences of many major organisms are available, which have helped greatly in characterizing proteomes in model animal systems and humans. Through proteomics, global profiles of different disease states can be characterized (e.g. changes in types and relative levels as well as changes in PTMs such as glycosylation or phosphorylation). Although intracellular proteomics can provide a broad overview of physiology of cells and tissues, it has been difficult to quantify the low abundance proteins which can be important for understanding the diseased states and treatment progression. For this reason, there is increasing interest in coupling comparative proteomics methods with subcellular fractionation and enrichment techniques for membranes, nucleus, phosphoproteome, glycoproteome as well as low abundance serum proteins. In this review, we will provide examples of where the utilization of different proteomics-coupled enrichment techniques has aided target and biomarker discovery, understanding the drug targeting mechanism, and mAb discovery. Taken together, these improvements will help to provide a better understanding of the pathophysiology of various diseases including cancer, autoimmunity, inflammation, cardiovascular disease, and neurological conditions, and in the design and development of better medicines for treating these afflictions. C1 [Kumar, Amit; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Kumar, Amit; Baycin-Hizal, Deniz; Bowen, Michael A.] MedImmune LLC, Antibody Discovery & Prot Engn, Gaithersburg, MD USA. [Kumar, Amit; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. RP Betenbaugh, MJ (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. EM beten@jhu.edu NR 169 TC 8 Z9 8 U1 6 U2 24 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD FEB PY 2015 VL 9 IS 1-2 SI SI BP 33 EP 47 DI 10.1002/prca.201400097 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CB2DH UT WOS:000349436400005 PM 25523641 ER PT J AU Fan, W Lam, J Moen, P Kelly, E King, R McHale, S AF Fan, Wen Lam, Jack Moen, Phyllis Kelly, Erin King, Rosalind McHale, Susan TI Constrained choices ? Linking employees' and spouses' work time to health behaviors SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE US; Fast food consumption; Exercise; Work hours; Gender; Couple; Spouse; Constrained choices ID PHYSICAL-ACTIVITY; GENDER-DIFFERENCES; COPING STRATEGIES; FOOD-CONSUMPTION; POPULATION; EMPLOYMENT; EXERCISE; PERSPECTIVE; SPILLOVER; HOUSEWORK AB There are extensive literatures on work conditions and health and on family contexts and health, but less research asking how a spouse or partners' work conditions may affect health behaviors. Drawing on the constrained choices framework, we theorized health behaviors as a product of one's own time and spouses' work time as well as gender expectations. We examined fast food consumption and exercise behaviors using survey data from 429 employees in an Information Technology (IT) division of a U.S. Fortune 500 firm and from their spouses. We found fast food consumption is affected by men's work hours-both male employees' own work hours and the hours worked by husbands of women respondents-in a nonlinear way. The groups most likely to eat fast food are men working 50 h/week and women whose husbands work 45-50 h/week. Second, exercise is better explained if work time is conceptualized at the couple, rather than individual, level. In particular, neo-traditional arrangements (where husbands work longer than their wives) constrain women's ability to engage in exercise but increase odds of men exercising. Women in couples where both partners are working long hours have the highest odds of exercise. In addition, women working long hours with high schedule control are more apt to exercise and men working long hours whose wives have high schedule flexibility are as well. Our findings suggest different health behaviors may have distinct antecedents but gendered work-family expectations shape time allocations in ways that promote men's and constrain women's health behaviors. They also suggest the need to expand the constrained choices framework to recognize that long hours may encourage exercise if both partners are looking to sustain long work hours and that work resources, specifically schedule control, of one partner may expand the choices of the other. