FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Balter, BB Ciccone, DN Oettinger, MA Selsing, E AF Balter, Barbara B. Ciccone, David N. Oettinger, Marjorie A. Selsing, Erik TI Mice lacking S mu tandem repeats maintain RNA polymerase patterns but exhibit histone modification pattern shifts linked to class switch site locations SO MOLECULAR IMMUNOLOGY LA English DT Article DE Class switching; Histone modification; RNA polymerase ID HEAVY-CHAIN GENES; SOMATIC HYPERMUTATION; DNA DEAMINATION; B-CELLS; ANTIBODY DIVERSIFICATION; CHROMATIN MODIFICATIONS; REPETITIVE SEQUENCES; RECOMBINATION SITES; REGION CHROMATIN; IN-VIVO AB Antibody switching involves class switch recombination (CSR) events between switch (S) regions located upstream of heavy chain constant (C) genes. Mechanisms targeting CSR to S-regions are not clear. Deletion of S mu, tandem repeat (S mu TR) sequences causes CSR to shift into downstream regions that do not undergo CSR in WT B-cells, including the C mu-region. We now find that, in S mu TR-/- B cells, S mu chromatin histone modification patterns also shift downstream relative to WT and coincide with S mu TR-/- CSR locations. Our results suggest that histone H3 acetylation and methylation are involved in accessibility of switch regions and that these modifications are not dependent on the underlying sequence, but may be controlled by the location of upstream promoter or regulatory elements. Our studies also show RNA polymerase II (RNAPII) loading increases in the E mu/I mu region in stimulated B cells; these increases are independent of S mu TR sequences. Longer S mu deletions have been reported to eliminate increases in RNAPII density, therefore we suggest that sequences between I mu, and S mu, (possibly the I mu, splicing region as well as G-tracts that are involved in stable RNA:DNA complex formation during transcription) might control the RNAPII density increases. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Balter, Barbara B.; Selsing, Erik] Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. [Balter, Barbara B.; Selsing, Erik] Tufts Univ, Sch Med, Program Immunol, Boston, MA 02111 USA. [Ciccone, David N.; Oettinger, Marjorie A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Selsing, E (reprint author), Tufts Univ, Sch Med, Dept Pathol, 150 Harrison Ave, Boston, MA 02111 USA. EM erik.selsing@tufts.edu FU National Institutes of Health [5R01 AI024655, 5R01 AI083510, 5R01 GM048026]; Eshe Foundation FX This research was supported by National Institutes of Health (5R01 AI024655 ES; 5R01 AI083510 and 5R01 GM048026 MAO) and Eshe Foundation (ES) grants. NR 50 TC 1 Z9 1 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2012 VL 52 IS 1 BP 1 EP 8 DI 10.1016/j.molimm.2012.04.006 PG 8 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 960GC UT WOS:000305375000001 PM 22580346 ER PT J AU Keller, RB Gagne, KE Usmani, GN Asdourian, GK Williams, DA Hofmann, I Agarwal, S AF Keller, Rachel B. Gagne, Katelyn E. Usmani, G. Naheed Asdourian, George K. Williams, David A. Hofmann, Inga Agarwal, Suneet TI CTC1 Mutations in a patient with dyskeratosis congenita SO PEDIATRIC BLOOD & CANCER LA English DT Article DE aplastic anemia; bone marrow failure; molecular genetics; non-malignant hematology; telomerase ID MAINTENANCE COMPONENT 1; TELOMERE MAINTENANCE; COATS PLUS; COMPLEX; DISEASE; FIBROBLASTS; LENGTH AB Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotypephenotype complexity observed in telomere-related genetic disorders. Pediatr Blood Cancer 2012;59:311314. (c) 2012 Wiley Periodicals, Inc. C1 [Keller, Rachel B.; Gagne, Katelyn E.; Williams, David A.; Hofmann, Inga; Agarwal, Suneet] Childrens Hosp, Div Hematol Oncol, Stem Cell Program, Boston, MA 02115 USA. [Keller, Rachel B.; Gagne, Katelyn E.; Williams, David A.; Hofmann, Inga; Agarwal, Suneet] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Keller, Rachel B.; Gagne, Katelyn E.; Williams, David A.; Hofmann, Inga; Agarwal, Suneet] Harvard Univ, Sch Med, Boston, MA USA. [Keller, Rachel B.; Gagne, Katelyn E.; Williams, David A.; Agarwal, Suneet] Harvard Stem Cell Inst, Boston, MA USA. [Usmani, G. Naheed] Univ Massachusetts, Sch Med, Div Pediat Hematol Oncol, Worcester, MA USA. [Asdourian, George K.] UMass Mem Med Ctr, Dept Ophthalmol, Worcester, MA USA. RP Agarwal, S (reprint author), Childrens Hosp, Div Hematol Oncol, Stem Cell Program, CLS3002,3 Blackfan Circle, Boston, MA 02115 USA. EM suneet.agarwal@childrens.harvard.edu RI Keller, Rachel/A-2700-2015 OI Keller, Rachel/0000-0001-6138-9257 FU NIH [K08HL089150, 5RC1DK086861] FX Grant sponsor: NIH; Grant numbers: K08HL089150, 5RC1DK086861. NR 18 TC 49 Z9 51 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 311 EP 314 DI 10.1002/pbc.24193 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200020 PM 22532422 ER PT J AU Strouse, JJ Heeney, MM AF Strouse, John J. Heeney, Matthew M. TI Hydroxyurea for the treatment of sickle cell disease: Efficacy, barriers, toxicity, and management in children SO PEDIATRIC BLOOD & CANCER LA English DT Review DE children; efficacy; hydroxyurea; sickle cell disease ID FUNCTIONAL-ANALYSIS; YOUNG-CHILDREN; ANEMIA; TRIAL; HEMOGLOBIN; HYDROXYCARBAMIDE; PREVENTION; THERAPY; STROKE; HEALTH AB Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. Pediatr Blood Cancer 2012;59:365371. (c) 2012 Wiley Periodicals, Inc. C1 [Strouse, John J.] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Dept Pediat, Baltimore, MD 21205 USA. [Strouse, John J.] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Heeney, Matthew M.] Childrens Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02115 USA. [Heeney, Matthew M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Strouse, JJ (reprint author), Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Dept Pediat, 720 Rutland Ave,Ross 1125, Baltimore, MD 21205 USA. EM jstrous1@jhmi.edu RI Strouse, John/A-2690-2008; Heeney, Matthew/J-6838-2015 OI Strouse, John/0000-0003-0341-1457; Heeney, Matthew/0000-0002-1104-6843 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [5K23HL078819-02] FX Grant sponsor: National Heart, Lung, and Blood Institute of the National Institutes of Health; Grant number: 5K23HL078819-02. NR 48 TC 34 Z9 34 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2012 VL 59 IS 2 BP 365 EP 371 DI 10.1002/pbc.24178 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 956DE UT WOS:000305069200043 PM 22517797 ER PT J AU Cohn, N Paczynski, M Jackendoff, R Holcomb, PJ Kuperberg, GR AF Cohn, Neil Paczynski, Martin Jackendoff, Ray Holcomb, Phillip J. Kuperberg, Gina R. TI (Pea)nuts and bolts of visual narrative: Structure and meaning in sequential image comprehension SO COGNITIVE PSYCHOLOGY LA English DT Article DE Coherence; Comics; Discourse; ERPs; Event-related potentials; Film; Visual language; LAN; N300; N400 ID EVENT-RELATED POTENTIALS; LANGUAGE COMPREHENSION; SEMANTIC INTEGRATION; BRAIN POTENTIALS; STORY STRUCTURE; SITUATION MODELS; TIME SHIFTS; MEMORY; DISCOURSE; PICTURES AB Just as syntax differentiates coherent sentences from scrambled word strings, the comprehension of sequential images must also use a cognitive system to distinguish coherent narrative sequences from random strings of images. We conducted experiments analogous to two classic studies of language processing to examine the contributions of narrative structure and semantic relatedness to processing sequential images. We compared four types of comic strips: (1) Normal sequences with both structure and meaning, (2) Semantic Only sequences (in which the panels were related to a common semantic theme, but had no narrative structure), (3) Structural Only sequences (narrative structure but no semantic relatedness), and (4) Scrambled sequences of randomly-ordered panels. In Experiment 1, participants monitored for target panels in sequences presented panel-by-panel. Reaction times were slowest to panels in Scrambled sequences, intermediate in both Structural Only and Semantic Only sequences, and fastest in Normal sequences. This suggests that both semantic relatedness and narrative structure offer advantages to processing. Experiment 2 measured ERPs to all panels across the whole sequence. The N300/N400 was largest to panels in both the Scrambled and Structural Only sequences, intermediate in Semantic Only sequences and smallest in the Normal sequences. This implies that a combination of narrative structure and semantic relatedness can facilitate semantic processing of upcoming panels (as reflected by the N300/N400). Also, panels in the Scrambled sequences evoked a larger left-lateralized anterior negativity than panels in the Structural Only sequences. This localized effect was distinct from the N300/N400, and appeared despite the fact that these two sequence types were matched on local semantic relatedness between individual panels. These findings suggest that sequential image comprehension uses a narrative structure that may be independent of semantic relatedness. Altogether, we argue that the comprehension of visual narrative is guided by an interaction between structure and meaning. (C) 2012 Elsevier Inc. All rights reserved. C1 [Cohn, Neil; Paczynski, Martin; Holcomb, Phillip J.; Kuperberg, Gina R.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Jackendoff, Ray] Tufts Univ, Ctr Cognit Studies, Medford, MA 02155 USA. [Kuperberg, Gina R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Psychiat, Charlestown, MA 02129 USA. RP Cohn, N (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM neilcohn@emaki.net RI 江, 鈺麒/G-1379-2014 FU NIMH [R01 MH071635]; NICHD [HD25889]; NARSAD; Sidney Baer Trust; Tufts Center for Cognitive Studies FX This work was supported by NIMH (R01 MH071635), NICHD (HD25889) and NARSAD (with the Sidney Baer Trust), as well as funding from the Tufts Center for Cognitive Studies. Thanks go to research assistants Martina Santarsieri, Lauren Rose, Adrienne Ing, and especially Natalie Buzzeo. Tali Ditman and Eva Wittenberg are also thanked for their support and advice, and Nate Delaney-Busch for the title. NR 119 TC 34 Z9 34 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0010-0285 J9 COGNITIVE PSYCHOL JI Cogn. Psychol. PD AUG PY 2012 VL 65 IS 1 BP 1 EP 38 DI 10.1016/j.cogpsych.2012.01.003 PG 38 WC Psychology; Psychology, Experimental SC Psychology GA 940OP UT WOS:000303903200001 PM 22387723 ER PT J AU Zhang, X Wang, WC Bedigian, AV Coughlin, ML Mitchison, TJ Eggert, US AF Zhang, Xin Wang, Wenchao Bedigian, Anne V. Coughlin, Margaret L. Mitchison, Timothy J. Eggert, Ulrike S. TI Dopamine receptor D-3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE small-molecule inhibitor; endocytic tubulation; unconventional G protein-coupled receptor function; drug off-target effects; membrane trafficking ID PROTEIN-COUPLED RECEPTORS; LATE ENDOSOMES; CELLS; PATHWAYS; DISCOVERY; TRANSPORT; TARGETS; CANCER AB Macromolecules enter cells by endocytosis and are sorted to different cellular destinations in early/sorting endosomes. The mechanism and regulation of sorting are poorly understood, although transitions between vesicular and tubular endosomes are important. We found that the antihypertensive drug Prazosin inhibits endocytic sorting by an off-target perturbation of the G protein-coupled receptor dopamine receptor D-3 (DRD3). Prazosin is also a potent cytokinesis inhibitor, likely as a consequence of its effects on endosomes. Prazosin stabilizes a normally transient interaction between DRD3 and the coatomer COPI, a complex involved in membrane transport, and shifts endosomal morphology entirely to tubules, disrupting cargo sorting. RNAi depletion of DRD3 alone also inhibits endocytic sorting, indicating a noncanonical role for a G protein-coupled receptor. Prazosin is a powerful tool for rapid and reversible perturbation of endocytic dynamics. C1 [Zhang, Xin; Wang, Wenchao; Bedigian, Anne V.; Eggert, Ulrike S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Xin; Bedigian, Anne V.; Eggert, Ulrike S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Coughlin, Margaret L.; Mitchison, Timothy J.] Harvard Univ, Sch Med, Dept Biol Syst Engn, Dept Syst Biol, Boston, MA 02115 USA. [Zhang, Xin; Wang, Wenchao] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Peoples R China. [Eggert, Ulrike S.] Kings Coll London, Dept Chem, London SE1 1UL, England. [Eggert, Ulrike S.] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. RP Eggert, US (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM ulrike.eggert@kcl.ac.uk FU National Institutes of Health [R01 GM023928, R01 GM082834]; Dana-Farber Cancer Institute FX We thank the Nikon Imaging Center at Harvard Medical School for assistance with microscopy, the Flow Cytometry facility at the Dana-Farber Cancer Institute for assistance with flow cytometry, and Qingsong Liu and members of the U.S.E. laboratory for helpful discussions. We also thank Maria F. Sassano and Bryan L. Roth at the University of North Carolina and the National Institute of Mental Health Psychoactive Drug Screening Program for conducting the experiments shown in SI Appendix, Fig. S6. M.L.C. and T.J.M. were supported by National Institutes of Health Grant R01 GM023928. This project was funded by National Institutes of Health Grant R01 GM082834 (to U.S.E.) and the Dana-Farber Cancer Institute. NR 33 TC 14 Z9 15 U1 0 U2 11 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 JUL 31 PY 2012 VL 109 IS 31 BP 12485 EP 12490 DI 10.1073/pnas.1207821109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200048 PM 22802617 ER PT J AU Paquette, N Conlon, J Sweet, C Rus, F Wilson, L Pereira, A Rosadini, CV Goutagny, N Weber, ANR Lane, WS Shaffer, SA Maniatis, S Fitzgerald, KA Stuart, L Silverman, N AF Paquette, Nicholas Conlon, Joseph Sweet, Charles Rus, Florentina Wilson, Lindsay Pereira, Andrea Rosadini, Charles V. Goutagny, Nadege Weber, Alexander N. R. Lane, William S. Shaffer, Scott A. Maniatis, Stephanie Fitzgerald, Katherine A. Stuart, Lynda Silverman, Neal TI Serine/threonine acetylation of TGF beta-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Drosophila immunity; innate immunity ID NF-KAPPA-B; PROTEIN-KINASES; GENE-EXPRESSION; DOWN-REGULATION; IKK ACTIVATION; EFFECTOR YOPJ; TNF-ALPHA; DROSOPHILA; PHOSPHORYLATION; PATHWAY AB The Gram-negative bacteria Yersinia pestis, causative agent of plague, is extremely virulent. One mechanism contributing to Y. pestis virulence is the presence of a type-three secretion system, which injects effector proteins, Yops, directly into immune cells of the infected host. One of these Yop proteins, YopJ, is proapoptotic and inhibits mammalian NF-kappa B and MAP-kinase signal transduction pathways. Although the molecular mechanism remained elusive for some time, recent work has shown that YopJ acts as a serine/threonine acetyl-transferase targeting MAP2 kinases. Using Drosophila as a model system, we find that YopJ inhibits one innate immune NF-kappa B signaling pathway (IMD) but not the other (Toll). In fact, we show YopJ mediated serine/threonine acetylation and inhibition of dTAK1, the critical MAP3 kinase in the IMD pathway. Acetylation of critical serine/threonine residues in the activation loop of Drosophila TAK1 blocks phosphorylation of the protein and subsequent kinase activation. In addition, studies in mammalian cells show similar modification and inhibition of hTAK1. These data present evidence that TAK1 is a target for YopJ-mediated inhibition. C1 [Paquette, Nicholas; Conlon, Joseph; Sweet, Charles; Rus, Florentina; Wilson, Lindsay; Pereira, Andrea; Rosadini, Charles V.; Goutagny, Nadege; Fitzgerald, Katherine A.; Silverman, Neal] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis, Worcester, MA 01605 USA. [Shaffer, Scott A.; Maniatis, Stephanie] Univ Massachusetts, Sch Med, Prote & Mass Spectrometry Facil, Worcester, MA 01605 USA. [Paquette, Nicholas; Stuart, Lynda] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Dev Immunol,Dept Pediat, Boston, MA 02114 USA. [Weber, Alexander N. R.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Lane, William S.] Harvard Univ, Ctr Syst Biol, Mass Spectrometry & Prote Resource Lab, Cambridge, MA 02138 USA. RP Silverman, N (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis, Worcester, MA 01605 USA. EM neal.silverman@umassmed.edu FU New England Regional Center of Excellence [U54AI057159]; National Institutes of Health [AI060025, AI053809, 1R01AI079198]; Ellison Medical Foundation FX N.P. was supported by New England Regional Center of Excellence Grant U54AI057159. N.S. and L.S. were supported by National Institutes of Health Grants AI060025 and AI053809, and 1R01AI079198, respectively. N.S. was also supported by the Ellison Medical Foundation. NR 36 TC 46 Z9 46 U1 2 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 JUL 31 PY 2012 VL 109 IS 31 BP 12710 EP 12715 DI 10.1073/pnas.1008203109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200086 PM 22802624 ER PT J AU Cheng, CK Gustafson, WC Charron, E Houseman, BT Zunder, E Goga, A Gray, NS Pollok, B Oakes, SA James, CD Shokat, KM Weiss, WA Fan, QW AF Cheng, Christine K. Gustafson, W. Clay Charron, Elizabeth Houseman, Benjamin T. Zunder, Eli Goga, Andrei Gray, Nathanael S. Pollok, Brian Oakes, Scott A. James, C. David Shokat, Kevan M. Weiss, William A. Fan, Qi-Wen TI Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR RECEPTOR; PI3-KINASE P110-ALPHA INHIBITORS; CELL-CYCLE; BIOLOGICAL EVALUATION; RAPAMYCIN INHIBITOR; IN-VIVO; EXPRESSION; EFFICACY; CANCER; AMPLIFICATION AB Malignant glioma, the most common primary brain tumor, is generally incurable. Although phosphatidylinositol-3-kinase (PI3K) signaling features prominently in glioma, inhibitors generally block proliferation rather than induce apoptosis. Starting with an inhibitor of both lipid and protein kinases that induced prominent apoptosis and that failed early clinical development because of its broad target profile and overall toxicity, we identified protein kinase targets, the blockade of which showed selective synthetic lethality when combined with PI3K inhibitors. Prioritizing protein kinase targets for which there are clinical inhibitors, we demonstrate that cyclin-dependent kinase (CDK)1/2 inhibitors, siRNAs against CDK1/2, and the clinical CDK1/2 inhibitor roscovitine all cooperated with the PI3K inhibitor PIK-90, blocking the antiapoptotic protein Survivin and driving cell death. In addition, overexpression of CDKs partially blocked some of the apoptosis caused by PIK-75. Roscovitine and PIK-90, in combination, were well tolerated in vivo and acted in a synthetic-lethal manner to induce apoptosis in human glioblastoma xenografts. We also tested clinical Akt and CDK inhibitors, demonstrating induction of apoptosis in vitro and providing a preclinical rationale to test this combination therapy in patients. C1 [Cheng, Christine K.; Charron, Elizabeth; Weiss, William A.; Fan, Qi-Wen] Dana Farber Canc Inst, Dept Neurol, Boston, MA 02115 USA. [Cheng, Christine K.; Gustafson, W. Clay; Charron, Elizabeth; Weiss, William A.; Fan, Qi-Wen] Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. [Cheng, Christine K.; Charron, Elizabeth; James, C. David; Weiss, William A.; Fan, Qi-Wen] Dana Farber Canc Inst, Brain Tumor Res Ctr, Boston, MA 02115 USA. [Cheng, Christine K.; Charron, Elizabeth; James, C. David; Weiss, William A.; Fan, Qi-Wen] Dana Farber Canc Inst, Dept Neurol Surg, Boston, MA 02115 USA. [Houseman, Benjamin T.; Zunder, Eli; Shokat, Kevan M.] Dana Farber Canc Inst, Dept Cellular & Mol Pharmacol, Boston, MA 02115 USA. [Goga, Andrei] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Cheng, Christine K.; Gustafson, W. Clay; Charron, Elizabeth; Goga, Andrei; Oakes, Scott A.; James, C. David; Shokat, Kevan M.; Weiss, William A.; Fan, Qi-Wen] Dana Farber Canc Inst, Helen Diller Family Comprehens Canc Ctr, Boston, MA 02115 USA. [Houseman, Benjamin T.; Zunder, Eli; Shokat, Kevan M.] Dana Farber Canc Inst, Program Chem & Chem Biol, Boston, MA 02115 USA. [Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Pollok, Brian] Invitrogen Corp, Res & Dev, Carlsbad, CA 92008 USA. [Shokat, Kevan M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Oakes, Scott A.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA. RP Weiss, WA (reprint author), Dana Farber Canc Inst, Dept Neurol, Boston, MA 02115 USA. EM waweiss@gmail.com; qiwen.fan@ucsf.edu OI Weiss, William/0000-0003-2230-9132 FU Brain Tumor Society; Accelerate Brain Cancer Cure; Burroughs Wellcome Fund; Howard Hughes Medical Institute; Mount Zion Health Fund; National Institutes of Health (NIH) [CA097257, 1R01CA136717]; Susan G. Komen Foundation; Samuel Waxman Cancer Research Foundation FX This work was supported by grants from the Brain Tumor Society, Accelerate Brain Cancer Cure, the Burroughs Wellcome Fund, the Howard Hughes Medical Institute, the Mount Zion Health Fund, National Institutes of Health (NIH) Specialized Programs of Research Excellence (SPORE) Grant CA097257, NIH Grant 1R01CA136717, the Susan G. Komen Foundation, and the Samuel Waxman Cancer Research Foundation. NR 29 TC 17 Z9 19 U1 0 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 JUL 31 PY 2012 VL 109 IS 31 BP 12722 EP 12727 DI 10.1073/pnas.1202492109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200088 PM 22802621 ER PT J AU Ohashi, K Sequist, LV Arcila, ME Moran, T Chmielecki, J Lin, YL Pan, YM Wang, L de Stanchina, E Shien, K Aoe, K Toyooka, S Kiura, K Fernandez-Cuesta, L Fidias, P Yang, JCH Miller, VA Riely, GJ Kris, MG Engelman, JA Vnencak-Jones, CL Dias-Santagata, D Ladanyi, M Pao, W AF Ohashi, Kadoaki Sequist, Lecia V. Arcila, Maria E. Moran, Teresa Chmielecki, Juliann Lin, Ya-Lun Pan, Yumei Wang, Lu de Stanchina, Elisa Shien, Kazuhiko Aoe, Keisuke Toyooka, Shinichi Kiura, Katsuyuki Fernandez-Cuesta, Lynnette Fidias, Panos Yang, James Chih-Hsin Miller, Vincent A. Riely, Gregory J. Kris, Mark G. Engelman, Jeffrey A. Vnencak-Jones, Cindy L. Dias-Santagata, Dora Ladanyi, Marc Pao, William TI Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NRAS mutation; gefitinib; erlotinib ID GROWTH-FACTOR-RECEPTOR; SIGNALING PATHWAY GENES; MET AMPLIFICATION; T790M MUTATION; KINASE INHIBITORS; CELL-LINE; GEFITINIB; ERLOTINIB; ADENOCARCINOMAS; TUMORS AB Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/ BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. C1 [Ohashi, Kadoaki; Lin, Ya-Lun; Pan, Yumei; Pao, William] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Div Hematol Oncol,Sch Med, Nashville, TN 37232 USA. [Sequist, Lecia V.; Fidias, Panos; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sequist, Lecia V.; Fidias, Panos; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dias-Santagata, Dora] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Arcila, Maria E.; Wang, Lu; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [de Stanchina, Elisa] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Facil, New York, NY 10065 USA. [Miller, Vincent A.; Riely, Gregory J.; Kris, Mark G.] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Div Solid Tumor Oncol, Dept Med, New York, NY 10065 USA. [Moran, Teresa] Univ Autonoma Barcelona, Catalan Inst Oncol, Barcelona 08916, Spain. [Moran, Teresa] Hosp Badalona Germans Trias & Pujol, Barcelona 08916, Spain. [Chmielecki, Juliann] Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA. [Shien, Kazuhiko; Toyooka, Shinichi] Okayama Univ Hosp, Dept Thorac Surg, Okayama 7008558, Japan. [Aoe, Keisuke] Natl Hosp Org Yamaguchi, Ube Med Ctr, Dept Med Oncol, Ube, Yamaguchi 7550241, Japan. [Aoe, Keisuke] Natl Hosp Org Yamaguchi, Ube Med Ctr, Dept Clin Res, Ube, Yamaguchi 7550241, Japan. [Kiura, Katsuyuki] Okayama Univ, Dept Hematol Oncol & Resp Med, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008558, Japan. [Fernandez-Cuesta, Lynnette] Max Planck Gesell, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany. [Fernandez-Cuesta, Lynnette] Fac Med, D-50931 Cologne, Germany. [Yang, James Chih-Hsin] Natl Taiwan Univ, Grad Inst Oncol, Taipei 100, Taiwan. [Yang, James Chih-Hsin] Natl Taiwan Univ, Canc Res Ctr, Taipei 100, Taiwan. [Vnencak-Jones, Cindy L.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Dias-Santagata, Dora] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Pao, W (reprint author), Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Div Hematol Oncol,Sch Med, Nashville, TN 37232 USA. EM william.pao@vanderbilt.edu RI Shien, Kazuhiko/B-8560-2012; OI Kris, Mark/0000-0002-7317-5341; Shien, Kazuhiko/0000-0002-4959-4220; Yang, James Chih-Hsin/0000-0002-5586-5138 FU National Institutes of Health/National Cancer Institute (NCI [R01-CA121210, P01-CA129243, U54-CA143798]; Vanderbilt's Specialized Program of Research Excellence in Lung Cancer [CA90949]; Vanderbilt-Ingram Cancer Center Core [P30-CA68485]; NCI [1R21-156000]; Uniting Against Lung Cancer: New England; Marjorie E. Korff Fund; Clovis Oncology; GlaxoSmithKline; Celgene Corporation; Boehringer Ingelheim; Pfizer; Boehringer; Agios Pharmaceuticals; Novartis; AstraZeneca; Bio-Reference Laboratories; MolecularMD; Bristol-Myers Squibb; Symphony Evolution; Enzon; Xcovery; Symphogen FX This work was supported by National Institutes of Health/National Cancer Institute (NCI) Grants R01-CA121210, P01-CA129243, and U54-CA143798. W.P. received additional support from Vanderbilt's Specialized Program of Research Excellence in Lung Cancer Grant CA90949 and from Vanderbilt-Ingram Cancer Center Core Grant P30-CA68485. L.V.S. received additional support from NCI Grant 1R21-156000 and from Uniting Against Lung Cancer: New England and the Marjorie E. Korff Fund.; L.V.S. received consulting fees from Clovis Oncology, GlaxoSmithKline, and Celgene Corporation. J.C.-H.Y. received consulting fees from Boehringer Ingelheim. V.A.M. is an employee at Foundation Medicine and has equity value in the company. M.G.K. has received consulting fees from Boehringer Ingelheim and research funding for other projects from Pfizer and Boehringer. J.A.E. has received consulting fees and has stock option ownership in Agios Pharmaceuticals and has received research funding for other projects from Novartis, GlaxoSmithKline, and AstraZeneca. D.D.-S. received consulting fees from Bio-Reference Laboratories. W.P. has received consulting fees from MolecularMD, AstraZeneca, Bristol-Myers Squibb, Symphony Evolution, and Clovis Oncology and research funding for other projects from Enzon, Xcovery, AstraZeneca, and Symphogen. W.P. and V.A.M. are part of a patent regarding EGFR T790M mutation testing that was licensed by Memorial Sloan-Kettering Cancer Center to MolecularMD. NR 42 TC 159 Z9 165 U1 3 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 JUL 31 PY 2012 VL 109 IS 31 BP E2127 EP E2133 DI 10.1073/pnas.1203530109 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989CQ UT WOS:000307538200007 PM 22773810 ER PT J AU Zile, MR Baicu, CF Gottdiener, JS Hetzel, SJ McMurray, JJ Komajda, M McKelvie, R Massie, BM Carson, PE AF Zile, Michael R. Baicu, Catalin F. Gottdiener, John S. Hetzel, Scott J. McMurray, John J. Komajda, Michel McKelvie, Robert Massie, Barry M. Carson, Peter E. CA I-PRESERVE Investigators TI Response to Letters Regarding Article, "Prevalence and Significance of Alterations in Cardiac Structure and Function in Patients With Heart Failure and a Preserved Ejection Fraction" SO CIRCULATION LA English DT Letter C1 [Zile, Michael R.; Baicu, Catalin F.] RHJ Dept Vet Affairs Med Ctr, Charleston, SC USA. [Zile, Michael R.; Baicu, Catalin F.] Med Univ S Carolina, Charleston, SC 29425 USA. [Gottdiener, John S.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Hetzel, Scott J.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [McMurray, John J.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Komajda, Michel] Univ Paris 06, Pitie Salpetriere Hosp, Paris, France. [McKelvie, Robert] McMaster Univ, Hamilton, ON, Canada. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Carson, Peter E.; I-PRESERVE Investigators] Georgetown Univ, Washington, DC USA. [Carson, Peter E.] VAMC, Washington, DC USA. RP Zile, MR (reprint author), RHJ Dept Vet Affairs Med Ctr, Charleston, SC USA. OI mcmurray, john/0000-0002-6317-3975 NR 7 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 31 PY 2012 VL 126 IS 5 BP E64 EP E65 DI 10.1161/CIRCULATIONAHA.112.110809 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OK UT WOS:000306977500008 ER PT J AU Siddiqui, M Vakoc, BJ AF Siddiqui, Meena Vakoc, Benjamin J. TI Optical-domain subsampling for data efficient depth ranging in Fourier-domain optical coherence tomography SO OPTICS EXPRESS LA English DT Article ID SWEPT SEMICONDUCTOR-LASER; FREQUENCY COMB; DEGENERACY; MICROSCOPY; OCT AB Recent advances in optical coherence tomography (OCT) have led to higher-speed sources that support imaging over longer depth ranges. Limitations in the bandwidth of state-of-the-art acquisition electronics, however, prevent adoption of these advances into the clinical applications. Here, we introduce optical-domain subsampling as a method for imaging at high-speeds and over extended depth ranges but with a lower acquisition bandwidth than that required using conventional approaches. Optically subsampled laser sources utilize a discrete set of wavelengths to alias fringe signals along an extended depth range into a bandwidth limited frequency window. By detecting the complex fringe signals and under the assumption of a depth-constrained signal, optical-domain subsampling enables recovery of the depth-resolved scattering signal without overlapping artifacts from this bandwidth-limited window. We highlight key principles behind optical-domain subsampled imaging, and demonstrate this principle experimentally using a polygon-filter based swept-source laser that includes an intra-cavity Fabry-Perot (FP) etalon. (C) 2012 Optical Society of America C1 [Siddiqui, Meena; Vakoc, Benjamin J.] Harvard MIT, Dept Hlth Sci & Technol, Cambridge, MA 02139 USA. [Vakoc, Benjamin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Vakoc, Benjamin J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Siddiqui, M (reprint author), Harvard MIT, Dept Hlth Sci & Technol, Cambridge, MA 02139 USA. EM siddiqui@mit.edu FU Center for Biomedical OCT Research and Translation [P41EB015903]; NIH [K25CA127465]; National Science Foundation [11-031]; Wellman Center for Photomedicine Graduate Student Fellowship; National Institute on Deafness and Other Communication Disorders (NIDCD) [T32 DC00038]; National Center for Research Resources; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX This project was supported by the Center for Biomedical OCT Research and Translation through Grant Number P41EB015903, awarded by the National Center for Research Resources and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. This work was also supported by NIH grant K25CA127465, the National Science Foundation Graduate Research Fellowship under Grant No. (11-031), the Wellman Center for Photomedicine Graduate Student Fellowship, and the National Institute on Deafness and Other Communication Disorders (NIDCD) Grant Number T32 DC00038. NR 22 TC 3 Z9 3 U1 1 U2 8 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 30 PY 2012 VL 20 IS 16 BP 17938 EP 17951 DI 10.1364/OE.20.017938 PG 14 WC Optics SC Optics GA 986PR UT WOS:000307356300063 PM 23038343 ER PT J AU Wang, XV Blades, N Ding, J Sultana, R Parmigiani, G AF Wang, Xin Victoria Blades, Natalie Ding, Jie Sultana, Razvan Parmigiani, Giovanni TI Estimation of sequencing error rates in short reads SO BMC BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION; HUMAN GENOME; QUALITY; TRANSCRIPTOME; PROJECT; BIASES AB Background: Short-read data from next-generation sequencing technologies are now being generated across a range of research projects. The fidelity of this data can be affected by several factors and it is important to have simple and reliable approaches for monitoring it at the level of individual experiments. Results: We developed a fast, scalable and accurate approach to estimating error rates in short reads, which has the added advantage of not requiring a reference genome. We build on the fundamental observation that there is a linear relationship between the copy number for a given read and the number of erroneous reads that differ from the read of interest by one or two bases. The slope of this relationship can be transformed to give an estimate of the error rate, both by read and by position. We present simulation studies as well as analyses of real data sets illustrating the precision and accuracy of this method, and we show that it is more accurate than alternatives that count the difference between the sample of interest and a reference genome. We show how this methodology led to the detection of mutations in the genome of the PhiX strain used for calibration of Illumina data. The proposed method is implemented in an R package, which can be downloaded from http://bcb.dfci.harvard.edu/similar to vwang/shadowRegression.html. Conclusions: The proposed method can be used to monitor the quality of sequencing pipelines at the level of individual experiments without the use of reference genomes. Furthermore, having an estimate of the error rates gives one the opportunity to improve analyses and inferences in many applications of next-generation sequencing data. C1 [Wang, Xin Victoria; Ding, Jie; Sultana, Razvan; Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Wang, Xin Victoria; Ding, Jie; Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Blades, Natalie] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Sultana, Razvan] Boston Univ, Dept Bioinformat, Boston, MA 02215 USA. RP Parmigiani, G (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. EM gp@jimmy.harvard.edu FU National Science Foundation [1041698, 1042785] FX We thank John Quackenbush for sharing data from the Center for Cancer Computational Biology, and Victor Velculescu for insight into an earlier unpublished version of this algorithm for SAGE data. Funding: This work was supported by National Science Foundation award 1041698 and 1042785. NR 28 TC 18 Z9 18 U1 0 U2 10 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 JUL 30 PY 2012 VL 13 AR 185 DI 10.1186/1471-2105-13-185 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 038AZ UT WOS:000311148900001 PM 22846331 ER PT J AU Fard, AM Buckley, B Zlatanovic, S Bres, CS Radic, S Jalali, B AF Fard, A. M. Buckley, B. Zlatanovic, S. Bres, C. -S. Radic, S. Jalali, B. TI All-optical time-stretch digitizer SO APPLIED PHYSICS LETTERS LA English DT Article ID TO-DIGITAL CONVERSION; PARAMETRIC AMPLIFICATION; PERFORMANCE; CONVERTER; FIBER; OSCILLOSCOPE; LENS AB We propose and demonstrate an all-optical time-stretch digitizer for real-time capture of ultrafast optical signals, beyond the bandwidths achievable by electronics. This approach uniquely combines four-wave mixing and photonic time-stretch technique to slow down and record high-speed optical signals. As a proof-of-concept, real-time recording of 40-Gb/s non-return-to-zero on-off-keying optical data stream is experimentally demonstrated using a stretch factor of 54 and 1.5-GHz back-end electronic bandwidth. We also report on the observation of dispersion penalty and its mitigation via single-sideband conversion enabled by an optical bandpass filter. Our technique may provide a path to real-time capture of ultrahigh-speed optical data streams. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4742173] C1 [Fard, A. M.] Univ Calif Los Angeles, Photon Lab, Los Angeles, CA 90095 USA. [Buckley, B.; Jalali, B.] Univ Calif Los Angeles, Dept Elect Engn, Los Angeles, CA 90095 USA. [Zlatanovic, S.; Radic, S.] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. RP Fard, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM ali.fard@ucla.edu; jalali@ucla.edu FU National Science Foundation through CIAN NSF ERC [EEC-0812072] FX The authors would like to acknowledge the partial support from National Science Foundation through CIAN NSF ERC under Grant No. EEC-0812072. NR 30 TC 5 Z9 7 U1 0 U2 13 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUL 30 PY 2012 VL 101 IS 5 AR 051113 DI 10.1063/1.4742173 PG 5 WC Physics, Applied SC Physics GA 991BU UT WOS:000307676600013 ER PT J AU Martins, VC Ruggiero, E Schlenner, SM Madan, V Schmidt, M Fink, PJ von Kalle, C Rodewald, HR AF Martins, Vera C. Ruggiero, Eliana Schlenner, Susan M. Madan, Vikas Schmidt, Manfred Fink, Pamela J. von Kalle, Christof Rodewald, Hans-Reimer TI Thymus-autonomous T cell development in the absence of progenitor import SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID RECEPTOR-GAMMA CHAIN; C-KIT; RAG EXPRESSION; MICE; LYMPHOCYTES; DIFFERENTIATION; REPERTOIRE; PRECURSORS; THYMOCYTES; EXPANSION AB Thymus function is thought to depend on a steady supply of T cell progenitors from the bone marrow. The notion that the thymus lacks progenitors with self-renewal capacity is based on thymus transplantation experiments in which host-derived thymocytes replaced thymus-resident cells within 4 wk. Thymus grafting into T cell-deficient mice resulted in a wave of T cell export from the thymus, followed by colonization of the thymus by host-derived progenitors, and cessation of T cell development. Compound Rag2(-/-)gamma(-/-)(c)Kit(W/Wv) mutants lack competitive hematopoietic stem cells (HSCs) and are devoid of T cell progenitors. In this study, using this strain as recipients for wild-type thymus grafts, we noticed thymus-autonomous T cell development lasting several months. However, we found no evidence for export of donor HSCs from thymus to bone marrow. A diverse T cell antigen receptor repertoire in progenitor-deprived thymus grafts implied that many thymocytes were capable of self-renewal. Although the process was most efficient in Rag2(-/-)gamma(-/-)(c)Kit(W/Wv) hosts, gamma(c)-mediated signals alone played a key role in the competition between thymus-resident and bone marrow-derived progenitors. Hence, the turnover of each generation of thymocytes is not only based on short life span but is also driven via expulsion of resident thymocytes by fresh progenitors entering the thymus. C1 [Rodewald, Hans-Reimer] German Canc Res Ctr, Div Cellular Immunol, D-69120 Heidelberg, Germany. [Martins, Vera C.] Univ Ulm, Inst Immunol, D-89081 Ulm, Germany. [Ruggiero, Eliana; Schmidt, Manfred; von Kalle, Christof] Natl Ctr Tumor Dis, Dept Translat Oncol, D-69120 Heidelberg, Germany. [Schlenner, Susan M.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Madan, Vikas] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore. [Fink, Pamela J.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. RP Rodewald, HR (reprint author), German Canc Res Ctr, Div Cellular Immunol, D-69120 Heidelberg, Germany. EM hr.rodewald@dkfz.de RI Martins, Vera/M-1356-2015 OI Martins, Vera/0000-0001-8717-9709 FU DFG-KFO [142-P8]; ERC [233074]; National Institutes of Health [R01 AI064318]; Helmholtz Alliance on Immunotherapy of Cancer FX We thank Michel Nussenzweig for RAG2p-GFP reporter mice, Carmen Blum for technical assistance, Hans Jorg Fehling and Petra Kirsch for discussions and for support, Thorsten Feyerabend and Katrin Busch for critical reading of the manuscript, and Benedita Rocha for discussions. H.-R. Rodewald was supported by DFG-KFO 142-P8, and by ERC Advanced grant nr. 233074, and P.J. Fink was supported by National Institutes of Health grant R01 AI064318. TCR repertoire analyses and sequencing was supported by the Helmholtz Alliance on Immunotherapy of Cancer. NR 26 TC 43 Z9 43 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 30 PY 2012 VL 209 IS 8 BP 1409 EP 1417 DI 10.1084/jem.20120846 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 982BK UT WOS:000307016500004 PM 22778389 ER PT J AU Klein, F Gaebler, C Mouquet, H Sather, DN Lehmann, C Scheid, JF Kraft, Z Liu, Y Pietzsch, J Hurley, A Poignard, P Feizi, T Morris, L Walker, BD Fatkenheuer, G Seaman, MS Stamatatos, L Nussenzweig, MC AF Klein, Florian Gaebler, Christian Mouquet, Hugo Sather, D. Noah Lehmann, Clara Scheid, Johannes F. Kraft, Zane Liu, Yan Pietzsch, John Hurley, Arlene Poignard, Pascal Feizi, Ten Morris, Lynn Walker, Bruce D. Faetkenheuer, Gerd Seaman, Michael S. Stamatatos, Leonidas Nussenzweig, Michel C. TI Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; B-CELLS; PASSIVE TRANSFER; RATIONAL DESIGN; CHIMERIC VIRUS; POTENT; INFECTION; INDIVIDUALS; PROTECTION AB Two to three years after infection, a fraction of HIV-1-infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti-HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti-HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti-HIV-1 serologic breadth and potency should not be limited to single epitopes. C1 [Klein, Florian; Gaebler, Christian; Mouquet, Hugo; Scheid, Johannes F.; Pietzsch, John; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Hurley, Arlene] Rockefeller Univ, Rockefeller Univ Hosp, New York, NY 10065 USA. [Gaebler, Christian] Tech Univ Dresden, Fac Med Carl Gustav Carus, D-01307 Dresden, Germany. [Sather, D. Noah; Kraft, Zane; Stamatatos, Leonidas] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Lehmann, Clara; Faetkenheuer, Gerd] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany. [Scheid, Johannes F.] Charite, D-10117 Berlin, Germany. [Liu, Yan; Feizi, Ten] Univ London Imperial Coll Sci Technol & Med, Glycosci Lab, Dept Med, London W12 0NN, England. [Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Poignard, Pascal] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Morris, Lynn] Natl Inst Communicable Dis, AIDS Virus Res Unit, ZA-2131 Johannesburg, South Africa. [Walker, Bruce D.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. [Walker, Bruce D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI poignard, pascal/N-6678-2013; Mouquet, Hugo/M-2750-2014; Liu, Yan/D-9117-2013; OI Feizi, Ten/0000-0001-6495-0329 FU Rockefeller University; Research Council's Basic Technology Initiative 'Glycoarrays' [GRS/79268]; EPSRC [EP/G037604/1]; National Cancer Institute Alliance of Glycobiologists [U01CA128416]; National Institutes of Health [NIH 1 PO1 AI081677]; German Research Foundation (DFG) [KL 2389/1-1]; German National Academic Foundation; German Federal Ministry of Education and Research [BMBF 01 KI 0771]; Bill and Melinda Gates Foundation's Comprehensive Antibody Vaccine Immune Monitoring Consortium [1032144] FX This research was supported by The Rockefeller University, the UK Research Council's Basic Technology Initiative 'Glycoarrays' (GRS/79268), EPSRC Translational Grant (EP/G037604/1), the National Cancer Institute Alliance of Glycobiologists (U01CA128416), and the National Institutes of Health grant to M.C. Nussenzweig (NIH 1 PO1 AI081677). F. Klein was supported by the German Research Foundation (DFG, KL 2389/1-1). C. Gaebler was supported by The German National Academic Foundation. C. Lehmann and G.F tkenheuer are supported by the German Federal Ministry of Education and Research (BMBF 01 KI 0771). M.S. Seaman and L. Morris were supported by the Bill and Melinda Gates Foundation's Comprehensive Antibody Vaccine Immune Monitoring Consortium, grant number 1032144. M.C. Nussenzweig is a Howard Hughes Medical Institute investigator. M.C. Nussenzweig and F. Klein have a pending patent application for the antibodies 3BC176 and 3BC315 with the United States Patent and Trademark Office. These reagents are available with a Material Transfer Agreement. NR 57 TC 91 Z9 92 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 30 PY 2012 VL 209 IS 8 BP 1469 EP 1479 DI 10.1084/jem.20120423 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 982BK UT WOS:000307016500010 PM 22826297 ER PT J AU Elias, PZ Spector, M AF Elias, Paul Z. Spector, Myron TI Implantation of a collagen scaffold seeded with adult rat hippocampal progenitors in a rat model of penetrating brain injury SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Penetrating brain injury; Traumatic brain injury; Collagen scaffold; Brain tissue engineering; Stem cells; Adult hippocampal neural progenitors ID NEURAL STEM-CELLS; MAJOR HISTOCOMPATIBILITY COMPLEX; STEM/PROGENITOR CELLS; IN-VITRO; PERINEURONAL OLIGODENDROCYTES; NEURONAL DIFFERENTIATION; FUNCTIONAL RECOVERY; PARKINSONS-DISEASE; COGNITIVE FUNCTION; MHC EXPRESSION AB Penetrating brain injury (PBI) is a complex central nervous system injury in which mechanical damage to brain parenchyma results in hemorrhage, ischemia, broad areas of necrosis, and eventually cavitation. The permanent loss of brain tissue affords the possibility of treatment using a biomaterial scaffold to fill the lesion site and potentially deliver pharmacological or cellular therapeutic agents. The administration of cellular therapy may be of benefit in both mitigating the secondary injury process and promoting regeneration through replacement of certain cell populations. This study investigated the survival and differentiation of adult rat hippocampal neural progenitor cells delivered by a collagen scaffold in a rat model of PBI. The cell-scaffold construct was implanted 1 week after injury and was observed to remain intact with open pores upon analysis 4 weeks later. Implanted neural progenitors were found to have survived within the scaffold, and also to have migrated into the surrounding brain. Differentiated phenotypes included astrocytes, oligodendrocytes, vascular endothelial cells, and possibly macrophages. The demonstrated multipotency of this cell population in vivo in the context of traumatic brain injury has implications for regenerative therapies, but additional stimulation appears necessary to promote neuronal differentiation outside normally neurogenic regions. (c) 2012 Elsevier B.V. All rights reserved. C1 [Elias, Paul Z.; Spector, Myron] VA Boston Healthcare Syst, Tissue Engn Labs, Boston, MA 02130 USA. [Elias, Paul Z.