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Fan, Wen; Lam, Jack; Moen, Phyllis; Kelly, Erin] Univ Minnesota, Minneapolis, MN 55455 USA. [King, Rosalind] NICHHD, Bethesda, MD USA. [McHale, Susan] Penn State Univ, University Pk, PA 16802 USA. RP Fan, W (reprint author), Univ Minnesota, Dept Sociol, 267 19th Ave S, Minneapolis, MN 55455 USA. EM fanxx102@umn.edu RI Lam, Jack/B-4976-2016 OI Lam, Jack/0000-0002-7169-4930 FU NICHD NIH HHS [U01 HD051276, U01 HD051256] NR 52 TC 4 Z9 4 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2015 VL 126 BP 99 EP 109 DI 10.1016/j.socscimed.2014.12.015 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CB2AM UT WOS:000349429100011 PM 25531550 ER PT J AU Lopez, LM Hill, WD Harris, SE Hernandez, MV Maniega, SM Bastin, ME Bailey, E Smith, C McBride, M McClure, J Graham, D Dominiczak, A Yang, Q Fornage, M Ikram, MA Debette, S Launer, L Bis, JC Schmidt, R Seshadri, S Porteous, DJ Starr, J Deary, IJ Wardlaw, JM AF Lopez, Lorna M. Hill, W. David Harris, Sarah E. Hernandez, Maria Valdes Maniega, Susana Munoz Bastin, Mark E. Bailey, Emma Smith, Colin McBride, Martin McClure, John Graham, Delyth Dominiczak, Anna Yang, Qiong Fornage, Myriam Ikram, M. Arfan Debette, Stephanie Launer, Lenore Bis, Joshua C. Schmidt, Reinhold Seshadri, Sudha Porteous, David J. Starr, John Deary, Ian J. Wardlaw, Joanna M. TI Genes From a Translational Analysis Support a Multifactorial Nature of White Matter Hyperintensities SO STROKE LA English DT Article DE genetics; humans; leukoencephalopathies; magnetic resonance imaging ID GENOME-WIDE ASSOCIATION; ISCHEMIC-STROKE; ATAXIA-TELANGIECTASIA; LACUNAR STROKE; RISK-FACTORS; DISEASE; BRAIN; METAANALYSIS; EXPRESSION; PHENOTYPES AB Background and Purpose-White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative. Methods-We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE. Results-Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7x10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1). Conclusions-Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia. C1 [Lopez, Lorna M.; Hernandez, Maria Valdes; Maniega, Susana Munoz; Bastin, Mark E.; Starr, John; Deary, Ian J.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH4 2XU, Midlothian, Scotland. [Hernandez, Maria Valdes; Maniega, Susana Munoz; Bastin, Mark E.; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Div Neuroimaging Sci, Edinburgh EH4 2XU, Midlothian, Scotland. [Smith, Colin] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland. [Hill, W. David; Harris, Sarah E.; Porteous, David J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Med Genet Sect, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hill, W. David; Harris, Sarah E.; Porteous, David J.] Univ Edinburgh, MRC Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Bailey, Emma] Univ London Imperial Coll Sci Technol & Med, Dept Bioengn, London, England. [McBride, Martin; McClure, John; Graham, Delyth; Dominiczak, Anna] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Yang, Qiong; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Ikram, M. Arfan] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Debette, Stephanie] Univ Paris 07, INSERM U740 12, Bordeaux, France. [Debette, Stephanie] Bordeaux Univ, U708, Bordeaux, France. [Debette, Stephanie] Univ Paris 07, DHU Neurovasc Paris Sorbonne, Dept Neurol, Lariboisiere Hosp, Paris, France. [Debette, Stephanie] Univ Versailles St Quentin En Yvelines, Versailles, France. [Debette, Stephanie; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Launer, Lenore] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria. RP Wardlaw, JM (reprint author), Univ Edinburgh, Western Gen Hosp, Brain Res Imaging Ctr, Div Neuroimaging Sci, Bramwell Dott Bldg,Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland. EM joanna.wardlaw@ed.ac.uk OI Seshadri, Sudha/0000-0001-6135-2622; Ikram, Mohammad Arfan/0000-0003-0372-8585 FU Age UK's Disconnected Mind programme; Research Into Ageing [251, 258]; Biotechnology and Biological Sciences Research Council [BB/F019394/1]; Medical Research Council [G1001401, 8200]; Brain Research Imaging Centre, The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology [G0700704/84698]; Medical Research Council; British Neuropathological Society; Newby Fund; Scottish Funding Council Scottish Imaging Network A Platform for Scientific Excellence Collaboration; European Union Community [HEALTH-F4-2010-241504 EURATRANS]; National Institutes of Ageing (NIA) [N01-AG-12100]; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute (NHLBI); NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01-HC-85239]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH [UL1RR025005]; NIH Roadmap for Medical Research; Austrian Science Fond [P20545-P05, P13180]; National Institute of Neurological Disorders and Stroke; NIA [AG-023629, AG-15928, AG-20098, AG-027058]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences, Clinical and Translational Science Institute [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [DK063491]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Neurological Disorders and Stroke [R01 NS17950]; National Institute of Aging [R01s AG08122, AG16495, AG033193]; Netherlands Organization of Scientific Research (NOW) [175.010.2005.011]; Netherlands Genomics Initiative/NWO [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; NWO, the Netherlands Organization for the Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; Nederlandse