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Spector, Myron] Harvard Univ, Sch Med, Dept Orthoped Surg, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Elias, PZ (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, Mail Stop 151,150 S Huntington Ave, Boston, MA 02130 USA. EM pzelias@alum.mit.edu; mspector@rics.bwh.harvard.edu FU U.S. Department of Veterans Affairs; Veterans Health Administration, Rehabilitation Research and Development Service FX This research was supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service. NR 98 TC 5 Z9 8 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 30 PY 2012 VL 209 IS 1 BP 199 EP 211 DI 10.1016/j.jneumeth.2012.06.003 PG 13 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 983QB UT WOS:000307132700024 PM 22698665 ER PT J AU Iwasaki, M Ono, H Kuchiba, A Kasuga, Y Yokoyama, S Onuma, H Nishimura, H Kusama, R Yoshida, T Tsugane, S AF Iwasaki, Motoki Ono, Hiroe Kuchiba, Aya Kasuga, Yoshio Yokoyama, Shiro Onuma, Hiroshi Nishimura, Hideki Kusama, Ritsu Yoshida, Teruhiko Tsugane, Shoichiro TI Association of postmenopausal endogenous sex hormones with global methylation level of leukocyte DNA among Japanese women SO BMC CANCER LA English DT Article DE Cross-sectional study; Endogenous sex hormones; Global methylation level; Luminometric methylation assay; Peripheral blood leukocyte DNA ID BREAST-CANCER RISK; METHYLENETETRAHYDROFOLATE REDUCTASE; COMMON MUTATION; MOUSE UTERUS; HYPOMETHYLATION; FOLATE; BLOOD; EPIGENETICS; BRAZILIANS; BIOMARKER AB Background: Although global hypomethylation of leukocyte DNA has been associated with an increased risk of several sites of cancer, including breast cancer, determinants of global methylation level among healthy individuals remain largely unexplored. Here, we examined whether postmenopausal endogenous sex hormones were associated with the global methylation level of leukocyte DNA. Methods: A cross-sectional study was conducted using the control group of a breast cancer case-control study in Nagano, Japan. Subjects were postmenopausal women aged 55 years or over who provided blood samples. We measured global methylation level of peripheral blood leukocyte DNA by luminometric methylation assay; estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate, testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex-hormone binding globulin by immunoradiometric assay. A linear trend of association between methylation and hormone levels was evaluated by regression coefficients in a multivariable liner regression model. A total of 185 women were included in the analyses. Results: Mean global methylation level (standard deviation) was 70.3% (3.1) and range was from 60.3% to 79.2%. Global methylation level decreased 0.27% per quartile category for estradiol and 0.39% per quartile category for estrone while it increased 0.41% per quartile category for bioavailable estradiol. However, we found no statistically significant association of any sex hormone level measured in the present study with global methylation level of leukocyte DNA. Conclusions: Our findings suggest that endogenous sex hormones are not major determinants of the global methylation level of leukocyte DNA. C1 [Iwasaki, Motoki; Tsugane, Shoichiro] Natl Canc Ctr, Epidemiol & Prevent Div, Res Ctr Canc Prevent & Screening, Chuo Ku, Tokyo 1040045, Japan. [Ono, Hiroe; Kuchiba, Aya; Yoshida, Teruhiko] Natl Canc Ctr, Div Genet, Res Inst, Chuo Ku, Tokyo 1040045, Japan. [Ono, Hiroe] Tokyo Med & Dent Univ, Biomed Sci PhD Program, Bunkyo Ku, Tokyo 1138510, Japan. [Kuchiba, Aya] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kasuga, Yoshio] Matsushiro Gen Hosp, Dept Surg, Nagano 3811231, Japan. [Yokoyama, Shiro; Onuma, Hiroshi] Nagano Red Cross Hosp, Dept Breast & Thyroid Surg, Nagano 3808582, Japan. [Nishimura, Hideki] Nagano Municipal Hosp, Dept Surg, Nagano 3818551, Japan. [Kusama, Ritsu] Nagano Hokushin Gen Hosp, Dept Surg, Nagano 3838505, Japan. RP Iwasaki, M (reprint author), Natl Canc Ctr, Epidemiol & Prevent Div, Res Ctr Canc Prevent & Screening, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. EM moiwasak@ncc.go.jp RI Tsugane, Shocichiro/A-2424-2015 FU Ministry of Health, Labor and Welfare of Japan; National Institute of Biomedical Innovation (NIBIO); Ministry of Education, Culture, Sports, Science, and Technology of Japan [17015049, 221S0001, 22700934]; Japan Society for the Promotion of Science; Foundation for Promotion of Cancer Research in Japan FX This study was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control and for the Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan; by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), by Grants-in-Aid for Scientific Research on Priority Areas (17015049), and for Scientific Research on Innovative Areas (221S0001), and for Young Scientists (B) (22700934) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Japan Society for the Promotion of Science, and by Foundation for Promotion of Cancer Research in Japan. NR 30 TC 5 Z9 5 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 29 PY 2012 VL 12 AR 323 DI 10.1186/1471-2407-12-323 PG 9 WC Oncology SC Oncology GA 026YC UT WOS:000310318000001 PM 22839213 ER PT J AU Dang, AT Cotton, S Sankaran-Walters, S Li, CS Lee, CYM Dandekar, S Paster, BJ George, MD AF Dang, Angeline T. Cotton, Sean Sankaran-Walters, Sumathi Li, Chin-Shang Lee, Chia-Yuan Michael Dandekar, Satya Paster, Bruce J. George, Michael D. TI Evidence of an increased pathogenic footprint in the lingual microbiome of untreated HIV infected patients SO BMC MICROBIOLOGY LA English DT Article DE HIV; Microbiota; Oral mucosa; Dysbiosis; CD4+T cells; Streptococcus; Commensal; Microbiome; HOMIM ID T-CELL DEPLETION; OROPHARYNGEAL CANDIDIASIS; ORAL LESIONS; TH17 CELLS; HEALTH; RESPONSES; BACTERIAL; COLONIZATION; VEILLONELLA; IMMUNITY AB Background: Opportunistic oral infections can be found in over 80% of HIV + patients, often causing debilitating lesions that also contribute to deterioration in nutritional health. Although appreciation for the role that the microbiota is likely to play in the initiation and/or enhancement of oral infections has grown considerably in recent years, little is known about the impact of HIV infection on host-microbe interactions within the oral cavity. In the current study, we characterize modulations in the bacterial composition of the lingual microbiome in patients with treated and untreated HIV infection. Bacterial species profiles were elucidated by microarray assay and compared between untreated HIV infected patients, HIV infected patients receiving antiretroviral therapy, and healthy HIV negative controls. The relationship between clinical parameters (viral burden and CD4+ T cell depletion) and the loss or gain of bacterial species was evaluated in each HIV patient group. Results: In untreated HIV infection, elevated viremia was associated with significantly higher proportions of potentially pathogenic Veillonella, Prevotella, Megasphaera, and Campylobacter species in the lingual microbiome than observed in healthy controls. The upsurge in the prevalence of potential pathogens was juxtaposed by diminished representation of commensal Streptococcus and Veillonella species. Colonization of Neisseria flavescens was lower in the lingual microbiome of HIV infected patients receiving antiretroviral therapy than in uninfected controls. Conclusions: Our findings provide novel insights into the potential impact of HIV infection and antiretroviral therapy on the community structure of the oral microbiome, and implicate potential mechanisms that may increase the capacity of non-commensal species to gain a stronger foothold. C1 [Dang, Angeline T.; Sankaran-Walters, Sumathi; Dandekar, Satya; George, Michael D.] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. [Cotton, Sean; Paster, Bruce J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Li, Chin-Shang] Univ Calif Davis, Dept Publ Hlth Serv, Davis, CA 95616 USA. [Dang, Angeline T.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Lee, Chia-Yuan Michael] Univ Calif Los Angeles, Neurosci Undergraduate Interdept Program, Los Angeles, CA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP George, MD (reprint author), Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. EM mdgeorge@ucdavis.edu FU California Research Center for the Biology of HIV in Minorities (CRCBHM); National Center for Research Resources (NCRR) [UL1 RR024146] FX The authors would like to thank the clinicians and staff at the Center for AIDS Research and Education (CARES) Clinic in Sacramento, CA for their help in scheduling patient appointments and collecting samples. This study was funded through a pilot grant from the California Research Center for the Biology of HIV in Minorities (CRCBHM). Statistical support was made possible through funding (UL1 RR024146) from the National Center for Research Resources (NCRR). NR 43 TC 22 Z9 22 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JUL 28 PY 2012 VL 12 AR 153 DI 10.1186/1471-2180-12-153 PG 10 WC Microbiology SC Microbiology GA 002VG UT WOS:000308564200001 PM 22838383 ER PT J AU Eccles, MP Foy, R Sales, A Wensing, M Mittman, B AF Eccles, Martin P. Foy, Robbie Sales, Anne Wensing, Michel Mittman, Brian TI Implementation Science six years on-our evolving scope and common reasons for rejection without review SO IMPLEMENTATION SCIENCE LA English DT Editorial Material AB Implementation Science has been published for six years and over that time has gone from receiving 100 articles in 2006 to receiving 354 in 2011; our impact factor has risen from 2.49 in June 2010 to 3.10 in June 2012. Whilst our article publication rate has also risen, it has risen much less slowly than our submission rate-we published 29 papers in 2006 and 134 papers in 2011 and we now publish only around 40 % of submissions. About one-half of submitted manuscripts are rejected without being sent out for peer review; it has become clear that there are a number of common issues that result in manuscripts being rejected at this stage. We hope that by publishing this editorial on our common reasons for rejection without peer review we can help authors to better judge the relevance of their papers to Implementation Science. C1 [Eccles, Martin P.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. [Foy, Robbie] Univ Leeds, Leeds Inst Hlth Sci, Leeds LS2 9LJ, W Yorkshire, England. [Wensing, Michel] Radboud Univ Nijmegen, Med Ctr, Sci Inst Qual Healthcare, NL-6525 ED Nijmegen, Netherlands. [Mittman, Brian] VA Greater Los Angeles Healthcare Syst, VA Ctr Implementat Practice & Res Support, Sepulveda, CA 91343 USA. [Sales, Anne] Ann Arbor VA HSR&D Ctr Excellence, VA Inpatient Evaluat Ctr, Ann Arbor, MI USA. RP Eccles, MP (reprint author), Newcastle Univ, Inst Hlth & Soc, Baddiley Clark Bldg,Richardson Rd, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. EM martin.eccles@ncl.ac.uk RI Wensing, Michel/H-8113-2014; OI Sales, Anne/0000-0001-9360-3334 NR 6 TC 15 Z9 15 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 27 PY 2012 VL 7 AR 71 DI 10.1186/1748-5908-7-71 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 011HK UT WOS:000309155500001 PM 22839967 ER PT J AU Babu, MA Nahed, BV Heary, RF AF Babu, Maya A. Nahed, Brian V. Heary, Robert F. TI Investigating the Scope of Resident Patient Care Handoffs within Neurosurgery SO PLOS ONE LA English DT Article ID SIGN-OUT; MEDICAL ERRORS; HOUSE STAFF; HEALTH-CARE; COMMUNICATION; STRATEGIES; INTERNS; OPPORTUNITIES; IMPROVEMENT; FATIGUE AB Introduction: Handoffs are defined as verbal and written communications during patient care transitions. With the passage of recent ACMGE work hour rules further limiting the hours interns can spend in the hospital, many fear that more handoffs will occur, putting patient safety at risk. The issue of handoffs has not been studied in the neurosurgical literature. Methods: A validated, 20-question online-survey was sent to neurosurgical residents in all 98 accredited U.S. neurosurgery programs. Survey results were analyzed using tabulations. Results: 449 surveys were completed yielding a 56% response rate. 63% of neurosurgical residents surveyed had not received formal instruction in what constitutes an effective handoff; 24% believe there is high to moderate variability among their co-residents in terms of the quality of the handoff provided; 55% experience three or more interruptions during handoffs on average. 90% of neurosurgical residents surveyed say that handoff most often occurs in a quiet, private area and 56% report a high level of comfort for knowing the potential acute, critical issues affecting a patient when receiving a handoff. Conclusions: There needs to be more focused education devoted to learning effective patient-care handoffs in neurosurgical training programs. Increasingly, handing off a patient adequately and safely is becoming a required skill of residency. C1 [Babu, Maya A.] Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Neurol Surg, Rochester, MN 55905 USA. [Nahed, Brian V.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Heary, Robert F.] Neurol Inst New Jersey, Dept Neurosurg, Newark, NJ USA. RP Babu, MA (reprint author), Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Neurol Surg, Rochester, MN 55905 USA. EM babu.maya@mayo.edu NR 48 TC 9 Z9 9 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2012 VL 7 IS 7 AR e41810 DI 10.1371/journal.pone.0041810 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200110 PM 22848615 ER PT J AU Cronin, KR Mangan, TP Carew, JA AF Cronin, Katherine R. Mangan, Thomas P. Carew, Josephine A. TI Upregulation of the Coagulation Factor VII Gene during Glucose Deprivation Is Mediated by Activating Transcription Factor 4 SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED-PROTEIN RESPONSE; ASPARAGINE SYNTHETASE GENE; FACTOR PROCOAGULANT ACTIVITY; FACTOR-BINDING PROTEIN-1; AMINO-ACID LIMITATION; TISSUE FACTOR; ER STRESS; MESSENGER-RNA; C/EBP-BETA AB Background: Constitutive production of blood coagulation proteins by hepatocytes is necessary for hemostasis. Stressful conditions trigger adaptive cellular responses and delay processing of most proteins, potentially affecting plasma levels of proteins secreted exclusively by hepatocytes. We examined the effect of glucose deprivation on expression of coagulation proteins by the human hepatoma cell line, HepG2. Methodology/Principal Findings: Expression of coagulation factor VII, which is required for initiation of blood coagulation, was elevated by glucose deprivation, while expression of other coagulation proteins decreased. Realtime PCR and ELISA demonstrated that the relative percentage expression +/- SD of steady-state F7 mRNA and secreted factor VII antigen were significantly increased (from 100+/-15% to 188+/-27% and 100+/-8.8% to 176.3+/-17.3% respectively, p < 0.001) at 24 hr of treatment. The integrated stress response was induced, as indicated by upregulation of transcription factor ATF4 and of additional stress-responsive genes. Small interfering RNAs directed against ATF4 potently reduced basal F7 expression, and prevented F7 upregulation by glucose deprivation. The response of the endogenous F7 gene was replicated in reporter gene assays, which further indicated that ATF4 effects were mediated via interaction with an amino acid response element in the F7 promoter. Conclusions/Significance: Our data indicated that glucose deprivation enhanced F7 expression in a mechanism reliant on prior ATF4 upregulation primarily due to increased transcription from the ATF4 gene. Of five coagulation protein genes examined, only F7 was upregulated, suggesting that its functions may be important in a systemic response to glucose deprivation stress. C1 [Cronin, Katherine R.; Mangan, Thomas P.; Carew, Josephine A.] VA Boston Healthcare Syst, Dept Res, W Roxbury, MA USA. [Carew, Josephine A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Cronin, KR (reprint author), VA Boston Healthcare Syst, Dept Res, W Roxbury, MA USA. EM josephine_carew@hms.harvard.edu FU Department of Veteran's Affairs of the United States government FX This work was funded by a Merit-1 research award (to JAC) by the Department of Veteran's Affairs of the United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 96 TC 2 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2012 VL 7 IS 7 AR e40994 DI 10.1371/journal.pone.0040994 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200037 PM 22848420 ER PT J AU Lau, FH Xia, F Kaplan, A Cerrato, F Greene, AK Taghinia, A Cowan, CA Labow, BI AF Lau, Frank H. Xia, Fang Kaplan, Adam Cerrato, Felecia Greene, Arin K. Taghinia, Amir Cowan, Chad A. Labow, Brian I. TI Expression Analysis of Macrodactyly Identifies Pleiotrophin Upregulation SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; GROWTH-FACTOR; DIVERSE FUNCTIONS; PROTEUS SYNDROME; DEVELOPING BRAIN; BONE-FORMATION; BREAST-CANCER; ANGIOGENESIS; CYTOKINE; CELLS AB Macrodactyly is a rare family of congenital disorders characterized by the diffuse enlargement of 1 or more digits. Multiple tissue types within the affected digits are involved, but skeletal patterning and gross morphological features are preserved. Not all tissues are equally involved and there is marked heterogeneity with respect to clinical phenotype. The molecular mechanisms responsible for these growth disturbances offer unique insight into normal limb growth and development, in general. To date, no genes or loci have been implicated in the development of macrodactyly. In this study, we performed the first transcriptional profiling of macrodactyly tissue. We found that pleiotrophin (PTN) was significantly overexpressed across all our macrodactyly samples. The mitogenic functions of PTN correlate closely with the clinical characteristics of macrodactyly. PTN thus represents a promising target for further investigation into the etiology of overgrowth phenotypes. C1 [Lau, Frank H.; Xia, Fang; Kaplan, Adam; Cowan, Chad A.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Lau, Frank H.; Xia, Fang; Kaplan, Adam; Cowan, Chad A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Cerrato, Felecia; Greene, Arin K.; Taghinia, Amir; Labow, Brian I.] Childrens Hosp Boston, Dept Plast & Oral Surg, Boston, MA USA. RP Lau, FH (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM Brian.labow@childrens.harvard.edu NR 32 TC 4 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2012 VL 7 IS 7 AR e40423 DI 10.1371/journal.pone.0040423 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200019 PM 22848377 ER PT J AU McFarland, KN Das, S Sun, TT Leyfer, D Xia, E Sangrey, GR Kuhn, A Luthi-Carter, R Clark, TW Sadri-Vakili, G Cha, JHJ AF McFarland, Karen N. Das, Sudeshna Sun, Ting Ting Leyfer, Dmitri Xia, Eva Sangrey, Gavin R. Kuhn, Alexandre Luthi-Carter, Ruth Clark, Timothy W. Sadri-Vakili, Ghazaleh Cha, Jang-Ho J. TI Genome-Wide Histone Acetylation Is Altered in a Transgenic Mouse Model of Huntington's Disease SO PLOS ONE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SODIUM-BUTYRATE; DEACETYLASE INHIBITOR; MUTANT HUNTINGTIN; TRANSCRIPTIONAL DYSREGULATION; ALZHEIMERS-DISEASE; GENE-EXPRESSION; CELL-LINES; CHROMATIN; MICE AB In Huntington's disease (HD; MIM ID # 143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression. However, the question remains whether changes in histone modifications correlate with transcriptional abnormalities across the entire transcriptome. Using chromatin immunoprecipitation paired with microarray hybridization (ChIP-chip), we interrogated AcH3-gene interactions genome-wide in striata of 12-week old wild-type (WT) and transgenic (TG) R6/2 mice, an HD mouse model, and correlated these interactions with gene expression levels. At the level of the individual gene, we found decreases in the number of sites occupied by AcH3 in the TG striatum. In addition, the total number of genes bound by AcH3 was decreased. Surprisingly, the loss of AcH3 binding sites occurred within the coding regions of the genes rather than at the promoter region. We also found that the presence of AcH3 at any location within a gene strongly correlated with the presence of its transcript in both WT and TG striatum. In the TG striatum, treatment with histone deacetylase (HDAC) inhibitors increased global AcH3 levels with concomitant increases in transcript levels; however, AcH3 binding at select gene loci increased only slightly. This study demonstrates that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in histone H3 acetylation. C1 [McFarland, Karen N.; Sun, Ting Ting; Xia, Eva; Sangrey, Gavin R.; Sadri-Vakili, Ghazaleh; Cha, Jang-Ho J.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA USA. [Das, Sudeshna; Leyfer, Dmitri; Clark, Timothy W.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, MIND Informat, Cambridge, MA USA. [Kuhn, Alexandre; Luthi-Carter, Ruth] Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland. RP McFarland, KN (reprint author), Univ Florida, McKnight Brain Inst, Dept Neurol, Gainesville, FL 32610 USA. EM j.cha@merck.com OI Clark, Timothy/0000-0003-4060-7360 FU Huntington's Disease Society of America Coalition for the Cure; Glendorn Foundation; National Institutes of Health (NIH) [NS38106, NS45242]; Massachusetts General Hospital Fund for Medical Discovery FX This work was supported by the Huntington's Disease Society of America Coalition for the Cure, the Glendorn Foundation, the National Institutes of Health (NIH NS38106, NS45242) and the Massachusetts General Hospital Fund for Medical Discovery. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 32 Z9 32 U1 0 U2 10 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 JUL 27 PY 2012 VL 7 IS 7 AR e41423 DI 10.1371/journal.pone.0041423 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200063 PM 22848491 ER PT J AU Poignard, P Moldt, B Maloveste, K Campos, N Olson, WC Rakasz, E Watkins, DI Burton, DR AF Poignard, Pascal Moldt, Brian Maloveste, Karla Campos, Noelie Olson, William C. Rakasz, Eva Watkins, David I. Burton, Dennis R. TI Protection against High-Dose Highly Pathogenic Mucosal SIV Challenge at Very Low Serum Neutralizing Titers of the Antibody-Like Molecule CD4-IgG2 SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1/SIV CHIMERIC VIRUS; MONOCLONAL-ANTIBODIES; PASSIVE TRANSFER; RHESUS-MONKEYS; VACCINE; HIV; MACAQUES; INFECTION; CELL AB Passive transfer studies using monoclonal or polyclonal antibodies in the macaque model have been valuable for determining conditions for antibody protection against immunodeficiency virus challenge. Most studies have employed hybrid simian/human immunodeficiency virus (SHIV) challenge in conjunction with neutralizing human monoclonal antibodies. Passive protection against SIV, particularly the pathogenic prototype virus SIVmac239, has been little studied because of the paucity of neutralizing antibodies to this virus. Here, we show that the antibody-like molecule CD4-IgG2 potently neutralizes SIVmac239 in vitro. When administered by an osmotic pump to maintain concentrations given the short half-life of CD4-IgG2 in macaques, the molecule provided sterilizing immunity/protection against high-dose mucosal viral challenge to a high proportion of animals (5/7 at a 200 mg dose CD4-IgG2 and 3/6 at a 20 mg dose) at serum concentrations below 1.5 mu g/ml. The neutralizing titers of such sera were predicted to be very low and indeed sera at a 1: 4 dilution produced no neutralization in a pseudovirus assay. Macaque anti-human CD4 titers did develop weakly at later time points in some animals but were not associated with the level of protection against viral challenge. The results show that, although SIVmac239 is considered a highly pathogenic virus for which vaccine-induced T cell responses in particular have provided limited benefit against high dose challenge, the antibody-like CD4-IgG2 molecule at surprisingly low serum concentration affords sterilizing immunity/protection to a majority of animals. C1 [Poignard, Pascal; Moldt, Brian; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Poignard, Pascal; Moldt, Brian; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Poignard, Pascal] Int AIDS Vaccine Initiat, New York, NY USA. [Poignard, Pascal; Maloveste, Karla; Campos, Noelie] CNRS, Marseille, France. [Poignard, Pascal; Maloveste, Karla; Campos, Noelie] INSERM, F-13258 Marseille, France. [Poignard, Pascal; Maloveste, Karla; Campos, Noelie] Ctr Immunol Marseille Luminy, Marseille, France. [Olson, William C.] Progen Pharmaceut Inc, Tarrytown, NY USA. [Rakasz, Eva; Watkins, David I.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Watkins, David I.] Univ Miami, Dept Pathol, Miami, FL USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. RP Poignard, P (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM poignard@scripps.edu; burton@scripps.edu RI poignard, pascal/N-6678-2013 FU National Institutes of Health(NIH)/National Institute of Allergy and Infectious Diseases [R01 AI055332]; The International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium; The Ragon Institute of Massachusetts General Hospital; Massachusetts Institute of Technology and Harvard; NIH/National Center for Research Resources [P51 RR000167]; Alfred Benzon Fellowship; Research Facilities Improvement Program [RR15459, RR020141] FX This work was funded by National Institutes of Health(NIH)/National Institute of Allergy and Infectious Diseases grant R01 AI055332 (DRB), The International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium (DRB), The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard (DRB), NIH/National Center for Research Resources grant P51 RR000167 (Wisconsin National Primate Research Center) and by an Alfred Benzon Fellowship (BM). This work was conducted in part at a facility constructed with support from Research Facilities Improvement Program grants RR15459 and RR020141 (Wisconsin National Primate Research Center). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2012 VL 7 IS 7 AR e42209 DI 10.1371/journal.pone.0042209 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200182 PM 22848744 ER PT J AU Rettig, M Trinidad, K Pezeshkpour, G Frost, P Sharma, S Moatamed, F Tamanoi, F Mortazavi, F AF Rettig, Matthew Trinidad, Kenny Pezeshkpour, G. Frost, Patrick Sharma, Sherven Moatamed, Farhad Tamanoi, Fuyuhiko Mortazavi, Fariborz TI PAK1 Kinase Promotes Cell Motility and Invasiveness through CRK-II Serine Phosphorylation in Non-Small Cell Lung Cancer Cells SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; EPIDERMAL-GROWTH-FACTOR; RHO-FAMILY GTPASES; P120 CATENIN; ADAPTER PROTEINS; P21-ACTIVATED-KINASE-1 PAK1; CADHERIN EXPRESSION; ONCOGENE PRODUCT; P120-CATENIN; APOPTOSIS AB The role of c-Crk (CRK) in promoting metastasis is well described however the role of CRK phosphorylation and the corresponding signaling events are not well explained. We have observed CRK-II serine 41 phosphorylation is inversely correlated with p120-catenin and E-cadherin expressions in non-small cell lung cancer (NSCLC) cells. Therefore, we investigated the role of CRK-II serine 41 phosphorylation in the down-regulation of p120-catenin, cell motility and cell invasiveness in NSCLC cells. For this purpose, we expressed phosphomimetic and phosphodeficient CRK-II serine 41 mutants in NSCLC cells. NSCLC cells expressing phosphomimetic CRK-II seine 41 mutant showed lower p120-catenin level while CRK-II seine 41 phosphodeficient mutant expression resulted in higher p120-catenin. In addition, A549 cells expressing CRK-II serine 41 phosphomimetic mutant demonstrated more aggressive behavior in wound healing and invasion assays and, on the contrary, expression of phosphodeficient CRK-II serine 41 mutant in A549 cells resulted in reduced cell motility and invasiveness. We also provide evidence that PAK1 mediates CRK-II serine 41 phosphorylation. RNAi mediated silencing of PAK1 increased p120-catenin level in A549 and H157 cells. Furthermore, PAK1 silencing decreased cell motility and invasiveness in A549 cells. These effects were abrogated in A549 cells expressing phosphomimetic CRK-II serine 41. In summary, these data provide evidence for the role of PAK1 in the promotion of cell motility, cell invasiveness and the down regulation of p120-catenin through CRK serine 41 phosphorylation in NSCLC cells. C1 [Rettig, Matthew; Trinidad, Kenny; Frost, Patrick; Mortazavi, Fariborz] W Los Angeles VA, Div Hematol Oncol, Los Angeles, CA USA. [Rettig, Matthew; Sharma, Sherven; Mortazavi, Fariborz] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Rettig, Matthew; Tamanoi, Fuyuhiko; Mortazavi, Fariborz] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Pezeshkpour, G.; Moatamed, Farhad] W Los Angeles VA, Dept Pathol, Los Angeles, CA USA. [Sharma, Sherven] W Los Angeles VA, Div Mol Med, Los Angeles, CA USA. [Tamanoi, Fuyuhiko] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. RP Rettig, M (reprint author), W Los Angeles VA, Div Hematol Oncol, Los Angeles, CA USA. EM fredmortazavi@ucla.edu OI Frost, Patrick/0000-0003-3348-5983 NR 49 TC 22 Z9 22 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 27 PY 2012 VL 7 IS 7 AR e42012 DI 10.1371/journal.pone.0042012 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ER UT WOS:000306950200146 PM 22848689 ER PT J AU Peterson, RT AF Peterson, Randall T. TI New Mechanisms of 5-Nitrofuran Toxicity SO CHEMISTRY & BIOLOGY LA English DT Editorial Material C1 [Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peterson, Randall T.] Broad Inst, Chem Biol Program, Cambridge, MA 02142 USA. RP Peterson, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM peterson@cvrc.mgh.harvard.edu NR 3 TC 0 Z9 0 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUL 27 PY 2012 VL 19 IS 7 BP 789 EP 790 DI 10.1016/j.chembiol.2012.07.001 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 985JS UT WOS:000307261100003 PM 22840765 ER PT J AU Tokhtaeva, E Clifford, RJ Kaplan, JH Sachs, G Vagin, O AF Tokhtaeva, Elmira Clifford, Rebecca J. Kaplan, Jack H. Sachs, George Vagin, Olga TI Subunit Isoform Selectivity in Assembly of Na,K-ATPase alpha-beta Heterodimers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; CENTRAL-NERVOUS-SYSTEM; NA+-K+-ATPASE; ADHESION MOLECULE; CELL-ADHESION; EXPRESSION; ISOZYMES; IDENTIFICATION; EPILEPSY; GLIA AB To catalyze ion transport, the Na,K-ATPase must contain one alpha and one beta subunit. When expressed by transfection in various expression systems, each of the four alpha subunit isoforms can assemble with each of the three beta subunit isoforms and form an active enzyme, suggesting the absence of selective alpha-beta isoform assembly. However, it is unknown whether in vivo conditions the alpha-beta assembly is random or isoform-specific. The alpha(2)-beta(2) complex was selectively immunoprecipitated by both anti-alpha(2) and anti-beta(2) antibodies from extracts of mouse brain, which contains cells co-expressing multiple Na,K-ATPase isoforms. Neither alpha(1)-beta(2) nor alpha(2)-beta(1) complexes were detected in the immunoprecipitates. Furthermore, in MDCK cells co-expressing alpha(1), beta(1), and beta(2) isoforms, a greater fraction of the beta(2) subunits was unassembled with alpha(1) as compared with that of the beta(1) subunits, indicating preferential association of the alpha(1) isoform with the beta(1) isoform. In addition, the alpha(1)-beta(2) complex was less resistant to various detergents than the alpha(1)-beta(1) complex isolated from MDCK cells or the alpha(2)-beta(2) complex isolated from mouse brain. Therefore, the diversity of the alpha-beta Na,K-ATPase heterodimers in vivo is determined not only by cell-specific co-expression of particular isoforms, but also by selective association of the alpha and beta subunit isoforms. C1 [Tokhtaeva, Elmira; Sachs, George; Vagin, Olga] Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. [Tokhtaeva, Elmira; Sachs, George; Vagin, Olga] Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. [Clifford, Rebecca J.; Kaplan, Jack H.] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. RP Vagin, O (reprint author), VAG LAHS W LA, 11301 Wilshire Blvd,Bldg 113,Rm 324, Los Angeles, CA 90073 USA. EM olgav@ucla.edu OI Kaplan, Jack/0000-0002-7048-6574 FU National Institutes of Health [DK077149, DK058333, GM39500] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK077149 (to O. V.), DK058333 (to G. S.), and GM39500 (to J. H. K.). NR 58 TC 24 Z9 24 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 27 PY 2012 VL 287 IS 31 BP 26115 EP 26125 DI 10.1074/jbc.M112.370734 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 980TN UT WOS:000306916300039 PM 22696220 ER PT J AU Moriguchi, H Zhang, Y Mihara, M Sato, C AF Moriguchi, Hisashi Zhang, Yue Mihara, Makoto Sato, Chifumi TI Successful cryopreservation of human ovarian cortex tissues using supercooling SO SCIENTIFIC REPORTS LA English DT Article AB The development of new method to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life (QOL) of female cancer patients. Here we show novel cryopreservation method of human ovarian cortex tissues by using supercooling (S.C.) procedure. Our method will be helpful in order to preserve fertility of female cancer patients. C1 [Moriguchi, Hisashi; Mihara, Makoto] Univ Tokyo, Sch Med, Dept Plast & Reconstruct Surg, Div IPS Cell Res & Applicat, Tokyo 113, Japan. [Moriguchi, Hisashi] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moriguchi, Hisashi; Zhang, Yue] Harvard Univ, Sch Med, Boston, MA USA. [Zhang, Yue] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Sato, Chifumi] Tokyo Med & Dent Univ, Grad Sch Hlth Care Sci, Dept Analyt Hlth Sci, Tokyo, Japan. RP Moriguchi, H (reprint author), Univ Tokyo, Sch Med, Dept Plast & Reconstruct Surg, Div IPS Cell Res & Applicat, Tokyo 113, Japan. EM moriguchi-tky@umin.ac.jp NR 4 TC 7 Z9 7 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 27 PY 2012 VL 2 AR 537 DI 10.1038/srep00537 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982VK UT WOS:000307073300001 PM 22844578 ER PT J AU Kaelin, WG AF Kaelin, William G., Jr. TI Use and Abuse of RNAi to Study Mammalian Gene Function SO SCIENCE LA English DT Editorial Material ID HUMAN-CELLS; SCREENS; INTERFERENCE; EXPRESSION C1 Dana Farber Canc Inst, Dept Adult Oncol, Off M457, Boston, MA 02215 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Off M457, 450 Brookline Ave, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA068490, R01 CA076120] NR 15 TC 66 Z9 66 U1 0 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 27 PY 2012 VL 337 IS 6093 BP 421 EP 422 DI 10.1126/science.1225787 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979FS UT WOS:000306802300029 PM 22837515 ER PT J AU Josephson, CD Granger, S Assmann, SF Castillejo, MI Strauss, RG Slichter, SJ Steiner, ME Journeycake, JM Thornburg, CD Bussel, J Grabowski, EF Neufeld, EJ Savage, W Sloan, SR AF Josephson, Cassandra D. Granger, Suzanne Assmann, Susan F. Castillejo, Marta-Ines Strauss, Ronald G. Slichter, Sherrill J. Steiner, Marie E. Journeycake, Janna M. Thornburg, Courtney D. Bussel, James Grabowski, Eric F. Neufeld, Ellis J. Savage, William Sloan, Steven R. TI Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia SO BLOOD LA English DT Article ID REFLECTION COEFFICIENTS; ACUTE-LEUKEMIA; ANGIOPOIETIN-1; PERMEABILITY; FILTRATION; RABBIT AB Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 x 10(11), 2.2 x 10(11), or 4.4 x 10(11) platelets/m(2) per transfusion, given for morning counts of <= 10 000 platelets/mu L. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. This trial was registered at www.clinicaltrials.gov as #NCT00128713. (Blood. 2012; 120(4):748-760) C1 [Josephson, Cassandra D.; Castillejo, Marta-Ines] Childrens Healthcare Atlanta, Aflac Canc Ctr, Dept Pathol, Atlanta, GA 30322 USA. [Josephson, Cassandra D.; Castillejo, Marta-Ines] Childrens Healthcare Atlanta, Blood Disorders Serv, Atlanta, GA 30322 USA. [Josephson, Cassandra D.; Castillejo, Marta-Ines] Emory Univ, Dept Pathol & Lab Med, Ctr Transfus & Cellular Therapies, Atlanta, GA 30322 USA. [Granger, Suzanne; Assmann, Susan F.] New England Res Inst, Ctr Stat Anal & Res, Watertown, MA 02172 USA. [Strauss, Ronald G.] Univ Iowa, Coll Med, Iowa City, IA USA. [Slichter, Sherrill J.] Univ Washington, Med Ctr, Puget Sound Blood Ctr, Seattle, WA 98195 USA. [Slichter, Sherrill J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Steiner, Marie E.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Journeycake, Janna M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Thornburg, Courtney D.] Duke Univ, Durham, NC USA. [Bussel, James] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Grabowski, Eric F.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Neufeld, Ellis J.; Sloan, Steven R.] Harvard Univ, Boston Childrens Hosp, Boston, MA 02115 USA. [Savage, William] Johns Hopkins Univ, Baltimore, MD USA. RP Josephson, CD (reprint author), Childrens Healthcare Atlanta, Aflac Canc Ctr, Dept Pathol, 1405 Clifton Rd NE, Atlanta, GA 30322 USA. EM cjoseph@emory.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health to the Data Coordinating Center at New England Research Institutes [HL072268]; Case Western Reserve University [HL072033]; Children's Hospital Boston [HL072291]; Cornell University [HL072196]; Duke University [HL072291]; Emory University [HL072248]; Johns Hopkins University [HL072191]; Massachusetts General Hospital [HL072299]; Puget Sound Blood Center [HL072305]; Tulane [HL072274]; University of Iowa [HL072028]; University of Maryland [HL072359]; University of Minnesota [HL072027]; University of North Carolina [HL072355]; University of Oklahoma [HL072283]; University of Pennsylvania [HL072346]; University of Pittsburgh [HL072331]; Blood Center of Wisconsin [HL072290] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health to the Data Coordinating Center at New England Research Institutes (grant HL072268), Case Western Reserve University (grant HL072033), Children's Hospital Boston (grant HL072291), Cornell University (grant HL072196), Duke University (grant HL072291), Emory University (grant HL072248), Johns Hopkins University (grant HL072191), Massachusetts General Hospital (grant HL072299), Puget Sound Blood Center (grant HL072305), Tulane (grant HL072274), University of Iowa (grant HL072028), University of Maryland (grant HL072359), University of Minnesota (grant HL072027), University of North Carolina (grant HL072355), University of Oklahoma (grant HL072283), University of Pennsylvania (grant HL072346), University of Pittsburgh (grant HL072331), and the Blood Center of Wisconsin (grant HL072290). NR 24 TC 29 Z9 29 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 26 PY 2012 VL 120 IS 4 BP 748 EP 760 DI 10.1182/blood-2011-11-389569 PG 13 WC Hematology SC Hematology GA 987VH UT WOS:000307445400009 PM 22538854 ER PT J AU Chang, KH Sanchez-Aguilera, A Shen, SH Sengupta, A Madhu, MN Ficker, AM Dunn, SK Kuenzi, AM Arnett, JL Santho, RA Agirre, X Perentesis, JP Deininger, MW Zheng, Y Bustelo, XR Williams, DA Cancelas, JA AF Chang, Kyung Hee Sanchez-Aguilera, Abel Shen, Shuhong Sengupta, Amitava Madhu, Malav N. Ficker, Ashley M. Dunn, Susan K. Kuenzi, Ashley M. Arnett, Jorden L. Santho, Rebecca A. Agirre, Xabier Perentesis, John P. Deininger, Michael W. Zheng, Yi Bustelo, Xose R. Williams, David A. Cancelas, Jose A. TI Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; BCR-ABL; PHILADELPHIA-CHROMOSOME; INITIATING CELLS; FAMILY PROTEINS; IMATINIB; RAC2; BAD; PHOSPHORYLATION AB Despite the introduction of tyrosine kinase inhibitor therapy, the prognosis for p190-BCR-ABL(+) acute lymphoblastic leukemia remains poor. In the present study, we present the cellular and molecular roles of the Rho GTPase guanine nucleotide exchange factor Vav in lymphoid leukemogenesis and explore the roles of Vav proteins in BCR-ABL-dependent signaling. We show that genetic deficiency of the guanine nucleotide exchange factor Vav3 delays leukemogenesis by p190-BCR-ABL and phenocopies the effect of Rac2 deficiency, a downstream effector of Vav3. Compensatory up-regulation of expression and activation of Vav3 in Vav1/Vav2-deficient B-cell progenitors increases the transformation ability of p190-BCR-ABL. Vav3 deficiency induces apoptosis of murine and human leukemic lymphoid progenitors, decreases the activation of Rho GTPase family members and p21-activated kinase, and is associated with increased Bad phosphorylation and up-regulation of Bax, Bak, and Bik. Finally, Vav3 activation only partly depends on ABL TK activity, and Vav3 deficiency collaborates with tyrosine kinase inhibitors to inhibit CrkL activation and impair leukemogenesis in vitro and in vivo. We conclude that Vav3 represents a novel specific molecular leukemic effector for multitarget therapy in p190-BCR-ABL-expressng acute lymphoblastic leukemia. (Blood. 2012;120(4):800-811) C1 [Chang, Kyung Hee; Sengupta, Amitava; Madhu, Malav N.; Ficker, Ashley M.; Kuenzi, Ashley M.; Arnett, Jorden L.; Santho, Rebecca A.; Zheng, Yi; Cancelas, Jose A.] Cincinnati Childrens Hosp, Cincinnati Childrens Res Fdn, Div Expt Hematol, Med Ctr, Cincinnati, OH USA. [Chang, Kyung Hee; Dunn, Susan K.; Cancelas, Jose A.] Univ Cincinnati, Coll Med, Hoxworth Blood Ctr, Cincinnati, OH USA. [Sanchez-Aguilera, Abel; Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Hematol Oncol,Childrens Hosp Boston, Boston, MA 02115 USA. [Sanchez-Aguilera, Abel; Williams, David A.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Shen, Shuhong] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Dept Hematol Oncol, Pediat Translat Med Inst,Med Sch, Shanghai 200030, Peoples R China. [Agirre, Xabier] Univ Navarra, Dept Hematol, Clin Univ Navarra, E-31080 Pamplona, Spain. [Agirre, Xabier] Univ Navarra, Clin Univ Navarra, Fdn Appl Med Res, Area Cell Therapy, E-31080 Pamplona, Spain. [Perentesis, John P.] Cincinnati Childrens Hosp, Div Oncol, Med Ctr, Cincinnati, OH USA. [Deininger, Michael W.] Univ Utah, Huntsman Canc Inst, Div Hematol & Hematol Malignancies, Salt Lake City, UT USA. [Bustelo, Xose R.] Univ Salamanca, Ctr Invest Canc, E-37008 Salamanca, Spain. RP Cancelas, JA (reprint author), CCHMC, EHCB Div, 3333 BurnetAve, Cincinnati, OH 45229 USA. EM jose.cancelas@cchmc.org RI Zheng, Yi/J-7235-2015 OI Zheng, Yi/0000-0001-7089-6074 FU National Institutes of Health [R01 HL087159, R01 DK62757, CA113969, R01 CA73735]; Alex's Lemonade Stand Foundation; Cancer Free Kids Foundation; Department of Defense [CM064050]; Spanish Ministry of Science and Innovation [SAF2009-07172, RD06/0020/0001]; Castilla y Leon Autonomous Government [GR97]; 7th Framework European Union Program [FP7-HEALTH-2007-A-201862] FX This project was funded in part by the National Institutes of Health (R01 HL087159 and supplement to J.A.C., R01 DK62757 and CA113969 to D.A.W., and R01 CA73735 to X.R.B.); Alex's Lemonade Stand Foundation, Cancer Free Kids Foundation, and the Department of Defense (CM064050 to J.A.C.); the Spanish Ministry of Science and Innovation (SAF2009-07172 and RD06/0020/0001), the Castilla y Leon Autonomous Government (GR97), and the 7th Framework European Union Program (FP7-HEALTH-2007-A-201862 to X.R.B.). NR 50 TC 11 Z9 13 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 26 PY 2012 VL 120 IS 4 BP 800 EP 811 DI 10.1182/blood-2011-06-361709 PG 12 WC Hematology SC Hematology GA 987VH UT WOS:000307445400014 PM 22692505 ER PT J AU Armand, P Gibson, CJ Cutler, C Ho, VT Koreth, J Alyea, EP Ritz, J Sorror, ML Lee, SJ Deeg, HJ Storer, BE Appelbaum, FR Antin, JH Soiffer, RJ Kim, HT AF Armand, Philippe Gibson, Christopher J. Cutler, Corey Ho, Vincent T. Koreth, John Alyea, Edwin P. Ritz, Jerome Sorror, Mohamed L. Lee, Stephanie J. Deeg, H. Joachim Storer, Barry E. Appelbaum, Frederick R. Antin, Joseph H. Soiffer, Robert J. Kim, Haesook T. TI A disease risk index for patients undergoing allogeneic stem cell transplantation SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; PROGRESSION-FREE SURVIVAL; NON-HODGKIN-LYMPHOMA; RETROSPECTIVE ANALYSIS; MALIGNANT DISEASES; COMORBIDITY INDEX; MYELOID-LEUKEMIA; INTENSITY; EXPERIENCE AB The outcome of allogeneic HSCT varies considerably by the disease and remission status at the time of transplantation. Any retrospective or prospective HSCT study that enrolls patients across disease types must account for this heterogeneity; yet, current methods are neither standardized nor validated. We conducted a retrospective study of 1539 patients who underwent transplantation at Dana-Farber Cancer Institute/Brigham and Women's Hospital from 2000 to 2009. Using multivariable models for overall survival, we created a disease risk index. This tool uses readily available information about disease and disease status to categorize patients into 4 risk groups with significantly different overall survival and progression-free survival on the basis of primarily differences in the relapse risk. This scheme applies regardless of conditioning intensity, is independent of comorbidity index, and was validated in an independent cohort of 672 patients from the Fred Hutchinson Cancer Research Center. This simple and validated scheme could be used to risk-stratify patients in both retrospective and prospective HSCT studies, to calibrate HSCT outcomes across studies and centers, and to promote the design of HSCT clinical trials that enroll patients across diseases and disease states, increasing our ability to study nondisease-specific outcomes in HSCT. (Blood. 2012;120(4):905-913) C1 [Armand, Philippe; Cutler, Corey; Ho, Vincent T.; Koreth, John; Alyea, Edwin P.; Ritz, Jerome; Antin, Joseph H.; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Gibson, Christopher J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Storer, Barry E.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Clin Stat Program, Seattle, WA 98104 USA. [Sorror, Mohamed L.] Univ Washington, Sch Med, Dept Med, Div Med Oncol, Seattle, WA 98195 USA. [Storer, Barry E.] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. RP Armand, P (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org OI Ritz, Jerome/0000-0001-5526-4669 FU American Society of Hematology; ASCO/Conquer Cancer Foundation; National Institutes of Health [HL088021]; National Institute of Allergy and Infectious Diseases [U19 AI29530]; National Heart, Lung, and Blood Institute [PO1 HL070149]; National Cancer Institute [PO1 CA18029] FX P.A. is supported by an American Society of Hematology Scholar Award and by an ASCO/Conquer Cancer Foundation Career Development Award. M.L.S. is supported by a National Institutes of Health Pathway to Independence Award (HL088021). This work also was supported by National Institute of Allergy and Infectious Diseases U19 AI29530, National Heart, Lung, and Blood Institute PO1 HL070149, and National Cancer Institute PO1 CA18029. NR 32 TC 88 Z9 89 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 26 PY 2012 VL 120 IS 4 BP 905 EP 913 DI 10.1182/blood-2012-03-418202 PG 9 WC Hematology SC Hematology GA 987VH UT WOS:000307445400025 PM 22709687 ER PT J AU Savechenkov, PY Zhang, X Chiara, DC Stewart, DS Ge, RL Zhou, XJ Raines, DE Cohen, JB Forman, SA Miller, KW Bruzik, KS AF Savechenkov, Pavel Y. Zhang, Xi Chiara, David C. Stewart, Deirdre S. Ge, Rile Zhou, Xiaojuan Raines, Douglas E. Cohen, Jonathan B. Forman, Stuart A. Miller, Keith W. Bruzik, Karol S. TI Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; GABA(A) RECEPTOR; DIARYLIODONIUM SALTS; ABSOLUTE CONFIGURATION; ACETYLCHOLINE-RECEPTOR; TORPEDO-CALIFORNICA; OPTICAL ISOMERS; BINDING-SITE; A RECEPTORS; ACID AB We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the H-3-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC50 approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human alpha 1 beta 2/3 gamma 2L GABA(A) receptors. Finally, R-()-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both alpha 1 and beta 3 subunits of human alpha 1 beta 3 GABA(A) receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors. C1 [Savechenkov, Pavel Y.; Bruzik, Karol S.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Zhang, Xi; Stewart, Deirdre S.; Ge, Rile; Zhou, Xiaojuan; Raines, Douglas E.; Forman, Stuart A.; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Chiara, David C.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Bruzik, KS (reprint author), Univ Illinois, Dept Med Chem & Pharmacognosy, 833 S Wood St,M-C 781, Chicago, IL 60612 USA. EM kbruzik@uic.edu OI Zhang, Xi/0000-0003-2755-7901 FU National Institute for General Medicine [GM 58448]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817] FX This research was supported by a grant from the National Institute for General Medicine to K.W.M. (GM 58448). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (grant 085P1000817). We thank Dr. Alan Kozikowski of the Department of Medicinal Chemistry and Pharmacognosy of UIC for making available for us the HPLC equipment for chiral separations, and Dr. Arsen Gaisin for assistance. NR 66 TC 23 Z9 23 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 26 PY 2012 VL 55 IS 14 BP 6554 EP 6565 DI 10.1021/jm300631e PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 978SA UT WOS:000306764600027 PM 22734650 ER PT J AU MacArthur, D AF MacArthur, Daniel TI Face up to false positives SO NATURE LA English DT Editorial Material ID DNA-SEQUENCE DIFFERENCES; HUMAN TRANSCRIPTOME; WIDESPREAD RNA C1 Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP MacArthur, D (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM macarthur@atgu.mgh.harvard.edu NR 9 TC 26 Z9 27 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2012 VL 487 IS 7408 BP 427 EP 428 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979KD UT WOS:000306815300015 PM 22836983 ER PT J AU Rozenblatt-Rosen, O Deo, RC Padi, M Adelmant, G Calderwood, MA Rolland, T Grace, M Dricot, A Askenazi, M Tavares, M Pevzner, SJ Abderazzaq, F Byrdsong, D Carvunis, AR Chen, AA Cheng, JW Correll, M Duarte, M Fan, CY Feltkamp, MC Ficarro, SB Franchi, R Garg, BK Gulbahce, N Hao, T Holthaus, AM James, R Korkhin, A Litovchick, L Mar, JC Pak, TR Rabello, S Rubio, R Shen, Y Singh, S Spangle, JM Tasan, M Wanamaker, S Webber, JT Roecklein-Canfield, J Johannsen, E Barabasi, AL Beroukhim, R Kieff, E Cusick, ME Hill, DE Munger, K Marto, JA Quackenbush, J Roth, FP DeCaprio, JA Vidal, M AF Rozenblatt-Rosen, Orit Deo, Rahul C. Padi, Megha Adelmant, Guillaume Calderwood, Michael A. Rolland, Thomas Grace, Miranda Dricot, Amelie Askenazi, Manor Tavares, Maria Pevzner, Samuel J. Abderazzaq, Fieda Byrdsong, Danielle Carvunis, Anne-Ruxandra Chen, Alyce A. Cheng, Jingwei Correll, Mick Duarte, Melissa Fan, Changyu Feltkamp, Mariet C. Ficarro, Scott B. Franchi, Rachel Garg, Brijesh K. Gulbahce, Natali Hao, Tong Holthaus, Amy M. James, Robert Korkhin, Anna Litovchick, Larisa Mar, Jessica C. Pak, Theodore R. Rabello, Sabrina Rubio, Renee Shen, Yun Singh, Saurav Spangle, Jennifer M. Tasan, Murat Wanamaker, Shelly Webber, James T. Roecklein-Canfield, Jennifer Johannsen, Eric Barabasi, Albert-Laszlo Beroukhim, Rameen Kieff, Elliott Cusick, Michael E. Hill, David E. Muenger, Karl Marto, Jarrod A. Quackenbush, John Roth, Frederick P. DeCaprio, James A. Vidal, Marc TI Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins SO NATURE LA English DT Article ID EPSTEIN-BARR-VIRUS; NEXT-GENERATION; DNA-DAMAGE; DISEASE; ASSOCIATION; MUTATIONS; COMPLEX AB Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations(1). Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer(2). However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations(3). Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer. C1 [Rozenblatt-Rosen, Orit; Deo, Rahul C.; Padi, Megha; Adelmant, Guillaume; Calderwood, Michael A.; Rolland, Thomas; Dricot, Amelie; Askenazi, Manor; Tavares, Maria; Abderazzaq, Fieda; Byrdsong, Danielle; Chen, Alyce A.; Duarte, Melissa; Fan, Changyu; Ficarro, Scott B.; Franchi, Rachel; Garg, Brijesh K.; Gulbahce, Natali; Hao, Tong; Holthaus, Amy M.; James, Robert; Korkhin, Anna; Litovchick, Larisa; Mar, Jessica C.; Rabello, Sabrina; Rubio, Renee; Shen, Yun; Spangle, Jennifer M.; Tasan, Murat; Johannsen, Eric; Barabasi, Albert-Laszlo; Kieff, Elliott; Cusick, Michael E.; Hill, David E.; Muenger, Karl; Marto, Jarrod A.; Quackenbush, John; Roth, Frederick P.; DeCaprio, James A.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA. [Rozenblatt-Rosen, Orit; Tavares, Maria; Cheng, Jingwei; Korkhin, Anna; Litovchick, Larisa; Beroukhim, Rameen; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Rozenblatt-Rosen, Orit; Tavares, Maria; Cheng, Jingwei; Korkhin, Anna; Litovchick, Larisa; Rabello, Sabrina; Barabasi, Albert-Laszlo; Beroukhim, Rameen; DeCaprio, James A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Deo, Rahul C.; Adelmant, Guillaume; Askenazi, Manor; Ficarro, Scott B.; Garg, Brijesh K.; Singh, Saurav; Tasan, Murat; Webber, James T.; Marto, Jarrod A.; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Deo, Rahul C.] Univ Calif San Francisco, Dept Med, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Deo, Rahul C.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Padi, Megha; Abderazzaq, Fieda; Correll, Mick; Mar, Jessica C.; Rubio, Renee; Quackenbush, John] Dana Farber Canc Inst, CCCB, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Padi, Megha; Adelmant, Guillaume; Calderwood, Michael A.; Rolland, Thomas; Dricot, Amelie; Askenazi, Manor; Tavares, Maria; Pevzner, Samuel J.; Abderazzaq, Fieda; Byrdsong, Danielle; Carvunis, Anne-Ruxandra; Correll, Mick; Duarte, Melissa; Fan, Changyu; Ficarro, Scott B.; Franchi, Rachel; Garg, Brijesh K.; Gulbahce, Natali; Hao, Tong; James, Robert; Mar, Jessica C.; Rabello, Sabrina; Rubio, Renee; Shen, Yun; Singh, Saurav; Wanamaker, Shelly; Webber, James T.; Roecklein-Canfield, Jennifer; Barabasi, Albert-Laszlo; Beroukhim, Rameen; Cusick, Michael E.; Hill, David E.; Marto, Jarrod A.; Quackenbush, John; Roth, Frederick P.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Padi, Megha; Mar, Jessica C.; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Adelmant, Guillaume; Askenazi, Manor; Tavares, Maria; Ficarro, Scott B.; Garg, Brijesh K.; Singh, Saurav; Webber, James T.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Calderwood, Michael A.; Rolland, Thomas; Dricot, Amelie; Pevzner, Samuel J.; Byrdsong, Danielle; Carvunis, Anne-Ruxandra; Fan, Changyu; Hao, Tong; James, Robert; Shen, Yun; Wanamaker, Shelly; Cusick, Michael E.; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Calderwood, Michael A.; Duarte, Melissa; Holthaus, Amy M.; Johannsen, Eric; Kieff, Elliott] Brigham & Womens Hosp, Channing Lab, Div Infect Dis, Boston, MA 02115 USA. [Calderwood, Michael A.; Grace, Miranda; Chen, Alyce A.; Duarte, Melissa; Holthaus, Amy M.; Spangle, Jennifer M.; Johannsen, Eric; Kieff, Elliott; Muenger, Karl] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Calderwood, Michael A.; Duarte, Melissa; Holthaus, Amy M.; Johannsen, Eric; Kieff, Elliott] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Pevzner, Samuel J.] Boston Univ, Dept Biomed Engn, Boston, MA 02118 USA. [Pevzner, Samuel J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Feltkamp, Mariet C.] Leiden Univ, Med Ctr, Dept Med Microbiol, NL-2300 RC Leiden, Netherlands. [Franchi, Rachel; Wanamaker, Shelly; Roecklein-Canfield, Jennifer] Simmons Coll, Dept Chem, Boston, MA 02115 USA. [Gulbahce, Natali; Rabello, Sabrina; Barabasi, Albert-Laszlo] Northeastern Univ, CCNR, Boston, MA 02115 USA. [Gulbahce, Natali; Rabello, Sabrina; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Gulbahce, Natali] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Pak, Theodore R.; Tasan, Murat; Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5G 1X5, Canada. [Pak, Theodore R.; Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1X5, Canada. [Pak, Theodore R.; Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Comp Sci, Toronto, ON M5G 1X5, Canada. [Pak, Theodore R.; Tasan, Murat; Roth, Frederick P.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Beroukhim, Rameen] Broad Inst, Cambridge, MA 02142 USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, CCSB, Genom Anal Network Perturbat Ctr Excellence Genom, Boston, MA 02215 USA. EM jarrod_marto@dfci.harvard.edu; johnq@jimmy.harvard.edu; fritz.roth@utoronto.ca; james_decaprio@dfci.harvard.edu; marc_vidal@dfci.harvard.edu RI Hill, David/B-6617-2011; Roth, Frederick/H-6308-2011; Calderwood, Mike/B-2475-2014; Feltkamp, Mariet/A-3788-2010; OI Webber, James/0000-0001-8594-9888; Calderwood, Mike/0000-0001-6475-1418; Feltkamp, Mariet/0000-0001-5993-9846; Carvunis, Anne-Ruxandra/0000-0002-6474-6413; Roth, Frederick/0000-0002-6628-649X; Munger, Karl/0000-0003-3288-9935 FU Center of Excellence in Genomic Science (CEGS) from the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) [P50HG004233]; Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative; NIH [R01HG001715, R01CA093804, R01CA063113, P01CA050661, R01CA081135, R01CA066980, U01CA141583, R01CA131354, R01CA047006, R01CA085180, T32HL007208, K08HL098361, K08CA122833, F32GM095284, K25HG006031]; Canada Excellence Research Chairs (CERC) Program, Canadian Institute for Advanced Research Fellowship and Ontario Research Fund; James S. McDonnell Foundation [220020084] FX We thank members of the Center for Cancer Systems Biology (CCSB) and J. Aster, M. Meyerson, W. Kaelin, G. Superti-Furga and S. Sunyaev for discussions, and J. W. Harper, W. Hahn, P. Howley, Y. Jacob, M. Imperiale, I. Koralnik, H. Pfister and D. Wang for reagents. This work was primarily supported by Center of Excellence in Genomic Science (CEGS) grant P50HG004233 from the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) awarded to M. V. (principal investigator), A.-L. B., J. A. D., E. K., J. A. M., K. M., J. Q. and F. P. R. Additional funding included Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative to M. V.; NIH grants R01HG001715 to M. V., D. E. H. and F. P. R.; R01CA093804, R01CA063113 and P01CA050661 to J. A. D.; R01CA081135, R01CA066980 and U01CA141583 to K. M.; R01CA131354, R01CA047006 and R01CA085180 to E. K.; T32HL007208 and K08HL098361 to R. C. D.; K08CA122833 to R. B.; F32GM095284 and K25HG006031 to M. P.; Canada Excellence Research Chairs (CERC) Program, Canadian Institute for Advanced Research Fellowship and Ontario Research Fund to F. P. R.; and James S. McDonnell Foundation grant 220020084 to A.-L. B. M. V. is a 'Chercheur Qualifie Honoraire' from the Fonds de la Recherche Scientifique (Wallonia-Brussels Federation, Belgium). NR 29 TC 138 Z9 141 U1 5 U2 75 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2012 VL 487 IS 7408 BP 491 EP 495 DI 10.1038/nature11288 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979KD UT WOS:000306815300040 PM 22810586 ER PT J AU Straussman, R Morikawa, T Shee, K Barzily-Rokni, M Qian, ZR Du, JY Davis, A Mongare, MM Gould, J Frederick, DT Cooper, ZA Chapman, PB Solit, DB Ribas, A Lo, RS Flaherty, KT Ogino, S Wargo, JA Golub, TR AF Straussman, Ravid Morikawa, Teppei Shee, Kevin Barzily-Rokni, Michal Qian, Zhi Rong Du, Jinyan Davis, Ashli Mongare, Margaret M. Gould, Joshua Frederick, Dennie T. Cooper, Zachary A. Chapman, Paul B. Solit, David B. Ribas, Antoni Lo, Roger S. Flaherty, Keith T. Ogino, Shuji Wargo, Jennifer A. Golub, Todd R. TI Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion SO NATURE LA English DT Article ID C-MET; ACQUIRED-RESISTANCE; COLORECTAL-CANCER; V600E MUTATION; GROWTH-FACTOR; COLON-CANCER; MELANOMA; BRAF; VEMURAFENIB; OVEREXPRESSION AB Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance(1-4). Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance. C1 [Straussman, Ravid; Shee, Kevin; Barzily-Rokni, Michal; Du, Jinyan; Davis, Ashli; Mongare, Margaret M.; Gould, Joshua; Golub, Todd R.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Morikawa, Teppei; Qian, Zhi Rong; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Frederick, Dennie T.; Cooper, Zachary A.; Flaherty, Keith T.; Wargo, Jennifer A.] Massachusetts Gen Hosp, Div Surg Oncol Med Oncol & Dermatol, Boston, MA 02114 USA. [Chapman, Paul B.; Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Solit, David B.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Ribas, Antoni] Univ Calif Los Angeles, Div Hematol & Oncol, Dept Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Ribas, Antoni; Lo, Roger S.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Lo, Roger S.] Univ Calif Los Angeles, Div Dermatol, Dept Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Golub, TR (reprint author), Eli & Edythe L Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM golub@broadinstitute.org OI Qian, Zhi rong/0000-0003-1633-4120; Cooper, Zachary/0000-0003-1059-0940 FU Howard Hughes Medical Institute; National Cancer Institute [P50CA093683, U54CA112962]; Melanoma Research Alliance Team Science Award FX We thank all members of the Golub laboratory for discussions. We thank C. M. Johannessen, I. Rabinowitch, N. Shoresh and A. Goren for critical reading of the manuscript, and L. Gaffney for expert assistance with the graphics. This work was supported by the Howard Hughes Medical Institute, National Cancer Institute grants P50CA093683 and U54CA112962 (T. R. G.) and a Melanoma Research Alliance Team Science Award. NR 30 TC 676 Z9 693 U1 18 U2 183 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2012 VL 487 IS 7408 BP 500 EP U118 DI 10.1038/nature11183 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979KD UT WOS:000306815300042 PM 22763439 ER PT J AU Yu, M Ting, DT Stott, SL Wittner, BS Ozsolak, F Paul, S Ciciliano, JC Smas, ME Winokur, D Gilman, AJ Ulman, MJ Xega, K Contino, G Alagesan, B Brannigan, BW Milos, PM Ryan, DP Sequist, LV Bardeesy, N Ramaswamy, S Toner, M Maheswaran, S Haber, DA AF Yu, Min Ting, David T. Stott, Shannon L. Wittner, Ben S. Ozsolak, Fatih Paul, Suchismita Ciciliano, Jordan C. Smas, Malgorzata E. Winokur, Daniel Gilman, Anna J. Ulman, Matthew J. Xega, Kristina Contino, Gianmarco Alagesan, Brinda Brannigan, Brian W. Milos, Patrice M. Ryan, David P. Sequist, Lecia V. Bardeesy, Nabeel Ramaswamy, Sridhar Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis SO NATURE LA English DT Article ID STEM-CELL; TRANSCRIPTOME; PATHWAY AB Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases(1). Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device(2) for efficient capture of CTCs from an endogenous mouse pancreatic cancer model(3) and subjected CTCs to single-molecule RNA sequencing(4), identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer. C1 [Yu, Min; Ting, David T.; Stott, Shannon L.; Wittner, Ben S.; Paul, Suchismita; Ciciliano, Jordan C.; Smas, Malgorzata E.; Winokur, Daniel; Gilman, Anna J.; Ulman, Matthew J.; Xega, Kristina; Contino, Gianmarco; Alagesan, Brinda; Brannigan, Brian W.; Ryan, David P.; Sequist, Lecia V.; Bardeesy, Nabeel; Ramaswamy, Sridhar; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Ctr Engn Med, Boston, MA 02114 USA. [Yu, Min; Ting, David T.; Stott, Shannon L.; Wittner, Ben S.; Paul, Suchismita; Ciciliano, Jordan C.; Smas, Malgorzata E.; Winokur, Daniel; Gilman, Anna J.; Ulman, Matthew J.; Xega, Kristina; Contino, Gianmarco; Alagesan, Brinda; Brannigan, Brian W.; Ryan, David P.; Sequist, Lecia V.; Bardeesy, Nabeel; Ramaswamy, Sridhar; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Yu, Min; Ting, David T.; Stott, Shannon L.; Wittner, Ben S.; Paul, Suchismita; Ciciliano, Jordan C.; Smas, Malgorzata E.; Winokur, Daniel; Gilman, Anna J.; Ulman, Matthew J.; Xega, Kristina; Contino, Gianmarco; Alagesan, Brinda; Brannigan, Brian W.; Ryan, David P.; Sequist, Lecia V.; Bardeesy, Nabeel; Ramaswamy, Sridhar; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. [Yu, Min; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Ozsolak, Fatih; Milos, Patrice M.] Helicos BioSci Corp, Cambridge, MA 02139 USA. RP Maheswaran, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Engn Med, Boston, MA 02114 USA. EM maheswaran@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu OI Contino, Gianmarco/0000-0001-5874-0405; Ting, David/0000-0002-3261-2322 FU Stand Up To Cancer; Howard Hughes Medical Institute; NIBIB [5R01EB008047]; NIH [CA129933]; Pancreatic Cancer Action Network - AACR Fellowship; Warshaw Institute for Pancreatic Cancer Research; K12 Paul Calabresi Award for Clinical Oncology Clinical Research Career Development Program NIH [5K12CA87723-09] FX We thank C. Koris and the MGH clinical research coordinators for help with clinical studies, J. Gentry for computer informatics support, L. Libby for mouse studies, J. Walsh for microscopy expertise, Z. Nakamura for technical support, D. Jones for sequencing, and M. Rivera and S. Akhavanfard for RNA-ISH. This work was supported by Stand Up To Cancer (D. A. H., M. T., S. M.), Howard Hughes Medical Institute (D. A. H.), NIBIB Quantum Grant 5R01EB008047 (M. T.), NIH CA129933 (D. A. H.), Pancreatic Cancer Action Network - AACR Fellowship (D. T. T.), the Warshaw Institute for Pancreatic Cancer Research (D. T. T.), and the K12 Paul Calabresi Award for Clinical Oncology Clinical Research Career Development Program NIH 5K12CA87723-09 (D.T.T.). NR 14 TC 178 Z9 184 U1 8 U2 118 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2012 VL 487 IS 7408 BP 510 EP U130 DI 10.1038/nature11217 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979KD UT WOS:000306815300044 PM 22763454 ER PT J AU Hoffmann, U Truong, QA Schoenfeld, DA Chou, ET Woodard, PK Nagurney, JT Pope, JH Hauser, TH White, CS Weiner, SG Kalanjian, S Mullins, ME Mikati, I Peacock, WF Zakroysky, P Hayden, D Goehler, A Lee, H Gazelle, GS Wiviott, SD Fleg, JL Udelson, JE AF Hoffmann, Udo Truong, Quynh A. Schoenfeld, David A. Chou, Eric T. Woodard, Pamela K. Nagurney, John T. Pope, J. Hector Hauser, Thomas H. White, Charles S. Weiner, Scott G. Kalanjian, Shant Mullins, Michael E. Mikati, Issam Peacock, W. Frank Zakroysky, Pearl Hayden, Douglas Goehler, Alexander Lee, Hang Gazelle, G. Scott Wiviott, Stephen D. Fleg, Jerome L. Udelson, James E. CA Romicat-II Investigators TI Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; EMERGENCY-DEPARTMENT PATIENTS; DIAGNOSTIC PERFORMANCE; ARTERY-DISEASE; ASSISTED TOMOGRAPHY; TRIAL; ASSOCIATION; MULTICENTER; RADIATION; OUTCOMES AB BACKGROUND It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS The rate of acute coronary syndromes among 1000 patients with a mean (+/- SD) age of 54 +/- 8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P = 0.65). CONCLUSIONS In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.) C1 [Hoffmann, Udo; Truong, Quynh A.; Zakroysky, Pearl; Goehler, Alexander] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo; Zakroysky, Pearl; Goehler, Alexander; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Schoenfeld, David A.; Hayden, Douglas; Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Goehler, Alexander; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hoffmann, Udo; Truong, Quynh A.; Schoenfeld, David A.; Hauser, Thomas H.; Goehler, Alexander; Lee, Hang; Gazelle, G. Scott; Wiviott, Stephen D.] Harvard Univ, Sch Med, Boston, MA USA. [Pope, J. Hector] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Hauser, Thomas H.] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Udelson, James E.] Tufts Med Ctr, CardioVasc Ctr, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Weiner, Scott G.] Tufts Med Ctr, Dept Emergency Med, Boston, MA USA. [Mullins, Michael E.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Chou, Eric T.; Kalanjian, Shant] Kaiser Permanente Fontana Med Ctr, Fontana, CA USA. [White, Charles S.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Mikati, Issam] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Dept Emergency Med,Dept Med, Chicago, IL 60611 USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Houston, TX 77030 USA. [Wiviott, Stephen D.] Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org OI Mullins, Michael/0000-0001-8605-0217 FU National Heart, Lung, and Blood Institute [U01HL092040, U01HL092022]; National Institutes of Health [UL1RR025758, K23HL098370, L30HL093896]; GE Healthcare; Astellas; Harvard Clinical Research Institute; American College of Radiology Imaging Network; Bracco Diagnostics; Genentech; Siemens Healthcare; Alere (Biosite); Brahms Diagnostica (Fischer); Nanosphere; St. Jude Medical; Qi Imaging; Arena Pharmaceuticals; AstraZeneca; Bayer; Bristol-Myers Squibb; Ortho-McNeil; Daiichi Sankyo; Eli Lilly; Merck; Schering-Plough; Novartis FX Supported by grants from the National Heart, Lung, and Blood Institute (U01HL092040 and U01HL092022) and the National Institutes of Health (UL1RR025758, K23HL098370, and L30HL093896, to Dr. Truong).; Dr. Gazelle reports receiving consulting fees from GE Healthcare; Dr. Hauser, receiving consulting fees from Astellas and the Harvard Clinical Research Institute; Dr. Hoffmann, receiving grant support from the American College of Radiology Imaging Network, Bracco Diagnostics, Genentech, and Siemens Healthcare on behalf of his institution; Dr. Nagurney, receiving grant support from Alere (Biosite), Brahms Diagnostica (Fischer), and Nanosphere on behalf of his institution; Dr. Truong, receiving grant support from St. Jude Medical and Qi Imaging on behalf of her institution and travel support from Medconvent and the Society of Cardiac Computed Tomography; Dr. Wiviott, receiving consulting fees from Arena Pharmaceuticals, AstraZeneca, Bayer, Bristol-Myers Squibb, and Ortho-McNeil, grant support from AstraZeneca, Daiichi Sankyo, Eli Lilly, and Merck and Schering-Plough on behalf of his institution, and lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, and Schering-Plough; and Dr. Udelson, being on the scientific advisory board of Lantheus Medical Imaging. No other potential conflict of interest relevant to this article was reported. NR 18 TC 261 Z9 266 U1 1 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 26 PY 2012 VL 367 IS 4 BP 299 EP 308 DI 10.1056/NEJMoa1201161 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 978KD UT WOS:000306738300004 PM 22830462 ER PT J AU Xavier, RJ Gala, MK Bronzo, BK Kelly, PJ AF Xavier, Ramnik J. Gala, Manish K. Bronzo, Brian K. Kelly, Paul J. TI Case 23-2012: A 59-Year-Old Man with Abdominal Pain and Weight Loss Strongyloides stercoralis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; CELIAC-DISEASE; TROPICAL SPRUE; CROHNS-DISEASE; SPECTRUM C1 [Xavier, Ramnik J.; Gala, Manish K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bronzo, Brian K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kelly, Paul J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Xavier, Ramnik J.; Gala, Manish K.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bronzo, Brian K.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kelly, Paul J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 22 TC 0 Z9 0 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 26 PY 2012 VL 367 IS 4 BP 363 EP 373 DI 10.1056/NEJMcpc1109275 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 978KD UT WOS:000306738300012 PM 22830467 ER PT J AU Wang, TJ AF Wang, Thomas J. TI The Natriuretic Peptides and Fat Metabolism SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Wang, TJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 5 TC 20 Z9 21 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 26 PY 2012 VL 367 IS 4 BP 377 EP 378 DI 10.1056/NEJMcibr1204796 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 978KD UT WOS:000306738300014 PM 22830469 ER PT J AU Tian, JW Hou, JB Xing, L Kim, SJ Yonetsu, T Kato, K Lee, H Zhang, SS Yu, B Jang, IK AF Tian, Jinwei Hou, Jingbo Xing, Lei Kim, Soo-Joong Yonetsu, Taishi Kato, Koji Lee, Hang Zhang, Shaosong Yu, Bo Jang, Ik-Kyung TI Does neovascularization predict response to statin therapy? Optical coherence tomography study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Neovascularization; Atherosclerosis; Statins; Optical coherence tomography C1 [Tian, Jinwei; Hou, Jingbo; Xing, Lei; Yu, Bo] Harbin Med Univ, Key Labs, Educ Minist Myocardial Ischemia Mech & Treatment, Dept Cardiol,Affiliated Hosp 2, Harbin 150086, Peoples R China. [Kim, Soo-Joong; Yonetsu, Taishi; Kato, Koji; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. [Zhang, Shaosong] St Jude Med, Westford, MA USA. RP Yu, B (reprint author), Harbin Med Univ, Key Labs, Educ Minist Myocardial Ischemia Mech & Treatment, Dept Cardiol,Affiliated Hosp 2, Harbin 150086, Peoples R China. EM yubodr@163.com NR 4 TC 5 Z9 6 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 26 PY 2012 VL 158 IS 3 BP 469 EP 470 DI 10.1016/j.ijcard.2012.05.043 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 970JI UT WOS:000306123800045 PM 22640690 ER PT J AU Moukarbel, GV Kitkungvan, D Safiia, MA Aragam, J Kinlay, S AF Moukarbel, George V. Kitkungvan, Danai Safiia, Muhamed Adeeb Aragam, Jayashri Kinlay, Scott TI Asymptomatic embolized HELEX (R) PFO closure device: Catheter based retrieval and value of routine echocardiography the following day SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Patent foramen ovale; Closure device; Embolization; Catheter-based retrieval; Echocardiography ID ATRIAL SEPTAL-DEFECT; OCCLUDER; COMPLICATIONS; RESCUE C1 [Kinlay, Scott] Brigham & Womens Hosp, Cardiac Catheterizat Lab, VA Boston Healthcare Syst, Div Cardiovasc, W Roxbury, MA 02132 USA. [Moukarbel, George V.; Aragam, Jayashri; Kinlay, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Moukarbel, George V.; Aragam, Jayashri; Kinlay, Scott] Harvard Univ, Sch Med, Boston, MA USA. [Kitkungvan, Danai; Safiia, Muhamed Adeeb] Boston Med Ctr, Div Cardiol, Boston, MA USA. [Kitkungvan, Danai; Safiia, Muhamed Adeeb] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Kinlay, S (reprint author), Brigham & Womens Hosp, Cardiac Catheterizat Lab, VA Boston Healthcare Syst, Div Cardiovasc, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM scott.kinlay@va.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 26 PY 2012 VL 158 IS 3 BP E57 EP E59 DI 10.1016/j.ijcard.2011.10.111 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 970JI UT WOS:000306123800007 PM 22104997 ER PT J AU Dobelis, P Staley, KJ Cooper, DC AF Dobelis, Peter Staley, Kevin J. Cooper, Donald C. TI Lack of Modulation of Nicotinic Acetylcholine Alpha-7 Receptor Currents by Kynurenic Acid in Adult Hippocampal Interneurons SO PLOS ONE LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; RAT HIPPOCAMPUS; GABAERGIC INTERNEURONS; SYNAPTIC-TRANSMISSION; POTENTIAL ROLE; ACH RECEPTORS; MOUSE-BRAIN; NEURONS; CHANNELS; SUBTYPES AB Kynurenic acid (KYNA), a classical ionotropic glutamate receptor antagonist is also purported to block the alpha 7-subtype nicotinic acetylcholine receptor (alpha 7* nAChR). Although many published studies cite this potential effect, few have studied it directly. In this study, the alpha 7*-selective agonist, choline, was pressure-applied to interneurons in hippocampal subregions, CA1 stratum radiatum and hilus of acute brain hippocampal slices from adolescent to adult mice and adolescent rats. Stable alpha 7* mediated whole-cell currents were measured using voltage-clamp at physiological temperatures. The effects of bath applied KYNA on spontaneous glutamatergic excitatory postsynaptic potentials (sEPSC) as well as choline-evoked alpha 7* currents were determined. In mouse hilar interneurons, KYNA totally blocked sEPSC whole-cell currents in a rapid and reversible manner, but had no effect on choline-evoked alpha 7* whole-cell currents. To determine if this lack of KYNA effect on alpha 7* function was due to regional and/or species differences in alpha 7* nAChRs, the effects of KYNA on choline-evoked alpha 7* whole-cell currents in mouse and rat stratum radiatum interneurons were tested. KYNA had no effect on either mouse or rat stratum radiatum interneuron choline-evoked alpha 7* whole-cell currents. Finally, to test whether the lack of effect of KYNA was due to unlikely slow kinetics of KYNA interactions with alpha 7* nAChRs, recordings of alpha 7*-mediated currents were made from slices that were prepared and stored in the presence of 1 mM KYNA (>90 minutes exposure). Under these conditions, KYNA had no measurable effect on alpha 7* nAChR function. The results show that despite KYNA-mediated blockade of glutamatergic sEPSCs, two types of hippocampal interneurons that express choline-evoked alpha 7* nAChR currents fail to show any degree of modulation by KYNA. Our results indicate that under our experimental conditions, which produced complete KYNA-mediated blockade of sEPSCs, claims of KYNA effects on choline-evoked alpha 7* nAChR function should be made with caution. C1 [Dobelis, Peter; Cooper, Donald C.] Univ Colorado, Ctr Neurosci, Inst Behav Genet, Dept Neurosci, Boulder, CO 80309 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Dobelis, P (reprint author), Univ Colorado, Ctr Neurosci, Inst Behav Genet, Dept Neurosci, Boulder, CO 80309 USA. EM dcooper@Colorado.edu FU American Epilepsy Foundation/Milken Family Foundation; NIH [R21 DA026918]; National Institute on Drug Abuse [R01-DA24040]; NIDA K award [K-01DA017750]; NINDS [R01 NS034700]; Colorado Tobacco Research Program [1F-059] FX This work was funded and supported by the American Epilepsy Foundation/Milken Family Foundation Fellowship (PD), R21 DA026918 NIH (J. Stitzel), National Institute on Drug Abuse grant R01-DA24040 (DCC), NIDA K award K-01DA017750 (DCC), NINDS R01 NS034700 (KJS), and the Colorado Tobacco Research Program (1F-059). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 16 Z9 16 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 25 PY 2012 VL 7 IS 7 AR e41108 DI 10.1371/journal.pone.0041108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979GX UT WOS:000306806600040 PM 22848433 ER PT J AU Ramos, FJ Chen, SC Garelick, MG Dai, DF Liao, CY Schreiber, KH MacKay, VL An, EH Strong, R Ladiges, WC Rabinovitch, PS Kaeberlein, M Kennedy, BK AF Ramos, Fresnida J. Chen, Steven C. Garelick, Michael G. Dai, Dao-Fu Liao, Chen-Yu Schreiber, Katherine H. MacKay, Vivian L. An, Elroy H. Strong, Randy Ladiges, Warren C. Rabinovitch, Peter S. Kaeberlein, Matt Kennedy, Brian K. TI Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C-Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GENETICALLY HETEROGENEOUS MICE; GIRDLE MUSCULAR-DYSTROPHY; DILATED CARDIOMYOPATHY; PRESSURE-OVERLOAD; HEART-FAILURE; SINGLE BOUT; LIFE-SPAN; IN-VIVO; P70 S6; AUTOPHAGY AB Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. C1 [Chen, Steven C.; Garelick, Michael G.; MacKay, Vivian L.; Kennedy, Brian K.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Ramos, Fresnida J.; Dai, Dao-Fu; An, Elroy H.; Rabinovitch, Peter S.; Kaeberlein, Matt] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Liao, Chen-Yu; Schreiber, Katherine H.; Kennedy, Brian K.] Buck Inst Res Aging, Novara, CA 94945 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Strong, Randy] S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX 78284 USA. [Strong, Randy] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78284 USA. [Ladiges, Warren C.] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. RP Kennedy, BK (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA. EM kaeber@uw.edu; bkennedy@buckinstitute.org FU National Institute on Aging [R01 AG024287, R01 AG033373, U01 AG022307]; NIH [T32AG000057, T32 HL007312] FX This study was supported by National Institute on Aging grants R01 AG024287 and R01 AG033373 (to B. K. K.) and U01 AG022307 (to R. S.). F.J.R. and M. G. G. are supported by NIH training grant T32AG000057. S. C. C. is supported by the cardiovascular and pathology training grant NIH T32 HL007312. M. K. is an Ellison Medical Foundation New Scholar in Aging. NR 63 TC 91 Z9 92 U1 4 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 25 PY 2012 VL 4 IS 144 AR 144ra103 DI 10.1126/scitranslmed.3003802 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 981LC UT WOS:000306968700006 PM 22837538 ER PT J AU Walker, KR Kang, EL Whalen, MJ Shen, Y Tesco, G AF Walker, Kendall R. Kang, Eugene L. Whalen, Michael J. Shen, Yong Tesco, Giuseppina TI Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRAUMATIC BRAIN-INJURY; AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE ACTIVITY; ALZHEIMERS-DISEASE PATHOGENESIS; APP TRANSGENIC MICE; TRANSLATIONAL REGULATION; OXIDATIVE STRESS; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATION; CLEAVING ENZYME-1 AB Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of A beta. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro, indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and A beta levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury. C1 [Walker, Kendall R.; Kang, Eugene L.; Tesco, Giuseppina] Tufts Univ, Sch Med, Dept Neurosci, Alzheimers Dis Res Lab, Boston, MA 02111 USA. [Whalen, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Neurosci, Boston, MA 02129 USA. [Whalen, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA 02129 USA. [Shen, Yong] Roskamp Inst, CATSBD, Sarasota, FL 34243 USA. RP Tesco, G (reprint author), Tufts Univ, Sch Med, Dept Neurosci, Alzheimers Dis Res Lab, 136 Harrison Ave,St 328A, Boston, MA 02111 USA. EM Giuseppina.Tesco@Tufts.edu FU National Institute on Aging [R01AG033016, 1R01AG025952]; Cure Alzheimer's Fund FX This work was supported by Award Number R01AG033016 (to G.T.) and 1R01AG025952 (to G.T.) from the National Institute on Aging, and a grant from Cure Alzheimer's Fund (to G.T.). We thank Dr. Rudy Tanzi for his useful comments in the preparation and editing of this manuscript. NR 77 TC 30 Z9 31 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 25 PY 2012 VL 32 IS 30 BP 10423 EP 10437 DI 10.1523/JNEUROSCI.5491-11.2012 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 983NF UT WOS:000307125300030 PM 22836275 ER PT J AU Subramanian, S Tawakol, A Burdo, TH Abbara, S Wei, J Vijayakumar, J Corsini, E Abdelbaky, A Zanni, MV Hoffmann, U Williams, KC Lo, J Grinspoon, SK AF Subramanian, Sharath Tawakol, Ahmed Burdo, Tricia H. Abbara, Suhny Wei, Jeffrey Vijayakumar, Jayanthi Corsini, Erin Abdelbaky, Amr Zanni, Markella V. Hoffmann, Udo Williams, Kenneth C. Lo, Janet Grinspoon, Steven K. TI Arterial Inflammation in Patients With HIV SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ATHEROSCLEROTIC PLAQUE INFLAMMATION; POPULATION-BASED COHORT; ACTIVATED MACROPHAGES; CARDIOVASCULAR EVENTS; SOLUBLE CD163; RISK; DISEASE; CALCIUM; MARKER AB Context Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. Objective To assess arterial wall inflammation in HIV, using (18)fluorine-2-deoxy-D-glucose positron emission tomography (F-18-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. Design, Setting, and Participants A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n=27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n=27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). Main Outcome Measure Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). Results Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/mu L; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P=.87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P=.29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P=.002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P <= .01). Aortic TBR was associated with sCD163 level (P=.04) but not with C-reactive protein (P=.65) or D-dimer (P=.08) among patients with HIV. Conclusion Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation. JAMA. 2012;308(4):379-386 www.jama.com C1 [Zanni, Markella V.; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Zanni, Markella V.; Lo, Janet; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Subramanian, Sharath; Tawakol, Ahmed; Abbara, Suhny; Vijayakumar, Jayanthi; Corsini, Erin; Abdelbaky, Amr; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. [Subramanian, Sharath; Tawakol, Ahmed; Abbara, Suhny; Vijayakumar, Jayanthi; Corsini, Erin; Abdelbaky, Amr; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Burdo, Tricia H.; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 5 Longfellow Pl,Room 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU National Institutes of Health [R01 HL 095123, K23 HL092792, NS37654, NS40237, K24 DK064545]; General Clinical Research Center [M01 RR01066-25S1]; Merck Co; GlaxoSmithKline; Genetech/Roche; Vascular Biogenics Ltd; Bristol-Myers Squibb; Bracco and Becton; Dickinson and Company; Elsevier and Amirsys; Siemens Healthcare; GE Healthcare; Bracco Diagnostics; American College of Radiology Imaging Network; National Institutes of Health; Amgen; Theratechnologies; Ferrer; sanofi-aventis FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tawakol reported consulting for Roche, Bristol-Myers Squibb, and Novartis, and receiving grant support from Merck & Co, GlaxoSmithKline, Genetech/Roche, Vascular Biogenics Ltd, and Bristol-Myers Squibb, all unrelated to the manuscript. Dr Abbara reported consulting for Perceptive Informatics and Partners Imaging, receiving grant support from Bracco and Becton, Dickinson and Company, and receiving royalties from Elsevier and Amirsys, all unrelated to the manuscript. Dr Hoffmann reported receiving research support from Siemens Healthcare, GE Healthcare, Bracco Diagnostics, the American College of Radiology Imaging Network, and National Institutes of Health, all unrelated to the manuscript. Dr Grinspoon reported receiving research support from Amgen, Bristol-Myers Squibb, and Theratechnologies; consulting for Aileron, Theratechnologies, Alize Pharmaceuticals, Hoffmann-La Roche, and Serono; and receiving lecture fees from Ferrer and sanofi-aventis, all unrelated to the manuscript. No other authors reported any disclosures.; This work was supported by grant R01 HL 095123 from the National Institutes of Health (Dr Grinspoon). Relevant grants supporting investigators from the National Institutes of Health were K23 HL092792 (Dr Lo), NS37654 and NS40237 (Dr Williams), and K24 DK064545 (Dr Grinspoon). The General Clinical Research Center grant is M01 RR01066-25S1. NR 28 TC 156 Z9 156 U1 0 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 JUL 25 PY 2012 VL 308 IS 4 BP 379 EP 386 DI 10.1001/jama.2012.6698 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 977SR UT WOS:000306685500026 PM 22820791 ER PT J AU Land, TG Rigotti, NA Levy, DE Schilling, T Warner, D Li, WJ AF Land, Thomas G. Rigotti, Nancy A. Levy, Douglas E. Schilling, Thad Warner, Donna Li, Wenjun TI The Effect of Systematic Clinical Interventions with Cigarette Smokers on Quit Status and the Rates of Smoking-Related Primary Care Office Visits SO PLOS ONE LA English DT Article AB Background: The United States Public Health Service (USPHS) Guideline for Treating Tobacco Use and Dependence includes ten key recommendations regarding the identification and the treatment of tobacco users seen in all health care settings. To our knowledge, the impact of system-wide brief interventions with cigarette smokers on smoking prevalence and health care utilization has not been examined using patient population-based data. Methods and Findings: Data on clinical interventions with cigarette smokers were examined for primary care office visits of 104,639 patients at 17 Harvard Vanguard Medical Associates (HVMA) sites. An operational definition of "systems change" was developed. It included thresholds for intervention frequency and sustainability. Twelve sites met the criteria. Five did not. Decreases in self-reported smoking prevalence were 40% greater at sites that achieved systems change (13.6% vs. 9.7%, p<.01). On average, the likelihood of quitting increased by 2.6% (p<0.05, 95% CI: 0.1%-4.6%) per occurrence of brief intervention. For patients with a recent history of current smoking whose home site experienced systems change, the likelihood of an office visit for smoking-related diagnoses decreased by 4.3% on an annualized basis after systems change occurred (p<0.05, 95% CI: 0.5%-8.1%). There was no change in the likelihood of an office visit for smoking-related diagnoses following systems change among non-smokers. Conclusions: The clinical practice data from HVMA suggest that a systems approach can lead to significant reductions in smoking prevalence and the rate of office visits for smoking-related diseases. Most comprehensive tobacco intervention strategies focus on the provider or the tobacco user, but these results argue that health systems should be included as an integral component of a comprehensive tobacco intervention strategy. The HVMA results also give us an indication of the potential health impacts when meaningful use core tobacco measures are widely adopted. C1 [Land, Thomas G.] Massachusetts Dept Publ Hlth, Boston, MA USA. [Rigotti, Nancy A.; Levy, Douglas E.] Harvard Univ, Sch Med, Boston, MA USA. [Rigotti, Nancy A.; Levy, Douglas E.] Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.; Levy, Douglas E.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Schilling, Thad] Atrius Hlth Harvard Vanguard Med Associates, Newton, MA USA. [Warner, Donna] Multistate Collaborat Hlth Syst Change Reduce Tob, Georgetown, MA USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA USA. RP Land, TG (reprint author), Massachusetts Dept Publ Hlth, Boston, MA USA. EM Thomas.Land@state.ma.us RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU Centers for Disease Control and Prevention (through TA Consulting) [C-1691, 1141-0021] FX This work was funded, in part, by the Centers for Disease Control and Prevention (subcontract C-1691; task number 1141-0021 through TA Consulting). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 11 TC 11 Z9 11 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2012 VL 7 IS 7 AR e41649 DI 10.1371/journal.pone.0041649 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300061 PM 22911834 ER PT J AU Pant, A Lee, II Lu, ZX Rueda, BR Schink, J Kim, JJ AF Pant, Alok Lee, Irene I. Lu, Zhenxiao Rueda, Bo R. Schink, Julian Kim, J. Julie TI Inhibition of AKT with the Orally Active Allosteric AKT Inhibitor, MK-2206, Sensitizes Endometrial Cancer Cells to Progestin SO PLOS ONE LA English DT Article ID WELL-DIFFERENTIATED CARCINOMA; FORKHEAD TRANSCRIPTION FACTOR; GENE-EXPRESSION; RECEPTOR; GROWTH; PATHWAY; ADENOCARCINOMA; HYPERPLASIA; FERTILITY; THERAPY AB Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204) ERK or p(Thr13/Tyr185) SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT. C1 [Pant, Alok; Schink, Julian] Northwestern Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Chicago, IL 60611 USA. [Lee, Irene I.; Lu, Zhenxiao; Kim, J. Julie] Northwestern Univ, Div Reprod Biol Res, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Rueda, Bo R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Dept Obstet & Gynecol, Boston, MA USA. RP Pant, A (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Chicago, IL 60611 USA. EM j-kim4@northwestern.edu FU National Institutes of Health [R21 CA127674]; National Institutes of Health/National Cancer Institute [T32CA09560]; Malkin Scholars Program from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University FX National Institutes of Health R21 CA127674 (JJK), National Institutes of Health/National Cancer Institute training grant T32CA09560, and from the Malkin Scholars Program from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (IIL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 21 Z9 24 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 24 PY 2012 VL 7 IS 7 AR e41593 DI 10.1371/journal.pone.0041593 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 978NX UT WOS:000306751300056 PM 22911820 ER PT J AU Ball, MP Thakuria, JV Zaranek, AW Clegg, T Rosenbaum, AM Wu, XD Angrist, M Bhak, J Bobe, J Callow, MJ Cano, C Chou, MF Chung, WK Douglas, SM Estep, PW Gore, A Hulick, P Labarga, A Lee, JH Lunshof, JE Kim, BC Kim, JI Li, Z Murray, MF Nilsen, GB Peters, BA Raman, AM Rienhoff, HY Robasky, K Wheeler, MT Vandewege, W Vorhaus, DB Yang, JL Yang, LH Aach, J Ashley, EA Drmanac, R Kim, SJ Li, JB Peshkin, L Seidman, CE Seo, JS Zhang, K Rehm, HL Church, GM AF Ball, Madeleine P. Thakuria, Joseph V. Zaranek, Alexander Wait Clegg, Tom Rosenbaum, Abraham M. Wu, Xiaodi Angrist, Misha Bhak, Jong Bobe, Jason Callow, Matthew J. Cano, Carlos Chou, Michael F. Chung, Wendy K. Douglas, Shawn M. Estep, Preston W. Gore, Athurva Hulick, Peter Labarga, Alberto Lee, Je-Hyuk Lunshof, Jeantine E. Kim, Byung Chul Kim, Jong-Il Li, Zhe Murray, Michael F. Nilsen, Geoffrey B. Peters, Brock A. Raman, Anugraha M. Rienhoff, Hugh Y. Robasky, Kimberly Wheeler, Matthew T. Vandewege, Ward Vorhaus, Daniel B. Yang, Joyce L. Yang, Luhan Aach, John Ashley, Euan A. Drmanac, Radoje Kim, Seong-Jin Li, Jin Billy Peshkin, Leonid Seidman, Christine E. Seo, Jeong-Sun Zhang, Kun Rehm, Heidi L. Church, George M. TI A public resource facilitating clinical use of genomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome interpretation; genomic medicine; human genetics ID REGULATORY LIGHT-CHAINS; PLURIPOTENT STEM-CELLS; CA2+ BINDING; MUTATIONS; MYOSIN; MUSCLE; GENES AB Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board-approved "open consent" process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain-we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research. C1 [Ball, Madeleine P.; Thakuria, Joseph V.; Zaranek, Alexander Wait; Rosenbaum, Abraham M.; Wu, Xiaodi; Chou, Michael F.; Douglas, Shawn M.; Lee, Je-Hyuk; Raman, Anugraha M.; Robasky, Kimberly; Yang, Joyce L.; Yang, Luhan; Aach, John; Li, Jin Billy; Seidman, Christine E.; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Thakuria, Joseph V.] Massachusetts Gen Hosp, Div Med Genet, Boston, MA 02114 USA. [Thakuria, Joseph V.; Zaranek, Alexander Wait; Clegg, Tom; Vandewege, Ward] Clin Future Inc, Cambridge, MA 02142 USA. [Rosenbaum, Abraham M.] Ion Torrent Life Technol, Guilford, CT 06437 USA. [Wu, Xiaodi] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Angrist, Misha] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27708 USA. [Bhak, Jong] TheragenEtex Inc, Theragen BiO Inst, Suwon 443270, South Korea. [Bhak, Jong; Kim, Byung Chul] Personal Genom Inst, Genom Dept, Suwon 443766, South Korea. [Bobe, Jason; Estep, Preston W.] PersonalGenomes Org, Boston, MA 02215 USA. [Callow, Matthew J.; Nilsen, Geoffrey B.; Peters, Brock A.; Drmanac, Radoje] Complete Genom Inc, Mountain View, CA 94043 USA. [Cano, Carlos; Labarga, Alberto] Univ Granada, Dept Comp Sci & AI, E-18071 Granada, Spain. [Chung, Wendy K.] Columbia Univ, Dept Pediat, New York, NY 10032 USA. [Chung, Wendy K.] Columbia Univ, Dept Med, New York, NY 10032 USA. [Estep, Preston W.] TeloMe Inc, Waltham, MA 02451 USA. [Gore, Athurva; Li, Zhe; Zhang, Kun] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Hulick, Peter] NorthShore Univ HealthSyst, Div Genet, Evanston, IL 60201 USA. [Lunshof, Jeantine E.] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Mol Cell Physiol, NL-1081 HV Amsterdam, Netherlands. [Lunshof, Jeantine E.] Maastricht Univ, Fac Hlth Med & Life Sci, NL-6200 MD Maastricht, Netherlands. [Kim, Jong-Il; Seo, Jeong-Sun] Seoul Natl Univ, Coll Med, Genom Med Inst, Med Res Ctr, Seoul, South Korea. [Kim, Jong-Il] Psoma Therapeut Inc, Seoul 153781, South Korea. [Murray, Michael F.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Rienhoff, Hugh Y.] Www MyDaughtersDNA Org, San Carlos, CA 94070 USA. [Robasky, Kimberly] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Wheeler, Matthew T.; Ashley, Euan A.] Stanford Univ, Sch Med, Stanford Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA. [Vorhaus, Daniel B.] Robinson Bradshaw & Hinson PA, Chapel Hill, NC 27517 USA. [Ashley, Euan A.] Personalis Inc, Palo Alto, CA 94301 USA. [Kim, Seong-Jin] Cha Univ Med & Sci, Cha Canc Inst, Seoul 135081, South Korea. [Li, Jin Billy] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Peshkin, Leonid] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Seo, Jeong-Sun] Macrogen, Seoul, South Korea. [Rehm, Heidi L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Church, GM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM gchurch@genetics.med.harvard.edu RI KIM, JONG-IL/D-1019-2011; Seo, Jeong-Sun/J-2763-2012; Labarga, Alberto/J-9077-2014; OI KIM, JONG-IL/0000-0002-7240-3744; Labarga, Alberto/0000-0001-6781-893X; Bobe, Jason/0000-0003-1864-8609; Clegg, Tom/0000-0001-6751-2930; Ball, Madeleine/0000-0003-0544-5925 FU National Institutes of Health [P50HG005550, R01HL094963]; PersonalGenomes.org. FX We thank all members of the G. M. C. laboratory and other members of the Personal Genome Project Community, Ting Wu, and other members of the Personal Genetics Education Project for their help and advice; and Gerard T. Berry, Gerald Cox, Dongliang Ge, Ho Ghang, Taehyung Kim, Min Seob Lee, Sunghoon Lee, Stephen Quake, Kevin V. Shianna, and Anne West for contributions of data, assistance in analyses, and advice to our previous genome analysis efforts. This work was supported in part by National Institutes of Health Grants P50HG005550 (National Human Genome Research Institute) and R01HL094963 (National Heart, Lung, and Blood Institute), and by PersonalGenomes.org. NR 48 TC 71 Z9 71 U1 2 U2 29 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 JUL 24 PY 2012 VL 109 IS 30 BP 11920 EP 11927 DI 10.1073/pnas.1201904109 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700018 PM 22797899 ER PT J AU Grant, SS Kaufmann, BB Chand, NS Haseley, N Hung, DT AF Grant, Sarah Schmidt Kaufmann, Benjamin B. Chand, Nikhilesh S. Haseley, Nathan Hung, Deborah T. TI Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STATIONARY-PHASE CULTURES; MYCOBACTERIUM-TUBERCULOSIS; MULTIDRUG TOLERANCE; ESCHERICHIA-COLI; OXIDATIVE DAMAGE; DEATH; CELLS; LETHALITY; MECHANISM; BIOFILMS AB During Mycobacterium tuberculosis infection, a population of bacteria likely becomes refractory to antibiotic killing in the absence of genotypic resistance, making treatment challenging. We describe an in vitro model capable of yielding a phenotypically antibiotic-tolerant subpopulation of cells, often called persisters, within populations of Mycobacterium smegmatis and M. tuberculosis. We find that persisters are distinct from the larger antibiotic-susceptible population, as a small drop in dissolved oxygen (DO) saturation (20%) allows for their survival in the face of bactericidal antibiotics. In contrast, if high levels of DO are maintained, all cells succumb, sterilizing the culture. With increasing evidence that bactericidal antibiotics induce cell death through the production of reactive oxygen species (ROS), we hypothesized that the drop in DO decreases the concentration of ROS, thereby facilitating persister survival, and maintenance of high DO yields sufficient ROS to kill persisters. Consistent with this hypothesis, the hydroxylradical scavenger thiourea, when added to M. smegmatis cultures maintained at high DO levels, rescues the persister population. Conversely, the antibiotic clofazimine, which increases ROS via an NADH-dependent redox cycling pathway, successfully eradicates the persister population. Recent work suggests that environmentally induced antibiotic tolerance of bulk populations may result from enhanced antioxidant capabilities. We now show that the small persister subpopulation within a larger antibiotic-susceptible population also shows differential susceptibility to antibiotic-induced hydroxyl radicals. Furthermore, we show that stimulating ROS production can eradicate persisters, thus providing a potential strategy to managing persistent infections. C1 [Grant, Sarah Schmidt; Kaufmann, Benjamin B.; Haseley, Nathan; Hung, Deborah T.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Grant, Sarah Schmidt; Hung, Deborah T.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Grant, Sarah Schmidt; Kaufmann, Benjamin B.; Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Grant, Sarah Schmidt; Kaufmann, Benjamin B.; Hung, Deborah T.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Kaufmann, Benjamin B.; Chand, Nikhilesh S.; Haseley, Nathan; Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Chand, Nikhilesh S.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Haseley, Nathan] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hung, DT (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM dhung@broadinstitute.org OI , /0000-0003-2616-4030 FU Massachusetts General Hospital Executive Committee on Research and New York Community Trust; National Institutes of Health [K08 AI085033]; National Human Genome Research Institute [T32 HG002295] FX We thank T. Kawate and J. Gomez for helpful discussions. B.B.K. thanks the Massachusetts General Hospital Executive Committee on Research and New York Community Trust Heiser Postdoctoral Fellowships for support. S.S.G. is supported by National Institutes of Health Grant K08 AI085033. N.H. is supported by National Human Genome Research Institute Grant T32 HG002295. NR 48 TC 87 Z9 89 U1 1 U2 43 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 JUL 24 PY 2012 VL 109 IS 30 BP 12147 EP 12152 DI 10.1073/pnas.1203735109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700057 PM 22778419 ER PT J AU Choi, H Chang, LH Shibata, K Sasaki, Y Watanabe, T AF Choi, Hoon Chang, Li-Hung Shibata, Kazuhisa Sasaki, Yuka Watanabe, Takeo TI Resetting capacity limitations revealed by long-lasting elimination of attentional blink through training SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE learning in temporal attention; color-salient training; plasticity ID SERIAL VISUAL PRESENTATION; SURFACE-BASED ANALYSIS; RETINOTOPIC ORGANIZATION; COORDINATE SYSTEM; FUNCTIONAL MRI; CORTEX; TASK; SUPPRESSION; VISION; AREAS AB As with other cognitive phenomena that are based upon the capacity limitations of visual processing, it is thought that attentional blink (AB) cannot be eliminated, even after extensive training. We report in this paper that just 1 h of specific attentional training can completely eliminate AB, and that this effect is robust enough to persist for a few months after training. Results of subsequent behavioral and functional magnetic resonance imaging (fMRI) experiments indicate that this learning effect is associated with improvements in temporal resolution, which are mainly due to processing in the prefrontal areas. Contrary to prior wisdom, we conclude that capacity limitations can be overcome by short-term training. C1 [Choi, Hoon; Chang, Li-Hung; Shibata, Kazuhisa; Watanabe, Takeo] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Choi, Hoon; Chang, Li-Hung; Shibata, Kazuhisa; Sasaki, Yuka; Watanabe, Takeo] Brown Univ, Dept Cognit Linguist & Psychol Sci, Providence, RI 02912 USA. [Chang, Li-Hung; Sasaki, Yuka] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sasaki, Yuka] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02215 USA. RP Choi, H (reprint author), Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. EM hoonchoi@bu.edu FU National Institutes of Health [R01 EY015980, R01 EY019466]; National Center for Research Resources [P41RR14075, S10RR022976, S10RR019933] FX This work was supported by National Institutes of Health Grants R01 EY015980 and R01 EY019466 and National Center for Research Resources Grants P41RR14075, S10RR022976, and S10RR019933. NR 30 TC 24 Z9 27 U1 0 U2 8 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 JUL 24 PY 2012 VL 109 IS 30 BP 12242 EP 12247 DI 10.1073/pnas.1203972109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981TD UT WOS:000306992700073 PM 22778408 ER PT J AU Bonaca, MP Scirica, BM Sabatine, MS Jarolim, P Murphy, SA Chamberlin, JS Rhodes, DW Southwick, PC Braunwald, E Morrow, DA AF Bonaca, Marc P. Scirica, Benjamin M. Sabatine, Marc S. Jarolim, Petr Murphy, Sabina A. Chamberlin, Janna S. Rhodes, Daniel W. Southwick, Paula C. Braunwald, Eugene Morrow, David A. TI Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome(s); atherothrombosis; ischemia; metalloproteinase; PAPP-A ID HEART-FAILURE; CARDIOVASCULAR DEATH; NATRIURETIC PEPTIDE; 36 TRIAL; ELEVATION; BIOMARKERS; RISK; ISCHEMIA; INFLAMMATION; RANOLAZINE AB Objectives This study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Background PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality. Methods We measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 mu IU/ml was chosen from pilot work in this cohort. Results PAPP-A >6.0 mu IU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p < 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 mu g/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine. Conclusions PAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications. (J Am Coll Cardiol 2012;60:332-8) (C) 2012 by the American College of Cardiology Foundation C1 [Bonaca, Marc P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Chamberlin, Janna S.; Rhodes, Daniel W.; Southwick, Paula C.] Beckman Coulter Inc, Carlsbad, CA USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM mbonaca@partners.org FU Accumetrics; AstraZeneca; Bayer Healthcare; Beckman Coulter; Biosite; Bristol-Myers Squibb; CV Therapeutics; Daiichi Sankyo; Eli Lilly Co.; GlaxoSmithKline; Merck Co.; Nanosphere; Novartis Pharmaceuticals; Ortho-Clinical Diagnostics; Pfizer; Roche Diagnostics; Sanofi-Aventis; Schering-Plough; Siemens; Singulex; Gilead; Johnson Johnson; National Health, Lung, and Blood Institute [R01 HL096738, R01 HL098280, HHSN268201000033C]; Beckman-Coulter; Amgen; BRAHMS; Abbott; Roche; Menarini International FX This substudy was supported by Beckman Coulter. The TIMI Study Group has received significant research grant support from Accumetrics, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Daiichi Sankyo, Eli Lilly Co., GlaxoSmithKline, Merck & Co., Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Schering-Plough, Siemens, and Singulex. Dr. Scirica has received honoraria for educational presentations from CV Therapeutics and has served as a consultant to Eli Lilly Co., Gilead, Lexicon, and Cogentus. He has also received research grants from Gilead, AstraZeneca, Bristol-Myers Squibb; Daiichi Sankyo, Merck & Co., Johnson & Johnson, Bayer Healthcare, GlaxoSmithKline, and Novartis. Dr. Sabatine has served as a consultant to Critical Diagnostics, Abbott, Roche, BRAHMS, and Nanosphere; and he was also supported in part by grant R01 HL096738, grant R01 HL098280, and contract HHSN268201000033C from the National Health, Lung, and Blood Institute. Dr. Jarolim has received research grant support from Beckman-Coulter, Amgen, BRAHMS, Daiichi Sankyo, Merck & Co., Abbott, Ortho-Clinical Diagnostics, Roche, and Siemens; and he has received honoraria from Ortho-Clinical Diagnostics. He has also served as a consultant to T2 Biosystems and Quanterix. Ms. Chamberlin and Drs. Rhodes and Southwick are employees of Beckman Coulter. Dr. Braunwald has received honoraria for educational presentations and consulting from CV Therapeutics; grant support from Merck, AstraZeneca, Johnson & Johnson; Beckman Coulter, Eli Lilly Co., Roche Diagnostics, Sanofi-Aventis, Daiichi Sankyo, Bristol-Myers Squibb, and GlaxoSmithKline; lecture fees from Menarini International, Gilead, Merck & Co., Eli Lilly Co., Daiichi Sankyo, and CVRx; and served as a consultant to Genzyme, Amorcyte, CVRx, Daiichi Sankyo, The Medicines Co., Ikaria, CardioRentis, Merck & Co., and Sanofi-Aventis. Dr. Morrow has received honoraria for educational presentations from CV Therapeutics and Sanofi-Aventis; grant support from Amgen, Critical Diagnostics, Integrated Therapeutics, Millennium Pharmaceuticals, Novelo, and Sanofi-Synthelab; and has served as a consultant for Beckman Coulter, Critical Diagnostics, Gilead, Instrumentation Laboratories, Menarini, Merck & Co., Ortho-Clinical Diagnostics, Roche, Sanofi-Aventis, Schering-Plough, and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 27 TC 23 Z9 25 U1 0 U2 7 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 JUL 24 PY 2012 VL 60 IS 4 BP 332 EP 338 DI 10.1016/j.jacc.2012.04.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 975DE UT WOS:000306486300010 PM 22813612 ER PT J AU Kim, TH Shivdasani, RA AF Kim, Tae-Hee Shivdasani, Ramesh A. TI Stem Cell Niches: Famished Paneth Cells, Gluttonous Stem Cells SO CURRENT BIOLOGY LA English DT Editorial Material ID SMALL-INTESTINE; LGR5; GROWTH; POPULATIONS; RENEWAL; STRESS; MARKER; BOWEL C1 [Kim, Tae-Hee] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Kim, TH (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU NIDDK NIH HHS [K99 DK095983] NR 20 TC 2 Z9 2 U1 0 U2 5 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 JUL 24 PY 2012 VL 22 IS 14 BP R579 EP R580 DI 10.1016/j.cub.2012.06.017 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 979MI UT WOS:000306823700014 PM 22835795 ER PT J AU Fountzilas, E Kelly, AD Perez-Atayde, AR Goldsmith, J Konstantinopoulos, PA Francoeur, N Correll, M Rubio, R Hu, L Gebhardt, MC Quackenbush, J Spentzos, D AF Fountzilas, Elena Kelly, Andrew D. Perez-Atayde, Antonio R. Goldsmith, Jeffrey Konstantinopoulos, Panagiotis A. Francoeur, Nancy Correll, Mick Rubio, Renee Hu, Lan Gebhardt, Mark C. Quackenbush, John Spentzos, Dimitrios TI A microRNA activity map of human mesenchymal tumors: connections to oncogenic pathways; an integrative transcriptomic study SO BMC GENOMICS LA English DT Article DE MicroRNA; Microarray; RAS; Mesenchymal tumors; MicroRNA biogenesis ID PARAFFIN-EMBEDDED TISSUE; SQUAMOUS-CELL CARCINOMA; GENE-EXPRESSION; HUMAN CANCERS; DASL ASSAY; RNA; SARCOMAS; METASTASIS; TARGETS; SIGNATURES AB Background: MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with many tumorigenic processes. miRNA expression levels have been used in profiling studies, but some evidence suggests that expression levels do not fully capture miRNA regulatory activity. In this study we integrate multiple gene expression datasets to determine miRNA activity patterns associated with cancer phenotypes and oncogenic pathways in mesenchymal tumors - a very heterogeneous class of malignancies. Results: Using a computational method, we identified differentially activated miRNAs between 77 normal tissue specimens and 135 sarcomas and we validated many of these findings with microarray interrogation of an independent, paraffin-based cohort of 18 tumors. We also showed that miRNA activity is imperfectly correlated with miRNA expression levels. Using next-generation miRNA sequencing we identified potential base sequence alterations which may explain differential activity. We then analyzed miRNA activity changes related to the RAS-pathway and found 21 miRNAs that switch from silenced to activated status in parallel with RAS activation. Importantly, nearly half of these 21 miRNAs were predicted to regulate integral parts of the miRNA processing machinery, and our gene expression analysis revealed significant reductions of these transcripts in RAS-active tumors. These results suggest an association between RAS signaling and miRNA processing in which miRNAs may attenuate their own biogenesis. Conclusions: Our study represents the first gene expression-based investigation of miRNA regulatory activity in human sarcomas, and our findings indicate that miRNA activity patterns derived from integrated transcriptomic data are reproducible and biologically informative in cancer. We identified an association between RAS signaling and miRNA processing, and demonstrated sequence alterations as plausible causes for differential miRNA activity. Finally, our study highlights the value of systems level integrative miRNA/mRNA assessment with high-throughput genomic data, and the applicability of paraffin-tissue-derived RNA for validation of novel findings. C1 [Fountzilas, Elena; Kelly, Andrew D.; Konstantinopoulos, Panagiotis A.; Francoeur, Nancy; Spentzos, Dimitrios] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol,Sarcoma Program,Dept Med, Boston, MA 02215 USA. [Goldsmith, Jeffrey] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Correll, Mick; Rubio, Renee; Hu, Lan; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Perez-Atayde, Antonio R.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pathol, Boston, MA 02215 USA. [Gebhardt, Mark C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. RP Spentzos, D (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol,Sarcoma Program,Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM dspentzo@bidmc.harvard.edu OI Kelly, Andrew/0000-0002-5338-7689 FU National Institutes of Health [U19 CA148065, K22 CA138716-01A2]; Dana-Farber Cancer Institute Strategic Plan Fund FX Supported by the National Institutes of Health [U19 CA148065 to J.Q., K22 CA138716-01A2 to D. S.]; the Dana-Farber Cancer Institute Strategic Plan Fund [to M. C., J.Q.]; and a donation by Dr Richard and Virginia Clemmer to the sarcoma program at Beth Israel Deaconess Medical Center [to D. S., M.C.G.]. NR 47 TC 2 Z9 2 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 23 PY 2012 VL 13 AR 332 DI 10.1186/1471-2164-13-332 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 008DU UT WOS:000308938400002 PM 22823907 ER PT J AU Lahtinen, AM Noseworthy, PA Havulinna, AS Jula, A Karhunen, PJ Kettunen, J Perola, M Kontula, K Newton-Cheh, C Salomaa, V AF Lahtinen, Annukka M. Noseworthy, Peter A. Havulinna, Aki S. Jula, Antti Karhunen, Pekka J. Kettunen, Johannes Perola, Markus Kontula, Kimmo Newton-Cheh, Christopher Salomaa, Veikko TI Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; LONG QT SYNDROME; MIDDLE-AGED MEN; INTERVAL DURATION; RISK-FACTORS; ARTERY-DISEASE; CHANNEL GENE; POPULATION; MUTATIONS; ARRHYTHMIAS AB Background: Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD. Methodology/Principal Findings: We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11-1.45, P = 3.4x10(-4)) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11-1.48, P = 7.9x10(-4)). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01-1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P < 0.05). Conclusions/Significance: Two novel genetic variants, one in the cardiac sodium channel gene SCN5A and another at 4q25 previously associated with atrial fibrillation, are associated with SCD. C1 [Lahtinen, Annukka M.; Kontula, Kimmo] Univ Helsinki, Res Programs Unit, Helsinki, Finland. [Lahtinen, Annukka M.; Kontula, Kimmo] Univ Helsinki, Dept Med, Helsinki, Finland. [Noseworthy, Peter A.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Noseworthy, Peter A.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Noseworthy, Peter A.; Newton-Cheh, Christopher] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Havulinna, Aki S.; Perola, Markus; Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Jula, Antti] Natl Inst Hlth & Welf, Turku, Finland. [Karhunen, Pekka J.] Tampere Univ Hosp, Ctr Lab Med, Tampere, Finland. [Karhunen, Pekka J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Kettunen, Johannes; Perola, Markus] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland. RP Lahtinen, AM (reprint author), Univ Helsinki, Res Programs Unit, Helsinki, Finland. EM cnewtoncheh@chgr.mgh.harvard.edu; veikko.salomaa@thl.fi OI Tuiskula, Annukka/0000-0002-6538-635X FU Finnish Cultural Foundation; Max Schaldach Fellowship in Cardiac Pacing and Electrophysiology; Burroughs Wellcome Fund travel grant; Finnish Academy SALVE program "Pubgensense" [10404]; Wellcome Trust; Academy of Finland [129494]; Finnish Foundation for Cardiovascular Research; Sigrid Juselius Foundation; United States National Institutes of Health [HL080025, HL098283]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund FX This work was supported by the Finnish Cultural Foundation (to A. M. L.); the Max Schaldach Fellowship in Cardiac Pacing and Electrophysiology (to P.A.N.); a Burroughs Wellcome Fund travel grant (to P.A.N.); Finnish Academy SALVE program "Pubgensense" (#10404 to M.P.); the Wellcome Trust, the Academy of Finland (to K.K. and #129494 to V.S.); the Finnish Foundation for Cardiovascular Research (to K.K. and V.S.); the Sigrid Juselius Foundation (to K.K. and V.S.); the United States National Institutes of Health (HL080025, HL098283 to C.N.-C.); the Doris Duke Charitable Foundation (to C.N.-C.); and the Burroughs Wellcome Fund (to C.N.-C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 18 Z9 18 U1 0 U2 8 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 JUL 23 PY 2012 VL 7 IS 7 AR e41675 DI 10.1371/journal.pone.0041675 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977TM UT WOS:000306687700139 PM 22844511 ER PT J AU Patel, A Zhu, YH Kuzhikandathil, EV Banks, WA Siegel, A Zalcman, SS AF Patel, Ankur Zhu, Youhua Kuzhikandathil, Eldo V. Banks, William A. Siegel, Allan Zalcman, Steven S. TI Soluble Interleukin-6 Receptor Induces Motor Stereotypies and Co-Localizes with Gp130 in Regions Linked to Cortico-Striato-Thalamo-Cortical Circuits SO PLOS ONE LA English DT Article ID BETA-PROTEIN ANTIBODY; BLOOD-BRAIN-BARRIER; IL-6 RECEPTOR; RHEUMATOID-ARTHRITIS; ALZHEIMERS-DISEASE; MULTIPLE-MYELOMA; CYTOKINE NETWORK; MOUSE MODEL; SCHIZOPHRENIA; AMPHETAMINE AB Soluble cytokine receptors are normal constituents of body fluids that regulate peripheral cytokine and lymphoid activity and whose levels are increased in states of immune activation. Soluble interleukin-6 receptor (sIL-6R) levels positively correlate with disease progression in some autoimmune conditions and psychiatric disorders. Particularly strong links between levels of sIL-6R and the severity of psychotic symptoms occur in schizophrenia, raising the possibility that sIL-6R is involved in this disease. However, there is no evidence that peripheral sIL-6R induces relevant behavioral disturbances. We showed that single subcutaneous injections of sIL-6R (0-1 mu g), stimulated novelty stress-induced exploratory motor behaviors in male Balb/c mice within 20-40-min of injection. A progressive increase in vertical stereotypies was observed 40-80 min post injection, persisting for the remainder of the test session. Paralleling these stimulant-like effects, sIL-6R pretreatment significantly enhanced stereotypy scores following challenge with GBR 12909. We found that peripherally administered sIL-6R crossed the blood-brain barrier, localizing in brain regions associated with cortico-striatal-thalamo-cortical (CSTC) circuits, which are putative neuroanatomical substrates of disorders associated with repetitive stereotypies. Peripherally administered sIL-6R co-localized with gp130, a transmembrane protein involved in IL-6 trans-signaling, in the nucleus accumbens, caudate-putamen, motor and infralimbic cortices, and thalamic nuclei, but not with gp130 in the ventral tegmental area, substantia nigra, or sensorimotor cortex,. The results suggest that peripheral sIL-6R can act as a neuroimmune messenger, crossing the blood brain barrier (BBB) to selectively target CSTC circuits rich in IL-6 trans-signaling protein, and inducing repetitive stereotypies. As such sIL-6R may represent a novel therapeutic agent for relevant psychiatric disorders. C1 [Patel, Ankur; Siegel, Allan] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Zhu, Youhua; Zalcman, Steven S.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Psychiat, Newark, NJ 07103 USA. [Kuzhikandathil, Eldo V.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. [Banks, William A.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Div Gerontol & Geriatr Med, Dept Med,Geriatr Res Educ & Clin Ctr, Seattle, WA 98195 USA. RP Patel, A (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, 185 S Orange Ave, Newark, NJ 07103 USA. EM dr.ankur@yahoo.com FU National Institutes of Health [R01 MH74689, T32 5A74309] FX This work was supported by National Institutes of Health Grant R01 MH74689 (SSZ) and National Institutes of Health Training Fellowship T32 5A74309 (AP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 12 Z9 12 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2012 VL 7 IS 7 AR e41623 DI 10.1371/journal.pone.0041623 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977TM UT WOS:000306687700127 PM 22911828 ER PT J AU Via, LE Tsytsykova, AV Rajsbaum, R Falvo, JV Goldfeld, AE AF Via, Laura E. Tsytsykova, Alla V. Rajsbaum, Ricardo Falvo, James V. Goldfeld, Anne E. TI The Transcription Factor NFATp Plays a Key Role in Susceptibility to TB in Mice SO PLOS ONE LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA GENE; MYCOBACTERIUM-TUBERCULOSIS INFECTION; CREB-BINDING-PROTEIN; IFN-GAMMA PRODUCTION; HUMAN B-CELLS; INTERFERON-GAMMA; TNF GENE; IN-VIVO; NUCLEAR FACTOR AB In T cells, the transcription factor nuclear factor of activated T cells p (NFATp) is a key regulator of the cytokine genes tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma). Here, we show that NFATp-deficient (NFATp(-/-)) mice have a dramatic and highly significant increase in mortality after Mycobacterium tuberculosis (MTb) infection as compared to mortality of control animals after MTb infection. Animals deficient in NFATp have significantly impaired levels of TNF and IFN-gamma transcription and protein expression in naive or total CD4(+) T cells, but display wild-type levels of TNF mRNA or protein from MTb-stimulated dendritic cells (DC). The rapid mortality and disease severity observed in MTb-infected NFATp(-/-) mice is associated with dysregulated production of TNF and IFN-gamma in the lungs, as well as with increased levels of TNF, in their serum. Furthermore, global blocking of TNF production by injection of a TNF neutralizaing agent at 6 weeks, but not 12 weeks, post-MTb-infection further decreased the survival rate of both wild-type and NFATp(-/-) mice, indicating an early role for TNF derived from cells from the monocyte lineage in containment of infection. These results thus demonstrate that NFATp plays a critical role in immune containment of TB disease in vivo, through the NFATp-dependent expression of TNF and IFN-gamma in T cells. C1 [Via, Laura E.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Tsytsykova, Alla V.; Rajsbaum, Ricardo; Falvo, James V.; Goldfeld, Anne E.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Tsytsykova, Alla V.; Rajsbaum, Ricardo; Falvo, James V.; Goldfeld, Anne E.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. RP Via, LE (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM goldfeld@idi.harvard.edu RI Rajsbaum, Ricardo/F-2046-2014; OI Via, Laura/0000-0001-6074-9521 FU NIH [HL-059838, GM076685]; NIH, NIAID; Comparative Medicine Branch of NIAID FX This work was supported by grants from the NIH to A. E. G. (HL-059838 and GM076685). In addition, the work was partly supported by the Intramural Research Program of the NIH, NIAID and the Comparative Medicine Branch of NIAID is thankfully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 2 Z9 2 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2012 VL 7 IS 7 AR e41427 DI 10.1371/journal.pone.0041427 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977TM UT WOS:000306687700088 PM 22844476 ER PT J AU Bao, YR Dalrymple, L Chertow, GM Kaysen, GA Johansen, KL AF Bao, Yeran Dalrymple, Lorien Chertow, Glenn M. Kaysen, George A. Johansen, Kirsten L. TI Frailty, Dialysis Initiation, and Mortality in End-Stage Renal Disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; HEMODIALYSIS; HARMFUL; ADULTS; OLDER AB Background: In light of the recent trend toward earlier dialysis initiation and its association with mortality among patients with end-stage renal disease, we hypothesized that frailty is associated with higher estimated glomerular filtration rate (eGFR) at dialysis start and may confound the relation between earlier dialysis initiation and mortality. Methods: We examined frailty among participants of the Comprehensive Dialysis Study (CDS), a special study of the US Renal Data System, which enrolled incident patients from September 1, 2005, through June 1, 2007. Patients were followed for vital status through September 30, 2009, and for time to first hospitalization through December 31, 2008. We used multivariate logistic regression to model the association of frailty with eGFR at dialysis start and proportional hazards regression to assess the outcomes of death or hospitalization. Results: Among 1576 CDS participants included, the prevalence of frailty was 73%. In multivariate analysis, higher eGFR at dialysis initiation was associated with higher odds of frailty (odds ratio [OR], 1.44 [95% CI, 1.23-1.68] per 5 mL/min/1.73 m(2); P<.001). Frailty was independently associated with mortality (hazard ratio [HR], 1.57 [95% CI, 1.25-1.97]; P<.001) and time to first hospitalization (HR, 1.26 [95% CI, 1.09-1.45]; P < .001). While higher eGFR at dialysis initiation was associated with mortality (HR, 1.12 [95% CI, 1.02-1.23] per 5 mL/min/1.73 m2; P=.02), the association was no longer statistically significant after frailty was accounted for (HR, 1.08 [95% CI, 0.98-1.19] per 5 mL/min/1.73 m(2); P=.11). Conclusions: Frailty is extremely common among patients starting dialysis in the United States and is associated with higher eGFR at dialysis initiation. Recognition of signs and symptoms of frailty by clinicians may prompt earlier initiation of dialysis and may explain, at least in part, the well-described association between eGFR at dialysis initiation and mortality. C1 [Bao, Yeran] Univ Calif San Francisco, Div Endocrinol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Dalrymple, Lorien; Kaysen, George A.] Univ Calif Davis, Div Nephrol, Davis, CA 95616 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Chertow, Glenn M.; Kaysen, George A.; Johansen, Kirsten L.] USRDS Nutr Special Studies Ctr, San Francisco, CA USA. [Johansen, Kirsten L.] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA USA. [Johansen, Kirsten L.] USRDS Rehabil Qual Life Special Studies Ctr, Atlanta, GA USA. RP Bao, YR (reprint author), Univ Calif San Francisco, Div Endocrinol, 400 Parnassus Ave,A550,Box 1222, San Francisco, CA 94143 USA. EM yeran.bao@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-7-0005]; Graduate Medical Education funding through the VA [69734]; National Institutes of Health [T32 2T32DK007418-31]; National Center for Research Resources [UL1 RR024146]; NIDDK [1K24DK085153] FX This work was supported through contracts N01-DK-7-0005 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr Bao's effort was supported by grant No. 69734 from the Graduate Medical Education funding through the VA and by T32 2T32DK007418-31 from the National Institutes of Health. Dr Dalrymple's effort was supported by grant No. UL1 RR024146 from the National Center for Research Resources. A portion of Dr Johansen's effort was supported by 1K24DK085153 from the NIDDK. NR 21 TC 79 Z9 79 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1071 EP 1077 DI 10.1001/archinternmed.2012.3020 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000005 PM 22733312 ER PT J AU Perissinotto, CM Cenzer, IS Covinsky, KE AF Perissinotto, Carla M. Cenzer, Irena Stijacic Covinsky, Kenneth E. TI Loneliness in Older Persons A Predictor of Functional Decline and Death SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DEPRESSIVE SYMPTOMS; SOCIAL SUPPORT; ADULTS; HEALTH; PEOPLE; ASSOCIATION; IMPAIRMENT; MORTALITY; LIFE AB Background: Loneliness is a common source of distress, suffering, and impaired quality of life in older persons. We examined the relationship between loneliness, functional decline, and death in adults older than 60 years in the United States. Methods: This is a longitudinal cohort study of 1604 participants in the psychosocial module of the Health and Retirement Study, a nationally representative study of older persons. Baseline assessment was in 2002 and follow-up assessments occurred every 2 years until 2008. Subjects were asked if they (1) feel left out, (2) feel isolated, or (3) lack companionship. Subjects were categorized as not lonely if they responded hardly ever to all 3 questions and lonely if they responded some of the time or often to any of the 3 questions. The primary outcomes were time to death over 6 years and functional decline over 6 years on the following 4 measures: difficulty on an increased number of activities of daily living (ADL), difficulty in an increased number of upper extremity tasks, decline in mobility, or increased difficulty in stair climbing. Multivariate analyses adjusted for demographic variables, socioeconomic status, living situation, depression, and various medical conditions. Results: The mean age of subjects was 71 years. Fifty-nine percent were women; 81% were white, 11%, black, and 6%, Hispanic; and 18% lived alone. Among the elderly participants, 43% reported feeling lonely. Loneliness was associated with all outcome measures. Lonely subjects were more likely to experience decline in ADL (24.8% vs 12.5%; adjusted risk ratio [RR], 1.59; 95% CI, 1.23-2.07); develop difficulties with upper extremity tasks (41.5% vs 28.3%; adjusted RR, 1.28; 95% CI, 1.08-1.52); experience decline in mobility (38.1% vs 29.4%; adjusted RR, 1.18; 95% CI, 0.99-1.41); or experience difficulty in climbing (40.8% vs 27.9%; adjusted RR, 1.31; 95% CI, 1.10-1.57). Loneliness was associated with an increased risk of death (22.8% vs 14.2%; adjusted HR, 1.45; 95% CI, 1.11-1.88). Conclusion: Among participants who were older than 60 years, loneliness was a predictor of functional decline and death. C1 [Perissinotto, Carla M.; Cenzer, Irena Stijacic; Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. [Covinsky, Kenneth E.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Perissinotto, CM (reprint author), Univ Calif San Francisco, Dept Med, Div Geriatr, 3333 Calif St,Ste 380, San Francisco, CA 94143 USA. EM carla.perissinotto@ucsf.edu FU National Institute on Aging [5R01AG028481-03, 1K24AG029812-01A1]; Geriatric Academic Career Award, Health Resources and Services Administration [K01HP20489] FX This project was supported by grant 5R01AG028481-03 (Depressive Symptoms, Aging, Disability and Health Outcomes) from the National Institute on Aging. Dr Perissinotto is also supported in part by the Geriatric Academic Career Award, Health Resources and Services Administration (K01HP20489). Dr Covinsky is supported in part by grant 1K24AG029812-01A1 (Mid-career Mentoring Award for Patient-Oriented Research in Aging) from the National Institute on Aging. NR 27 TC 126 Z9 132 U1 4 U2 63 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1078 EP 1083 DI 10.1001/archinternined.2012.1993 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000006 PM 22710744 ER PT J AU Udell, JA Steg, PG Scirica, BM Smith, SC Ohman, EM Eagle, KA Goto, S Cho, JI Bhatt, DL AF Udell, Jacob A. Steg, Philippe Gabriel Scirica, Benjamin M. Smith, Sidney C., Jr. Ohman, E. Magnus Eagle, Kim A. Goto, Shinya Cho, Jang Ik Bhatt, Deepak L. CA REduction Atherothrombosis Continu TI Living Alone and Cardiovascular Risk in Outpatients at Risk of or With Atherothrombosis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; LARGE SOCIAL NETWORK; PSYCHOSOCIAL INFLUENCES; 52 COUNTRIES; EVENT RATES; SUPPORT; MORTALITY; ASSOCIATION; DEPRESSION AB Background: Living alone, a proxy for social support, has been inconsistently linked with cardiovascular risk. Methods: We investigated whether living alone was associated with increased mortality and cardiovascular risk in the global REduction of Atherothrombosis for Continued Health (REACH) Registry. Stable outpatients at risk of or with atherothrombosis were recruited from December 1, 2003, through December 31, 2004, and followed up to 4 years for cardiovascular events. Events were examined by living arrangement with risk adjustment for age, sex, clinical risk factors, therapy, preexisting vascular disease, and sociodemographic factors. Effect modification was tested by age, sex, employment, ethnicity, education, and geography. Results: Among the 44 573 REACH participants, 8594 (19%) were living alone. Living alone was associated with higher 4-year mortality (14.1% vs 11.1%) and cardiovascular death (8.6% vs 6.8%; log-rank P<.01 for both comparisons); however, there was significant effect modification by age (P value for interaction =.03). Specifically, among younger participants, living alone compared with those living with others was associated with higher mortality (age 45-65 years: 7.7% vs 5.7%; adjusted hazard ratio [HR], 1.24 195% CI, 1.01-1.511; age 66-80 years: 13.2% vs 12.3%; adjusted HR, 1.12 [95% CI, 1.01-1.261), but this was not observed among older participants (age > 80 years: 24.6% vs 28.4%; adjusted HR, 0.92 [95% CI, 0.79-1.061). A similar trend was observed for the risk of cardiovascular death. Conclusions: In an international outpatient population with atherothrombosis aged 45 years or older, living alone was associated with increased mortality among all but the most elderly patients, although this observation warrants confirmation. C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Dept Med, Boston, MA 02132 USA. [Udell, Jacob A.; Scirica, Benjamin M.; Cho, Jang Ik; Bhatt, Deepak L.] Harvard Univ, Sch Med, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA USA. [Udell, Jacob A.; Scirica, Benjamin M.; Cho, Jang Ik; Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, Sch Med,Dept Med, Boston, MA 02115 USA. [Udell, Jacob A.] Univ Toronto, Dept Med, Div Cardiovasc, Womens Coll Hosp, Toronto, ON, Canada. [Steg, Philippe Gabriel] INSERM U698, Paris, France. [Steg, Philippe Gabriel] Univ Paris Diderot, Paris, France. [Steg, Philippe Gabriel] Hop Bichat Claude Bernard, AP HP, Dept Cardiol, F-75877 Paris, France. [Smith, Sidney C., Jr.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Ohman, E. Magnus] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. [Eagle, Kim A.] Univ Michigan, Dept Med, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Goto, Shinya] Tokai Univ, Dept Med, Sch Med, Hiratsuka, Kanagawa 25912, Japan. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, Dept Med, 1400 VFW Pkwy, Boston, MA 02132 USA. EM dlbhattmd@post.harvard.edu FU TIMI Study Group; AstraZeneca Pharmaceuticals LP; Daiichi-Sankyo Inc; Merck Co Inc; Johnson & Johnson Pharmaceutical Research and Development LLC; Bayer HealthCare Pharmaceuticals; Bristol-Myers-Squibb Co; Gilead Science; Daiichi-Sankyo; Maquet; sanofi-aventis; Eisai; Boehringer-Ingelheim; Amarin; AstraZeneca; Bristol-Myers Squibb; Ethicon; Medtronic; Medicines Company; Waksman Foundation (Tokyo, Japan); Canadian Institutes for Health Research; Canadian Foundation for Women's Health FX Dr Steg has been a consultant or on advisory boards for Ablynx, Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi-Sankyo-Lilly, Eisai, GlaxoSmithKline, Medtronic, MSD, Pfizer, Roche, sanofi-aventis, Servier, and The Medicines Co, and is a stockholder and cofounder of Aterovax. Dr Scirica has received grants for clinical research via the TIMI Study Group and Brigham and Women's Hospital from AstraZeneca Pharmaceuticals LP, Daiichi-Sankyo Inc, Merck & Co Inc, Johnson & Johnson Pharmaceutical Research and Development LLC, Bayer HealthCare Pharmaceuticals, Bristol-Myers-Squibb Co, and Gilead Science, and has served as a consultant for Gilead Sciences Inc, Arena Pharmaceuticals, and Lexicon. Dr Ohman's university salary is partially supported by Daiichi-Sankyo and Maquet, and he has been a consultant for AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Gilead Sciences, Liposcience, Merck, Pozen Inc, Roche, sanofi-aventis, The Medicines Co, and WebMD. Dr Goto has received research grants from sanofi-aventis, Eisai, and Boehringer-Ingelheim, and has been a consultant or on advisory boards for Eisai, sanofi-aventis, and Otsuka. Dr Bhatt has been on the advisory board for Medscape Cardiology; on the board of directors for Boston VA Research Institute and the Society of Chest Pain Centers; the chair for the American Heart Association Get With The Guidelines Science Subcommittee; received honoraria from the American College of Cardiology (editor, Clinical Trials, Cardio-source), Duke Clinical Research Institute (clinical trial steering committees) and Slack Publications (chief medical editor, Cardiology Today Intervention), WebMD (CME steering committees); has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, sanofi aventis, and The Medicines Company; and has done unfunded research for PLx Pharma and Takeda.; The REACH Registry is sponsored by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). The REACH Registry is endorsed by the World Heart Federation. Dr Udell is a recipient of a Postdoctoral Research Fellowship from the Canadian Institutes for Health Research and Canadian Foundation for Women's Health. NR 36 TC 41 Z9 41 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1086 EP 1095 DI 10.1001/archinternmed.2012.2782 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000009 PM 22711020 ER PT J AU Caverly, TJ Al-Khatib, SM Kutner, JS Masoudi, FA Matlock, DD AF Caverly, Tanner J. Al-Khatib, Sana M. Kutner, Jean S. Masoudi, Frederick A. Matlock, Daniel D. TI LESS IS MORE Patient Preference in the Decision to Place Implantable Cardioverter-Defibrillators SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID HEART-FAILURE; CONSEQUENCES C1 [Matlock, Daniel D.] Univ Colorado, Div Gen Internal Med, Dept Med, Sch Med,Acad Off 1, Aurora, CO 80045 USA. [Caverly, Tanner J.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Al-Khatib, Sana M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Duke Cardiovasc Ctr Educ & Res Therapeut, Durham, NC USA. [Al-Khatib, Sana M.] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Masoudi, Frederick A.; Matlock, Daniel D.] Colorado Cardiovasc Outcomes Res Inst, Denver, CO USA. [Masoudi, Frederick A.; Matlock, Daniel D.] Kaiser Permanente, Colorado Inst Hlth Res, Denver, CO USA. RP Matlock, DD (reprint author), Univ Colorado, Div Gen Internal Med, Dept Med, Sch Med,Acad Off 1, 12631 E 17th Ave,Campus Box B-180, Aurora, CO 80045 USA. EM Daniel.Matlock@ucdenver.edu FU AHRQ HHS [U18HS016964, U18 HS016964]; NCRR NIH HHS [UL1RR025780, UL1 RR025780]; NIA NIH HHS [K23 AG040696-01, K23 AG040696]; PHS HHS [T32HP1006] NR 8 TC 9 Z9 9 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1104 EP 1105 DI 10.1001/archinternmed.2012.2177 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000013 PM 22688654 ER PT J AU Jena, AB Meltzer, DO Press, VG Arora, VM AF Jena, Anupam B. Meltzer, David O. Press, Valerie G. Arora, Vineet M. TI Why Physicians Work When Sick SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Jena, Anupam B.] Harvard Univ, Dept Med, Massachusetts Gen Hosp, Sch Med,Wang Ambulatory Care Ctr, Boston, MA 02114 USA. [Meltzer, David O.; Press, Valerie G.; Arora, Vineet M.] Univ Chicago, Chicago, IL 60637 USA. RP Jena, AB (reprint author), Harvard Univ, Dept Med, Massachusetts Gen Hosp, Sch Med,Wang Ambulatory Care Ctr, 15 Parkman St, Boston, MA 02114 USA. EM jena.anupam@mgh.harvard.edu RI Meltzer, David/C-2926-2009; OI Meltzer, David/0000-0003-2790-7393; Arora, Vineet/0000-0002-4745-7599 NR 6 TC 6 Z9 6 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1107 EP 1108 DI 10.1001/archinternmed.2012.1998 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000015 PM 22710803 ER PT J AU Grady, D Redberg, RF AF Grady, Deborah Redberg, Rita F. TI A Different Perspective Regarding Prostate-Specific Antigen Testing In reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Grady, Deborah; Redberg, Rita F.