Hartstichting [2009B102]; ZonMW Veni-grant [916.13.054]; NHLBI. [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268200960009C, HHSN268201200036C, HL080295, HL087652, HL105756, N01-HC-25195, U01 HL096917, R01 HL093029]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [HL093029] FX Lothian Birth Cohort 1936 was funded by Age UK's Disconnected Mind programme (http://www.disconnectedmind.ed.ac.uk) and by Research Into Ageing (references 251 and 285). Whole-genome association was funded by Biotechnology and Biological Sciences Research Council (reference BB/F019394/1), brain image analysis was funded by Medical Research Council (G1001401 and 8200), and imaging was funded by Brain Research Imaging Centre (http://www.bric.ed.ac.uk), The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (http://www.ccace.ed.ac.uk, G0700704/84698). The SHRSP analysis was funded by Medical Research Council (Dr Bailey), British Neuropathological Society, Newby Fund, Scottish Funding Council Scottish Imaging Network A Platform for Scientific Excellence Collaboration (http://www.sinapse.ac.uk), and European Union Community's FP7/2007-2013, grant agreement HEALTH-F4-2010-241504 EURATRANS. The Aging Gene-Environment Susceptibility-Reykjavik Study was funded by National Institutes of Ageing (NIA), contract N01-AG-12100, National Eye Institute, National Institute on Deafness and Other Communication Disorders, National Heart, Lung, and Blood Institute (NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, and HHSN268201100011C, HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C; NIH grant number UL1RR025005, and NIH Roadmap for Medical Research and grant number HL093029. The Austrian Stroke Prevention Study was funded by the Austrian Science Fond grant numbers P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The Cardiovascular Health Study was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268200960009C, and HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke, AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA (http://www.chs-nhlbi.org/pi.htm). DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR), the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Framingham Heart Study was supported by the NHLBI (Contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract no.; N02-HL-6-4278); some of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; and grants from the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Institute of Aging (R01s AG08122, AG16495, and AG033193), and the NHLBI (U01 HL096917 and R01 HL093029). The Rotterdam Study Genome-Wide Association database was funded by the Netherlands Organization of Scientific Research (NOW; no. 175.010.2005.011); the study was further supported by the Netherlands Genomics Initiative/NWO project no. 050-060-810; the Erasmus Medical Center and Erasmus University, Rotterdam; NWO, the Netherlands Organization for the Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Dr Graham, XII), and the Municipality of Rotterdam and Dr Ikram was supported by the Nederlandse Hartstichting grant 2009B102 and ZonMW Veni-grant 916.13.054. NR 43 TC 6 Z9 6 U1 1 U2 6 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 FEB PY 2015 VL 46 IS 2 BP 341 EP 347 DI 10.1161/STROKEAHA.114.007649 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AZ8AS UT WOS:000348437800022 PM 25586835 ER PT J AU Qu, W Waalkes, MP AF Qu, Wei Waalkes, Michael P. TI Metallothionein blocks oxidative DNA damage induced by acute inorganic arsenic exposure SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Arsenic; Oxidative DNA damage; Metallothionein; Reactive oxygen species ID GLUTATHIONE CONJUGATE; HUMAN-DISEASE; LIVER-CELLS; NULL MICE; IN-VITRO; TOXICITY; STRESS; RESISTANCE; CARCINOGENESIS; TRANSCRIPTION AB We studied how protein metallothionein (MT) impacts arsenic-induced oxidative DNA damage (ODD) using cells that poorly express MT (MT-I/II double knockout embryonic cells; called MT-null cells) and wild-type (WT) MT competent cells. Arsenic (as NaAsO2) was less cytolethal over 24 h in WT cells (LC50 = 11.0 +/- 1.3 mu M; mean +/- SEM) than in MT-null cells (LC50 = 5.6 +/- 1.2 mu M). ODD was measured by the immuno-spin trapping method. Arsenic (1 or 5 mu M; 24 h) induced much less ODD in WT cells (121% and 141% of control, respectively) than in MT-null cells (202% and 260%). In WT cells arsenic caused concentration-dependent increases in MT expression (transcript and protein), and in the metal-responsive transcription factor-1 (MTF-1), which is required to induce the MT gene. In contrast, basal MT levels were not detectable in MT-null cells and unaltered by arsenic exposure. Transfection of MT-I gene into the MT-null cells markedly reduced arsenic-induced ODD levels. The transport genes, Abcc1 and Abcc2 were increased by arsenic in WT cells but either showed no or very limited increases in MT-null cells. Arsenic caused increases in oxidant stress defense genes HO-1 and GST alpha 2 in both WT and MT-null cells, but to much higher levels in WT cells. WT cells appear more adept at activating metal transport systems and oxidant response genes, although the role of MT in these responses is unclear. Overall, MT protects against arsenic-induced ODD in MT competent cells by potential sequestration of scavenging oxidant radicals and/or arsenic. Published by Elsevier Inc. C1 [Qu, Wei; Waalkes, Michael P.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. RP Qu, W (reprint author), NIEHS, Box 12233,Mail Drop E1-07,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM qu@niehs.nih.gov FU NIH, NIEHS, DNTP [ES-102925] FX The authors thank Drs. William M. Gwinn and Olive Ngalame for critical review of this manuscript. The authors also thank Matthew W. Bell for aid with the graphics. All funds for this research were supplied by the NIH, NIEHS, DNTP (Project # ES-102925). NR 51 TC 6 Z9 7 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 1 PY 2015 VL 282 IS 3 BP 267 EP 274 DI 10.1016/j.taap.2014.11.014 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA CB3EB UT WOS:000349509900005 PM 25485709 ER PT J AU Zhou, LQ Dean, J AF Zhou, Li-quan Dean, Jurrien TI Reprogramming the genome to totipotency in mouse embryos SO TRENDS IN CELL BIOLOGY LA English DT Review DE reprogramming; totipotency; epigenetic modification; embryonic genome activation; preimplantation development ID HISTONE VARIANT H3.3; ZYGOTIC PATERNAL GENOME; PLURIPOTENT STEM-CELLS; EARLY MAMMALIAN EMBRYO; PREIMPLANTATION EMBRYOS; DNA-METHYLATION; GENE-EXPRESSION; SPERM CHROMATIN; TET PROTEINS; IN-VIVO AB Despite investigative interest, the artificial derivation of pluripotent stem cells remains inefficient and incomplete reprogramming hinders its potential as a reliable tool in regenerative medicine. By contrast, fusion of terminally differentiated gametes at fertilization activates efficient epigenetic reprogramming to ensure totipotency of early embryos. Understanding the epigenetic mechanisms required for the transition from the fertilized egg to the embryo can improve efforts to reprogram differentiated cells to pluripotent/totipotent cells for therapeutic use. We review recent discoveries that are providing insight into the molecular mechanisms required for epigenetic reprogramming to totipotency in vivo. C1 [Zhou, Li-quan; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jurriend@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, NIDDK [ZIA-DK015603] FX We thank Dr M.E. Torres-Padilla for her critical reading of the manuscript and useful suggestions. We apologize to authors whose work could not be cited because of space constraints. This research was supported by the Intramural Research Program of the National Institutes of Health, NIDDK (ZIA-DK015603). NR 102 TC 9 Z9 10 U1 11 U2 39 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD FEB PY 2015 VL 25 IS 2 BP 82 EP 91 DI 10.1016/j.tcb.2014.09.006 PG 10 WC Cell Biology SC Cell Biology GA CB4HT UT WOS:000349589500005 PM 25448353 ER PT J AU Achee, NL Youngblood, L Bangs, MJ Lavery, JV James, S AF Achee, Nicole L. Youngblood, Laura Bangs, Michael J. Lavery, James V. James, Stephanie TI Considerations for the Use of Human Participants in Vector Biology Research: A Tool for Investigators and Regulators SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Review DE Vector; Epidemiology; Risk assessment; Vector control; Entomology ID HUMAN LANDING CATCHES; REED ARMY INSTITUTE; ANOPHELES-GAMBIAE; COMPARATIVE SUSCEPTIBILITY; MALARIA TRANSMISSION; DIPTERA-CULICIDAE; INFECTION; AFRICAN; MODEL; MOSQUITOS AB A thorough search of the existing literature has revealed that there are currently no published recommendations or guidelines for the interpretation of US regulations on the use of human participants in vector biology research (VBR). An informal survey of vector biologists has indicated that issues related to human participation in vector research have been largely debated by academic, national, and local Institutional Review Boards (IRBs) in the countries where the research is being conducted, and that interpretations and subsequent requirements made by these IRBs have varied widely. This document is intended to provide investigators and corresponding scientific and ethical review committee members an introduction to VBR methods involving human participation and the legal and ethical framework in which such studies are conducted with a focus on US Federal Regulations. It is also intended to provide a common perspective for guiding researchers, IRB members, and other interested parties (i.e., public health officials conducting routine entomological surveillance) in the interpretation of human subjects regulations pertaining to VBR. C1 [Achee, Nicole L.