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA. [Grady, Deborah] San Francisco VA Med Ctr, San Francisco, CA USA. RP Grady, D (reprint author), Univ Calif San Francisco, Dept Med, 1635 Divisadero St,Ste 600, San Francisco, CA 94115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 23 PY 2012 VL 172 IS 14 BP 1111 EP 1111 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 976JY UT WOS:000306582000019 PM 22825065 ER PT J AU Zhang, YF Shi, J Yu, HP Feng, AN Fan, XS Lauwers, GY Mashimo, H Gold, JS Chen, G Huang, Q AF Zhang, Yi-Fen Shi, Jiong Yu, Hui-Ping Feng, An-Ning Fan, Xiang-Shan Lauwers, Gregory Y. Mashimo, Hiroshi Gold, Jason S. Chen, Gang Huang, Qin TI Factors predicting survival in patients with proximal gastric carcinoma involving the esophagus SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Cancer; Esophagus; Gastroesophageal junction; Staging; Stomach ID GASTROESOPHAGEAL JUNCTION CARCINOMAS; LYMPH-NODE INVOLVEMENT; CANCER STAGING SYSTEM; LONG-TERM SURVIVAL; ESOPHAGOGASTRIC JUNCTION; PROGNOSTIC-FACTORS; SURGICAL-TREATMENT; DISTAL ESOPHAGUS; ADENOCARCINOMA; CARDIA AB AIM: To investigate the clinicopathologic features which predict surgical overall survival in patients with proximal gastric carcinoma involving the esophagus (PGCE). METHODS: Electronic pathology database established in the Department of Pathology of the Nanjing Drum Tower Hospital was searched for consecutive resection cases of proximal gastric carcinoma over the period from May 2004 through July 2009. Each retrieved pathology report was reviewed and the cases with tumors crossing the gastroesophageal junction line were selected as PGCE. Each tumor was re-staged, following the guidelines on esophageal adenocarcinoma, according to the 7th edition of the American Joint Commission on Cancer Staging Manual. All histology slides were studied along with the pathology report for a retrospective analysis of 13 clinicopathologic features, i.e., age, gender, Helicobacter pylori (H. pylori) infection, surgical modality, Siewert type, tumor Bormann's type, size, differentiation, histology type, surgical margin, lymphovascular and perineural invasion, and pathologic stage in relation to survival after surgical resection. Prognostic factors for overall survival were assessed with uni- and multi-variate analyses. RESULTS: Patients' mean age was 65 years (range: 47-90 years). The male: female ratio was 3.3. The 1-, 3- and 5-year overall survival rates were 87%, 61% and 32%, respectively. By univariate analysis, age, male gender, H. pylori, tumor Bormann's type, size, histology type, surgical modality, positive surgical margin, lymphovascular invasion, and pT stage were not predictive for overall survival; in contrast, perineural invasion (P = 0.003), poor differentiation (P = 0.0003), > 15 total lymph nodes retrieved (P = 0.008), positive lymph nodes (P = 0.001), and distant metastasis (P = 0.005) predicted poor post-operative overall survival. Celiac axis nodal metastasis was associated with significantly worse overall survival (P = 0.007). By multivariate analysis, >= 16 positive nodes (P = 0.018), lymph node ratio > 0.2 (P = 0.003), and overall pathologic stage (P = 0.002) were independent predictors for poor overall survival after resection. CONCLUSION: Patients with PGCE showed worse overall survival in elderly, high nodal burden and advanced pathologic stage. This cancer may be more accurately staged as gastric, than esophageal, cancer. (c) 2012 Baishideng. All rights reserved. C1 [Huang, Qin] Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Pathol & Lab Med, W Roxbury, MA 02132 USA. [Zhang, Yi-Fen; Shi, Jiong; Yu, Hui-Ping; Feng, An-Ning; Fan, Xiang-Shan; Huang, Qin] Nanjing Univ, Sch Med, Affiliated Hosp, Nanjing Drum Tower Hosp,Dept Pathol, Nanjing 210008, Jiangsu, Peoples R China. [Lauwers, Gregory Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Mashimo, Hiroshi] Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Gastroenterol, W Roxbury, MA 02132 USA. [Gold, Jason S.] Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Surg, W Roxbury, MA 02132 USA. [Chen, Gang] Nanjing Univ, Sch Med, Nanjing Drum Tower Hosp, Affiliated Hosp,Dept Surg, Nanjing 210008, Jiangsu, Peoples R China. RP Huang, Q (reprint author), Harvard Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Dept Pathol & Lab Med, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM qinhuang0122@gmail.com RI Gold, Jason/O-5112-2014 OI Gold, Jason/0000-0002-2925-4755 FU Key Grants from the Science and Technology Development Project of the Nanjing City [ZKX05013, ZKX07011]; Special Grant from the Nanjing Drum Tower Hospital, Nanjing, China FX Supported by Key Grants from the Science and Technology Development Project of the Nanjing City, No. ZKX05013 and ZKX07011; A Special Grant from the Nanjing Drum Tower Hospital, Nanjing, China NR 37 TC 11 Z9 16 U1 0 U2 5 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 21 PY 2012 VL 18 IS 27 BP 3602 EP 3609 DI 10.3748/wjg.v18.i27.3602 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 980KP UT WOS:000306892400017 PM 22826627 ER PT J AU Zettergren, E Swamy, T Runnels, J Lin, CP Niedre, M AF Zettergren, Eric Swamy, Tushar Runnels, Judith Lin, Charles P. Niedre, Mark TI Tomographic sensing and localization of fluorescently labeled circulating cells in mice in vivo SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID TUMOR-CELLS; MULTIPLE-MYELOMA; FLOW-CYTOMETRY; BREAST-CANCER; METASTASIS; BLOOD AB Sensing and enumeration of specific types of circulating cells in small animals is an important problem in many areas of biomedical research. Microscopy-based fluorescence in vivo flow cytometry methods have been developed previously, but these are typically limited to sampling of very small blood volumes, so that very rare circulating cells may escape detection. Recently, we described the development of a 'diffuse fluorescence flow cytometer' (DFFC) that allows sampling of much larger blood vessels and therefore circulating blood volumes in the hindlimb, forelimb or tail of a mouse. In this work, we extend this concept by developing and validating a method to tomographically localize circulating fluorescently labeled cells in the cross section of a tissue simulating optical flow phantom and mouse limb. This was achieved using two modulated light sources and an array of six fiber-coupled detectors that allowed rapid, high-sensitivity acquisition of full tomographic data sets at 10 Hz. These were reconstructed into two-dimensional cross-sectional images using Monte Carlo models of light propagation and the randomized algebraic reconstruction technique. We were able to obtain continuous images of moving cells in the sample cross section with 0.5 mm accuracy or better. We first demonstrated this concept in limb-mimicking optical flow photons with up to four flow channels, and then in the tails of mice with fluorescently labeled multiple myeloma cells. This approach increases the overall diagnostic utility of our DFFC instrument. C1 [Zettergren, Eric; Swamy, Tushar; Niedre, Mark] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. [Runnels, Judith; Lin, Charles P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Runnels, Judith; Lin, Charles P.] Harvard Univ, Ctr Syst Biol, Sch Med, Boston, MA 02114 USA. [Runnels, Judith; Lin, Charles P.] Wellman Ctr Photomed, Boston, MA 02114 USA. RP Niedre, M (reprint author), Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. EM mniedre@ece.neu.edu FU National Institutes of Health [5R21HL098750]; Massachusetts Life Sciences Center FX This work was funded with a grant from the National Institutes of Health (5R21HL098750) and from a New Investigator award from the Massachusetts Life Sciences Center. The assistance of Mr James Brock in computing the Monte Carlo forward models is gratefully acknowledged. NR 36 TC 4 Z9 4 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2012 VL 57 IS 14 BP 4627 EP 4641 DI 10.1088/0031-9155/57/14/4627 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 969RC UT WOS:000306072500014 PM 22750660 ER PT J AU Durant, RW Parmar, G Shuaib, F Le, A Brown, TM Roth, DL Hovater, M Halanych, JH Shikany, JM Prineas, RJ Samdarshi, TJ Safford, MM AF Durant, Raegan W. Parmar, Gaurav Shuaib, Faisal Le, Anh Brown, Todd M. Roth, David L. Hovater, Martha Halanych, Jewell H. Shikany, James M. Prineas, Ronald J. Samdarshi, Tandaw J. Safford, Monika M. TI Awareness and management of chronic disease, insurance status, and health professional shortage areas in the REasons for Geographic And Racial Differences in Stroke (REGARDS): a cross-sectional study SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID NUTRITION EXAMINATION SURVEY; PRIMARY-CARE; CARDIOVASCULAR-DISEASE; NATIONAL-HEALTH; US ADULTS; MEDICARE BENEFICIARIES; MYOCARDIAL-INFARCTION; RISK-FACTORS; HYPERTENSION; PREVALENCE AB Background: Limited financial and geographic access to primary care can adversely influence chronic disease outcomes. We examined variation in awareness, treatment, and control of hypertension, diabetes, and hyperlipidemia according to both geographic and financial access to care. Methods: We analyzed data on 17,458 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study with either hypertension, hyperlipidemia, or diabetes and living in either complete Health Professional Shortage Area (HPSA) counties or non-HPSA counties in the U. S. All analyses were stratified by insurance status and adjusted for sociodemographics and health behaviors. Results: 2,261 residents lived in HPSA counties and 15,197 in non-HPSA counties. Among the uninsured, HPSA residents had higher awareness of both hypertension (adjusted OR 2.30, 95% CI 1.08, 4.89) and hyperlipidemia (adjusted OR 1.50, 95% CI 1.01, 2.22) compared to non-HPSA residents. Also among the uninsured, HPSA residents with hypertension had lower blood pressure control (adjusted OR 0.45, 95% CI 0.29, 0.71) compared with non-HPSA residents. Similar differences in awareness and control according to HPSA residence were absent among the insured. Conclusions: Despite similar or higher awareness of some chronic diseases, uninsured HPSA residents may achieve control of hypertension at lower rates compared to uninsured non-HPSA residents. Federal allocations in HPSAs should target improved quality of care as well as increasing the number of available physicians. C1 [Durant, Raegan W.; Parmar, Gaurav; Shuaib, Faisal; Brown, Todd M.; Halanych, Jewell H.; Shikany, James M.; Safford, Monika M.] Univ Alabama Birmingham, Med Sch Birmingham, Birmingham, AL 35294 USA. [Durant, Raegan W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Le, Anh; Roth, David L.; Hovater, Martha] Univ Alabama Birmingham, Birmingham Sch Publ Hlth, Birmingham, AL 35294 USA. [Prineas, Ronald J.] Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. [Samdarshi, Tandaw J.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Durant, RW (reprint author), Univ Alabama Birmingham, Med Sch Birmingham, 1717 11th Ave S, Birmingham, AL 35294 USA. EM rdurant@dopm.uab.edu FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service [U01 NS041588]; National Heart, Lung and Blood Institute [R01 HL80477, R01 HL080477-02 S1] FX This research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis or interpretation of the data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. Additional funding was provided by an investigator-initiated grant R01 HL80477 and a supplemental grant R01 HL080477-02 S1 from the National Heart, Lung and Blood Institute. NR 47 TC 4 Z9 4 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 20 PY 2012 VL 12 AR 208 DI 10.1186/1472-6963-12-208 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 088DJ UT WOS:000314813700001 PM 22818296 ER PT J AU Crenshaw, CM Nam, K Oo, K Kutchukian, PS Bowman, BR Karplus, M Verdine, GL AF Crenshaw, Charisse M. Nam, Kwangho Oo, Kimberly Kutchukian, Peter S. Bowman, Brian R. Karplus, Martin Verdine, Gregory L. TI Enforced Presentation of an Extrahelical Guanine to the Lesion Recognition Pocket of Human 8-Oxoguanine Glycosylase, hOGG1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVE DNA-DAMAGE; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; REPAIR ENZYME; 8-HYDROXYGUANINE 7,8-DIHYDRO-8-OXOGUANINE; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; UNDAMAGED DNA; PROTEIN; SYSTEM AB A poorly understood aspect of DNA repair proteins is their ability to identify exceedingly rare sites of damage embedded in a large excess of nearly identical undamaged DNA, while catalyzing repair only at the damaged sites. Progress toward understanding this problem has been made by comparing the structures and biochemical behavior of these enzymes when they are presented with either a target lesion or a corresponding undamaged nucleobase. Trapping and analyzing such DNA-protein complexes is particularly difficult in the case of base extrusion DNA repair proteins because of the complexity of the repair reaction, which involves extrusion of the target base from DNA followed by its insertion into the active site where glycosidic bond cleavage is catalyzed. Here we report the structure of a human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, in which a normal guanine from DNA has been forcibly inserted into the enzyme active site. Although the interactions of the nucleobase with the active site are only subtly different for G versus oxoG, hOGG1 fails to catalyze excision of the normal nucleobase. This study demonstrates that even if hOGG1 mistakenly inserts a normal base into its active site, the enzyme can still reject it on the basis of catalytic incompatibility. C1 [Crenshaw, Charisse M.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Nam, Kwangho; Oo, Kimberly; Kutchukian, Peter S.; Bowman, Brian R.; Karplus, Martin; Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Crenshaw, Charisse M.; Nam, Kwangho; Kutchukian, Peter S.; Bowman, Brian R.; Verdine, Gregory L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol & Chem Biol Initiat, Boston, MA 02115 USA. [Karplus, Martin] Univ Strasbourg, Inst Sci & Ingn Supramol, F-67000 Strasbourg, France. RP Verdine, GL (reprint author), 12 Oxford St, Cambridge, MA 02138 USA. EM gregory_verdine@harvard.edu RI Kutchukian, Peter/A-9826-2016 OI Kutchukian, Peter/0000-0002-5684-1971 FU National Institutes of Health [GM044853, CA100742, GM030804]; National Science Foundation; National Cancer Center; Harvard College Program for Research in Science and Engineering; Herchel Smith Harvard Summer Undergraduate Research Fellowship; Harvard College Research Program; Ruth Kirschstein National Research Service Award Fellowship [F32 GM077935-01]; United States Dept. of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX This work was supported, in whole or in part, by National Institutes of Health Grants GM044853 and CA100742 (to G. L. V.) and GM030804 (to M. K.), pre-doctoral fellowships from the National Science Foundation (2004) (to C. M. C. and P. S. K.), a postdoctoral fellowship from the National Cancer Center (to K. N.), the Harvard College Program for Research in Science and Engineering (2007) (to K. O.), Herchel Smith Harvard Summer Undergraduate Research Fellowship (2007) (to K. O.), the Harvard College Research Program (2008) (to K. O.), and Ruth Kirschstein National Research Service Award Fellowship F32 GM077935-01 (to B. R. B.).; We thank the staff at the NE-CAT at the Advanced Photon Source, especially C. Narayanasami Sukumar, for assistance during data collection, the National Energy Research Scientific Computing Center and FAS Science Division Research Computing Group at Harvard University for providing computer resources. We also thank Drs. Lourdes Gude-Rodriguez, Seongmin Lee, Danaya Pakotiprapha, Marie Spong, and especially Gordon Louie for critical reading of the manuscript, and data analysis advice. We also thank Rachelle Gaudet and David Jeruzalmi and other laboratory members for useful discussions and guidance on data processing. Use of the Advanced Photon Source was supported by the United States Dept. of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. NR 67 TC 22 Z9 23 U1 0 U2 16 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 JUL 20 PY 2012 VL 287 IS 30 BP 24916 EP 24928 DI 10.1074/jbc.M111.316497 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IW UT WOS:000306651700006 PM 22511791 ER PT J AU Blackwell, KL Burstein, HJ Storniolo, AM Rugo, HS Sledge, G Aktan, G Ellis, C Florance, A Vukelja, S Bischoff, J Baselga, J O'Shaughnessy, J AF Blackwell, Kimberly L. Burstein, Harold J. Storniolo, Anna Maria Rugo, Hope S. Sledge, George Aktan, Gursel Ellis, Catherine Florance, Allison Vukelja, Svetislava Bischoff, Joachim Baselga, Jose O'Shaughnessy, Joyce TI Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN-RECEPTOR; RANDOMIZED-TRIAL; ERBB RECEPTORS; PROGRESSION; WOMEN; PLUS; AMPLIFICATION; PACLITAXEL; ONCOGENE; THERAPY AB Purpose Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here. Patients and Methods Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit. Results In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates. Conclusion These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC. C1 [Blackwell, Kimberly L.] Duke Univ, Med Ctr, Dept Med Med Oncol, Durham, NC 27710 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA USA. [Baselga, Jose] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Storniolo, Anna Maria; Sledge, George] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Rugo, Hope S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Aktan, Gursel; Ellis, Catherine; Florance, Allison] GlaxoSmithKline, Collegeville, PA USA. [Vukelja, Svetislava] US Oncol, Texas Oncol, Tyler, TX USA. [O'Shaughnessy, Joyce] US Oncol, Texas Oncol, Baylor Sammons Canc Ctr, Dallas, TX USA. [Bischoff, Joachim] Otto Von Guericke Univ, Magdeburg, Germany. RP Blackwell, KL (reprint author), Duke Univ, Med Ctr, Dept Med Med Oncol, Box 3893, Durham, NC 27710 USA. EM black034@mc.duke.edu FU GlaxoSmithKline; Genentech/Roche; Mundipharma Expert Testimony FX Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Gursel Aktan, GlaxoSmithKline (C); Catherine Ellis, GlaxoSmithKline (C); Allison Florance, GlaxoSmithKline (C) Consultant or Advisory Role: Kimberly Blackwell, GlaxoSmithKline (C); Joachim Bischoff, GlaxoSmithKline (C), Novartis (C), Roche (C); Jose Baselga, GlaxoSmithKline (U), Roche (C); Joyce O'Shaughnessy, Genentech (C), GlaxoSmithKline (C) Stock Ownership: Catherine Ellis, GlaxoSmithKline; Allison Florance, GlaxoSmithKline Honoraria: Kimberly L. Blackwell, GlaxoSmithKline; Anna Maria Storniolo, GlaxoSmithKline; Joachim Bischoff, Amgen, GlaxoSmithKline, sanofi-aventis; Joyce O'Shaughnessy, Genentech, GlaxoSmithKline Research Funding: Anna Maria Storniolo, GlaxoSmithKline; Hope S. Rugo, GlaxoSmithKline, Genentech/Roche; Joachim Bischoff, GlaxoSmithKline, Mundipharma Expert Testimony: None Other Remuneration: Joachim Bischoff, GlaxoSmithKline, Roche NR 26 TC 217 Z9 224 U1 1 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP 2585 EP 2592 DI 10.1200/JCO.2011.35.6725 PG 8 WC Oncology SC Oncology GA 976CA UT WOS:000306556900009 PM 22689807 ER PT J AU Carey, LA Rugo, HS Marcom, PK Mayer, EL Esteva, FJ Ma, CX Liu, MC Storniolo, AM Rimawi, MF Forero-Torres, A Wolff, AC Hobday, TJ Ivanova, A Chiu, WK Ferraro, M Burrows, E Bernard, PS Hoadley, KA Perou, CM Winer, EP AF Carey, Lisa A. Rugo, Hope S. Marcom, P. Kelly Mayer, Erica L. Esteva, Francisco J. Ma, Cynthia X. Liu, Minetta C. Storniolo, Anna Maria Rimawi, Mothaffar F. Forero-Torres, Andres Wolff, Antonio C. Hobday, Timothy J. Ivanova, Anastasia Chiu, Wing-Keung Ferraro, Madlyn Burrows, Emily Bernard, Philip S. Hoadley, Katherine A. Perou, Charles M. Winer, Eric P. TI TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MOLECULAR CHARACTERIZATION; EXPRESSION PROFILES; SUBTYPES; TUMORS; CHEMOTHERAPY; PORTRAITS; CARCINOMA; PATTERNS; CAROLINA; SURVIVAL AB Purpose Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m(2) load then 250 mg/m(2) per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation. C1 [Carey, Lisa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Marcom, P. Kelly] Duke Univ, Durham, NC USA. [Rugo, Hope S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mayer, Erica L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Esteva, Francisco J.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Rimawi, Mothaffar F.] Baylor Univ, Coll Med, Houston, TX 77030 USA. [Ma, Cynthia X.] Washington Univ, St Louis, MO USA. [Liu, Minetta C.] Georgetown Univ, Washington, DC USA. [Storniolo, Anna Maria] Indiana Univ, Indianapolis, IN 46204 USA. [Forero-Torres, Andres] Univ Alabama Birmingham, Birmingham, AL USA. [Wolff, Antonio C.] Johns Hopkins Univ, Baltimore, MD USA. [Hobday, Timothy J.] Mayo Clin, Rochester, MN USA. [Bernard, Philip S.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. RP Carey, LA (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7305,170 Manning Dr,3rd Floor, Chapel Hill, NC 27599 USA. EM lisa_carey@med.unc.edu OI Wolff, Antonio/0000-0003-3734-1063; Esteva, Francisco/0000-0003-2437-3920; Perou, Charles/0000-0001-9827-2247 FU Bristol-Myers Squibb; University of North Carolina Breast Cancer Specialized Program of Research Excellence Award [NCI CA58223]; National Cancer Institute; Avon Partners-for-Progress awards; National Institutes of Health Grant [M01RR00046]; Breast Cancer Research Foundation; Avon Foundation; Susan G. Komen for the Cure; Veridex FX Supported by Bristol-Myers Squibb, by University of North Carolina Breast Cancer Specialized Program of Research Excellence Award No. NCI CA58223 from the National Cancer Institute, by Avon Partners-for-Progress awards (L.A.C., H.S.R., P.K.M., E.P.W.), and by National Institutes of Health Grant No. M01RR00046 (L.A.C). The Translational Breast Cancer Research Consortium is supported by the Breast Cancer Research Foundation, the Avon Foundation, and Susan G. Komen for the Cure.; Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Philip S. Bernard, Bioclassifier (U); Charles M. Perou, University Genomics (U) Consultant or Advisory Role: Lisa A. Carey, Bristol-Myers Squibb (U); Erica L. Mayer, Bristol-Myers Squibb (C); Philip S. Bernard, Bioclassifier (U); Charles M. Perou, Bristol-Myers Squibb (C); Eric P. Winer, Verastem (C) Stock Ownership: Philip S. Bernard, Bioclassifier; Charles M. Perou, Bioclassifier Honoraria: Minetta C. Liu, Bristol-Myers Squibb Research Funding: Lisa A. Carey, Bristol-Myers Squibb; Hope S. Rugo, Bristol-Myers Squibb, Veridex; Minetta C. Liu, Bristol-Myers Squibb; Mothaffar F. Rimawi, Bristol-Myers Squibb; Andres Forero-Torres, Bristol-Myers Squibb; Charles M. Perou, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None NR 31 TC 158 Z9 166 U1 2 U2 12 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP 2615 EP 2623 DI 10.1200/JCO.2010.34.5579 PG 9 WC Oncology SC Oncology GA 976CA UT WOS:000306556900013 PM 22665533 ER PT J AU Sanoff, HK Carpenter, WR Sturmer, T Goldberg, RM Martin, CF Fine, JP McCleary, NJ Meyerhardt, JA Niland, J Kahn, KL Schymura, MJ Schrag, D AF Sanoff, Hanna K. Carpenter, William R. Stuermer, Til Goldberg, Richard M. Martin, Christopher F. Fine, Jason P. McCleary, Nadine Jackson Meyerhardt, Jeffrey A. Niland, Joyce Kahn, Katherine L. Schymura, Maria J. Schrag, Deborah TI Effect of Adjuvant Chemotherapy on Survival of Patients With Stage III Colon Cancer Diagnosed After Age 75 Years SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ELDERLY-PATIENTS; POOLED ANALYSIS; COMORBIDITY INDEX; COLORECTAL-CANCER; NSABP C-07; FLUOROURACIL; OXALIPLATIN; LEUCOVORIN; TRIAL; POPULATION AB Purpose Few patients 75 years of age and older participate in clinical trials, thus whether adjuvant chemotherapy for stage III colon cancer (CC) benefits this group is unknown. Methods A total of 5,489 patients >= 75 years of age with resected stage III CC, diagnosed between 2004 and 2007, were selected from four data sets containing demographic, stage, treatment, and survival information. These data sets included SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, and prospective cohort studies Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and the National Comprehensive Cancer Network. Data sets were analyzed in parallel using covariate adjusted and propensity score (PS) matched proportional hazards models to evaluate the effect of treatment on survival. PS trimming was used to mitigate the effects of selection bias. Results Use of adjuvant therapy declined with age and comorbidity. Chemotherapy receipt was associated with a survival benefit of comparable magnitude to clinical trials results (SEER-Medicare PS-matched mortality, hazard ratio [HR], 0.60; 95% CI, 0.53 to 0.68). The incremental benefit of oxaliplatin over non-oxaliplatin-containing regimens was also of similar magnitude to clinical trial results (SEER-Medicare, HR, 0.84; 95% CI, 0.69 to 1.04; NYSCR-Medicare, HR, 0.82, 95% CI, 0.51 to 1.33) in two of three examined data sources. However, statistical significance was inconsistent. The beneficial effect of chemotherapy and oxaliplatin did not seem solely attributable to confounding. Conclusion The noninvestigational experience suggests patients with stage III CC >= 75 years of age may anticipate a survival benefit from adjuvant chemotherapy. Oxaliplatin offers no more than a small incremental benefit. Use of adjuvant chemotherapy after the age of 75 years merits consideration in discussions that weigh individual risks and preferences. C1 [McCleary, Nadine Jackson; Meyerhardt, Jeffrey A.; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sanoff, Hanna K.] Univ Virginia, Charlottesville, VA USA. [Carpenter, William R.; Stuermer, Til; Goldberg, Richard M.; Martin, Christopher F.; Fine, Jason P.] Univ N Carolina, Chapel Hill, NC USA. [Niland, Joyce] City Hope Canc Ctr, Duarte, CA USA. [Niland, Joyce] Natl Comprehens Canc Ctr, Data Coordinating Ctr, Duarte, CA USA. [Kahn, Katherine L.] RAND Corp, Santa Monica, CA USA. [Kahn, Katherine L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Schymura, Maria J.] New York State Dept Hlth, New York State Canc Registry, Albany, NY USA. RP Schrag, D (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM deb_schrag@dfci.harvard.edu RI Goldberg , Richard/M-1311-2013; Carpenter, William/E-5125-2013 FU Merck; sanofi-aventis; AstraZeneca; Bristol-Myers Squibb; Agency for Healthcare Research and Quality(AHRQ); US Department of Health and Human Services [HSA290-2005-0016-I-TO7-WA1, 36-BWH-1, HHSA290-2005-0040-I-TO4-WA1, 36-UNC]; National Cancer Institute (NCI) [R01CA131847]; National Cancer Institute [U01 CA093344, U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA01013, U01 CA093326]; Department of Veteran's Affairs [U01CDA093344, MOU, HARO03-438MO-03]; National Institute on Aging [R01AG023178]; National Institute of Diabetes and Digestive and Kidney Diseases [2P30DK034987]; US Centers for Disease Control and Prevention through the Association of Schools of Public Health [S3888] FX Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Til Sturmer, GlaxoSmithKline (U); Richard M. Goldberg, sanofi-aventis (C); Jeffrey A. Meyerhardt, Bayer Healthcare Pharmaceuticals (C), sanofi-aventis (C) Stock Ownership: None Honoraria: None Research Funding: Til Sturmer, Merck, sanofi-aventis; Richard M. Goldberg, sanofi-aventis; Jeffrey A. Meyerhardt, AstraZeneca, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None; Primary funding for this project was obtained from the Agency for Healthcare Research and Quality(AHRQ), US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness program; contracts No. HSA290-2005-0016-I-TO7-WA1, 36-BWH-1, and HHSA290-2005-0040-I-TO4-WA1, 36-UNC. The authors of the report are responsible for its content. Statements in the report should not be construed as endorsement by the AHRQ or of any funding agencies that funded creation of data sets used in these analyses.; The project relied on existing data sources that were created from other funded grants. These sources include the National Cancer Institute (NCI; grant No. R01CA131847, D.S., principal investigator) funded work that facilitated creation of the New York State-Medicaid-Medicare data. The NCI also curates the SEER-Medicare data. The Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study was supported by grants from the National Cancer Institute to the CanCORS Statistical Coordinating Center and Primary Data Collection and Research Centers (grants No. U01 CA093344, U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA01013, and U01 CA093326), and by a grant from the Department of Veteran's Affairs to the Durham VA Medical Center (grants No. U01CDA093344, MOU, and HARO03-438MO-03). Also supported by the National Institute on Aging, (grant No. R01AG023178, T.S., principal investigator), the National Institute of Diabetes and Digestive and Kidney Diseases (grant No. 2P30DK034987, R.S., principal investigator), and the US Centers for Disease Control and Prevention through the Association of Schools of Public Health (grant No. S3888, M.J.S., principal investigator).; Funding sources and collaborating agencies were not directly involved with the design, analysis and interpretation, or writing of the manuscript. Final manuscript approval was provided by AHRQ, the CanCORS publication committee, the New York State Cancer Registry, the National Comprehensive Cancer Network publication committee, and SEER-Medicare NR 35 TC 70 Z9 70 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP 2624 EP 2634 DI 10.1200/JCO.2011.41.1140 PG 11 WC Oncology SC Oncology GA 976CA UT WOS:000306556900014 PM 22665536 ER PT J AU Jakacki, RI Burger, PC Zhou, TN Holmes, EJ Kocak, M Onar, A Goldwein, J Mehta, M Packer, RJ Tarbell, N Fitz, C Vezina, G Hilden, J Pollack, IF AF Jakacki, Regina I. Burger, Peter C. Zhou, Tianni Holmes, Emiko J. Kocak, Mehmet Onar, Arzu Goldwein, Joel Mehta, Minesh Packer, Roger J. Tarbell, Nancy Fitz, Charles Vezina, Gilbert Hilden, Joanne Pollack, Ian F. TI Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BRAIN-TUMORS; CHEMOTHERAPY; RADIATION; CHILDHOOD; TRIAL; SENSITIVITY; CISPLATIN AB Purpose We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB. Patients and Methods After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B). Results In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose x 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival +/- SE and progression-free survival +/- SE for M+ patients treated at the RP2D on regimen A was 82% +/- 9% and 71% +/- 11% versus 68% +/- 10% and 59% +/- 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome. Conclusion The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy. C1 [Jakacki, Regina I.; Fitz, Charles; Pollack, Ian F.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA. [Goldwein, Joel] Univ Penn, Philadelphia, PA 19104 USA. [Burger, Peter C.] Johns Hopkins Univ, Baltimore, MD USA. [Zhou, Tianni] Univ So Calif, Los Angeles, CA USA. [Holmes, Emiko J.] Childrens Oncol Grp, Arcadia, CA USA. [Kocak, Mehmet] Univ Tennessee, Hlth Sci Ctr, Knoxville, TN 37996 USA. [Kocak, Mehmet; Onar, Arzu] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Mehta, Minesh] Northwestern Univ, Chicago, IL 60611 USA. [Packer, Roger J.; Vezina, Gilbert] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Tarbell, Nancy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hilden, Joanne] Childrens Hosp Colorado, Aurora, CO USA. RP Jakacki, RI (reprint author), Childrens Hosp Pittsburgh, 4401 Penn Ave,Suite 8000 Fac Pavil, Pittsburgh, PA 15224 USA. EM regina.jakacki@chp.edu OI Kocak, Mehmet/0000-0002-3386-1734; mehta, minesh/0000-0002-4812-5713 FU Children's Oncology Group [U10 CA 98543] FX Supported by Grant No. U10 CA 98543 from the Children's Oncology Group. NR 21 TC 42 Z9 45 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP 2648 EP 2653 DI 10.1200/JCO.2011.40.2792 PG 6 WC Oncology SC Oncology GA 976CA UT WOS:000306556900017 PM 22665539 ER PT J AU Alsop, K Fereday, S Meldrum, C deFazio, A Emmanuel, C George, J Dobrovic, A Birrer, MJ Webb, PM Stewart, C Friedlander, M Fox, S Bowtell, D Mitchell, G AF Alsop, Kathryn Fereday, Sian Meldrum, Cliff deFazio, Anna Emmanuel, Catherine George, Joshy Dobrovic, Alexander Birrer, Michael J. Webb, Penelope M. Stewart, Colin Friedlander, Michael Fox, Stephen Bowtell, David Mitchell, Gillian TI BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation-Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; IMPROVED SURVIVAL; CLEAR-CELL; CARCINOMA; RESISTANCE; CARRIERS; CHEMOTHERAPY; FEATURES; TUMORS AB Purpose The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. Patients and Methods Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. Results Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin- based treatment were more likely to carry somatic BRCA1/2 mutations. Conclusion BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. C1 [Alsop, Kathryn; Fereday, Sian; Meldrum, Cliff; George, Joshy; Dobrovic, Alexander; Fox, Stephen; Bowtell, David; Mitchell, Gillian] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [deFazio, Anna; Emmanuel, Catherine] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [deFazio, Anna; Emmanuel, Catherine] Westmead Hosp, Sydney, NSW, Australia. [Alsop, Kathryn; George, Joshy; Dobrovic, Alexander; Fox, Stephen; Bowtell, David; Mitchell, Gillian] Univ Melbourne, Parkville, Vic 3052, Australia. [Webb, Penelope M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Stewart, Colin] King Edward Mem Hosp Women, Perth, WA, Australia. [Friedlander, Michael] Prince Wales Hosp, Randwick, NSW 2031, Australia. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bowtell, D (reprint author), Peter MacCallum Canc Ctr, St Andrews Pl, Melbourne, Vic 3002, Australia. EM d.bowtell@petermac.org RI friedlander, michael/G-3490-2013; deFazio, Anna/D-3939-2013; Bowtell, David/H-1007-2016; OI friedlander, michael/0000-0002-6488-0604; deFazio, Anna/0000-0003-0057-4744; Bowtell, David/0000-0001-9089-7525; Webb, Penelope/0000-0003-0733-5930; Fox, Stephen/0000-0002-7648-8896; Dobrovic, Alexander/0000-0003-3414-112X FU Ovarian Cancer Research Program of the US Department of Defense [W81XWH-08-1-0684, W81XWH-08-1-0685]; Cancer Australia/National Breast Cancer Foundation [509303, 509366, 632595]; Peter MacCallum Cancer Centre Foundation; Cancer Council Victoria; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; National Health and Medical Research Council of Australia [400281, 400413]; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Foundation of Western Australia; Cancer Council Tasmania FX Supported by Grants No. W81XWH-08-1-0684 and W81XWH-08-1-0685 of the Ovarian Cancer Research Program of the US Department of Defense, Grants No. 509303, 509366, and 632595 from Cancer Australia/National Breast Cancer Foundation, the Peter MacCallum Cancer Centre Foundation, and the Cancer Council Victoria (postgraduate scholarship to K.A.). The Australia Ovarian Cancer Study was supported by Grant No. DAMD17-01-1-0729 of the U.S. Army Medical Research and Materiel Command; Grants No. 400281 and 400413 of the National Health and Medical Research Council of Australia; Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, and Cancer Council Tasmania. NR 50 TC 246 Z9 249 U1 1 U2 26 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP 2654 EP 2663 DI 10.1200/JCO.2011.39.8545 PG 10 WC Oncology SC Oncology GA 976CA UT WOS:000306556900018 PM 22711857 ER PT J AU Vleugels, FR Girouard, SD Schmults, CD Ng, AK Russell, SE Wang, LC Buzney, EA AF Vleugels, Frank R. Girouard, Sasha D. Schmults, Chrysalyne D. Ng, Andrea K. Russell, Sara E. Wang, Linda C. Buzney, Elizabeth A. TI Metastatic Eccrine Porocarcinoma After Mohs Micrographic Surgery: A Case Report SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID THERAPEUTIC PROTOCOL; POROMA C1 [Vleugels, Frank R.] Univ Cincinnati, Sch Med, Cincinnati, OH 45221 USA. [Girouard, Sasha D.] Harvard Univ, Sch Med, Boston, MA USA. [Schmults, Chrysalyne D.; Wang, Linda C.; Buzney, Elizabeth A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Schmults, Chrysalyne D.; Ng, Andrea K.; Russell, Sara E.; Wang, Linda C.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Schmults, Chrysalyne D.; Russell, Sara E.] Faulkner Hosp, Boston, MA USA. RP Vleugels, FR (reprint author), Univ Cincinnati, Sch Med, Cincinnati, OH 45221 USA. NR 23 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2012 VL 30 IS 21 BP E188 EP E191 DI 10.1200/JCO.2011.40.6843 PG 4 WC Oncology SC Oncology GA 976CA UT WOS:000306556900003 PM 22689795 ER PT J AU Hodis, E Watson, IR Kryukov, GV Arold, ST Imielinski, M Theurillat, JP Nickerson, E Auclair, D Li, LR Place, C DiCara, D Ramos, AH Lawrence, MS Cibulskis, K Sivachenko, A Voet, D Saksena, G Stransky, N Onofrio, RC Winckler, W Ardlie, K Wagle, N Wargo, J Chong, K Morton, DL Stemke-Hale, K Chen, G Noble, M Meyerson, M Ladbury, JE Davies, MA Gershenwald, JE Wagner, SN Hoon, DSB Schadendorf, D Lander, ES Gabriel, SB Getz, G Garraway, LA Chin, L AF Hodis, Eran Watson, Ian R. Kryukov, Gregory V. Arold, Stefan T. Imielinski, Marcin Theurillat, Jean-Philippe Nickerson, Elizabeth Auclair, Daniel Li, Liren Place, Chelsea DiCara, Daniel Ramos, Alex H. Lawrence, Michael S. Cibulskis, Kristian Sivachenko, Andrey Voet, Douglas Saksena, Gordon Stransky, Nicolas Onofrio, Robert C. Winckler, Wendy Ardlie, Kristin Wagle, Nikhil Wargo, Jennifer Chong, Kelly Morton, Donald L. Stemke-Hale, Katherine Chen, Guo Noble, Michael Meyerson, Matthew Ladbury, John E. Davies, Michael A. Gershenwald, Jeffrey E. Wagner, Stephan N. Hoon, Dave S. B. Schadendorf, Dirk Lander, Eric S. Gabriel, Stacey B. Getz, Gad Garraway, Levi A. Chin, Lynda TI A Landscape of Driver Mutations in Melanoma SO CELL LA English DT Article ID B-CELL LYMPHOMA; SOMATIC MUTATIONS; HUMAN CANCER; MALIGNANT-MELANOMA; GENOMIC ANALYSES; PROTEIN COMPLEX; RAS; CARCINOMA; AURORA; DISCOVERY AB Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. C1 [Hodis, Eran; Kryukov, Gregory V.; Imielinski, Marcin; Theurillat, Jean-Philippe; Nickerson, Elizabeth; Auclair, Daniel; DiCara, Daniel; Ramos, Alex H.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey; Voet, Douglas; Saksena, Gordon; Stransky, Nicolas; Onofrio, Robert C.; Winckler, Wendy; Ardlie, Kristin; Wagle, Nikhil; Noble, Michael; Meyerson, Matthew; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Garraway, Levi A.; Chin, Lynda] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Hodis, Eran; Kryukov, Gregory V.; Ramos, Alex H.; Wagle, Nikhil; Meyerson, Matthew; Garraway, Levi A.; Chin, Lynda] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Watson, Ian R.; Li, Liren; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Arold, Stefan T.; Ladbury, John E.] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Arold, Stefan T.; Ladbury, John E.] Univ Texas MD Anderson Canc Ctr, Ctr Biomol Struct & Funct, Houston, TX 77030 USA. [Stemke-Hale, Katherine; Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Chen, Guo; Davies, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Watson, Ian R.; Li, Liren; Place, Chelsea; Meyerson, Matthew; Garraway, Levi A.; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Meyerson, Matthew; Garraway, Levi A.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Kryukov, Gregory V.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Wargo, Jennifer] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Chong, Kelly; Hoon, Dave S. B.] John Wayne Canc Inst, Dept Mol Oncol, Santa Monica, CA 90404 USA. [Morton, Donald L.] John Wayne Canc Inst, Melanoma Dept, Santa Monica, CA 90404 USA. [Wagner, Stephan N.] Med Univ Vienna, Div Immunol Allergy & Infect Dis, Dept Dermatol, A-1090 Vienna, Austria. [Wagner, Stephan N.] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria. [Schadendorf, Dirk] Univ Hosp Essen, Dept Dermatol, D-45122 Essen, Germany. [Lander, Eric S.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. RP Garraway, LA (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM levi_garraway@dfci.harvard.edu; lchin@mdanderson.org RI Meyerson, Matthew/E-7123-2012; Kryukov, Gregory/A-9592-2008; Stemke-Hale, Katherine/K-9113-2013; OI Stemke-Hale, Katherine/0000-0002-1231-4192; Arold, Stefan T/0000-0001-5278-0668; Hoon, Dave/0000-0003-1915-3683; Kryukov, Gregory/0000-0002-6131-9483; Wagner, Stephan/0000-0003-4941-7029 FU NHGRI [U54 HG003067]; Melanoma Research Alliance; University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence and Melanoma Informatics, Tissue Resource, and Pathology [P50 CA93459]; NCI [CA-16672, R33CA126674, R01 CA093947]; Canadian Institutes of Health Research; Swiss National Science Foundation [PASMP3_134379/1]; G. Harold and Leila Y. Mathers Charitable Foundation; FWF-Austrian Science Fund [L590-B12]; NIH [DP2OD002750]; Starr Cancer Consortium; TCGA GDAC [U24 CA143845]; Milestein Innovation Award in Melanoma Research; Novartis FX We thank L. Ambrogio and E. Bevilacuqa for management of sequencing data production. We thank A. McKenna, L. Zou, S.L. Carter, P. Stojanov, P. Lin, L. Lichtenstein, and the rest of the Broad Cancer Genome Analysis group. We thank C.Z. Zhang and C. Johannessen for helpful discussion, as well as the members of the Garraway and Chin labs. This work was supported by the NHGRI Large Scale Sequencing Program; grant U54 HG003067 to the Broad Institute (PI, E.S.L.); the Melanoma Research Alliance; The University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence and Melanoma Informatics, Tissue Resource, and Pathology (core grant P50 CA93459) (PI, J.E.G., M.A.D.); and the NCI Support Grant (CA-16672). I.R.W. is a recipient of the Canadian Institutes of Health Research Fellowship. J.-P.T. is supported by the Swiss National Science Foundation (PASMP3_134379/1). J.E.L. is supported by The G. Harold and Leila Y. Mathers Charitable Foundation. S.N.W. was supported by the FWF-Austrian Science Fund (L590-B12). L.A.G. is supported by the NIH New Innovator Award (DP2OD002750), NCI (R33CA126674), the Melanoma Research Alliance, and the Starr Cancer Consortium. L.C. is supported by NCI RO1 (R01 CA093947), TCGA GDAC (U24 CA143845), and the Melanoma Research Alliance. L.C. is a recipient of the Milestein Innovation Award in Melanoma Research and is a CPRIT Scholar. N.W. is a consultant and shareholder in Foundation Medicine. L.A.G. is an equity holder and consultant in Foundation Medicine, a consultant to Novartis and Millennium/Takeda, and a recipient of a grant from Novartis. NR 53 TC 748 Z9 760 U1 14 U2 117 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 20 PY 2012 VL 150 IS 2 BP 251 EP 263 DI 10.1016/j.cell.2012.06.024 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 976PB UT WOS:000306595700006 PM 22817889 ER PT J AU Li, JX McQuade, T Siemer, AB Napetschnig, J Moriwaki, K Hsiao, YS Damko, E Moquin, D Walz, T McDermott, A Chan, FKM Wu, H AF Li, Jixi McQuade, Thomas Siemer, Ansgar B. Napetschnig, Johanna Moriwaki, Kenta Hsiao, Yu-Shan Damko, Ermelinda Moquin, David Walz, Thomas McDermott, Ann Chan, Francis Ka-Ming Wu, Hao TI The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis SO CELL LA English DT Article ID RECEPTOR-INTERACTING PROTEIN; NF-KAPPA-B; HOMOTYPIC INTERACTION MOTIF; INNATE IMMUNE-RESPONSE; SOLID-STATE NMR; CELL-DEATH; TNF-ALPHA; RIP3; APOPTOSIS; DOMAIN AB RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of beta-amyloids, as shown by Thioflavin T (ThT) and Congo red (CR) binding, circular dichroism, infrared spectroscopy, X-ray diffraction, and solid-state NMR. Structured amyloid cores are mapped in RIP1 and RIP3 that are flanked by regions of mobility. The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure, whereas necrosis is partially inhibited by ThT, CR, and another amyloid dye, HBX. Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. The current study provides insight into the structural changes that occur when RIP kinases are triggered to execute different signaling outcomes and expands the realm of amyloids to complex formation and signaling. C1 [Li, Jixi; Napetschnig, Johanna; Damko, Ermelinda; Wu, Hao] Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. [McQuade, Thomas; Moriwaki, Kenta; Moquin, David; Chan, Francis Ka-Ming] Univ Massachusetts, Sch Med, Program Immunol & Virol, Dept Pathol, Worcester, MA 01655 USA. [Siemer, Ansgar B.; McDermott, Ann] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Hsiao, Yu-Shan; Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Wu, H (reprint author), Childrens Hosp Boston, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. EM hao.wu@childrens.harvard.edu RI Chan, Francis/E-9647-2014; Chan, Francis K. L./F-4851-2010; OI Chan, Francis/0000-0002-4803-8353; Chan, Francis K. L./0000-0001-7388-2436; McDermott, Ann/0000-0002-9249-1649 FU NIH [T32 AI07349]; [AI083497]; [AI088502]; [AI045937] FX We thank L. Cohen-Gould for help with EM imaging at the Weill Cornell Microscopy Facility, S.M. Damo for initial work on this project, Q. Li for insect cell expression, V. Kumar for ThT measurement of endogenous complexes, and D. Porter (Novartis) for the generous gift of LBW242. This work was supported by grants to F.K.C. (AI083497 and AI088502) and H.W. (AI045937). F.K.C. is a member of the UMass DERC (DK32520). J.N. is an Irvington Institute postdoctoral fellow of the Cancer Research Institute, and D.M. is supported by NIH training grant T32 AI07349. T.W. is an investigator in the Howard Hughes Medical Institute. NR 59 TC 237 Z9 244 U1 8 U2 74 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 20 PY 2012 VL 150 IS 2 BP 339 EP 350 DI 10.1016/j.cell.2012.06.019 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 976PB UT WOS:000306595700013 PM 22817896 ER PT J AU Wu, J Bostrom, P Sparks, LM Ye, L Choi, JH Giang, AH Khandekar, M Virtanen, KA Nuutila, P Schaart, G Huang, KX Tu, H Lichtenbelt, WDV Hoeks, J Enerback, S Schrauwen, P Spiegelman, BM AF Wu, Jun Bostrom, Pontus Sparks, Lauren M. Ye, Li Choi, Jang Hyun Giang, An-Hoa Khandekar, Melin Virtanen, Kirsi A. Nuutila, Pirjo Schaart, Gert Huang, Kexin Tu, Hua Lichtenbelt, Wouter D. van Marken Hoeks, Joris Enerbaeck, Sven Schrauwen, Patrick Spiegelman, Bruce M. TI Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human SO CELL LA English DT Article ID BROWN ADIPOSE-TISSUE; WHITE FAT; TRANSCRIPTIONAL CONTROL; SKELETAL-MUSCLE; IN-VIVO; IDENTIFICATION; PROGENITORS; ACTIVATION; INDUCTION; OBESITY AB Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. C1 [Wu, Jun; Bostrom, Pontus; Ye, Li; Choi, Jang Hyun; Giang, An-Hoa; Khandekar, Melin; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Wu, Jun; Bostrom, Pontus; Ye, Li; Choi, Jang Hyun; Giang, An-Hoa; Khandekar, Melin; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA. [Sparks, Lauren M.; Lichtenbelt, Wouter D. van Marken; Hoeks, Joris; Schrauwen, Patrick] Maastricht Univ Med Ctr, NUTRIM Sch Nutr Toxicol & Metab, Dept Human Biol, NL-6229 ER Maastricht, Netherlands. [Schaart, Gert] Maastricht Univ Med Ctr, NUTRIM Sch Nutr Toxicol & Metab, Dept Human Movement Sci, NL-6229 ER Maastricht, Netherlands. [Enerbaeck, Sven] Gothenburg Univ, Inst Biomed, S-40530 Gothenburg, Sweden. [Virtanen, Kirsi A.; Nuutila, Pirjo] Univ Turku, Turku PET Ctr, FI-20521 Turku, Finland. [Huang, Kexin; Tu, Hua] Lakepharma Inc, Belmont, CA 94002 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. EM bruce_spiegelman@dfci.harvard.edu RI Choi, Jang Hyun/B-3055-2012; Nuutila, Pirjo/J-2087-2012; OI Sparks, Lauren/0000-0002-9257-5666; schrauwen, patrick/0000-0002-0973-847X FU NIH [DK31405, DK90861]; JPB Foundation; Netherlands Organization for Scientific Research; American Heart Association [09POST2010078]; American Heart Association (National Center) [12SDG8070003] FX We thank Y. Wang (Center for Cancer Computational Biology at Dana-Farber Cancer Institute) for assistance with affymetrix gene chip analysis, S. White (Beth Israel Deaconess Medical Center Histology Core) for cryosectioning, and A. Korde for technical help. We are grateful to Drs. P. Seale, R. Gupta, P. Cohen, S. Kleiner, and J. Lo for useful discussions. B.M.S. is supported by NIH grants DK31405 and DK90861 and by a grant from the JPB Foundation. P.S. is supported by a VICI research grant for innovative research from the Netherlands Organization for Scientific Research. J.W. was supported in part by a postdoctoral fellowship from the American Heart Association (Founders Affiliate, 09POST2010078) and by a Scientist Developmental Grant from the American Heart Association (National Center, 12SDG8070003). J.W. and B.M.S. conceived and designed the experiments. J.W., P.B., L.M.S., L.Y., J.H.C., A.G., M.K., G.S., and J.H. performed experiments. All authors analyzed the data. P.N., W.D.M.L., and S.E. provided reagents and samples, and J.W. and B.M.S. wrote the manuscript. B.M.S. and S.E. are shareholders and consultants to Ember Therapeutics, which has licensed the rights to irisin from the DFCI. NR 39 TC 808 Z9 852 U1 22 U2 180 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 20 PY 2012 VL 150 IS 2 BP 366 EP 376 DI 10.1016/j.cell.2012.05.016 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 976PB UT WOS:000306595700015 PM 22796012 ER PT J AU Maughan-Brown, B Venkataramani, AS AF Maughan-Brown, Brendan Venkataramani, Atheendar S. TI Learning That Circumcision Is Protective against HIV: Risk Compensation among Men and Women in Cape Town, South Africa SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PREVENTION; INFECTION; KENYA; BEHAVIOR; KISUMU; UGANDA; RAKAI AB Objectives: We examined whether knowledge of the HIV-protective benefits of male circumcision (MC) led to risk compensating behavior in a traditionally circumcising population in South Africa. We extend the current literature by examining risk compensation among women, which has hitherto been unexplored. Methods: We used data on Xhosa men and women from the 2009 Cape Area Panel Study. Respondents were asked if they had heard that MC reduces a man's risk of contracting HIV, about their perceived risk of contracting HIV, and condom use. For each gender group we assessed whether risk perception and condom use differed by knowledge of the protective benefits of MC using bivariate and then multivariate models controlling for demographic characteristics, HIV knowledge/beliefs, and previous sexual behaviors. In a further check for confounding, we used data from the 2005 wave to assess whether individuals who would eventually become informed about the protective benefits of circumcision were already different in terms of HIV risk perception and condom use. Results: 34% of men (n = 453) and 27% of women (n = 690) had heard that circumcision reduces a man's risk of HIV infection. Informed men perceived slightly higher risk of contracting HIV and were more likely to use condoms at last sex (p < 0.10). Informed women perceived lower HIV risk (p < 0.05), were less likely to use condoms both at last sex (p < 0.10) and more generally (p < 0.01), and more likely to forego condoms with partners of positive or unknown serostatus (p < 0.01). The results were robust to covariate adjustment, excluding people living with HIV, and accounting for risk perceptions and condom use in 2005. Conclusions: We find evidence consistent with risk compensation among women but not men. Further attention should be paid to the role of new information regarding MC, and drivers of HIV risk more broadly, in modulating sexual behavior among women. C1 [Maughan-Brown, Brendan] Univ Cape Town, So Africa Labour & Dev Res Unit, ZA-7925 Cape Town, South Africa. [Venkataramani, Atheendar S.] Massachusetts Gen Hosp, MGH Charlestown HealthCare Ctr, Dept Med, Charlestown, MA USA. RP Maughan-Brown, B (reprint author), Univ Cape Town, So Africa Labour & Dev Res Unit, ZA-7925 Cape Town, South Africa. EM avenkataramani@partners.org FU United States National Institute for Child Health and Human Development; Andrew W. Mellon Foundation; National Institute on Aging; Health Economics & HIV/AIDS Research Division (HEARD) at the University of KwaZulu-Natal; European Union; NRF Research Chair in Poverty and Inequality Research; University Research Committee at the University of Cape Town FX Funding for the Cape Area Panel Study was provided by the United States National Institute for Child Health and Human Development, the Andrew W. Mellon Foundation, the National Institute on Aging, the Health Economics & HIV/AIDS Research Division (HEARD) at the University of KwaZulu-Natal, and the European Union. Brendan Maughan-Brown is grateful for funding from the NRF Research Chair in Poverty and Inequality Research and the University Research Committee at the University of Cape Town for his Postdoctoral Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 9 Z9 9 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 JUL 19 PY 2012 VL 7 IS 7 AR e40753 DI 10.1371/journal.pone.0040753 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981GZ UT WOS:000306956300021 PM 22829883 ER PT J AU Chen, YB McDonough, S Hasserjian, R Chen, HD Coughlin, E Illiano, C Park, IS Jagasia, M Spitzer, TR Cutler, CS Soiffer, RJ Ritz, J AF Chen, Yi-Bin McDonough, Sean Hasserjian, Robert Chen, Heidi Coughlin, Erin Illiano, Christina Park, In Sun Jagasia, Madan Spitzer, Thomas R. Cutler, Corey S. Soiffer, Robert J. Ritz, Jerome TI Expression of CD30 in patients with acute graft-versus-host disease SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; T-CELLS; MARROW-TRANSPLANTATION; REFRACTORY ACUTE; THERAPY; SUBSET; DEFINES AB Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8(+) T cells with the difference especially pronounced in the central memory subset (CD8(+)CD45RO(+)CD62L(+)): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4(+) T cells, and regulatory (CD4+CD127(low)CD25(+)) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30(+) infiltrating lymphocytes present. These results suggest that CD30 expression on CD8(+) T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD. (Blood. 2012;120(3):691-696) C1 [Chen, Yi-Bin; Coughlin, Erin; Illiano, Christina; Spitzer, Thomas R.] Massachusetts Gen Hosp, Dept Hematol Oncol, Bone Marrow Transplantat Unit, Boston, MA 02114 USA. [McDonough, Sean; Park, In Sun; Cutler, Corey S.; Soiffer, Robert J.; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Hasserjian, Robert] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chen, Heidi] Vanderbilt Univ, Dept Biostat, Nashville, TN USA. [Jagasia, Madan] Vanderbilt Univ, Dept Med, Div Hematol Oncol, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Dept Hematol Oncol, Bone Marrow Transplant Unit, Cox 106,55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org OI Ritz, Jerome/0000-0001-5526-4669 FU Seattle Genetics; Rogers Family Foundation; Ted and Eileen Pasquarello Research Fund; [PO1 CA142106] FX This work was supported in part by Seattle Genetics, the Rogers Family Foundation, the Ted and Eileen Pasquarello Research Fund, and PO1 CA142106. NR 20 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 19 PY 2012 VL 120 IS 3 BP 691 EP 696 DI 10.1182/blood-2012-03-415422 PG 6 WC Hematology SC Hematology GA 987TH UT WOS:000307440100027 PM 22661699 ER PT J AU Dutta, P Courties, G Wei, Y Leuschner, F Gorbatov, R Robbins, CS Iwamoto, Y Thompson, B Carlson, AL Heidt, T Majmudar, MD Lasitschka, F Etzrodt, M Waterman, P Waring, MT Chicoine, AT van der Laan, AM Niessen, HWM Piek, JJ Rubin, BB Butany, J Stone, JR Katus, HA Murphy, SA Morrow, DA Sabatine, MS Vinegoni, C Moskowitz, MA Pittet, MJ Libby, P Lin, CP Swirski, FK Weissleder, R Nahrendorf, M AF Dutta, Partha Courties, Gabriel Wei, Ying Leuschner, Florian Gorbatov, Rostic Robbins, Clinton S. Iwamoto, Yoshiko Thompson, Brian Carlson, Alicia L. Heidt, Timo Majmudar, Maulik D. Lasitschka, Felix Etzrodt, Martin Waterman, Peter Waring, Michael T. Chicoine, Adam T. van der Laan, Anja M. Niessen, Hans W. M. Piek, Jan J. Rubin, Barry B. Butany, Jagdish Stone, James R. Katus, Hugo A. Murphy, Sabina A. Morrow, David A. Sabatine, Marc S. Vinegoni, Claudio Moskowitz, Michael A. Pittet, Mikael J. Libby, Peter Lin, Charles P. Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias TI Myocardial infarction accelerates atherosclerosis SO NATURE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ACUTE CORONARY SYNDROMES; MONOCYTE SUBSETS; PROGENITOR CELLS; ARTERY-DISEASE; BONE-MARROW; INFLAMMATION; PLAQUES; NICHE; IDENTIFICATION AB During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe(-/-) mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression. C1 [Dutta, Partha; Courties, Gabriel; Leuschner, Florian; Gorbatov, Rostic; Robbins, Clinton S.; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Majmudar, Maulik D.; Etzrodt, Martin; Waterman, Peter; Stone, James R.; Vinegoni, Claudio; Pittet, Mikael J.; Lin, Charles P.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Dutta, Partha; Courties, Gabriel; Leuschner, Florian; Gorbatov, Rostic; Robbins, Clinton S.; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; Majmudar, Maulik D.; Etzrodt, Martin; Waterman, Peter; Stone, James R.; Vinegoni, Claudio; Pittet, Mikael J.; Lin, Charles P.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wei, Ying; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Stroke & Neurovasc Regulat Lab, Charlestown, MA 02129 USA. [Wei, Ying; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Stroke & Neurovasc Regulat Lab, Charlestown, MA 02129 USA. [Leuschner, Florian; Katus, Hugo A.] Med Univ Hosp Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany. [Majmudar, Maulik D.; Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Lasitschka, Felix] Univ Heidelberg Hosp, Inst Pathol, D-69120 Heidelberg, Germany. [Waring, Michael T.; Chicoine, Adam T.] MIT & Harvard Massachusetts Gen Hosp, Ragon Inst MGH, Charlestown, MA 02129 USA. [Waring, Michael T.; Chicoine, Adam T.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [van der Laan, Anja M.; Piek, Jan J.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Niessen, Hans W. M.] Vrije Univ Amsterdam Med Ctr, ICaR VU, Dept Pathol & Cardiac Surg, NL-1081 HV Amsterdam, Netherlands. [Rubin, Barry B.] Univ Toronto, Toronto Gen Hosp, Peter Munk Cardiac Ctr, Div Vasc Surg, Toronto, ON M5G 2C4, Canada. [Butany, Jagdish] Univ Toronto, Peter Munk Cardiac Ctr, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Murphy, Sabina A.; Morrow, David A.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, TIMI Study Grp, Boston, MA 02145 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; mnahrendorf@mgh.harvard.edu RI Wei, Yen/H-5329-2012; Etzrodt, Martin/P-3325-2015; Katus, Hugo/P-1712-2016 OI Etzrodt, Martin/0000-0003-1928-3904; FU National Institute of Health [R01-HL096576, R01-HL095629, R01-EB006432, T32-CA79443, P50-CA086355]; Deutsche Forschungsgemeinschaft [SFB 938/Z2] FX We thank the CSB Mouse Imaging Program (J. Truelove, D. Jeon, J. Donahoe, B. Marinelli) and K. Naxerova for helpful discussions. This work was funded by grants from the National Institute of Health R01-HL096576, R01-HL095629 (M.N.); R01-EB006432, T32-CA79443, P50-CA086355 (R.W.). F.L. was funded in part by Deutsche Forschungsgemeinschaft SFB 938/Z2. Fig. 5e was produced using Servier Medical Art (http://www.servier.com). NR 36 TC 285 Z9 294 U1 6 U2 74 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 JUL 19 PY 2012 VL 487 IS 7407 BP 325 EP 329 DI 10.1038/nature11260 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JB UT WOS:000306506500034 PM 22763456 ER PT J AU Muzny, DM Bainbridge, MN Chang, K Dinh, HH Drummond, JA Fowler, G Kovar, CL Lewis, LR Morgan, MB Newsham, IF Reid, JG Santibanez, J Shinbrot, E Trevino, LR Wu, YQ Wang, M Gunaratne, P Donehower, LA Creighton, CJ Wheeler, DA Gibbs, RA Lawrence, MS Voet, D Jing, R Cibulskis, K Sivachenko, A Stojanov, P McKenna, A Lander, ES Gabriel, S Getz, G Ding, L Fulton, RS Koboldt, DC Wylie, T Walker, J Dooling, DJ Fulton, L Delehaunty, KD Fronick, CC Demeter, R Mardis, ER Wilson, RK Chu, A Chun, HJE Mungall, AJ Pleasance, E Robertson, AG Stoll, D Balasundaram, M Birol, I Butterfield, YSN Chuah, E Coope, RJN Dhalla, N Guin, R Hirst, C Hirst, M Holt, RA Lee, D Li, HI Mayo, M Moore, RA Schein, JE Slobodan, JR Tam, A Thiessen, N Varhol, R Zeng, T Zhao, Y Jones, SJM Marra, MA Bass, AJ Ramos, AH Saksena, G Cherniack, AD Schumacher, SE Tabak, B Carter, SL Pho, NH Nguyen, H Onofrio, RC Crenshaw, A Ardlie, K Beroukhim, R Winckler, W Getz, G Meyerson, M Protopopov, A Zhang, J Hadjipanayis, A Lee, E Xi, R Yang, L Ren, X Zhang, H Sathiamoorthy, N Shukla, S Chen, PC Haseley, P Xiao, Y Lee, S Seidman, J Chin, L Park, PJ Kucherlapati, R Auman, JT Hoadley, KA Du, Y Wilkerson, MD Shi, Y Liquori, C Meng, S Li, L Turman, YJ Topal, MD Tan, D Waring, S Buda, E Walsh, J Jones, CD Mieczkowski, PA Singh, D Wu, J Gulabani, A Dolina, P Bodenheimer, T Hoyle, AP Simons, JV Soloway, M Mose, LE Jefferys, SR Balu, S O'Connor, BD Prins, JF Chiang, DY Hayes, DN Perou, CM Hinoue, T Weisenberger, DJ Maglinte, DT Pan, F Berman, BP Van den Berg, DJ Shen, H Jr, TT Baylin, SB Laird, PW Getz, G Noble, M Voet, D Saksena, G Gehlenborg, N DiCara, D Zhang, J Zhang, H Wu, CJ Liu, SY Shukla, S Lawrence, MS Zhou, L Sivachenko, A Lin, P Stojanov, P Jing, R Park, RW Nazaire, MD Robinson, J Thorvaldsdottir, H Mesirov, J Park, PJ Chin, L Thorsson, V Reynolds, SM Bernard, B Kreisberg, R Lin, J Iype, L Bressler, R Erkkila, T Gundapuneni, M Liu, Y Norberg, A Robinson, T Da Yang Zhang, W Shmulevich, I De Ronde, JJ Schultz, N Cerami, E Ciriello, G Goldberg, AP Gross, B Jacobsen, A Gao, J Kaczkowski, B Sinha, R Aksoy, BA Antipin, Y Reva, B Shen, R Taylor, BS Chan, TA Ladanyi, M Sander, C Akbani, R Zhang, N Broom, BM Casasent, T Unruh, A Wakefield, C Hamilton, SR Cason, RC Baggerly, KA Weinstein, JN Haussler, D Benz, CC Stuart, JM Benz, SC Sanborn, JZ Vaske, CJ Zhu, J Szeto, C Scott, GK Yau, C Ng, S Goldstein, T Ellrott, K Collisson, E Cozen, AE Zerbino, D Wilks, C Craft, B Spellman, P Penny, R Shelton, T Hatfield, M Morris, S Yena, P Shelton, C Sherman, M Paulauskis, J Gastier-Foster, JM Bowen, J Ramirez, NC Black, A Pyatt, R Wise, L White, P Bertagnolli, M Brown, J Chan, TA Chu, GC Czerwinski, C Denstman, F Dhir, R Doerner, A Fuchs, CS Guillem, JG Iacocca, M Juhl, H Kaufman, A Kohl, B Van Le, X Mariano, MC Medina, EN Meyers, M Nash, GM Paty, PB Petrelli, N Rabeno, B Richards, WG Solit, D Swanson, P Temple, L Tepper, JE Thorp, R Vakiani, E Weiser, MR Willis, JE Witkin, G Zeng, Z Zinner, MJ Zornig, C Jensen, MA Sfeir, R Kahn, AB Chu, AL Kothiyal, P Wang, Z Snyder, EE Pontius, J Pihl, TD Ayala, B Backus, M Walton, J Whitmore, J Baboud, J Berton, DL Nicholls, MC Srinivasan, D Raman, R Girshik, S Kigonya, PA Alonso, S Sanbhadti, RN Barletta, SP Greene, JM Pot, DA Shaw, KRM Dillon, LAL Buetow, K Davidsen, T Demchok, JA Eley, G Ferguson, M Fielding, P Schaefer, C Sheth, M Yang, L Guyer, MS Ozenberger, BA Palchik, JD Peterson, J Sofia, HJ Thomson, E AF Muzny, Donna M. Bainbridge, Matthew N. Chang, Kyle Dinh, Huyen H. Drummond, Jennifer A. Fowler, Gerald Kovar, Christie L. Lewis, Lora R. Morgan, Margaret B. Newsham, Irene F. Reid, Jeffrey G. Santibanez, Jireh Shinbrot, Eve Trevino, Lisa R. Wu, Yuan-Qing Wang, Min Gunaratne, Preethi Donehower, Lawrence A. Creighton, Chad J. Wheeler, David A. Gibbs, Richard A. Lawrence, Michael S. Voet, Douglas Jing, Rui Cibulskis, Kristian Sivachenko, Andrey Stojanov, Petar McKenna, Aaron Lander, Eric S. Gabriel, Stacey Getz, Gad Ding, Li Fulton, Robert S. Koboldt, Daniel C. Wylie, Todd Walker, Jason Dooling, David J. Fulton, Lucinda Delehaunty, Kim D. Fronick, Catrina C. Demeter, Ryan Mardis, Elaine R. Wilson, Richard K. Chu, Andy Chun, Hye-Jung E. Mungall, Andrew J. Pleasance, Erin Robertson, A. Gordon Stoll, Dominik Balasundaram, Miruna Birol, Inanc Butterfield, Yaron S. N. Chuah, Eric Coope, Robin J. N. Dhalla, Noreen Guin, Ranabir Hirst, Carrie Hirst, Martin Holt, Robert A. Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Schein, Jacqueline E. Slobodan, Jared R. Tam, Angela Thiessen, Nina Varhol, Richard Zeng, Thomas Zhao, Yongjun Jones, Steven J. M. Marra, Marco A. Bass, Adam J. Ramos, Alex H. Saksena, Gordon Cherniack, Andrew D. Schumacher, Stephen E. Tabak, Barbara Carter, Scott L. Pho, Nam H. Nguyen, Huy Onofrio, Robert C. Crenshaw, Andrew Ardlie, Kristin Beroukhim, Rameen Winckler, Wendy Getz, Gad Meyerson, Matthew Protopopov, Alexei Zhang, Juinhua Hadjipanayis, Angela Lee, Eunjung Xi, Ruibin Yang, Lixing Ren, Xiaojia Zhang, Hailei Sathiamoorthy, Narayanan Shukla, Sachet Chen, Peng-Chieh Haseley, Psalm Xiao, Yonghong Lee, Semin Seidman, Jonathan Chin, Lynda Park, Peter J. Kucherlapati, Raju Auman, J. Todd Hoadley, Katherine A. Du, Ying Wilkerson, Matthew D. Shi, Yan Liquori, Christina Meng, Shaowu Li, Ling Turman, Yidi J. Topal, Michael D. Tan, Donghui Waring, Scot Buda, Elizabeth Walsh, Jesse Jones, Corbin D. Mieczkowski, Piotr A. Singh, Darshan Wu, Junyuan Gulabani, Anisha Dolina, Peter Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Matthew Mose, Lisle E. Jefferys, Stuart R. Balu, Saianand O'Connor, Brian D. Prins, Jan F. Chiang, Derek Y. Hayes, D. Neil Perou, Charles M. Hinoue, Toshinori Weisenberger, Daniel J. Maglinte, Dennis T. Pan, Fei Berman, Benjamin P. Van den Berg, David J. Shen, Hui Jr, Timothy Triche Baylin, Stephen B. Laird, Peter W. Getz, Gad Noble, Michael Voet, Doug Saksena, Gordon Gehlenborg, Nils DiCara, Daniel Zhang, Juinhua Zhang, Hailei Wu, Chang-Jiun Liu, Spring Yingchun Shukla, Sachet Lawrence, Michael S. Zhou, Lihua Sivachenko, Andrey Lin, Pei Stojanov, Petar Jing, Rui Park, Richard W. Nazaire, Marc-Danie Robinson, Jim Thorvaldsdottir, Helga Mesirov, Jill Park, Peter J. Chin, Lynda Thorsson, Vesteinn Reynolds, Sheila M. Bernard, Brady Kreisberg, Richard Lin, Jake Iype, Lisa Bressler, Ryan Erkkilae, Timo Gundapuneni, Madhumati Liu, Yuexin Norberg, Adam Robinson, Tom Da Yang Zhang, Wei Shmulevich, Ilya De Ronde, Jorma J. Schultz, Nikolaus Cerami, Ethan Ciriello, Giovanni Goldberg, Arthur P. Gross, Benjamin Jacobsen, Anders Gao, Jianjiong Kaczkowski, Bogumil Sinha, Rileen Aksoy, B. Arman Antipin, Yevgeniy Reva, Boris Shen, Ronglai Taylor, Barry S. Chan, Timothy A. Ladanyi, Marc Sander, Chris Akbani, Rehan Zhang, Nianxiang Broom, Bradley M. Casasent, Tod Unruh, Anna Wakefield, Chris Hamilton, Stanley R. Cason, R. Craig Baggerly, Keith A. Weinstein, John N. Haussler, David Benz, Christopher C. Stuart, Joshua M. Benz, Stephen C. Sanborn, J. Zachary Vaske, Charles J. Zhu, Jingchun Szeto, Christopher Scott, Gary K. Yau, Christina Ng, Sam Goldstein, Ted Ellrott, Kyle Collisson, Eric Cozen, Aaron E. Zerbino, Daniel Wilks, Christopher Craft, Brian Spellman, Paul Penny, Robert Shelton, Troy Hatfield, Martha Morris, Scott Yena, Peggy Shelton, Candace Sherman, Mark Paulauskis, Joseph Gastier-Foster, Julie M. Bowen, Jay Ramirez, Nilsa C. Black, Aaron Pyatt, Robert Wise, Lisa White, Peter Bertagnolli, Monica Brown, Jen Chan, Timothy A. Chu, Gerald C. Czerwinski, Christine Denstman, Fred Dhir, Rajiv Doerner, Arnulf Fuchs, Charles S. Guillem, Jose G. Iacocca, Mary Juhl, Hartmut Kaufman, Andrew Kohl, Bernard, III Van Le, Xuan Mariano, Maria C. Medina, Elizabeth N. Meyers, Michael Nash, Garrett M. Paty, Phillip B. Petrelli, Nicholas Rabeno, Brenda Richards, William G. Solit, David Swanson, Pat Temple, Larissa Tepper, Joel E. Thorp, Richard Vakiani, Efsevia Weiser, Martin R. Willis, Joseph E. Witkin, Gary Zeng, Zhaoshi Zinner, Michael J. Zornig, Carsten Jensen, Mark A. Sfeir, Robert Kahn, Ari B. Chu, Anna L. Kothiyal, Prachi Wang, Zhining Snyder, Eric E. Pontius, Joan Pihl, Todd D. Ayala, Brenda Backus, Mark Walton, Jessica Whitmore, Jon Baboud, Julien Berton, Dominique L. Nicholls, Matthew C. Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter A. Alonso, Shelley Sanbhadti, Rashmi N. Barletta, Sean P. Greene, John M. Pot, David A. Shaw, Kenna R. Mills Dillon, Laura A. L. Buetow, Ken Davidsen, Tanja Demchok, John A. Eley, Greg Ferguson, Martin Fielding, Peter Schaefer, Carl Sheth, Margi Yang, Liming Guyer, Mark S. Ozenberger, Bradley A. Palchik, Jacqueline D. Peterson, Jane Sofia, Heidi J. Thomson, Elizabeth TI Comprehensive molecular characterization of human colon and rectal cancer SO NATURE LA English DT Article ID COLORECTAL-CANCER; INTESTINAL EPITHELIUM; SOMATIC MUTATIONS; HUMAN BREAST; WILMS-TUMOR; GENE; DIFFERENTIATION; ONCOGENE; CELLS; WTX AB To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. C1 [Hadjipanayis, Angela; Chen, Peng-Chieh; Seidman, Jonathan; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Donehower, Lawrence A.; Creighton, Chad J.; Sivachenko, Andrey] Baylor Coll Med, Human Genome Sequencing Ctr, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Gunaratne, Preethi] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Lawrence, Michael S.; Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Bass, Adam J.; Ramos, Alex H.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Meyerson, Matthew; Chin, Lynda; Noble, Michael; Voet, Doug; Gehlenborg, Nils; DiCara, Daniel; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet; Zhou, Lihua; Sivachenko, Andrey; Lin, Pei; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Bass, Adam J.; Ramos, Alex H.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Meyerson, Matthew; Chin, Lynda; Noble, Michael; Voet, Doug; Gehlenborg, Nils; DiCara, Daniel; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet; Zhou, Lihua; Sivachenko, Andrey; Lin, Pei; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill] Harvard Univ, Cambridge, MA 02142 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lander, Eric S.] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA. [Ding, Li; Fulton, Robert S.; Koboldt, Daniel C.; Wylie, Todd; Walker, Jason; Dooling, David J.; Fulton, Lucinda; Delehaunty, Kim D.; Fronick, Catrina C.; Demeter, Ryan; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Ding, Li; Dooling, David J.; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63108 USA. [Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO 63108 USA. [Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Stoll, Dominik; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron S. N.; Chuah, Eric; Coope, Robin J. N.; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Schein, Jacqueline E.; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard; Zeng, Thomas; Zhao, Yongjun; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Protopopov, Alexei; Zhang, Juinhua; Ren, Xiaojia; Zhang, Hailei; Shukla, Sachet; Xiao, Yonghong; Chin, Lynda; Zhang, Juinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Shukla, Sachet] Dana Farber Canc Inst, Dept Med Oncol, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Hadjipanayis, Angela; Lee, Eunjung; Chen, Peng-Chieh; Haseley, Psalm; Park, Peter J.; Kucherlapati, Raju] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Lee, Eunjung; Xi, Ruibin; Yang, Lixing; Haseley, Psalm; Lee, Semin; Park, Peter J.; Gehlenborg, Nils; Park, Richard W.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Sathiamoorthy, Narayanan; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Inst Pharmacogenet & Individualized Therapy, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mieczkowski, Piotr A.; Chiang, Derek Y.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Topal, Michael D.; Mose, Lisle E.; Jefferys, Stuart R.; Perou, Charles M.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Du, Ying; Wilkerson, Matthew D.; Shi, Yan; Liquori, Christina; Meng, Shaowu; Li, Ling; Turman, Yidi J.; Topal, Michael D.; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Wu, Junyuan; Gulabani, Anisha; Dolina, Peter; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew; Balu, Saianand; O'Connor, Brian D.; Chiang, Derek Y.; Hayes, D. Neil; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Tan, Donghui] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Jones, Corbin D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Singh, Darshan; Prins, Jan F.] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Hayes, D. Neil] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC USA. [Hinoue, Toshinori; Weisenberger, Daniel J.; Maglinte, Dennis T.; Pan, Fei; Berman, Benjamin P.; Van den Berg, David J.; Shen, Hui; Jr, Timothy Triche; Laird, Peter W.] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90089 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Canc Biol, Baltimore, MD 21231 USA. [Thorsson, Vesteinn; Reynolds, Sheila M.; Bernard, Brady; Kreisberg, Richard; Lin, Jake; Iype, Lisa; Bressler, Ryan; Erkkilae, Timo; Gundapuneni, Madhumati; Norberg, Adam; Robinson, Tom; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Liu, Yuexin; Da Yang; Zhang, Wei; Hamilton, Stanley R.; Cason, R. Craig] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX 77030 USA. [De Ronde, Jorma J.; Schultz, Nikolaus; Cerami, Ethan; Ciriello, Giovanni; Goldberg, Arthur P.; Gross, Benjamin; Jacobsen, Anders; Gao, Jianjiong; Kaczkowski, Bogumil; Sinha, Rileen; Antipin, Yevgeniy; Reva, Boris; Taylor, Barry S.; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [De Ronde, Jorma J.] Netherlands Canc Inst, Div Expt Therapy, NL-1066 CX Amsterdam, Netherlands. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Dept Pathol, New York, NY 10065 USA. [Akbani, Rehan; Zhang, Nianxiang; Broom, Bradley M.; Casasent, Tod; Unruh, Anna; Wakefield, Chris; Baggerly, Keith A.; Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Sanborn, J. Zachary; Vaske, Charles J.; Zhu, Jingchun; Szeto, Christopher; Ng, Sam; Goldstein, Ted; Ellrott, Kyle; Cozen, Aaron E.; Zerbino, Daniel; Wilks, Christopher; Craft, Brian] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Joshua M.; Benz, Stephen C.; Sanborn, J. Zachary; Vaske, Charles J.; Zhu, Jingchun; Szeto, Christopher; Ng, Sam; Goldstein, Ted; Ellrott, Kyle; Cozen, Aaron E.; Zerbino, Daniel; Wilks, Christopher; Craft, Brian] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Benz, Christopher C.; Scott, Gary K.; Yau, Christina] Buck Inst Age Res, Novato, CA 94945 USA. [Collisson, Eric] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA. [Spellman, Paul] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Penny, Robert; Shelton, Troy; Hatfield, Martha; Morris, Scott; Yena, Peggy; Shelton, Candace; Sherman, Mark; Paulauskis, Joseph] Int Genom Consortium, Phoenix, AZ 85004 USA. [Gastier-Foster, Julie M.; Bowen, Jay; Ramirez, Nilsa C.; Black, Aaron; Pyatt, Robert; Wise, Lisa; White, Peter] Nationwide Childrens Hosp, Res Inst, Nationwide Childrens Hosp Biospecimen Core Resour, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; Ramirez, Nilsa C.; Pyatt, Robert; White, Peter] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; White, Peter] Ohio State Univ, Dept Pediat, Coll Med, Columbus, OH 43205 USA. [Bertagnolli, Monica] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Brown, Jen; Czerwinski, Christine; Iacocca, Mary; Rabeno, Brenda; Swanson, Pat; Witkin, Gary] Christiana Care Hlth Syst, Dept Pathol, Newark, DE 19718 USA. [Chu, Gerald C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Brookline, MA 02115 USA. [Denstman, Fred; Petrelli, Nicholas] Helen F Graham Canc Ctr Christiana Care, Dept Surg, Newark, DC 19718 USA. [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Doerner, Arnulf] Krankenhaus Alten Eichen, Chirurg Klin, D-22527 Hamburg, Germany. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Brookline, MA 02115 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Brookline, MA 02115 USA. [Guillem, Jose G.; Nash, Garrett M.; Paty, Phillip B.; Weiser, Martin R.; Zeng, Zhaoshi] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Juhl, Hartmut] Indivumed Inc, Kensington, MD 20895 USA. [Kohl, Bernard, III; Van Le, Xuan; Thorp, Richard] ILSbio LLC, Chestertown, MD 21620 USA. [Tepper, Joel E.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Solit, David] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Willis, Joseph E.] Case Med Ctr, Dept Pathol, Cleveland, OH 44106 USA. [Zornig, Carsten] Israelit Krankenhaus, Chirurg Klin, D-22297 Hamburg, Germany. [Jensen, Mark A.; Sfeir, Robert; Kahn, Ari B.; Chu, Anna L.; Kothiyal, Prachi; Wang, Zhining; Snyder, Eric E.; Pontius, Joan; Pihl, Todd D.; Ayala, Brenda; Backus, Mark; Walton, Jessica; Whitmore, Jon; Baboud, Julien; Berton, Dominique L.; Nicholls, Matthew C.; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter A.; Alonso, Shelley; Sanbhadti, Rashmi N.; Barletta, Sean P.; Greene, John M.; Pot, David A.] SRA Int, Fairfax, VA 22033 USA. [Shaw, Kenna R. Mills; Dillon, Laura A. L.; Demchok, John A.; Fielding, Peter; Sheth, Margi; Yang, Liming] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. [Buetow, Ken; Davidsen, Tanja; Schaefer, Carl] NCI, Ctr Biomed Informat & Informat Technol CBIIT, NIH, Rockville, MD 20852 USA. [Eley, Greg] Scimentis LLC, Statham, GA 30666 USA. [Ferguson, Martin] MLF Consulting, Arlington, MA 02474 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Palchik, Jacqueline D.; Peterson, Jane; Sofia, Heidi J.; Thomson, Elizabeth] NHGRI, NIH, Bethesda, MD 20892 USA. RP Kucherlapati, R (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM rkucherlapati@partners.org RI Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Chiang, Daisy/C-9481-2011; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; Kaczkowski, Bogumil/D-5336-2017; Laird, Peter/G-8683-2012; White, Peter/E-4301-2011; Meyerson, Matthew/E-7123-2012; Yang, Lixing/A-7073-2013; Walker, Jason/A-9702-2013; Vaske, Charles/D-6018-2013; Schumacher, Steven/E-9821-2013; Reva, Boris/B-6436-2014; Tang, Macy/B-9798-2014; Berman, Benjamin/D-5942-2014; Holt, Robert/C-3303-2009; Jacobsen, Anders/K-1081-2013; Schein, Jacquie/G-3674-2015; Gao, Jianjiong/B-5673-2016; OI Chiang, Daisy/0000-0002-8205-4285; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; Kaczkowski, Bogumil/0000-0001-6554-5608; Schultz, Nikolaus/0000-0002-0131-4904; Benz, Stephen/0000-0002-4067-0602; Triche, Tim/0000-0001-5665-946X; Hayes, D. Neil/0000-0001-6203-7771; White, Peter/0000-0002-5218-5903; Walker, Jason/0000-0001-7547-5789; Vaske, Charles/0000-0001-8151-6612; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; Jacobsen, Anders/0000-0001-6847-4980; Gao, Jianjiong/0000-0002-5739-1781; Cozen, Aaron/0000-0003-2409-0023; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Zerbino, Daniel/0000-0001-5350-3056; Yang, Da/0000-0002-8336-9457; Gehlenborg, Nils/0000-0003-0327-8297 FU National Institutes of Health [U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079, U54HG003273] FX This work was supported by the following grants from the National Institutes of Health: U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079 and U54HG003273. NR 44 TC 1886 Z9 1917 U1 89 U2 503 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 JUL 19 PY 2012 VL 487 IS 7407 BP 330 EP 337 DI 10.1038/nature11252 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JB UT WOS:000306506500035 ER PT J AU Carvunis, AR Rolland, T Wapinski, I Calderwood, MA Yildirim, MA Simonis, N Charloteaux, B Hidalgo, CA Barbette, J Santhanam, B Brar, GA Weissman, JS Regev, A Thierry-Mieg, N Cusick, ME Vidal, M AF Carvunis, Anne-Ruxandra Rolland, Thomas Wapinski, Ilan Calderwood, Michael A. Yildirim, Muhammed A. Simonis, Nicolas Charloteaux, Benoit Hidalgo, Cesar A. Barbette, Justin Santhanam, Balaji Brar, Gloria A. Weissman, Jonathan S. Regev, Aviv Thierry-Mieg, Nicolas Cusick, Michael E. Vidal, Marc TI Proto-genes and de novo gene birth SO NATURE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; YEAST GENOME; EVOLUTION; ADAPTATION; SELECTION; PROTEINS; SEQUENCE; ORIGIN; DNA AB Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo(1,2). Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described(1,2). In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or 'non-genic' sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions(1,3-6). Here we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes(4) generated by widespread translational activity in non-genic sequences. Testing this model at the genome scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events seem to provide adaptive potential(7), as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify similar to 1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation. C1 [Carvunis, Anne-Ruxandra; Rolland, Thomas; Calderwood, Michael A.; Simonis, Nicolas; Charloteaux, Benoit; Barbette, Justin; Santhanam, Balaji; Cusick, Michael E.; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Rolland, Thomas; Calderwood, Michael A.; Simonis, Nicolas; Charloteaux, Benoit; Barbette, Justin; Santhanam, Balaji; Cusick, Michael E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Rolland, Thomas; Calderwood, Michael A.; Simonis, Nicolas; Charloteaux, Benoit; Barbette, Justin; Santhanam, Balaji; Cusick, Michael E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Carvunis, Anne-Ruxandra; Thierry-Mieg, Nicolas] UJF Grenoble 1, CNRS, TIMC IMAG, UMR 5525,Computat & Math Biol Grp, F-38031 Grenoble, France. [Wapinski, Ilan] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Yildirim, Muhammed A.] Harvard Univ, Cambridge, MA 02138 USA. [Yildirim, Muhammed A.] Ctr Int Dev, Cambridge, MA 02138 USA. [Charloteaux, Benoit] Univ Liege, GIGA R, Unit Anim Genom, B-4000 Liege, Wallonia Brusse, Belgium. [Hidalgo, Cesar A.] MIT, MIT Media Lab, Cambridge, MA 02142 USA. [Brar, Gloria A.; Weissman, Jonathan S.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Cell & Mol Pharmacol, San Francisco, CA 94158 USA. [Brar, Gloria A.; Weissman, Jonathan S.] Calif Inst Quantitat Biosci, San Francisco, CA 94158 USA. [Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. [Charloteaux, Benoit] Univ Liege, Fac Vet Med, B-4000 Liege, Belgium. RP Vidal, M (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. EM marc_vidal@dfci.harvard.edu RI Yildirim, Muhammed/J-3695-2014; Thierry-Mieg, Nicolas/M-6007-2014; Calderwood, Mike/B-2475-2014 OI , /0000-0002-6031-5982; Carvunis, Anne-Ruxandra/0000-0002-6474-6413; Yildirim, Muhammed/0000-0003-2826-1766; Calderwood, Mike/0000-0001-6475-1418 FU National Institute of Health; Scientific Interface from the Burroughs Wellcome Fund; Howard Hughes Medical Institute (HHMI); American Cancer Society [117945-PF-09-136-01-RMC]; National Human Genome Research Institute [R01-HG006061] FX We thank L. Duret, E. Levy, J. Vandenhaute, Q. Li, H. Yu, P. Braun, M. Dreze, C. Foo, M. Mann, N. Kulak, J. Cox, C. Maire and S. Jhavery-Schneider as well as members of the Center for Cancer Systems Biology (CCSB), in particular A. Dricot-Ziter, A. MacWilliams, F. Roth, Y. Jacob and D. Hill for discussions and proofreading. A.R. was supported by a National Institute of Health Pioneer Award, a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and the Howard Hughes Medical Institute (HHMI). I.W. is a HHMI fellow of the Damon Runyon Cancer Research Institute. G.A.B. was supported by American Cancer Society Postdoctoral fellowship 117945-PF-09-136-01-RMC. M.V. is a Chercheur Qualifie Honoraire from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). This work was supported by the grant R01-HG006061 from the National Human Genome Research Institute awarded to M.V. NR 30 TC 139 Z9 144 U1 5 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 19 PY 2012 VL 487 IS 7407 BP 370 EP 374 DI 10.1038/nature11184 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975JB UT WOS:000306506500044 PM 22722833 ER PT J AU Wilt, TJ Brawer, MK Jones, KM Barry, MJ Aronson, WJ Fox, S Gingrich, JR Wei, JT Gilhooly, P Grob, DM Nsouli, I Iyer, P Cartagena, R Snider, G Roehrborn, C Sharifi, R Blank, W Pandya, P Andriole, GL Culkin, D Wheeler, T AF Wilt, Timothy J. Brawer, Michael K. Jones, Karen M. Barry, Michael J. Aronson, William J. Fox, Steven Gingrich, Jeffrey R. Wei, John T. Gilhooly, Patricia Grob, B. Mayer Nsouli, Imad Iyer, Padmini Cartagena, Ruben Snider, Glenn Roehrborn, Claus Sharifi, Roohollah Blank, William Pandya, Parikshit Andriole, Gerald L. Culkin, Daniel Wheeler, Thomas CA Prostate Cancer Intervention Versu TI Radical Prostatectomy versus Observation for Localized Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSITIVE SURGICAL MARGINS; QUALITY-OF-LIFE; RANDOMIZED-TRIAL; PROGNOSTIC-SIGNIFICANCE; ACTIVE SURVEILLANCE; MEN; SPECIMENS; OUTCOMES; TRENDS; MANAGEMENT AB BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.) C1 [Wilt, Timothy J.] Univ Minnesota, Ctr Chron Dis Out comes Res, Minneapolis Vet Affairs VA, Hlth Care Syst, Minneapolis, MN 55455 USA. [Wilt, Timothy J.] Univ Minnesota, Sch Med, Sect Gen Med, Minneapolis, MN 55455 USA. [Brawer, Michael K.] Urol IDEA, Seattle, WA USA. [Jones, Karen M.] Coordinating Ctr, VA Cooperat Studies Program, Perry Point, MD USA. [Fox, Steven] Agcy Healthcare Res & Qual, Rockville, MD USA. [Barry, Michael J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Aronson, William J.] Greater Angeles Healthcare Syst, VA Med Ctr, Los Angeles, CA USA. [Iyer, Padmini] VA Med Ctr, Long Beach, CA USA. [Grob, B. Mayer] Richmond VA Med Ctr, Richmond, VA USA. [Gingrich, Jeffrey R.] Univ Pittsburgh, Dept Urol, Pittsburgh, PA USA. [Gingrich, Jeffrey R.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Wei, John T.] Univ Michigan, Ann Arbor, MI 48109 USA. [Gilhooly, Patricia] VA New Jer sey Hlth Care Syst, E Orange, NJ USA. [Nsouli, Imad] VA Med Ctr Syracuse, Syracuse, NY USA. [Blank, William] Brooklyn VA Med Ctr, Brooklyn, NY USA. [Cartagena, Ruben] VA Western New York Hlth Syst, Buffalo, NY USA. [Snider, Glenn] Louis Johnson VA Med Ctr, Clarksburg, WV USA. [Roehrborn, Claus] Univ Texas Dallas, SW Med Ctr, Dept Urol, Dallas, TX USA. [Pandya, Parikshit] Temple VA Med Ctr, Temple, TX USA. [Wheeler, Thomas] Baylor Coll Med, Houston, TX 77030 USA. [Sharifi, Roohollah] Jesse Brown VA Med Ctr, Chicago, IL USA. [Andriole, Gerald L.] Washington Univ, St Louis, MO USA. [Culkin, Daniel] Univ Oklahoma, Norman, OK 73019 USA. RP Wilt, TJ (reprint author), Univ Minnesota, Ctr Chron Dis Out comes Res, Minneapolis Vet Affairs VA, Hlth Care Syst, Minneapolis, MN 55455 USA. EM tim.wilt@va.gov RI Wei, John/E-8967-2012 FU Department of Veterans Affairs; National Cancer Institute; Agency for Healthcare Research and Quality; Sanofi-Aventis; Amgen; Augmenix; Bayer; Bristol-Myers Squibb; Cambridge Endo; Caris; GlaxoSmithKline; Janssen Biotech; Myriad Genetics; Steba Biotech; Ortho Clinical Diagnostics; Viking Medical; Envisioneering Medical; Johnson Johnson; Medivation; Wilex FX Supported by grants from the Department of Veterans Affairs Cooperative Studies Program, the National Cancer Institute, and the Agency for Healthcare Research and Quality.; Dr. Barry reports being employed by and serving as a board member of the Foundation for Informed Medical Decision Making, which receives royalties from Health Dialog. Dr. Wei reports serving on the board for Envisioneering, receiving consulting fees and grant support from Sanofi-Aventis, providing expert testimony for Genprobe concerning prostate-cancer detection, and serving as proctor for benign prostatic hyperplasia laser surgery for American Medical Systems. Dr. Andriole reports receiving consulting fees, payment for the development of presentations, and payment for travel, accommodation, and meeting expenses from Amgen; consulting fees, stock options, and payment for travel, accommodation, and meeting expenses from Augmenix; consulting fees and payment for travel, accommodation, and meeting expenses from Bayer; consulting fees and payment for travel, accommodation, and meeting expenses from Bristol-Myers Squibb; consulting fees, stock options, and payment for travel, accommodation, and meeting expenses from Cambridge Endo; consulting fees and payment for travel, accommodation, and meeting expenses from Caris; consulting fees and payment for travel, accommodation, and meeting expenses from GlaxoSmithKline; consulting fees and payment for travel, accommodation, and meeting expenses from Janssen Biotech; consulting fees and payment for travel, accommodation, and meeting expenses from Myriad Genetics; consulting fees and payment for travel, accommodation, and meeting expenses from Steba Biotech; consulting fees and payment for travel, accommodation, and meeting expenses from Ortho Clinical Diagnostics; consulting fees and stock options from Viking Medical; stock options from Envisioneering Medical; and grant support to his institution from Johnson & Johnson, Medivation, and Wilex; and being a member of an independent data monitoring committee for Amarex. Dr. Wheeler reports serving as a board member of Medscape; receiving consulting fees from GlaxoSmithKline; providing expert testimony for various law firms regarding medical malpractice, product liability, and toxic tort; receiving royalties from Metabolon; and receiving stock options from Digipath. No other potential conflict of interest relevant to this article was reported. NR 43 TC 788 Z9 801 U1 0 U2 59 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 JUL 19 PY 2012 VL 367 IS 3 BP 203 EP 213 DI 10.1056/NEJMoa1113162 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900004 PM 22808955 ER PT J AU Burks, AW Jones, SM Wood, RA Fleischer, DM Sicherer, SH Lindblad, RW Stablein, D Henning, AK Vickery, BP Liu, AH Scurlock, AM Shreffler, WG Plaut, M Sampson, HA AF Burks, A. Wesley Jones, Stacie M. Wood, Robert A. Fleischer, David M. Sicherer, Scott H. Lindblad, Robert W. Stablein, Donald Henning, Alice K. Vickery, Brian P. Liu, Andrew H. Scurlock, Amy M. Shreffler, Wayne G. Plaut, Marshall Sampson, Hugh A. CA Consortium Food Allergy Res CoFAR TI Oral Immunotherapy for Treatment of Egg Allergy in Children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COWS MILK ALLERGY; FOOD ALLERGY; NONANAPHYLACTIC CHILDREN; TOLERANCE INDUCTION; PEANUT ALLERGY; DOUBLE-BLIND; DESENSITIZATION; MECHANISMS; EFFICACY; EXTRACT AB BACKGROUND For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.) C1 [Burks, A. Wesley; Vickery, Brian P.] Univ N Carolina, Dept Pediat, Med Ctr, Chapel Hill, NC 27599 USA. [Jones, Stacie M.; Scurlock, Amy M.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Jones, Stacie M.; Scurlock, Amy M.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Wood, Robert A.] Johns Hopkins Univ, Med Ctr, Dept Pediat, Baltimore, MD 21218 USA. [Fleischer, David M.; Liu, Andrew H.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Sicherer, Scott H.; Henning, Alice K.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. [Lindblad, Robert W.; Stablein, Donald; Henning, Alice K.] EMMES, Rockville, MD USA. [Plaut, Marshall] NIH, Bethesda, MD 20892 USA. [Shreffler, Wayne G.] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Burks, AW (reprint author), Univ N Carolina, Dept Pediat, Med Ctr, 260 MacNider Bldg,Campus Box 7220, Chapel Hill, NC 27599 USA. EM wburks@email.unc.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [U19AI066738, U01AI066560]; National Institutes of Health-National Center for Research Resources and Clinical Research Centers [RR-024128, RR-025005, RR-025780, RR-029887, RR-029884] FX Supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (U19AI066738 and U01AI066560) and the National Institutes of Health-National Center for Research Resources Clinical Translational Science Awards and Clinical Research Centers (RR-024128, to Duke University Medical Center; RR-025005, to Johns Hopkins School of Medicine; RR-025780, to National Jewish Health; RR-029887, to Mount Sinai School of Medicine; and RR-029884, to the University of Arkansas for Medical Sciences). NR 38 TC 222 Z9 222 U1 5 U2 29 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 JUL 19 PY 2012 VL 367 IS 3 BP 233 EP 243 DI 10.1056/NEJMoa1200435 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900007 PM 22808958 ER PT J AU Konstantopoulos, WM Ewald, MB Pratt, DS AF Konstantopoulos, Wendy Macias Ewald, Michele Burns Pratt, Daniel S. TI Case 22-2012: A 34-Year-Old Man with Intractable Vomiting after Ingestion of an Unknown Substance Antimony poisoning due to ingestion of tartar emetic (antimony potassium tartrate) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE LIVER-FAILURE; HEPATIC-ENCEPHALOPATHY; MANAGEMENT; METABOLISM; RIFAXIMIN; HISTORY C1 [Konstantopoulos, Wendy Macias] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Pratt, Daniel S.