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Youngblood, Laura] Ctr Dis Control & Prevent, Atlanta, GA USA. [Bangs, Michael J.] Int SOS, Publ Hlth & Malaria Control, Papua, Indonesia. [Lavery, James V.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Ctr Eth Social & Cultural Risk, Toronto, ON M5B 1W8, Canada. [Lavery, James V.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. [Lavery, James V.] Univ Toronto, Joint Ctr Bioeth, Toronto, ON M5S 1A1, Canada. [James, Stephanie] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Achee, NL (reprint author), Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, 239 Galvin Life Sci Ctr, Notre Dame, IN 46556 USA. EM nachee@nd.edu NR 75 TC 4 Z9 4 U1 1 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 EI 1557-7759 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD FEB 1 PY 2015 VL 15 IS 2 BP 89 EP 102 DI 10.1089/vbz.2014.1628 PG 14 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CB5QL UT WOS:000349682500002 PM 25700039 ER PT J AU Healy, JM Reisen, WK Kramer, VL Fischer, M Lindsey, NP Nasci, RS Macedo, PA White, G Takahashi, R Khang, L Barker, CM AF Healy, Jessica M. Reisen, William K. Kramer, Vicki L. Fischer, Marc Lindsey, Nicole P. Nasci, Roger S. Macedo, Paula A. White, Gregory Takahashi, Richard Khang, La Barker, Christopher M. TI Comparison of the Efficiency and Cost of West Nile Virus Surveillance Methods in California SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE West Nile virus; California; Surveillance methods; Birds; Cost effectiveness ID CULEX-TARSALIS DIPTERA; MOSQUITOS; TRANSMISSION; CULICIDAE; CHICKENS; EPIDEMIOLOGY; INFECTIONS; PREVENTION; DYNAMICS; PATTERNS AB Surveillance systems for West Nile virus (WNV) combine several methods to determine the location and timing of viral amplification. The value of each surveillance method must be measured against its efficiency and costs to optimize integrated vector management and suppress WNV transmission to the human population. Here we extend previous comparisons of WNV surveillance methods by equitably comparing the most common methods after standardization on the basis of spatial sampling density and costs, and by estimating optimal levels of sampling effort for mosquito traps and sentinel chicken flocks. In general, testing for evidence of viral RNA in mosquitoes and public-reported dead birds resulted in detection of WNV approximately 2-5 weeks earlier than serological monitoring of sentinel chickens at equal spatial sampling density. For a fixed cost, testing of dead birds reported by the public was found to be the most cost effective of the methods, yielding the highest number of positive results per $1000. Increased spatial density of mosquito trapping was associated with more precise estimates of WNV infection prevalence in mosquitoes. Our findings also suggested that the most common chicken flock size of 10 birds could be reduced to six to seven without substantial reductions in timeliness or sensitivity. We conclude that a surveillance system that uses the testing of dead birds reported by the public complemented by strategically timed mosquito and chicken sampling as agency resources allow would detect viral activity efficiently in terms of effort and costs, so long as susceptible bird species that experience a high mortality rate from infection with WNV, such as corvids, are present in the area. C1 [Healy, Jessica M.; Reisen, William K.; Barker, Christopher M.] Univ Calif Davis, Ctr Vectorborne Dis, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Kramer, Vicki L.] Calif Dept Publ Hlth, Vector Borne Dis Sect, Sacramento, CA USA. [Fischer, Marc; Lindsey, Nicole P.; Nasci, Roger S.] Ctr Dis Control & Prevent, Div Vector Borne Dis, Ft Collins, CO USA. [Macedo, Paula A.] Sacramento Yolo Mosquito & Vector Control Dist, Elk Grove, CA USA. [White, Gregory] Coachella Valley Mosquito & Vector Control Dist, Indio, CA USA. [Takahashi, Richard; Khang, La] Kern Mosquito & Vector Control Dist, Bakersfield, CA USA. [Barker, Christopher M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Barker, CM (reprint author), Univ Calif Davis, Ctr Vector Borne Dis, Davis, CA 95616 USA. EM cmbarker@ucdavis.edu FU California Department of Public Health; US Centers for Disease Control and Prevention; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [F31AII08189]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank the Sacramento-Yolo, Kern, and Coachella Valley Mosquito and Vector Control Districts for their collection of the data used for this research. In particular, we want to add an additional note of appreciation to Richard Takahashi, who conducted enhanced surveillance at Kern MVCD for two years of the study. We also thank Bborie Park for data management, Kerry Padgett and Leslie Foss for their help with dead bird data, and the California Department of Public Health and the US Centers for Disease Control and Prevention for their support and funding, as well as the National Institute of Allergy and Infectious Diseases of the National Institutes of Health for their support of J. Healy under award number F31AII08189. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.M. Barker also acknowledges support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science & Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health. NR 32 TC 4 Z9 4 U1 2 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 EI 1557-7759 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD FEB 1 PY 2015 VL 15 IS 2 BP 147 EP 155 DI 10.1089/vbz.2014.1689 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CB5QL UT WOS:000349682500009 PM 25700046 ER PT J AU Soerensen, M Nygaard, M Dato, S Stevnsner, T Bohr, VA Christensen, K Christiansen, L AF Soerensen, Mette Nygaard, Marianne Dato, Serena Stevnsner, Tinna Bohr, Vilhelm A. Christensen, Kaare Christiansen, Lene TI Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals SO AGING CELL LA English DT Article DE aging phenotypes; association study; Forkhead box O3; oldest-old; SNPs ID TRANSCRIPTION FACTOR FOXO3A; HUMAN LONGEVITY; SIGNALING PATHWAY; MICE; EPIDEMIOLOGY; HOMEOSTASIS; ACTIVATION; FRACTURES; MORTALITY; AUTOPHAGY AB FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3A variation with ADL (P=0.044) and bone fracture (P=0.006). The single-SNP statistics behind the gene-based analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P=0.054), while ADL did not (P=0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n=1279, age 94-100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed. C1 [Soerensen, Mette; Nygaard, Marianne; Dato, Serena; Christensen, Kaare; Christiansen, Lene] Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, DK-5000 Odense C, Denmark. [Soerensen, Mette; Nygaard, Marianne; Christensen, Kaare] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark. [Dato, Serena] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Cs, Italy. [Stevnsner, Tinna; Bohr, Vilhelm A.] Aarhus Univ, Dept Mol Biol & Genet, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Christensen, Kaare] Odense Univ Hosp, Dept Biochem & Pharmacol, DK-5000 Odense C, Denmark. RP Soerensen, M (reprint author), Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, JB Winsloews Vej 9B, DK-5000 Odense C, Denmark. EM msoerensen@health.sdu.dk RI Christensen, Kaare/C-2360-2009; Soerensen, Mette/O-1817-2015; OI Christensen, Kaare/0000-0002-5429-5292; Soerensen, Mette/0000-0001-5268-3366; dato, serena/0000-0003-2589-7929 FU Max-Planck Institute for Demographic Research (Rostock, Germany); European Union [259679]; INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund); National Institute on Aging [P01 AG08761]; Novo Nordisk Foundation; Aase and Ejnar Danielsen Foundation; Brodrene Hartmann Foundation; King Christian the 10th Foundation; Einer Willumsens Mindelegat Foundation; VELUX Foundation; Danish Council for Independent Research - Medical Sciences FX The study was financially supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Brodrene Hartmann Foundation, the King Christian the 10th Foundation, and the Einer Willumsens Mindelegat Foundation. The Danish Aging Research Center is supported by a grant from the VELUX Foundation, while Mette Soerensen is supported by an individual postdoctoral grant from The Danish Council for Independent Research - Medical Sciences. NR 45 TC 8 Z9 8 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD FEB PY 2015 VL 14 IS 1 BP 60 EP 66 DI 10.1111/acel.12295 PG 7 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CA7KQ UT WOS:000349096600007 PM 25470651 ER PT J AU Mielke, MM Bandaru, VVR Han, DF An, Y Resnick, SM Ferrucci, L Haughey, NJ AF Mielke, Michelle M. Bandaru, Veera Venkata Ratnam Han, Dingfen An, Yang Resnick, Susan M. Ferrucci, Luigi Haughey, Norman J. TI Factors affecting longitudinal trajectories of plasma sphingomyelins: the Baltimore Longitudinal Study of Aging SO AGING CELL LA English DT Article DE aging; sphingomyelin; dihydrosphingomyelin; human; longitudinal; sex differences ID CORONARY-ARTERY-DISEASE; SPHINGOLIPID METABOLISM; CELL-MEMBRANES; RISK-FACTOR; ATHEROSCLEROSIS; PERTURBATION; FIBROBLASTS; BIOMARKERS; LONGEVITY; DEMENTIA AB Sphingomyelin metabolism has been linked to several diseases and to longevity. However, few epidemiological studies have quantified individual plasma sphingomyelin species (identified by acyl-chain length and saturation) or their relationship between demographic factors and disease processes. In this study, we determined plasma concentrations of distinct sphingomyelin species in 992 individuals, aged 55 and older, enrolled in the Baltimore Longitudinal Study of Aging. Participants were followed, with serial measures, up to 6 visits and 38years (3972 total samples). Quantitative analyses were performed on a high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess variation in specific sphingomyelin species and associations with demographics, diseases, medications or lifestyle factors, and plasma cholesterol and triglyceride levels. We found that most sphingomyelin species increased with age. Women had higher plasma levels of all sphingomyelin species and showed steeper trajectories of age-related increases compared to men. African Americans also showed higher circulating sphingomyelin concentrations compared to Caucasians. Diabetes, smoking, and plasma triglycerides were associated with lower levels of many sphingomyelins and dihydrosphingomyelins. Notably, these associations showed specificity to sphingomyelin acyl-chain length and saturation. These results demonstrate that longitudinal changes in circulating sphingomyelin levels are influenced by age, sex, race, lifestyle factors, and diseases. It will be important to further establish the intra-individual age- and sex-specific changes in each sphingomyelin species in relation to disease onset and progression. C1 [Mielke, Michelle M.] Mayo Clin, Dept Hlth Sci Res & Neurol, Rochester, MN 55905 USA. [Bandaru, Veera Venkata Ratnam; Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Han, Dingfen; Haughey, Norman J.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [An, Yang; Resnick, Susan M.; Ferrucci, Luigi] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Mielke, MM (reprint author), Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, 200 First St SW, Rochester, MN 55905 USA. EM mielke.michelle@mayo.edu FU National Institutes of Health/National Institute on Aging [U01 AG37526] FX This work was supported by a grant from the National Institutes of Health/National Institute on Aging (U01 AG37526) and by the Intramural Research Program of the National Institutes of Health/National Institute on Aging. NR 36 TC 4 Z9 4 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD FEB PY 2015 VL 14 IS 1 BP 112 EP 121 DI 10.1111/acel.12275 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CA7KQ UT WOS:000349096600012 PM 25345489 ER PT J AU Balachova, TN Batluk, JV Bryant, KJ Shaboltas, AV AF Balachova, Tatiana N. Batluk, Julia V. Bryant, Kendall J. Shaboltas, Alla V. TI International Collaboration in HIV Prevention Research: Evidence from a Research Seminar in Russia Abstracts SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID INJECTION-DRUG USERS; ST-PETERSBURG; ALCOHOL-CONSUMPTION; OPIOID DEPENDENCE; SEXUAL PARTNERS; RISK BEHAVIORS; TRANSMISSION; WOMEN; PREVALENCE; NALTREXONE AB HIV transmission is a major health concern. Global efforts are necessary to control the spread of infection. International collaborative studies in countries with high rates of new infections are essential for increasing knowledge on the behavioral, social, and biomedical aspects of HIV/AIDS and HIV transmission. Statistics indicate a growing HIV epidemic in Russia. There are alarming proportions of new cases attributed to heterosexual contact, and HIV is increasingly affecting people in the general population who are not part of any traditional high-risk group. Despite recent advances in HIV prevention, data on effective behavioral prevention approaches are limited. There is minimal evidence to suggest which types of prevention will be effective in reducing the risk for HIV transmission among people at risk in the general population. This article presents a review and discussion of an international research seminar, HIV Prevention Research: Evidence-Based Behavioral Approaches. Local and international interdisciplinary researchers gathered for the purposes of exchanging research results and information about ongoing studies, identifying gaps in knowledge, and discussing promising prevention strategies. The overarching goal was to advance HIV prevention research through scientific integration. The seminar provided an excellent platform for building research capacity in interdisciplinary HIV research in Russia and integrating research efforts with the international research community to contribute to HIV prevention research throughout the world. C1 [Balachova, Tatiana N.] Univ Oklahoma Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Batluk, Julia V.; Shaboltas, Alla V.] St Petersburg State Univ, Dept Psychol, St Petersburg 199034, Russia. [Bryant, Kendall J.] NIAAA, NIH, Rockville, MD 20852 USA. RP Balachova, TN (reprint author), Univ Oklahoma Hlth Sci Ctr, Dept Pediat, 940NE 13th St,Nicholson Tower,Suite 4900, Oklahoma City, OK 73104 USA. EM tatiana-balachova@ouhsc.edu FU National Institute on Alcohol Abuse and Alcoholism [R01AA016234, 3R01AA016234-05S1]; Fogarty International Center (Brain Disorders in the Developing World: Research Across the Lifespan), NIH; RFBR FX The seminar was organized by the Preventing FAS/ARND in Russian Children/Expansion to Interdisciplinary HIV Prevention in Women study group of the U.S.