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ewald, Michele Burns] Childrens Hosp, Div Emergency Med Toxicol, Boston, MA 02115 USA. [Konstantopoulos, Wendy Macias] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Ewald, Michele Burns] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pratt, Daniel S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Konstantopoulos, WM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. NR 35 TC 3 Z9 3 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 19 PY 2012 VL 367 IS 3 BP 259 EP 268 DI 10.1056/NEJMcpc1111580 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900012 ER PT J AU Gonzalez, RG AF Gonzalez, R. Gilberto TI Tenecteplase versus Alteplase for Acute Ischemic Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rggonzalez@partners.org NR 1 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 19 PY 2012 VL 367 IS 3 BP 275 EP 276 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 975PI UT WOS:000306522900018 PM 22808969 ER PT J AU Chong, NW Koekemoer, AL Ounzain, S Samani, NJ Shin, JT Shaw, SY AF Chong, Nelson W. Koekemoer, Andrea L. Ounzain, Samir Samani, Nilesh J. Shin, Jordan T. Shaw, Stanley Y. TI STARS Is Essential to Maintain Cardiac Development and Function In Vivo via a SRF Pathway SO PLOS ONE LA English DT Article ID SERUM RESPONSE FACTOR; STRIATED-MUSCLE ACTIVATOR; HUMAN SKELETAL-MUSCLE; GENE; EXPRESSION; ZEBRAFISH; TRANSCRIPTION; HYPERTROPHY; TARGETS AB Background: STARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein expressed early in cardiac development that acts as an acute stress sensor for pathological remodeling. However the role of STARS in cardiac development and function is incompletely understood. Here, we investigated the role of STARS in heart development and function in the zebrafish model and in vitro. Methodology and Principal Findings: Expression of zebrafish STARS (zSTARS) first occurs in the somites by the 16 somite stage [17 hours post fertilization (hpf)]. zSTARS is expressed in both chambers of the heart by 48 hpf, and also in the developing brain, jaw structures and pectoral fins. Morpholino-induced knockdown of zSTARS alters atrial and ventricular dimensions and decreases ventricular fractional shortening (measured by high-speed video microscopy), with pericardial edema and decreased or absent circulation [abnormal cardiac phenotypes in 126/164 (77%) of morpholino-injected embryos vs. 0/152 (0%) of control morpholino embryos]. Co-injection of zsrf (serum response factor) mRNA rescues the cardiac phenotype of zSTARS knockdown, resulting in improved fractional shortening and ventricular end-diastolic dimensions. Ectopic over-expression of STARS in vitro activates the STARS proximal promoter, which contains a conserved SRF site. Chromatin immunoprecipitation demonstrates that SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells. Conclusions/Significance: This study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-SRF feed-forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function. C1 [Chong, Nelson W.; Koekemoer, Andrea L.; Ounzain, Samir; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Clin Sci Wing, Leicester, Leics, England. [Shin, Jordan T.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Charlestown, MA USA. [Shin, Jordan T.] Harvard Univ, Sch Med, Charlestown, MA USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Ctr, Boston, MA 02114 USA. [Shaw, Stanley Y.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Chong, NW (reprint author), Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Clin Sci Wing, Leicester, Leics, England. EM nc69@le.ac.uk FU National Institutes of Health/National Heart, Lung, and Blood Institute [K08 HL077186, HL-085280]; Heart Research UK [RG2474/04/07] FX This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute K08 HL077186 (S.Y.S.), HL-085280 (J.T.S.) and the Heart Research UK (RG2474/04/07; N.W.C.). N.J.S. holds a British Heart Foundation Chair of Cardiology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 7 Z9 9 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2012 VL 7 IS 7 AR e40966 DI 10.1371/journal.pone.0040966 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975YY UT WOS:000306548900064 PM 22815879 ER PT J AU Lau, KS Zhang, TH Kendall, KR Lauffenburger, D Gray, NS Haigis, KM AF Lau, Ken S. Zhang, Tinghu Kendall, Krystle R. Lauffenburger, Douglas Gray, Nathanael S. Haigis, Kevin M. TI BAY61-3606 Affects the Viability of Colon Cancer Cells in a Genotype-Directed Manner SO PLOS ONE LA English DT Article ID SYNTHETIC LETHAL INTERACTION; GERMINAL CENTER KINASE; COLORECTAL-CANCER; K-RAS; MEDIATES RESISTANCE; AZD6244 ARRY-142886; PATHWAY ACTIVATION; RNA INTERFERENCE; IN-VIVO; INHIBITOR AB Background: K-RAS mutation poses a particularly difficult problem for cancer therapy. Activating mutations in K-RAS are common in cancers of the lung, pancreas, and colon and are associated with poor response to therapy. As such, targeted therapies that abrogate K-RAS-induced oncogenicity would be of tremendous value. Methods: We searched for small molecule kinase inhibitors that preferentially affect the growth of colorectal cancer cells expressing mutant K-RAS. The mechanism of action of one inhibitor was explored using chemical and genetic approaches. Results: We identified BAY61-3606 as an inhibitor of proliferation in colorectal cancer cells expressing mutant forms of K-RAS, but not in isogenic cells expressing wild-type K-RAS. In addition to its anti-proliferative effects in mutant cells, BAY61-3606 exhibited a distinct biological property in wild-type cells in that it conferred sensitivity to inhibition of RAF. In this context, BAY61-3606 acted by inhibiting MAP4K2 (GCK), which normally activates NFkb signaling in wild-type cells in response to inhibition of RAF. As a result of MAP4K2 inhibition, wild-type cells became sensitive to AZ-628, a RAF inhibitor, when also treated with BAY61-3606. Conclusions: These studies indicate that BAY61-3606 exerts distinct biological activities in different genetic contexts. C1 [Lau, Ken S.; Kendall, Krystle R.; Haigis, Kevin M.] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. [Lau, Ken S.; Kendall, Krystle R.; Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA USA. [Lau, Ken S.; Lauffenburger, Douglas] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lau, Ken S.; Lauffenburger, Douglas] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Zhang, Tinghu; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Lau, KS (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. EM khaigis@partners.org OI Lau, Ken/0000-0001-8438-0319 FU National Cancer Institute [K01-CA118425, P30-CA006516]; American Cancer Society [MGO-114877]; Merlino Family Endowment Fund FX This work was supported by grants from the National Cancer Institute (K01-CA118425 and P30-CA006516) and the American Cancer Society (MGO-114877) and a donation from the Merlino Family Endowment Fund. KSL is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 7 Z9 7 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2012 VL 7 IS 7 AR e41343 DI 10.1371/journal.pone.0041343 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975YY UT WOS:000306548900111 PM 22815993 ER PT J AU Vasilyev, A Liu, Y Hellman, N Pathak, N Drummond, IA AF Vasilyev, Aleksandr Liu, Yan Hellman, Nathan Pathak, Narendra Drummond, Iain A. TI Mechanical Stretch and PI3K Signaling Link Cell Migration and Proliferation to Coordinate Epithelial Tubule Morphogenesis in the Zebrafish Pronephros SO PLOS ONE LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; FORCES; DIFFERENTIATION; ACTIVATION; GROWTH; TRPV4; FLOW AB Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function "feeds back" to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology. C1 [Vasilyev, Aleksandr] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Vasilyev, Aleksandr; Liu, Yan; Hellman, Nathan; Pathak, Narendra; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA USA. [Drummond, Iain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Vasilyev, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. EM avasilyev@partners.org; idrummon@receptor.mgh.harvard.edu FU National Institutes of Heatlh/NIDDK [K08DK082782, DK053093, DK071041, DK070263]; HSCI [DP-0074-10-01] FX National Institutes of Heatlh/NIDDK(http://www2.niddk.nih.gov/): K08DK082782, DK053093, DK071041, DK070263; HSCI(http://www.hsci.harvard.edu/): DP-0074-10-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 14 Z9 14 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2012 VL 7 IS 7 AR e39992 DI 10.1371/journal.pone.0039992 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 975YY UT WOS:000306548900014 PM 22815719 ER PT J AU Reznichenko, L Cheng, Q Nizar, K Gratiy, SL Saisan, PA Rockenstein, EM Gonzalez, T Patrick, C Spencer, B Desplats, P Dale, AM Devor, A Masliah, E AF Reznichenko, Lidia Cheng, Qun Nizar, Krystal Gratiy, Sergey L. Saisan, Payam A. Rockenstein, Edward M. Gonzalez, Tanya Patrick, Christina Spencer, Brian Desplats, Paula Dale, Anders M. Devor, Anna Masliah, Eliezer TI In Vivo Alterations in Calcium Buffering Capacity in Transgenic Mouse Model of Synucleinopathy SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; MICE; NEURONS; OXYGENATION; PROTEIN; SYSTEM; CORTEX AB Abnormal accumulation of alpha-synuclein is centrally involved in the pathogenesis of many disorders with Parkinsonism and dementia. Previous in vitro studies suggest that alpha-synuclein dysregulates intracellular calcium. However, it is unclear whether these alterations occur in vivo. For this reason, we investigated calcium dynamics in transgenic mice expressing human WT alpha-synuclein using two-photon microscopy. We imaged spontaneous and stimulus-induced neuronal activity in the barrel cortex. Transgenic mice exhibited augmented, long-lasting calcium transients characterized by considerable deviation from the exponential decay. The most evident pathology was observed in response to a repetitive stimulation in which subsequent stimuli were presented before relaxation of calcium signal to the baseline. These alterations were detected in the absence of significant increase in neuronal spiking response compared with age-matched controls, supporting the possibility that alpha-synuclein promoted alterations in calcium dynamics via interference with intracellular buffering mechanisms. The characteristic shape of calcium decay and augmented response during repetitive stimulation can serve as in vivo imaging biomarkers in this model of neurodegeneration, to monitor progression of the disease and screen candidate treatment strategies. C1 [Reznichenko, Lidia; Cheng, Qun; Nizar, Krystal; Saisan, Payam A.; Rockenstein, Edward M.; Gonzalez, Tanya; Patrick, Christina; Spencer, Brian; Desplats, Paula; Dale, Anders M.; Devor, Anna; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Gratiy, Sergey L.; Dale, Anders M.; Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Devor, Anna] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Reznichenko, L (reprint author), Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr,MTF 335, La Jolla, CA 92093 USA. EM lydia.reznichenko@gmail.com FU NIA [AG-18440, AG-02270]; NINDS [NS-051188, NS-057198, NS-0507096]; National Institute of Biomedical Imaging and Bioengineering [EB-009118, EB000790]; Don and Marilyn Short Stein Institute for Research on Aging Foundation FX We gratefully acknowledge support from NIA (AG-18440 and AG-02270 to E. M.), NINDS (NS-051188 and NS-057198 to A. D. and NS-0507096 to E. M.), National Institute of Biomedical Imaging and Bioengineering (EB-009118 to A. D. and EB000790 to A. M. D.), and a Don and Marilyn Short Stein Institute for Research on Aging Foundation fellowship to L.R. NR 29 TC 11 Z9 12 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 JUL 18 PY 2012 VL 32 IS 29 BP 9992 EP 9998 DI 10.1523/JNEUROSCI.1270-12.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 975RI UT WOS:000306528200023 PM 22815513 ER PT J AU Rao, V DeAngelis, GC Snyder, LH AF Rao, Vinod DeAngelis, Gregory C. Snyder, Lawrence H. TI Neural Correlates of Prior Expectations of Motion in the Lateral Intraparietal and Middle Temporal Areas SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERCEPTUAL DECISION-MAKING; PROBABILISTIC POPULATION CODES; PARIETAL CORTEX; VISUAL-MOTION; BAYESIAN-INFERENCE; MACAQUE MONKEY; CORTICAL AREA; NEURONS; MT; DISCRIMINATION AB Successful decision making involves combining observations of the external world with prior knowledge. Recent studies suggest that neural activity in macaque lateral intraparietal area (LIP) provides a useful window into this process. This study examines how rapidly changing prior knowledge about an upcoming sensory stimulus influences the computations that convert sensory signals into plans for action. Two monkeys performed a cued direction discrimination task, in which an arrow cue presented at the start of each trial communicated the prior probability of the direction of stimulus motion. We hypothesized that the cue would either shift the initial level of LIP activity before sensory evidence arrived, or it would scale sensory responses according to the prior probability of each stimulus, manifesting as a change in slope of LIP firing rates. Neural recordings demonstrated a clear shift in the activity level of LIP neurons following the arrow cue, which persisted into the presentation of the motion stimulus. No significant change in slope of responses was observed, suggesting that sensory gain was not strongly modulated. To confirm the latter observation, middle temporal area (MT) neurons were recorded during a version of the cued direction discrimination task, and we found no change in MT responses resulting from the presentation of the directional cue. These results suggest that information about an immediately upcoming stimulus does not scale the sensory response, but rather changes the amount of evidence that must be accumulated to reach a decision in areas that are involved in planning action. C1 [Rao, Vinod; DeAngelis, Gregory C.; Snyder, Lawrence H.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Rao, Vinod] Massachusetts Gen Hosp, Dept Phys, Boston, MA 02114 USA. [DeAngelis, Gregory C.] Univ Rochester, Dept Brain & Cognit Sci, Rochester, NY 14627 USA. RP Snyder, LH (reprint author), Campus Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. EM larry@eye-hand.wustl.edu RI Snyder, Lawrence/A-4593-2017 FU National Eye Institute [EY013644, EY012135, EY002687]; National Institute for Mental Health [MH077368-01A1] FX This work was supported by National Eye Institute Grants EY013644, EY012135 and EY002687. V. R. was supported by National Institute for Mental Health F30 Grant MH077368-01A1. Special thanks to Donna Lalor, Amy Wickholm, and Jonathon Tucker for technical assistance. We thank Dora Angelaki, Maurizio Corbetta, and David Van Essen for helpful discussions. NR 37 TC 23 Z9 23 U1 1 U2 6 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 JUL 18 PY 2012 VL 32 IS 29 BP 10063 EP 10074 DI 10.1523/JNEUROSCI.5948-11.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 975RI UT WOS:000306528200030 PM 22815520 ER PT J AU Dudek, TE No, DC Seung, E Vrbanac, VD Fadda, L Bhoumik, P Boutwell, CL Power, KA Gladden, AD Battis, L Mellors, EF Tivey, TR Gao, XJ Altfeld, M Luster, AD Tager, AM Allen, TM AF Dudek, Timothy E. No, Daniel C. Seung, Edward Vrbanac, Vladimir D. Fadda, Lena Bhoumik, Priyasma Boutwell, Christian L. Power, Karen A. Gladden, Adrianne D. Battis, Laura Mellors, Elizabeth F. Tivey, Trevor R. Gao, Xiaojiang Altfeld, Marcus Luster, Andrew D. Tager, Andrew M. Allen, Todd M. TI Rapid Evolution of HIV-1 to Functional CD8(+) T Cell Responses in Humanized BLT Mice SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIGEN-PRESENTING CELLS; HUMAN IMMUNE-SYSTEM; CLASS-I ALLELES; LYMPHOCYTE ESCAPE; TYPE-1 INFECTION; REVERSE-TRANSCRIPTASE; CYNOMOLGUS MACAQUES; VACCINE DESIGN; MOUSE MODEL AB The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens. C1 [Dudek, Timothy E.; No, Daniel C.; Fadda, Lena; Bhoumik, Priyasma; Boutwell, Christian L.; Power, Karen A.; Gladden, Adrianne D.; Battis, Laura; Mellors, Elizabeth F.; Altfeld, Marcus; Allen, Todd M.] Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Charlestown, MA 02129 USA. [Seung, Edward; Vrbanac, Vladimir D.; Tivey, Trevor R.; Luster, Andrew D.; Tager, Andrew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Charlestown, MA 02129 USA. [Gao, Xiaojiang] Natl Canc Inst Frederick, Canc & Immunol Program, Expt Immunol Lab, Sci Applicat Int Corp Frederick, Frederick, MD 20882 USA. RP Allen, TM (reprint author), Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Charlestown, MA 02129 USA. EM tallen2@partners.org RI Allen, Todd/F-5473-2011 FU NIH [R01AI090698, P01AI07889, P30AI060354, P01AI078897]; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; Harvard University Center for AIDS Research [P30AI060354]; National Cancer Institute [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by NIH grants R01AI090698, P01AI07889, P30AI060354, and P01AI078897; a Platform Award from the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; the Harvard University Center for AIDS Research grant P30AI060354; the National Cancer Institute under contract no. 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 mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 73 TC 11 Z9 11 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 18 PY 2012 VL 4 IS 143 AR 143ra98 DI 10.1126/scitranslmed.3003984 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 975SD UT WOS:000306530400003 PM 22814851 ER PT J AU Fonarow, GC Pan, WQ Saver, JL Smith, EE Reeves, MJ Broderick, JP Kleindorfer, DO Sacco, RL Olson, DM Hernandez, AF Peterson, ED Schwamm, LH AF Fonarow, Gregg C. Pan, Wenqin Saver, Jeffrey L. Smith, Eric E. Reeves, Mathew J. Broderick, Joseph P. Kleindorfer, Dawn O. Sacco, Ralph L. Olson, DaiWai M. Hernandez, Adrian F. Peterson, Eric D. Schwamm, Lee H. TI Comparison of 30-Day Mortality Models for Profiling Hospital Performance in Acute Ischemic Stroke With vs Without Adjustment for Stroke Severity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEART-FAILURE; MEDICARE BENEFICIARIES; SCALE SCORE; PREDICTORS; OUTCOMES; QUALITY; RISK; RECLASSIFICATION; PROGRAM; CARE AB Context There is increasing interest in reporting risk-standardized outcomes for Medicare beneficiaries hospitalized with acute ischemic stroke, but whether it is necessary to include adjustment for initial stroke severity has not been well studied. Objective To evaluate the degree to which hospital outcome ratings and potential eligibility for financial incentives are altered after including initial stroke severity in a claims-based risk model for hospital 30-day mortality for acute ischemic stroke. Design, Setting, and Patients Data were analyzed from 782 Get With The Guidelines-Stroke participating hospitals on 127 950 fee-for-service Medicare beneficiaries with ischemic stroke who had a score documented for the National Institutes of Health Stroke Scale (NIHSS, a 15-item neurological examination scale with scores from 0 to 42, with higher scores indicating more severe stroke) between April 2003 and December 2009. Performance of claims-based hospital mortality risk models with and without inclusion of NIHSS scores for 30-day mortality was evaluated and hospital rankings from both models were compared. Main Outcomes Measures Model discrimination, hospital 30-day mortality outcome rankings, and value-based purchasing financial incentive categories. Results Across the study population, the mean (SD) NIHSS score was 8.23 (8.11) (median, 5; interquartile range, 2-12). There were 18 186 deaths (14.5%) within the first 30 days, including 7430 deaths (5.8%) during the index hospitalization. The hospital mortality model with NIHSS scores had significantly better discrimination than the model without (C statistic, 0.864; 95% CI, 0.861-0.867, vs 0.772; 95% CI, 0.769-0.776; P < .001). Among hospitals ranked in the top 20% or bottom 20% of performers by the claims model without NIHSS scores, 26.3% were ranked differently by the model with NIHSS scores. Of hospitals initially classified as having "worse than expected" mortality, 57.7% were reclassified to "as expected" by the model with NIHSS scores. The net reclassification improvement (93.1%; 95% CI, 91.6%-94.6%; P < .001) and integrated discrimination improvement (15.0%; 95% CI, 14.6%-15.3%; P < .001) indexes both demonstrated significant enhancement of model performance after the addition of NIHSS. Explained variance and model calibration was also improved with the addition of NIHSS scores. Conclusion Adding stroke severity as measured by the NIHSS to a hospital 30-day risk model based on claims data for Medicare beneficiaries with acute ischemic stroke was associated with considerably improved model discrimination and change in mortality performance rankings for a substantial portion of hospitals. C1 [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Pan, Wenqin; Olson, DaiWai M.; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Ctr, Durham, NC USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Broderick, Joseph P.; Kleindorfer, Dawn O.] Univ Cincinnati, Dept Neurol, Acad Hlth Ctr, Cincinnati, OH USA. [Sacco, Ralph L.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room 47-123 CHS, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Smith, Eric/C-5443-2012; Hernandez, Adrian F./A-7818-2016 OI Smith, Eric/0000-0003-3956-1668; Saver, Jeffrey/0000-0001-9141-2251; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616 FU National Institutes of Health; Michigan Stroke Registry; National Institute of Neurological Disorders and Stroke (NINDS); AHA Pharmaceutical Roundtable grant; Johnson Johnson; Amylin; Eli Lilly; Janssen Pharmaceuticals; Janssen Pharmaceutical Companies of Johnson Johnson; Boehringer-Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical; AHA Pharmaceutical Roundtable FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Fonarow reported serving as a member of the Get With The Guidelines (GWTG) Steering Committee and receiving research support from the National Institutes of Health and is an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Pan is a member of the Duke Clinical Research Institute (DCRI), which serves as the American Heart Association (AHA) GWTG data coordinating center. Dr Saver reported serving as a member of the GWTG Science Subcommittee and as a scientific consultant regarding trial design and conduct to Covidien, CoAxia, Talacris, Brainsgate, Sygnis, and Ev3 and is an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Smith reported having served on an advisory board to Genentech and is on the data safety and monitoring board for the MR Witness trial. Dr Reeves reported receiving salary support from the Michigan Stroke Registry and serving as a member of the AHA GWTG Quality Improvement Subcommittee. Dr Broderick reported receiving funding from the National Institute of Neurological Disorders and Stroke (NINDS) for multiple ongoing trials; receiving study medications from Genentech for 2 ongoing NINDS studies and having received payment as a consultant to Genentech; and having been reimbursed for travel to meetings by Genentech. Dr Sacco is immediate past president of the AHA. Dr Olson is a member of the DCRI, which serves as the AHA GWTG data coordinating center, and reported serving as a consultant to Bristol Myers Squibb/Sanofi. Dr Hernandez is a member of the DCRI, which serves as the AHAGWTG data coordinating center, and reported being a recipient of an AHA Pharmaceutical Roundtable grant and having received research support from Johnson & Johnson and Amylin. Dr Peterson reported serving as principal investigator of the Data Analytic Center for AHA GWTG; reported receiving research grants from Johnson & Johnson, Eli Lilly, and Janssen Pharmaceuticals; and reported serving as a consultant to Boehringer Ingelheim, Johnson & Johnson, Medscape, Merck, Novartis, Ortho-McNeil-Janssen, Pfizer, Westat, the Cardiovascular Research Foundation, WebMD, and United Healthcare. Dr Schwamm reported serving as chair of the AHA GWTG Steering Committee and as a consultant to the Massachusetts Department of Public Health. No other disclosures were reported.; The GWTG-Stroke program is provided by the AHA/American Stroke Association. The GWTG-Stroke program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable. The industry sponsors of GWTG-Stroke had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. NR 27 TC 81 Z9 81 U1 1 U2 9 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 JUL 18 PY 2012 VL 308 IS 3 BP 257 EP 264 DI 10.1001/jama.2012.7870 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 975AC UT WOS:000306477900026 PM 22797643 ER PT J AU Furrer, S Menke, MN Funk, J Toteberg-Harms, M AF Furrer, Sandra Menke, Marcel N. Funk, Jens Toeteberg-Harms, Marc TI Evaluation of filtering blebs using the 'Wuerzburg bleb classification score' compared to clinical findings SO BMC OPHTHALMOLOGY LA English DT Article DE Filtering bleb; Glaucoma; Filtration surgery; Bleb grading; Trabeculectomy ID OPTICAL COHERENCE TOMOGRAPHY; INTENSIFIED POSTOPERATIVE CARE; GLAUCOMA FILTRATION SURGERY; VIVO CONFOCAL MICROSCOPY; MITOMYCIN-C; FOLLOW-UP; TRABECULECTOMY; APPEARANCE; TRIAL; BETA AB Background: To determine the agreement between intraocular pressure and the 'Wuerzburg bleb classification score', as well as between single items of the score and intraocular pressure. Interobserver variability was analyzed. Methods: 57 post-trabeculectomy eyes were included. Colour photographs were used to score the filtering bleb in accordance to the Wuerzburg bleb classification score by two different examiners. At the same visit, clinical data such as intraocular pressure, best corrected visual acuity, slit lamp biomicroscopy and medical history were obtained by another examiner. Results: After trabeculectomy, 42 out of 57 eyes (73.7%) reached the target pressure (<= 21mmHg, and intraocular pressure reduction of at least 20%, without antiglaucoma medication, and without any additional intervention). Fair agreement was found between intraocular pressure and Wuerzburg bleb classification score >= 8 points and >= 7 points (kappa 0.24 and 0.27, respectively). Analyzing the subgroups of the morphological criteria, best agreement was found between occurrence of microcysts and target intraocular pressure (kappa 0.22 - 0.34). Conclusions: Evaluating filtering blebs after trabeculectomy by using the Wuerzburg bleb classification score is a good technique for predicting intraocular pressure control in eyes attaining a minimum score of seven points. The presence of microcysts on the filtering bleb predicts that the eye is likely to attain target pressure. C1 [Funk, Jens; Toeteberg-Harms, Marc] Univ Zurich Hosp, Dept Ophthalmol, CH-8091 Zurich, Switzerland. [Furrer, Sandra] Univ Zurich, Fac Med, Zurich, Switzerland. [Menke, Marcel N.] Univ Hosp Bern, Dept Ophthalmol, CH-3010 Bern, Switzerland. [Toeteberg-Harms, Marc] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Toteberg-Harms, M (reprint author), Univ Zurich Hosp, Dept Ophthalmol, Frauenklin Str 24, CH-8091 Zurich, Switzerland. EM MarcToeteberg@aol.com RI Toteberg-Harms, Marc/J-4954-2013 OI Toteberg-Harms, Marc/0000-0002-2134-1336 NR 39 TC 4 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2415 J9 BMC OPHTHALMOL JI BMC Ophthalmol. PD JUL 17 PY 2012 VL 12 AR 24 DI 10.1186/1471-2415-12-24 PG 7 WC Ophthalmology SC Ophthalmology GA 010QI UT WOS:000309108800001 PM 22805056 ER PT J AU Catalona, WJ D'Amico, AV Fitzgibbons, WF Kosoko-Lasaki, O Leslie, SW Lynch, HT Moul, JW Rendell, MS Walsh, PC AF Catalona, William J. D'Amico, Anthony V. Fitzgibbons, William F. Kosoko-Lasaki, Omofolasade Leslie, Stephen W. Lynch, Henry T. Moul, Judd W. Rendell, Marc S. Walsh, Patrick C. TI What the US Preventive Services Task Force Missed in Its Prostate Cancer Screening Recommendation SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID FOLLOW-UP; MORTALITY; TRIAL; LUNG C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Creighton Univ, Sch Med, Omaha, NE USA. Duke Univ, Sch Med, Durham, NC USA. Duke Canc Inst, Durham, NC USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. RP Rendell, MS (reprint author), Creighton Diabet Ctr, 601 N 30th St, Omaha, NE 68131 USA. EM Rendell@asndi.com NR 12 TC 42 Z9 42 U1 0 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 17 PY 2012 VL 157 IS 2 BP 137 EP + DI 10.7326/0003-4819-157-2-201207170-00463 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 992ON UT WOS:000307787900019 PM 22801676 ER PT J AU Vishwanatha, KS Wang, YP Keutmann, HT Mains, RE Eipper, BA AF Vishwanatha, K. S. Wang, Y. P. Keutmann, H. T. Mains, R. E. Eipper, B. A. TI Structural Organization of the Nine Spectrin Repeats of Kalirin SO BIOCHEMISTRY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; ERYTHROID SPECTRIN; CRYSTAL-STRUCTURE; HUMAN DYSTROPHIN; ACTIN-BINDING; ROD DOMAIN; ANALYTICAL ULTRACENTRIFUGATION; MEMBRANE-PROTEINS; ALPHA-SPECTRIN; BETA-SPECTRIN AB Sequence analysis suggests that KALRN, a Rho GDP/GTP exchange factor genetically linked to schizophrenia, could contain as many as nine tandem spectrin repeats (SRs). We expressed and purified fragments of Kalirin containing from one to five putative SRs to determine whether they formed nested structures that could endow Kalirin with the flexible rodlike properties characteristic of spectrin and dystrophin. Far-UV circular dichroism studies indicated that Kalirin contains nine SRs. On the basis of thermal denaturation, sensitivity to chemical denaturants, and the solubility of pairs of repeats, the nine SRs of Kalirin form nested structures. Modeling studies confirmed this conclusion and identified an exposed loop in SRS; consistent with the modeling, this loop was extremely labile to proteolytic cleavage. Analysis of a direpeat fragment (SR4:5) encompassing the region of Kalirin known to interact with NOS2, DISC-1, PAM, and Arf6 identified this as the least stable region. Analytical ultracentrifugation indicated that SR1:3, SR4:6, and SR7:9 were monomers and adopted an extended conformation. Gel filtration suggested that Delta Kal7, a natural isoform that includes SR5:9, was monomeric and was not more extended than SR5:9. Similarly, the nine SRs of Kal7, which was also monomeric, were not more extended than SR5:9. The rigidity and flexibility of the nine SRs of Kal7, which separate its essential N-terminal Sec14p domain from its catalytic domain, play an essential role in its contribution to the formation and function of dendritic spines. C1 [Vishwanatha, K. S.; Wang, Y. P.; Mains, R. E.; Eipper, B. A.] Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. [Eipper, B. A.] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA. [Keutmann, H. T.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02115 USA. RP Eipper, BA (reprint author), Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. EM eipper@uchc.edu FU National Institutes of Health [DK-32948]; Janice and Rodney Reynolds Endowment FX This work was supported by National Institutes of Health Grant DK-32948 to R.E.M. and by the Janice and Rodney Reynolds Endowment. NR 55 TC 7 Z9 7 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 17 PY 2012 VL 51 IS 28 BP 5663 EP 5673 DI 10.1021/bi300583s PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974NC UT WOS:000306441300013 PM 22738176 ER PT J AU Rajaiya, J Yousuf, MA Singh, G Stanish, H Chodosh, J AF Rajaiya, Jaya Yousuf, Mohammad A. Singh, Gurdeep Stanish, Heather Chodosh, James TI Heat Shock Protein 27 Mediated Signaling in Viral Infection SO BIOCHEMISTRY LA English DT Article ID NF-KAPPA-B; ACTIN REORGANIZATION; AKT ACTIVATION; CELL-MIGRATION; LEUKEMIA-CELLS; DOCKING SITES; MAP KINASES; P38 MAPK; EXPRESSION; HSP27 AB Heat shock proteins (HSPs) play a critical role in many intracellular processes, including apoptosis and delivery of other proteins to intracellular compartments. Small HSPs have been shown previously to participate in many cellular functions, including IL-8 induction. Human adenovirus infection activates intracellular signaling, involving particularly the c-Src and mitogen-activated protein kinases [Natarajan, K, et al. (2003) J. Immunol. 170, 6234-6243]. HSP27 and MK2 are also phosphorylated, and c-Src, and its downstream targets, p38, ERK1/2, and c-Jun-terminal kinase (JNK), differentially mediate IL-8 and MCP-1 expression. Specifically, activation and translocation of transcription factor NF kappa B-p65 occurs in a p38-dependent fashion [Rajaiya, J., et al. (2009) Mol. Vision 15, 2879-2889]. Herein, we report a novel role for HSP27 in an association of p38 with NF kappa B-p65. Immunoprecipitation assays of virus-infected but not mock-infected cells revealed a signaling complex including p38 and NF kappa B-p65. Transfection with HSP27 short interfering RNA (siRNA) but not scrambled RNA disrupted this association and reduced the level of IL-8 expression. Transfection with HSP27 siRNA also reduced the level of nuclear localization of NF kappa B-p65 and p38. By use of tagged p38 mutants, we found that amino acids 279-347 of p38 are necessary for the association of p38 with NF kappa B-p65. These studies strongly suggest that HSP27, p38, and NF kappa B-p65 form a signalosome in virus-infected cells and influence downstream expression of pro-inflammatory mediators. C1 [Rajaiya, Jaya; Yousuf, Mohammad A.; Singh, Gurdeep; Stanish, Heather; Chodosh, James] Harvard Univ, Sch Med, Dept Ophthalmol, Howe Lab,Mass Eye & Ear Infirm, Boston, MA 02114 USA. RP Chodosh, J (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU National Institutes of Health [EY013124, EY021558, EY014104]; Research to Prevent Blindness, Inc. (New York, NY); Massachusetts Lions Eye Research Fund FX This work was supported by National Institutes of Health Grants EY013124, EY021558, and EY014104, a Senior Scientific Investigator Award grant (to J.C.) from Research to Prevent Blindness, Inc. (New York, NY), and the Massachusetts Lions Eye Research Fund. NR 59 TC 8 Z9 9 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 17 PY 2012 VL 51 IS 28 BP 5695 EP 5702 DI 10.1021/bi3007127 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 974NC UT WOS:000306441300016 PM 22734719 ER PT J AU Villa, A Torre, S Stell, A Cook, J Brown, M Maggi, A AF Villa, Alessandro Della Torre, Sara Stell, Alessia Cook, Jennifer Brown, Myles Maggi, Adriana TI Tetradian oscillation of estrogen receptor alpha is necessary to prevent liver lipid deposition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE energy metabolism; estrogen action; steroid hormone physiology; selective estrogen receptor modulators ID GENE-EXPRESSION; MICE; ACTIVATION; SECRETION; MOUSE; HOMEOSTASIS; DEFICIENT; DYNAMICS; GROWTH; TISSUE AB In the liver of female mice, the transcriptional activity of estrogen receptor (ER) alpha oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver. C1 [Villa, Alessandro; Della Torre, Sara; Stell, Alessia; Maggi, Adriana] Univ Milan, Ctr Excellence Neurodegenerat Dis, I-20133 Milan, Italy. [Villa, Alessandro; Della Torre, Sara; Stell, Alessia; Maggi, Adriana] Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy. [Cook, Jennifer; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Cook, Jennifer; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Maggi, A (reprint author), Univ Milan, Ctr Excellence Neurodegenerat Dis, I-20133 Milan, Italy. EM adriana.maggi@unimi.it OI Brown, Myles/0000-0002-8213-1658 FU Pfizer; European Community [IP CRESCENDO LSHM-CT-2005-018652, STREP EWA LSHM-CT-2005-518245]; National Institutes of Health [RO1 AG027713, DK074967]; Pfizer Pharmaceutical Co. FX A.V., S.D.T., A.S., J.C., and M. B. declare no conflict of interest. A.M. has received grant support and consulting fees from Pfizer.; We thank Shirley Liu (Dana Farber Cancer Institute) for initial identification of ER alpha-IP regions by MAT algorithms, Paolo Ciana for thoughtful discussions, Valeria Benedusi for a critical reading of the manuscript, and Clara Meda and Monica Rebecchi for technical assistance. This work was supported by grants from the European Community (IP CRESCENDO LSHM-CT-2005-018652 and STREP EWA LSHM-CT-2005-518245) and the National Institutes of Health (RO1 AG027713 granted to A.M., DK074967 granted to M. B.), and by Pfizer Pharmaceutical Co. NR 40 TC 21 Z9 23 U1 0 U2 11 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 JUL 17 PY 2012 VL 109 IS 29 BP 11806 EP 11811 DI 10.1073/pnas.1205797109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 979RI UT WOS:000306837100065 PM 22761311 ER PT J AU Ix, JH Katz, R Kestenbaum, BR de Boer, IH Chonchol, M Mukamal, KJ Rifkin, D Siscovick, DS Sarnak, MJ Shlipak, MG AF Ix, Joachim H. Katz, Ronit Kestenbaum, Bryan R. de Boer, Ian H. Chonchol, Michel Mukamal, Kenneth J. Rifkin, Dena Siscovick, David S. Sarnak, Mark J. Shlipak, Michael G. TI Fibroblast Growth Factor-23 and Death, Heart Failure, and Cardiovascular Events in Community-Living Individuals CHS (Cardiovascular Health Study) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; elderly; fibroblast growth factor-23; heart failure; kidney disease; mineral metabolism ID CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; STAGE RENAL-DISEASE; CYSTATIN-C; SERUM PHOSPHORUS; BODY-COMPOSITION; ELDERLY PERSONS; RISK-FACTOR; OLDER MEN; MORTALITY AB Objectives This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting. Background FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown. Methods Plasma FGF-23 was measured in 3,107 community-living persons >= 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status. Results Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45). Conclusions FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD. (J Am Coll Cardiol 2012;60:200-7) (c) 2012 by the American College of Cardiology Foundation C1 [Ix, Joachim H.; Rifkin, Dena] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.; Rifkin, Dena] Univ Calif San Diego, Div Nephrol, San Diego, CA 92161 USA. [Ix, Joachim H.; Rifkin, Dena] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92161 USA. [Katz, Ronit] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Dept Biostat, Seattle, WA 98195 USA. [Kestenbaum, Bryan R.; de Boer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Kestenbaum, Bryan R.; de Boer, Ian H.] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA 98195 USA. [Chonchol, Michel] Univ Colorado Denver, Div Renal Dis & Hypertens, Dept Med, Aurora, CO USA. [Mukamal, Kenneth J.] Beth Israel Deaconness Med Ctr, Div Gen Med & Primary Care, Boston, MA USA. [Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Dept Med, Boston, MA USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu FU National Heart, Lung, and Blood Institute [R01HL096851, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295]; American Heart Association [0575021N]; National Institute of Aging [R01AG027002, AG-023629, AG-15928, AG-20098, AG-028058]; Amgen Inc. FX From the *Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California; dagger Divisions of Nephrology and Preventive Medicine, University of California San Diego, San Diego, California; Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, Washington; Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, Washington; parallel to Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado; Division of General Medicine and Primary Care, Beth Israel Deaconness Medical Center, Boston, Massachusetts; #Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; **Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts; dagger dagger General Internal Medicine Section, San Francisco Veterans Affairs Medical Center, San Francisco, California; and the double dagger double dagger Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California. This study was sponsored by grants from the National Heart, Lung, and Blood Institute (R01HL096851), American Heart Association (0575021N), National Institute of Aging (R01AG027002). This paper was also supported in part with resources of the Veterans Administration San Diego Healthcare System. The Cardiovascular Health Study was supported by National Heart, Lung, and Blood Institute contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133; and National Heart, Lung, and Blood Institute grant HL080295, with additional contribution from the National Institute on Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-028058 from the National Institute on Aging. Dr. Kestenbaum received grant funding from Amgen Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 44 TC 117 Z9 122 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 17 PY 2012 VL 60 IS 3 BP 200 EP 207 DI 10.1016/j.jacc.2012.03.040 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 972YQ UT WOS:000306318000006 PM 22703926 ER PT J AU Lee, H Shin, Y Kim, ST Reinherz, EL Lang, MJ AF Lee, Hyungsuk Shin, Yongdae Kim, Sun Taek Reinherz, Ellis L. Lang, Matthew J. TI Stochastic optical active rheology SO APPLIED PHYSICS LETTERS LA English DT Article ID NETWORKS; CELL; GELS AB We demonstrate a stochastic based method for performing active rheology using optical tweezers. By monitoring the displacement of an embedded particle in response to stochastic optical forces, a rapid estimate of the frequency dependent shear moduli of a sample is achieved in the range of 10(-1)-10(3) Hz. We utilize the method to probe linear viscoelastic properties of hydrogels at varied cross-linker concentrations. Combined with fluorescence imaging, our method demonstrates non-linear changes of bond strength between T cell receptors and an antigenic peptide due to force-induced cell activation. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4737159] C1 [Lang, Matthew J.] Vanderbilt Univ, Dept Chem & Biomol Engn, Nashville, TN 37235 USA. [Lang, Matthew J.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37235 USA. [Lee, Hyungsuk] Yonsei Univ, Sch Mech Engn, Seoul 120749, South Korea. [Shin, Yongdae] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Kim, Sun Taek; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Kim, Sun Taek; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, Sun Taek; Reinherz, Ellis L.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. RP Lang, MJ (reprint author), Vanderbilt Univ, Dept Chem & Biomol Engn, 221 Kirkland Hall, Nashville, TN 37235 USA. EM matt.lang@vanderbilt.edu FU NIH [R21CA133576, AI19807]; Yonsei University; NIGMS [GM076689]; NSF [0643745]; Samsung Foundation of Culture; Singapore-MIT Alliance for Research and Technology FX This work was supported by the NIH R21CA133576, Yonsei University Research Fund of 2012, NIGMS (GM076689), NIH AI19807, NSF Career Award (0643745), the Samsung Scholarship from the Samsung Foundation of Culture, and the Singapore-MIT Alliance for Research and Technology. NR 18 TC 4 Z9 4 U1 0 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUL 16 PY 2012 VL 101 IS 3 AR 031902 DI 10.1063/1.4737159 PG 4 WC Physics, Applied SC Physics GA 978NC UT WOS:000306748000023 PM 22893729 ER PT J AU Srivastava, MK Zhu, L Harris-White, M Kar, U Huang, M Johnson, MF Lee, JM Elashoff, D Strieter, R Dubinett, S Sharma, S AF Srivastava, Minu K. Zhu, Li Harris-White, Marni Kar, Upendra Huang, Min Johnson, Ming F. Lee, Jay M. Elashoff, David Strieter, Robert Dubinett, Steven Sharma, Sherven TI Myeloid Suppressor Cell Depletion Augments Antitumor Activity in Lung Cancer SO PLOS ONE LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; MHC CLASS-I; BONE-MARROW; TUMOR-ANTIGENS; DENDRITIC CELLS; NK CELLS; TOLERANCE; INDUCTION; MECHANISM; ANERGY AB Background: Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer. Principal Findings: Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFN gamma, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1& 2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls. Significance: Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion. C1 [Srivastava, Minu K.; Zhu, Li; Lee, Jay M.; Elashoff, David; Dubinett, Steven; Sharma, Sherven] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Lung Canc Res Program, Dept Med, Los Angeles, CA 90095 USA. [Lee, Jay M.; Elashoff, David; Dubinett, Steven; Sharma, Sherven] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Kar, Upendra] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. [Srivastava, Minu K.; Zhu, Li; Harris-White, Marni; Huang, Min; Johnson, Ming F.; Dubinett, Steven; Sharma, Sherven] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Gene Med Lab, Los Angeles, CA USA. [Strieter, Robert] Univ Virginia, Dept Med, Charlottesville, VA USA. RP Srivastava, MK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, UCLA Lung Canc Res Program, Dept Med, Los Angeles, CA 90095 USA. EM ssharma@mednet.ucla.edu FU University of California Los Angeles Lung Cancer Program; Department of Veterans Affairs Medical Research Funds; National Institutes of Health (NIH) [RO1 CA95686, RO1 CA126944, P50 CA90388]; National Center for Advancing Translational Sciences [UL1TR000124]; Tobacco Related Disease Program Award Program of University of California [15RT-0207, 20FT0082] FX This work was supported by the University of California Los Angeles Lung Cancer Program, Department of Veterans Affairs Medical Research Funds, National Institutes of Health (NIH) Grants (RO1 CA95686, RO1 CA126944 and P50 CA90388), National Center for Advancing Translational Sciences, Grant UL1TR000124, and Tobacco Related Disease Program Award Program of University of California (15RT-0207 and 20FT0082). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 60 Z9 60 U1 2 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 JUL 16 PY 2012 VL 7 IS 7 AR e40677 DI 10.1371/journal.pone.0040677 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974VS UT WOS:000306466100054 PM 22815789 ER PT J AU Yates-Binder, CC Rodgers, M Jaynes, J Wells, A Bodnar, RJ Turner, T AF Yates-Binder, Cecelia C. Rodgers, Margaret Jaynes, Jesse Wells, Alan Bodnar, Richard J. Turner, Timothy TI An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis SO PLOS ONE LA English DT Article ID CHEMOKINE RECEPTOR CXCR3; PROTEIN-KINASE-A; INDUCIBLE PROTEIN-9; CELL MOTILITY; GROWTH-FACTOR; MICE LACKING; WOUND REPAIR; CALPAIN; KERATINOCYTES; ACTIVATION AB Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP-10, spanning the a-helical domain residues 77-98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3-mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis. C1 [Yates-Binder, Cecelia C.; Jaynes, Jesse; Wells, Alan; Turner, Timothy] Tuskegee Univ, Ctr Canc Res, Tuskegee, AL 36088 USA. [Yates-Binder, Cecelia C.; Wells, Alan; Bodnar, Richard J.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Yates-Binder, Cecelia C.; Rodgers, Margaret; Wells, Alan; Bodnar, Richard J.