-Russia Collaborative HIV/AIDS Research Initiative, the National Institutes of Health (NIH), United States, and the Russian Foundation for Basic Research (RFBR), Russia. The study was supported by research grant R01AA016234 and an administrative supplement grant award 3R01AA016234-05S1 from the National Institute on Alcohol Abuse and Alcoholism and the Fogarty International Center (Brain Disorders in the Developing World: Research Across the Lifespan), NIH to T. Balachova at OUHSC and a grant award from RFBR to A. Shaboltas at SPSU. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NIAAA, and RFBR. NR 46 TC 1 Z9 1 U1 4 U2 7 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 FEB 1 PY 2015 VL 31 IS 2 BP 163 EP 172 DI 10.1089/aid.2014.0078 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CB0KP UT WOS:000349315100002 PM 25430518 ER PT J AU Munger, AM Chow, DC Playford, MP Parikh, NI Gangcuangco, LMA Nakamoto, BK Kallianpur, KJ Ndhlovu, LC Shikuma, CM Mehta, NN AF Munger, Alana M. Chow, Dominic C. Playford, Martin P. Parikh, Nisha I. Gangcuangco, Louie Mar A. Nakamoto, Beau K. Kallianpur, Kalpana J. Ndhlovu, Lishomwa C. Shikuma, Cecilia M. Mehta, Nehal N. TI Characterization of Lipid Composition and High-Density Lipoprotein Function in HIV-Infected Individuals on Stable Antiretroviral Regimens SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CHOLESTEROL EFFLUX CAPACITY; NUCLEAR-MAGNETIC-RESONANCE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; VITAMIN-D; THERAPY; HDL; WOMEN; RISK; DYSLIPIDEMIA AB There is an increase in the cardiovascular disease (CVD) morbidity in individuals infected with HIV that may be due to inflammatory lipid modulation not captured by traditional lipid measures. The objective of this study was to perform advanced lipoprotein phenotyping inclusive of the high-density lipoprotein (HDL) cholesterol efflux capacity and lipoprotein particle concentration and size in a well-phenotyped group of 118 patients infected with HIV. We used simple and multivariable analyses to determine the associations between advanced lipoprotein parameters and known cardiometabolic risk factors. Participants were on stable antiretroviral therapy (ART) and had benign traditional lipid panels [median total cholesterol, low-density lipoprotein (LDL)-C, HDL-C, and triglycerides of 178 mg/dl, 108 mg/dl, 44 mg/dl, and 122.5 mg/dl, respectively]. However, advanced lipoprotein phenotyping demonstrated an elevation of LDL particle number (median of 1,233 nmol/liter) and a decrease in LDL size (median of 20.4 nm), along with a decrease in protective, large HDL particles (median of 3.15 mu mol/liter) and reduced HDL cholesterol efflux capacity in comparison to controls of other studies. HDL cholesterol efflux capacity was associated with HDL levels (beta=0.395, p<0.001), small LDL particle concentration (beta=-0.198, p=0.031), insulin sensitivity by the Matsuda index (beta=0.218, p=0.029), and the Framingham Risk Score (beta=-0.184, p=0.046). We demonstrate an atherogenic lipoprotein profile by NMR spectroscopy and HDL efflux measurement in a group of HIV-infected patients on stable ART with normal lipid panels. C1 [Munger, Alana M.; Chow, Dominic C.; Parikh, Nisha I.; Gangcuangco, Louie Mar A.; Nakamoto, Beau K.; Kallianpur, Kalpana J.; Ndhlovu, Lishomwa C.; Shikuma, Cecilia M.] Univ Hawaii, Hawaii Ctr AIDS, Honolulu, HI 96822 USA. [Playford, Martin P.; Mehta, Nehal N.] NHLBI, NIH, Bethesda, MD 20892 USA. [Nakamoto, Beau K.] Straub Clin & Hosp, Honolulu, HI USA. [Ndhlovu, Lishomwa C.] Univ Hawaii, John A Burns Sch Med, Dept Trop Med, Honolulu, HI 96822 USA. RP Mehta, NN (reprint author), NHLBI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU Intramural Grant from the NIH; extramural NIH [R01HL095135, U54RR026136] FX This study was supported by an Intramural Grant from the NIH (N.N.M.), extramural NIH Grants R01HL095135 and U54RR026136 (C.M.S.). We thank our study participants and community physicians for their roles in this study. NR 33 TC 5 Z9 5 U1 0 U2 1 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 FEB 1 PY 2015 VL 31 IS 2 BP 221 EP 228 DI 10.1089/aid.2014.0239 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CB0KP UT WOS:000349315100011 PM 25416403 ER PT J AU Salmeron, BJ AF Salmeron, Betty Jo TI The Emotional Nature of Rescue Medicine Assessments SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 NIDA IRP, Neuroimaging Res Branch, Baltimore, MD 21224 USA. RP Salmeron, BJ (reprint author), NIDA IRP, Neuroimaging Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bsalmeron@mail.nih.gov RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 FU Intramural NIH HHS [Z99 DA999999] NR 10 TC 1 Z9 1 U1 0 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FEB 1 PY 2015 VL 15 IS 2 BP 27 EP 29 DI 10.1080/15265161.2014.990762 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA CB0RC UT WOS:000349333300006 PM 25674954 ER EF