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Yates-Binder, CC (reprint author), Tuskegee Univ, Ctr Canc Res, Tuskegee, AL 36088 USA. EM cey4@pitt.edu; Rjb8@pitt.edu OI Wells, Alan/0000-0002-1637-8150 FU National Center on Minority Health and Health Disparities, National Institute of General Medical Science of the National Institutes of Health [R01GM063569] FX These studies were supported by grants from the National Center on Minority Health and Health Disparities, National Institute of General Medical Science of the National Institutes of Health (R01GM063569) and in kind support from the Pittsburgh VA Medical Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 15 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 16 PY 2012 VL 7 IS 7 AR e40812 DI 10.1371/journal.pone.0040812 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 974VS UT WOS:000306466100073 PM 22815829 ER PT J AU Chen, JY Calhoun, VD Pearlson, GD Ehrlich, S Turner, JA Ho, BC Wassink, TH Michael, AM Liu, JY AF Chen, Jiayu Calhoun, Vince D. Pearlson, Godfrey D. Ehrlich, Stefan Turner, Jessica A. Ho, Beng-Choon Wassink, Thomas H. Michael, Andrew M. Liu, Jingyu TI Multifaceted genomic risk for brain function in schizophrenia SO NEUROIMAGE LA English DT Article DE Schizophrenia; fMRI; SNP; Parallel-ICA; Multivariate ID GLUTAMATE-RECEPTOR SUBUNIT; 1ST EPISODE SCHIZOPHRENIA; LARGE GENE LISTS; MUTANT MICE; RHEUMATOID-ARTHRITIS; SENSORIMOTOR CORTEX; PSYCHOTIC SYMPTOMS; CORTICAL FUNCTION; BIPOLAR DISORDER; VOLUME REDUCTION AB Recently, deriving candidate endophenotypes from brain imaging data has become a valuable approach to study genetic influences on schizophrenia (SZ), whose pathophysiology remains unclear. In this work we utilized a multivariate approach, parallel independent component analysis, to identify genomic risk components associated with brain function abnormalities in SZ. 5157 candidate single nucleotide polymorphisms (SNPs) were derived from genome-wide array based on their possible connections with SZ and further investigated for their associations with brain activations captured with functional magnetic resonance imaging (fMRI) during a sensorimotor task. Using data from 92 SZ patients and 116 healthy controls, we detected a significant correlation (r = 0.29; p = 2.41 x 10(-5)) between one fMRI component and one SNP component, both of which significantly differentiated patients from controls. The fMRI component mainly consisted of precentral and postcentral gyri, the major activated regions in the motor task. On average, higher activation in these regions was observed in participants with higher loadings of the linked SNP component, predominantly contributed to by 253 SNPs. 138 identified SNPs were from known coding regions of 100 unique genes. 31 identified SNPs did not differ between groups, but moderately correlated with some other group-discriminating SNPs, indicating interactions among alleles contributing toward elevated SZ susceptibility. The genes associated with the identified SNPs participated in four neurotransmitter pathways: GABA receptor signaling, dopamine receptor signaling, neuregulin signaling and glutamate receptor signaling. In summary, our work provides further evidence for the complexity of genomic risk to the functional brain abnormality in SZ and suggests a pathological role of interactions between SNPs, genes and multiple neurotransmitter pathways. (C) 2012 Elsevier Inc. All rights reserved. C1 [Chen, Jiayu; Calhoun, Vince D.; Turner, Jessica A.; Michael, Andrew M.; Liu, Jingyu] Mind Res Network, Albuquerque, NM 87106 USA. [Chen, Jiayu; Calhoun, Vince D.; Liu, Jingyu] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. [Calhoun, Vince D.; Pearlson, Godfrey D.] Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT 06106 USA. [Calhoun, Vince D.; Pearlson, Godfrey D.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [Michael, Andrew M.] Rochester Inst Technol, Ctr Imaging Sci, Rochester, NY 14623 USA. [Ehrlich, Stefan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,MIT, Charlestown, MA 02129 USA. [Ehrlich, Stefan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Ehrlich, Stefan] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Child & Adolescent Psychiat, D-01307 Dresden, Germany. [Ho, Beng-Choon; Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. RP Chen, JY (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM jchen@mrn.org RI Ho, Beng-Choon/D-6959-2011; Calhoun, Vince/H-7146-2013; Turner, Jessica/H-7282-2015; OI Ho, Beng-Choon/0000-0003-3976-1555; Calhoun, Vince/0000-0001-9058-0747; Turner, Jessica/0000-0003-0076-8434; Ehrlich, Stefan/0000-0003-2132-4445; Liu, Jingyu/0000-0002-1724-7523 FU National Institutes of Health [5 P20 RR 021938-03] FX We would like to thank Jill Fries and Marilee Morgan for preprocessing the fMRI and genetic data. This work was supported by the National Institutes of Health; Contract grant number: 5 P20 RR 021938-03. NR 73 TC 22 Z9 22 U1 4 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 866 EP 875 DI 10.1016/j.neuroimage.2012.03.022 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600014 PM 22440650 ER PT J AU Kenet, T Orekhova, EV Bharadwaj, H Shetty, NR Israeli, E Lee, AKC Agam, Y Elam, M Joseph, RM Hamalainen, MS Manoach, DS AF Kenet, Tal Orekhova, Elena V. Bharadwaj, Hari Shetty, Nandita R. Israeli, Emily Lee, Adrian K. C. Agam, Yigal Elam, Mikael Joseph, Robert M. Haemaelaeinen, Matti S. Manoach, Dara S. TI Disconnectivity of the cortical ocular motor control network in autism spectrum disorders SO NEUROIMAGE LA English DT Article DE Autism; ASD; Connectivity; Alpha synchrony; MEG ID FRONTAL EYE-FIELD; ANTERIOR CINGULATE CORTEX; VISUALLY GUIDED SACCADES; HIGH-FUNCTIONING AUTISM; POSITRON-EMISSION-TOMOGRAPHY; VOXEL-BASED MORPHOMETRY; SPACE SEPARATION METHOD; SURFACE-BASED ANALYSIS; EVENT-RELATED FMRI; PREPARATORY SET AB Response inhibition, or the suppression of prepotent but contextually inappropriate behaviors, is essential to adaptive, flexible responding. Individuals with autism spectrum disorders (ASD) consistently show deficient response inhibition during antisaccades. In our prior functional MRI study, impaired antisaccade performance was accompanied by reduced functional connectivity between the frontal eye field (FEF) and dorsal anterior cingulate cortex (dACC), regions critical to volitional ocular motor control. Here we employed magnetoencephalography (MEG) to examine the spectral characteristics of this reduced connectivity. We focused on coherence between FEF and dACC during the preparatory period of antisaccade and prosaccade trials, which occurs after the presentation of the task cue and before the imperative stimulus. We found significant group differences in alpha band mediated coherence. Specifically, neurotypical participants showed significant alpha band coherence between the right inferior FEF and right dACC and between the left superior FEF and bilateral dACC across antisaccade, prosaccade, and fixation conditions. Relative to the neurotypical group, ASD participants showed reduced coherence between these regions in all three conditions. Moreover, while neurotypical participants showed increased coherence between the right inferior FEF and the right dACC in preparation for an antisaccade compared to a prosaccade or fixation, ASD participants failed to show a similar increase in preparation for the more demanding antisaccade. These findings demonstrate reduced long-range functional connectivity in ASD, specifically in the alpha band. The failure in the ASD group to increase alpha band coherence with increasing task demand may reflect deficient top-down recruitment of additional neural resources in preparation to perform a difficult task. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kenet, Tal; Orekhova, Elena V.; Bharadwaj, Hari; Shetty, Nandita R.; Israeli, Emily; Lee, Adrian K. C.; Agam, Yigal; Haemaelaeinen, Matti S.; Manoach, Dara S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Kenet, Tal; Bharadwaj, Hari; Shetty, Nandita R.; Israeli, Emily] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lee, Adrian K. C.; Agam, Yigal; Manoach, Dara S.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Joseph, Robert M.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Elam, Mikael] Univ Gothenburg, Inst Neurosci & Physiol, SE-40530 Gothenburg, Sweden. RP Kenet, T (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,CNY-10-023, Charlestown, MA 02129 USA. EM tal@nmr.mgh.harvard.edu; dara@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; OI Orekhova, Elena/0000-0003-0950-1613; Lee, Adrian KC/0000-0002-7611-0500; Bharadwaj, Hari/0000-0001-8685-9630 FU Nancy Lurie Marks Family Foundation; Autism Speaks; NIMH [R01 MH67720]; Swedish Research Council [2009-3765]; National Center for Research Resources [P41RR14075]; National Institute for Biomedical Imaging and Bioengineering [5R01EB009048]; Cognitive Rhythms Collaborative: A Discovery Network [NFS 1042134]; Mental illness Neuroscience Discovery (MIND) Institute [DOE DE-FG02-99ER62764] FX The authors would like to acknowledge grants from the Nancy Lurie Marks Family Foundation and from Autism Speaks (TK); NIMH (R01 MH67720 - DSM); Swedish Research Council, grant 2009-3765 (EVO); The National Center for Research Resources (P41RR14075, MSH), National Institute for Biomedical Imaging and Bioengineering (5R01EB009048, MSH), Cognitive Rhythms Collaborative: A Discovery Network (NFS 1042134, MSH), and Mental illness Neuroscience Discovery (MIND) Institute (DOE DE-FG02-99ER62764, DSM). NR 93 TC 11 Z9 13 U1 2 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 1226 EP 1234 DI 10.1016/j.neuroimage.2012.03.010 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600048 PM 22433660 ER PT J AU Yucel, MA Huppert, TJ Boas, DA Gagnon, L AF Yuecel, Meryem A. Huppert, Theodore J. Boas, David A. Gagnon, Louis TI Calibrating the BOLD signal during a motor task using an extended fusion model incorporating DOT, BOLD and ASL data SO NEUROIMAGE LA English DT Article DE fNIRS; fMRI; ASL; CMRO2; BOLD calibration; Multimodal imaging ID NEAR-INFRARED SPECTROSCOPY; RAT SOMATOSENSORY CORTEX; CEREBRAL BLOOD-VOLUME; OXYGEN-METABOLISM; BRAIN ACTIVATION; PHOTON MIGRATION; FUNCTIONAL MRI; FMRI MEASUREMENTS; AUDITORY ODDBALL; NEURAL ACTIVITY AB Multimodal imaging improves the accuracy of the localization and the quantification of brain activation when measuring different manifestations of the hemodynamic response associated with cerebral activity. In this study, we incorporated cerebral blood flow (CBF) changes measured with arterial spin labeling (ASL), Diffuse Optical Tomography (DOT) and blood oxygen level-dependent (BOLD) recordings to reconstruct changes in oxy- (Delta HbO(2)) and deoxyhemoglobin (Delta HbR). Using the Grubb relation between relative changes in CBF and cerebral blood volume (CBV), we incorporated the ASL measurement as a prior to the total hemoglobin concentration change (Delta HbT). We applied this ASL fusion model to both synthetic data and experimental multimodal recordings during a 2-s finger-tapping task. Our results show that the new approach is very powerful in estimating Delta HbO(2) and Delta HbR with high spatial and quantitative accuracy. Moreover, our approach allows the computation of baseline total hemoglobin concentration (HbT(0)) as well as of the BOLD calibration factor M on a single subject basis. We obtained an average HbT(0) of 71 mu M, an average M value of 0.18 and an average increase of 13% in cerebral metabolic rate of oxygen (CMRO2), all of which are in agreement with values previously reported in the literature. Our method yields an independent measurement of M, which provides an alternative measurement to validate the hypercapnic calibration of the BOLD signal. (C) 2012 Elsevier Inc. All rights reserved. C1 [Yuecel, Meryem A.; Boas, David A.; Gagnon, Louis] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Med Sch, Charlestown, MA USA. [Huppert, Theodore J.] Univ Pittsburg, Dept Radiol & Bioengn, Pittsburgh, PA USA. [Boas, David A.; Gagnon, Louis] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Yucel, MA (reprint author), Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Med Sch, Charlestown, MA USA. EM mayucel@nmr.mgh.harvard.edu FU NIH [P41-RR14075, R01-EB006385, R90-DA023427]; MIT; Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT) FX The authors are grateful to Rick Hoge and Frederic Lesage for initial discussions related to this work. We also thank Qianqian Fang and Jay Dubb for their help with the Monte Carlo simulations and Gary Boas for his comments on the draft of this paper. This work was supported by NIH grants P41-RR14075, R01-EB006385 and R90-DA023427. L. Gagnon was supported by the Advanced Multimodal Neuroimaging Training Program at MIT and the Fonds Quebecois de la Recherche sur la Nature et les Technologies (FQRNT). NR 51 TC 13 Z9 13 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 1268 EP 1276 DI 10.1016/j.neuroimage.2012.04.036 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600052 PM 22546318 ER PT J AU McLaren, DG Ries, ML Xu, GF Johnson, SC AF McLaren, Donald G. Ries, Michele L. Xu, Guofan Johnson, Sterling C. TI A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches SO NEUROIMAGE LA English DT Article DE fMRI; Functional connectivity; Effective connectivity; PPI; Psychophysiological interactions; Context-dependent connectivity; Brain mapping ID FUNCTIONAL CONNECTIVITY; FMRI; NETWORKS; ACTIVATION; MEMORY AB Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner. The current implementation of PPI in Statistical Parametric Mapping (SPM8) is configured primarily to assess connectivity differences between two task conditions, when in practice fMRI tasks frequently employ more than two conditions. Here we evaluate how a generalized form of context-dependent PPI (gPPI; http://www.nitrc.org/projects/gppi), which is configured to automatically accommodate more than two task conditions in the same PPI model by spanning the entire experimental space, compares to the standard implementation in SPM8. These comparisons are made using both simulations and an empirical dataset. In the simulated dataset, we compare the interaction beta estimates to their expected values and model fit using the Akaike information criterion (AIC). We found that interaction beta estimates in gPPI were robust to different simulated data models, were not different from the expected beta value, and had better model fits than when using standard PPI (sPPI) methods. In the empirical dataset, we compare the model fit of the gPPI approach to sPPI. We found that the gPPI approach improved model fit compared to sPPI. There were several regions that became nonsignificant with gPPI. These regions all showed significantly better model fits with gPPI. Also, there were several regions where task-dependent connectivity was only detected using gPPI methods, also with improved model fit. Regions that were detected with all methods had more similar model fits. These results suggest that gPPI may have greater sensitivity and specificity than standard implementation in SPM. This notion is tempered slightly as there is no gold standard; however, data simulations with a known outcome support our conclusions about gPPI. In sum, the generalized form of context-dependent PPI approach has increased flexibility of statistical modeling, and potentially improves model fit, specificity to true negative findings, and sensitivity to true positive findings. Published by Elsevier Inc. C1 [McLaren, Donald G.; Ries, Michele L.; Xu, Guofan; Johnson, Sterling C.] Wm S Middleton Mem Vet Hosp, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. [McLaren, Donald G.] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [McLaren, Donald G.; Ries, Michele L.; Xu, Guofan; Johnson, Sterling C.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [McLaren, Donald G.] ENRM VA Med Ctr, Geriatr Res Educ & Clin Ctr, Bedford, MA 01730 USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [McLaren, Donald G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Johnson, SC (reprint author), Wm S Middleton Mem Vet Hosp, Geriatr Res Educ & Clin Ctr, 2500 Overlook Terrace,11G, Madison, WI 53705 USA. EM mclaren@nmr.mgh.harvard.edu; mlr@medicine.wisc.edu; gxu@uwhealth.org; scj@medicine.wisc.edu OI McLaren, Donald/0000-0002-0566-4610; Johnson, Sterling/0000-0002-8501-545X FU Department of Veterans Affairs Merit Review [I01CX000165]; National Institutes of Health [AG021155, AG000213] FX This study was supported by a grant from Department of Veterans Affairs Merit Review (I01CX000165; Dr. Sterling C. Johnson); and grants from the National Institutes of Health AG021155 (Dr. Sterling C. Johnson) and AG000213 (Dr. Sanjay Asthana). The study was also supported with resources and use of facilities at the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. The assistance of Brent W. Thiel, Michele E. Fitzgerald, Erik K. Kastman and the Waisman Center for Brain Imaging was greatly appreciated. Discussion and suggestions from Darren Gitelman, Karl Friston, and Bob Spunt were also greatly appreciated. "The contents do not represent the views of the Dept. of Veterans Affairs or the United States Government." NR 24 TC 230 Z9 231 U1 6 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 1277 EP 1286 DI 10.1016/j.neuroimage.2012.03.068 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600053 PM 22484411 ER PT J AU Reuter, M Schmansky, NJ Rosas, HD Fischl, B AF Reuter, Martin Schmansky, Nicholas J. Rosas, H. Diana Fischl, Bruce TI Within-subject template estimation for unbiased longitudinal image analysis SO NEUROIMAGE LA English DT Article DE Unbiased longitudinal image processing; MRI biomarkers; Reliability and power; Within-subject template; FreeSurfer ID HUMAN CEREBRAL-CORTEX; CONCORDANCE CORRELATION-COEFFICIENT; SURFACE-BASED ANALYSIS; CORTICAL THICKNESS; HUNTINGTONS-DISEASE; EVALUATE REPRODUCIBILITY; GEOMETRICALLY ACCURATE; HIPPOCAMPAL ATROPHY; COORDINATE SYSTEM; BRAIN CHANGE AB Longitudinal image analysis has become increasingly important in clinical studies of normal aging and neurodegenerative disorders. Furthermore, there is a growing appreciation of the potential utility of longitudinally acquired structural images and reliable image processing to evaluate disease modifying therapies. Challenges have been related to the variability that is inherent in the available cross-sectional processing tools, to the introduction of bias in longitudinal processing and to potential over-regularization. In this paper we introduce a novel longitudinal image processing framework, based on unbiased, robust, within-subject template creation, for automatic surface reconstruction and segmentation of brain MRI of arbitrarily many time points. We demonstrate that it is essential to treat all input images exactly the same as removing only interpolation asymmetries is not sufficient to remove processing bias. We successfully reduce variability and avoid over-regularization by initializing the processing in each time point with common information from the subject template. The presented results show a significant increase in precision and discrimination power while preserving the ability to detect large anatomical deviations; as such they hold great potential in clinical applications, e.g. allowing for smaller sample sizes or shorter trials to establish disease specific biomarkers or to quantify drug effects. (C) 2012 Elsevier Inc. All rights reserved. C1 [Reuter, Martin; Schmansky, Nicholas J.; Rosas, H. Diana; Fischl, Bruce] Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Reuter, Martin; Schmansky, Nicholas J.; Rosas, H. Diana; Fischl, Bruce] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Reuter, Martin; Fischl, Bruce] MIT Comp Sci & AI Lab, Cambridge, MA USA. RP Reuter, M (reprint author), Martinos Ctr Biomed Imaging, 143 13th St, Charlestown, MA USA. EM mreuter@nmr.mgh.harvard.edu RI Reuter, Martin/B-3456-2010 OI Reuter, Martin/0000-0002-2665-9693 FU National Center for Research Resources [P41RR14075]; NCRR BIRN [BIRN002, U24RR021382]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute on Aging [R01AG022381, U01AG024904]; National Institute for Neurological Disorders and Stroke [R01NS052585, R01NS042861, P01NS058793, R21NS072652, R01NS070963]; Ellison Medical Foundation; National Center for Alternative Medicine [RC1AT005728]; [S10RR023401]; [S10RR019307]; [S10RR023043]; [P50AG05681]; [P01AG03991]; [R01AG021910]; [P50MH071616]; [R01MH56584] FX Support for this research was provided in part by the National Center for Research Resources (P41RR14075, and the NCRR BIRN Morphometric Project BIRN002, U24RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01EB006758), the National Institute on Aging (R01AG022381, U01AG024904), the National Institute for Neurological Disorders and Stroke (R01NS052585, R01NS042861, P01NS058793, R21NS072652, R01NS070963). Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation, the National Center for Alternative Medicine (RC1AT005728), and was made possible by the resources provided by Shared Instrumentation Grants (S10RR023401, S10RR019307, S10RR023043). For the OASIS dataset we acknowledge the following grants (P50AG05681, P01AG03991, R01AG021910, P50MH071616, U24RR021382, R01MH56584). The authors would also like to thank Mert Sabuncu and Gheorghe Doros for helpful discussions and advice. NR 65 TC 375 Z9 375 U1 7 U2 34 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 1402 EP 1418 DI 10.1016/j.neuroimage.2012.02.084 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600064 PM 22430496 ER PT J AU Winkler, AM Sabuncu, MR Yeo, BTT Fischl, B Greve, DN Kochunov, P Nichols, TE Blangero, J Glahn, DC AF Winkler, Anderson M. Sabuncu, Mert R. Yeo, B. T. Thomas Fischl, Bruce Greve, Douglas N. Kochunov, Peter Nichols, Thomas E. Blangero, John Glahn, David C. TI Measuring and comparing brain cortical surface area and other areal quantities SO NEUROIMAGE LA English DT Article DE Brain surface area; Facewise analysis; Areal interpolation; Pycnophylactic interpolation ID HUMAN CEREBRAL-CORTEX; REGULAR LATITUDE-LONGITUDE; CUBED-SPHERE GRIDS; COORDINATE SYSTEM; GEOMETRICALLY ACCURATE; ALZHEIMERS-DISEASE; GENETIC INFLUENCES; FOLDING PATTERNS; MRI; SCHIZOPHRENIA AB Structural analysis of MRI data on the cortical surface usually focuses on cortical thickness. Cortical surface area, when considered, has been measured only over gross regions or approached indirectly via comparisons with a standard brain. Here we demonstrate that direct measurement and comparison of the surface area of the cerebral cortex at a fine scale is possible using mass conservative interpolation methods. We present a framework for analyses of the cortical surface area, as well as for any other measurement distributed across the cortex that is areal by nature. The method consists of the construction of a mesh representation of the cortex, registration to a common coordinate system and, crucially, interpolation using a pycnophylactic method. Statistical analysis of surface area is done with power-transformed data to address lognormality, and inference is done with permutation methods. We introduce the concept of facewise analysis, discuss its interpretation and potential applications. (C) 2012 Elsevier Inc. All rights reserved. C1 [Winkler, Anderson M.; Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Winkler, Anderson M.; Glahn, David C.] Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT USA. [Sabuncu, Mert R.; Fischl, Bruce] MIT, Dept Elect Engn & Comp Sci, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Sabuncu, Mert R.; Fischl, Bruce; Greve, Douglas N.] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Sch Med, Charlestown, MA USA. [Yeo, B. T. Thomas] Duke NUS Grad Med Sch, Dept Neurosci & Behav Disorders, Singapore, Singapore. [Kochunov, Peter] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Kochunov, Peter; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Warwick, Warwick Mfg Grp, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Oxford, Oxford Ctr Funct MRI Brain, Oxford OX1 2JD, England. RP Winkler, AM (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. EM anderson.winkler@yale.edu RI Winkler, Anderson/P-7773-2016; OI Winkler, Anderson/0000-0002-4169-9781; Nichols, Thomas/0000-0002-4516-5103; Yeo, B.T. Thomas/0000-0002-0119-3276 FU Harvard Catalyst (NIH) [1 KL2 RR025757-01]; Harvard University; NIBIB [EB006395]; NIMH [MH0708143, MH078111, MH083824]; Ellison Medical Foundation; NCRR BIRN [BIRN002, U24RR021382]; [1S10RR023401]; [1S10RR019307]; [1S10RR023043] FX We thank the anonymous reviewers for their helpful remarks. M. R. Sabuncu received support from a KL2 Medical Research Investigator Training grant awarded via Harvard Catalyst (NIH grant 1 KL2 RR025757-01 and financial contributions from Harvard University and its aliations). P. Kochunov received support from the NIBIB grant EB006395. This study was supported by NIMH grants MH0708143 (PI: D. C. Glahn), MH078111 (PI: J. Blangero) and MH083824 (PI: D. C. Glahn). Support for FreeSurfer was provided in part by the National Center for Research Resources (P41-RR14075, the NCRR BIRN Morphometric Project BIRN002, U24RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01EB006758), the National Institute on Aging (AG022381), the National Center for Alternative Medicine (RC1AT005728-01), the National Institute for Neurological Disorders and Stroke (R01-NS052585-01, 1R21-NS072652-01, 1R01-NS070963) and resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043; additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation. None of the authors have financial interests to disclose. We are also thankful to Andri Tziortzi for her scholarly assistance with terms from Greek NR 117 TC 46 Z9 46 U1 3 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 16 PY 2012 VL 61 IS 4 BP 1428 EP 1443 DI 10.1016/j.neuroimage.2012.03.026 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 967PP UT WOS:000305920600066 PM 22446492 ER PT J AU Agassandian, M Chen, BB Pulijala, R Kaercher, L Glasser, JR Mallampalli, RK AF Agassandian, Marianna Chen, Bill B. Pulijala, Roopa Kaercher, Leah Glasser, Jennifer R. Mallampalli, Rama K. TI Calcium-calmodulin kinase I cooperatively regulates nucleocytoplasmic shuttling of CCT alpha by accessing a nuclear export signal SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; PHOSPHATIDYLCHOLINE SYNTHESIS; TRANSCRIPTION FACTOR; DEPENDENT PATHWAYS; PROTEIN; ACTIVATION; CRM1; LOCALIZATION; PURIFICATION; SPECIFICITY AB We identified a new calmodulin kinase I (CaMKI) substrate, cytidyltransferase (CCT alpha), a crucial enzyme required for maintenance of cell membranes. CCT alpha becomes activated with translocation from the cytoplasm to the nuclear membrane, resulting in increased membrane phospholipids. Calcium-activated CCT alpha nuclear import is mediated by binding of its C-terminus to 14-3-3 zeta, a regulator of nuclear trafficking. Here CaMK1 phosphorylates residues within this C-terminus that signals association of CCT alpha with 14-3-3 zeta to initiate calcium-induced nuclear entry. CaMKI docks within the CCT alpha membrane-binding domain (residues 290-299), a sequence that displays similarities to a canonical nuclear export signal (NES) that also binds CRM1/exportin 1. Expression of a CFP-CCT alpha mutant lacking residues 290-299 in cells results in cytosolically retained enzyme. CRM1/exportin 1 was required for CCT alpha nuclear export, and its overexpression in cells was partially sufficient to trigger CCT alpha nuclear export despite calcium stimulation. An isolated CFP-290-299 peptide remained in the nucleus in the presence of leptomycin B but was able to target to the cytoplasm with farnesol. Thus CaMKI vies with CRM1/exportin 1 for access to a NES, and assembly of a CaMKI-14-3-3.-CCT alpha complex is a key effector mechanism that drives nuclear CCTa translocation. C1 [Agassandian, Marianna; Chen, Bill B.; Pulijala, Roopa; Kaercher, Leah; Glasser, Jennifer R.; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, 930 Scaife Hall, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU Merit Review Award from the U.S. Department of Veterans Affairs and National Institutes of Health [HL096376, HL097376, HL098174]; U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX We thank Jeffrey Brodsky for critical review of the manuscript. This material is based on work supported, in part, by the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was supported by a Merit Review Award from the U.S. Department of Veterans Affairs and National Institutes of Health RO1 Grants HL096376, HL097376, and HL098174 (to R.K.M.). The contents presented do not represent the views of the Department of Veterans Affairs of the United States Government. NR 45 TC 7 Z9 7 U1 1 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 15 PY 2012 VL 23 IS 14 BP 2755 EP 2769 DI 10.1091/mbc.E11-10-0863 PG 15 WC Cell Biology SC Cell Biology GA 052SB UT WOS:000312217600014 PM 22621903 ER PT J AU Narayan, A Carriero, NJ Gettinger, SN Kluytenaar, J Kozak, KR Yock, TI Muscato, NE Ugarelli, P Decker, RH Patel, AA AF Narayan, Azeet Carriero, Nicholas J. Gettinger, Scott N. Kluytenaar, Jeannie Kozak, Kevin R. Yock, Torunn I. Muscato, Nicole E. Ugarelli, Pedro Decker, Roy H. Patel, Abhijit A. TI Ultrasensitive Measurement of Hotspot Mutations in Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep Sequencing SO CANCER RESEARCH LA English DT Article ID LUNG-CANCER; MUTANT-DNA; PLASMA; QUANTIFICATION; GEFITINIB; SENSITIVITY; LEUKEMIA; THERAPY; SERUM; GENE AB Detection of cell-free tumor DNA in the blood has offered promise as a cancer biomarker, but practical clinical implementations have been impeded by the lack of a sensitive and accurate method for quantitation that is also simple, inexpensive, and readily scalable. Here we present an approach that uses next-generation sequencing to quantify the small fraction of DNA molecules that contain tumor-specific mutations within a background of normal DNA in plasma. Using layers of sequence redundancy designed to distinguish true mutations from sequencer misreads and PCR misincorporations, we achieved a detection sensitivity of approximately 1 variant in 5,000 molecules. In addition, the attachment of modular barcode tags to the DNA fragments to be sequenced facilitated the simultaneous analysis of more than 100 patient samples. As proof-of-principle, we showed the successful use of this method to follow treatment-associated changes in circulating tumor DNA levels in patients with non-small cell lung cancer. Our findings suggest that the deep sequencing approach described here may be applied to the development of a practical diagnostic test that measures tumor-derived DNA levels in blood. Cancer Res; 72(14); 3492-8. (c) 2012 AACR. C1 [Patel, Abhijit A.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Carriero, Nicholas J.] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Gettinger, Scott N.] Yale Univ, Dept Internal Med, New Haven, CT 06520 USA. [Kozak, Kevin R.] Univ Wisconsin, Dept Human Oncol, Madison, WI USA. [Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Muscato, Nicole E.] Lawrence Mem Hosp, Dept Pathol, New London, CT USA. [Ugarelli, Pedro] Lawrence Mem Hosp, Dept Hematol, New London, CT USA. RP Patel, AA (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, POB 208040, New Haven, CT 06520 USA. EM abhijit.patel@yale.edu FU Yale Cancer Center; American Cancer Society; Rudolph Anderson Fellowship from the National Center for Research Resources; Leslie Warner fellowship from the National Center for Research Resources; CTSA from the National Center for Research Resources [UL1RR024139, 5KL2RR024138] FX This work was supported by the Yale Cancer Center, the American Cancer Society, the Kalimeris Fund, a Rudolph Anderson Fellowship, a Leslie Warner fellowship, and CTSA grant numbers UL1RR024139 and 5KL2RR024138 from the National Center for Research Resources, a component of the U.S. NIH. NR 24 TC 52 Z9 54 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2012 VL 72 IS 14 BP 3492 EP 3498 DI 10.1158/0008-5472.CAN-11-4037 PG 7 WC Oncology SC Oncology GA 986OV UT WOS:000307353200008 PM 22581825 ER PT J AU Gandhi, L Janne, PA AF Gandhi, Leena Jaenne, Pasi A. TI Crizotinib for ALK-Rearranged Non-Small Cell Lung Cancer: A New Targeted Therapy for a New Target SO CLINICAL CANCER RESEARCH LA English DT Article ID ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; ANTITUMOR EFFICACY; MET AMPLIFICATION; C-MET; INHIBITOR; ADENOCARCINOMA; RESISTANCE; EGFR; CHEMOTHERAPY AB Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U. S. Food and Drug Administration for treatment of ALK-positive non-small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK-positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine. Clin Cancer Res; 18(14); 3737-42. (C)2012 AACR. C1 [Gandhi, Leena; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Gandhi, Leena; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Gandhi, Leena; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,HIM223, Boston, MA 02215 USA. EM pjanne@partners.org OI Gandhi, Leena/0000-0002-2398-9179 FU National Institutes of Health [R01CA136851]; National Cancer Institute Lung SPORE [P50CA090578] FX National Institutes of Health (R01CA136851 to P. A. Janne); National Cancer Institute Lung SPORE (P50CA090578 to P. A. Janne). NR 41 TC 44 Z9 52 U1 0 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2012 VL 18 IS 14 BP 3737 EP 3742 DI 10.1158/1078-0432.CCR-11-2393 PG 6 WC Oncology SC Oncology GA 988PN UT WOS:000307503100004 PM 22547770 ER PT J AU Brown, JR Hanna, M Tesar, B Werner, L Pochet, N Asara, JM Wang, YYE dal Cin, P Fernandes, SM Thompson, C MacConaill, L Wu, CJ Van de Peer, Y Correll, M Regev, A Neuberg, D Freedman, AS AF Brown, Jennifer R. Hanna, Megan Tesar, Bethany Werner, Lillian Pochet, Nathalie Asara, John M. Wang, Yaoyu E. dal Cin, Paola Fernandes, Stacey M. Thompson, Christina MacConaill, Laura Wu, Catherine J. Van de Peer, Yves Correll, Mick Regev, Aviv Neuberg, Donna Freedman, Arnold S. TI Integrative Genomic Analysis Implicates Gain of PIK3CA at 3q26 and MYC at 8q24 in Chronic Lymphocytic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID B-CELL; C-MYC; EMBRYONIC STEM; COLORECTAL-CANCER; 13Q14 DELETIONS; SURVIVAL; GENE; ABERRATIONS; RISK; ASSOCIATION AB Purpose: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT). Experimental Design: We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles. Results: Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the a subunit in three CLLs carrying PIK3CA amplification. Conclusions: Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL. Clin Cancer Res; 18(14); 3791-802. (C)2012 AACR. C1 [Brown, Jennifer R.; Tesar, Bethany; Fernandes, Stacey M.; Thompson, Christina; Wu, Catherine J.; Freedman, Arnold S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Werner, Lillian; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Hanna, Megan; MacConaill, Laura] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Wang, Yaoyu E.; Correll, Mick] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [dal Cin, Paola; MacConaill, Laura] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Brown, Jennifer R.; Asara, John M.; Wu, Catherine J.; Freedman, Arnold S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hanna, Megan; Pochet, Nathalie; Regev, Aviv] Broad Inst Harvard, Boston, MA USA. [Hanna, Megan; Pochet, Nathalie; Regev, Aviv] MIT, Cambridge, MA 02139 USA. [Regev, Aviv] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA. [Pochet, Nathalie; Van de Peer, Yves] Univ Ghent, Dept Plant Syst Biol, VIB, Dept Biotechnol & Genet, B-9000 Ghent, Belgium. RP Brown, JR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Jennifer_Brown@dfci.harvard.edu RI Van de Peer, Yves/D-4388-2009 OI Van de Peer, Yves/0000-0003-4327-3730 FU CCGD; Dana-Farber Strategic Plan Initiative; CCCB; Leukemia and Lymphoma Translational Research Program; Damon-Runyon Cancer Research Foundation [CI-38-07]; Career Award at the Scientific Interface from the Burroughs Wellcome Fund; NIH Pioneer award; HHMI; Merkin Foundation for Stem Cell Research at the Broad Institute; NIH [5PO1-CA120964, 5P30-CA006516, 5 PO1 CA092625, K23 CA115682]; Okonow-Lipton Fund; Melton Fund; Rosenbach Fund FX M. Hanna and L. MacConaill are supported through the CCGD and the Dana-Farber Strategic Plan Initiative. Y.E. Wang and M. Correll are supported through the CCCB and the Dana-Farber Strategic Plan Initiative. C.J. Wu acknowledges support from the Leukemia and Lymphoma Translational Research Program and is a Damon-Runyon Clinical Investigator supported in part by the Damon-Runyon Cancer Research Foundation (CI-38-07). N. Pochet is a postdoctoral research fellow of the Fund for Scientific Research-Flanders (FWO Vlaanderen) and a Broad Fellow of the Broad Institute. A. Regev is supported by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, an NIH Pioneer award, HHMI, and the Merkin Foundation for Stem Cell Research at the Broad Institute. J.M. Asara is supported by 5PO1-CA120964 and 5P30-CA006516 from the NIH. A. S. Freedman is supported in part by NIH 5 PO1 CA092625. J.R. Brown was supported by K23 CA115682 from the NIH and is a Scholar of the American Society of Hematology as well as a Scholar in Clinical Research of the Leukemia and Lymphoma Society. These studies were supported by the Okonow-Lipton Fund, the Melton Fund, and the Rosenbach Fund. NR 50 TC 41 Z9 43 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2012 VL 18 IS 14 BP 3791 EP 3802 DI 10.1158/1078-0432.CCR-11-2342 PG 12 WC Oncology SC Oncology GA 988PN UT WOS:000307503100010 PM 22623730 ER PT J AU Feng, S Shao, LJ Yu, WD Gavine, P Ittmann, M AF Feng, Shu Shao, Longjiang Yu, Wendong Gavine, Paul Ittmann, Michael TI Targeting Fibroblast Growth Factor Receptor Signaling Inhibits Prostate Cancer Progression SO CLINICAL CANCER RESEARCH LA English DT Article ID INTRAEPITHELIAL NEOPLASIA; INCREASED EXPRESSION; POTENTIAL TARGET; REACTIVE STROMA; TYROSINE KINASE; DOWN-REGULATION; PROLIFERATION; HYPERPLASIA; ACTIVATION; CARCINOMA AB Purpose: Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Experimental Design: Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. Results: AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Conclusions: Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer. Clin Cancer Res; 18(14); 3880-8. (C)2012 AACR. C1 [Feng, Shu; Shao, Longjiang; Yu, Wendong; Ittmann, Michael] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Feng, Shu; Shao, Longjiang; Yu, Wendong; Ittmann, Michael] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX USA. [Gavine, Paul] Astra Zeneca Res & Dev, Innovat Ctr China, Shanghai, Peoples R China. RP Ittmann, M (reprint author), Baylor Coll Med, Dept Pathol & Immunol, 1 Baylor Plaza, Houston, TX 77030 USA. EM mittmann@bcm.tmc.edu FU Department of Veterans Affairs; Prostate Cancer Foundation; NIH [U01CA141497] FX This work was supported by the Department of Veterans Affairs Merit Review program (to M. Ittmann), the Prostate Cancer Foundation (to M. Ittmann), and the NIH U01 Mouse Models of Human Cancer (U01CA141497; to M. Ittmann), and by the use of the facilities of the Michael E. DeBakey VAMC. NR 40 TC 23 Z9 23 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2012 VL 18 IS 14 BP 3880 EP 3888 DI 10.1158/1078-0432.CCR-11-3214 PG 9 WC Oncology SC Oncology GA 988PN UT WOS:000307503100018 PM 22573348 ER PT J AU Kerr, SE Schnabel, CA Sullivan, PS Zhang, Y Singh, V Carey, B Erlander, MG Highsmith, WE Dry, SM Brachtel, EF AF Kerr, Sarah E. Schnabel, Catherine A. Sullivan, Peggy S. Zhang, Yi Singh, Veena Carey, Brittany Erlander, Mark G. Highsmith, W. Edward Dry, Sarah M. Brachtel, Elena F. TI Multisite Validation Study to Determine Performance Characteristics of a 92-Gene Molecular Cancer Classifier SO CLINICAL CANCER RESEARCH LA English DT Article ID UNKNOWN PRIMARY SITE; GENE-EXPRESSION SIGNATURES; SALIVARY-DUCT-CARCINOMA; TRANSCRIPTION FACTOR-I; TUMOR CLASSIFICATION; CLINICAL-EVALUATION; TISSUE ORIGIN; IDENTIFICATION; PARADIGM; MELANOMA AB Purpose: Accurate tumor classification is essential for cancer management as patient outcomes improve with use of site-and subtype-specific therapies. Current clinicopathologic evaluation is varied in approach, yet standardized diagnoses are critical for determining therapy. While gene expression-based cancer classifiers may potentially meet this need, imperative to determining their application to patient care is validation in rigorously designed studies. Here, we examined the performance of a 92-gene molecular classifier in a large multi-institution cohort. Experimental Design: Case selection incorporated specimens from more than 50 subtypes, including a range of tumor grades, metastatic and primary tumors, and limited tissue samples. Formalin-fixed, paraffin-embedded tumors passed pathologist-adjudicated review between three institutions. Tumor classification using a 92-gene quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay was conducted on blinded tumor sections from 790 cases and compared with adjudicated diagnoses. Results: The 92-gene assay showed overall sensitivities of 87% for tumor type [95% confidence interval (CI), 84-89] and 82% for subtype (95% CI, 79-85). Analyses of metastatic tumors, high-grade tumors, or cases with limited tissue showed no decrease in comparative performance (P = 0.16, 0.58, and 0.16). High specificity (96%-100%) was showed for ruling in a primary tumor in organs commonly harboring metastases. The assay incorrectly excluded the adjudicated diagnosis in 5% of cases. Conclusions: The 92-gene assay showed strong performance for accurate molecular classification of a diverse set of tumor histologies. Results support potential use of the assay as a standardized molecular adjunct to routine clinicopathologic evaluation for tumor classification and primary site diagnosis. Clin Cancer Res; 18(14); 3952-60. (C)2012 AACR. C1 [Sullivan, Peggy S.; Dry, Sarah M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Kerr, Sarah E.; Highsmith, W. Edward] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Schnabel, Catherine A.; Zhang, Yi; Singh, Veena; Erlander, Mark G.] bioTheranostics Inc, San Diego, CA USA. [Carey, Brittany; Brachtel, Elena F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Dry, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, 13-145 CHS, Los Angeles, CA 90095 USA. EM sdry@mednet.ucla.edu NR 52 TC 15 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2012 VL 18 IS 14 BP 3952 EP 3960 DI 10.1158/1078-0432.CCR-12-0920 PG 9 WC Oncology SC Oncology GA 988PN UT WOS:000307503100025 PM 22648269 ER PT J AU Ferencik, M Schlett, CL Ghoshhajra, BB Kriegel, MF Joshi, SB Maurovich-Horvat, P Rogers, IS Banerji, D Bamberg, F Truong, QA Brady, TJ Nagurney, JT Hoffmann, U AF Ferencik, Maros Schlett, Christopher L. Ghoshhajra, Brian B. Kriegel, Mathias F. Joshi, Subodh B. Maurovich-Horvat, Pal Rogers, Ian S. Banerji, Dahlia Bamberg, Fabian Truong, Quynh A. Brady, Thomas J. Nagurney, John T. Hoffmann, Udo TI A Computed Tomography-Based Coronary Lesion Score to Predict Acute Coronary Syndrome Among Patients With Acute Chest Pain and Significant Coronary Stenosis on Coronary Computed Tomographic Angiogram SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; ATHEROSCLEROTIC PLAQUE; NONINVASIVE ASSESSMENT; CULPRIT LESIONS; STABLE ANGINA; CT; GUIDELINES AB We tested the hypothesis that morphologic lesion assessment helps detect acute coronary syndrome (ACS) during index hospitalization in patients with acute chest pain and significant stenosis on coronary computed tomographic angiogram (CTA). Patients who presented to an emergency department with chest pain but no objective signs of myocardial ischemia (nondiagnostic electrocardiogram and negative initial biomarkers) underwent CT angiography. CTA was analyzed for degree and length of stenosis, plaque area and volume, remodeling index, CT attenuation of plaque, and spotty calcium in all patients with significant stenosis (>50% in diameter) on CTA. ACS during index hospitalization was determined by a panel of 2 physicians blinded to results of CT angiography. For lesion characteristics associated with ACS, we determined cutpoints optimized for diagnostic accuracy and created lesion scores. For each score, we determined the odds ratio (OR) and discriminatory capacity for the prediction of ACS. Of the overall population of 368 patients, 34 had significant stenosis and 21 of those had ACS. Scores A (remodeling index plus spotty calcium: OR 3.5, 95% confidence interval [CI] 1.2 to 10.1, area under curve [AUC] 0.734), B (remodeling index plus spotty calcium plus stenosis length: OR 4.6, 95% CI 1.6 to 13.7, AUC 0.824), and C (remodeling index plus spotty calcium plus stenosis length plus plaque volume <90 HU: OR 3.4, 95% CI 1.5 to 7.9, AUC 0.833) were significantly associated with ACS. In conclusion, in patients presenting with acute chest pain and stenosis on coronary CTA, a CT-based score incorporating morphologic characteristics of coronary lesions had a good discriminatory value for detection of ACS during index hospitalization. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110: 183-189) C1 [Ferencik, Maros; Truong, Quynh A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ferencik, Maros; Schlett, Christopher L.; Ghoshhajra, Brian B.; Kriegel, Mathias F.; Joshi, Subodh B.; Maurovich-Horvat, Pal; Rogers, Ian S.; Banerji, Dahlia; Bamberg, Fabian; Truong, Quynh A.; Brady, Thomas J.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Schlett, Christopher L.; Ghoshhajra, Brian B.; Kriegel, Mathias F.; Joshi, Subodh B.; Maurovich-Horvat, Pal; Rogers, Ian S.; Banerji, Dahlia; Bamberg, Fabian; Truong, Quynh A.; Brady, Thomas J.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Bamberg, Fabian] Univ Munich, Dept Radiol, Munich, Germany. RP Ferencik, M (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM maros_ferencik@hms.harvard.edu OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU National Institutes of Health, Bethesda, Maryland [RO1 HL080053]; Siemens Medical Solutions, Forchheim, Germany; General Electric Healthcare, Princeton, New Jersey; National Institutes of Health [T32 HL076136]; Siemens Medical Solutions; General Electric Healthcare; Biosite, San Diego, California FX This work was supported by Grant RO1 HL080053 from the National Institutes of Health, Bethesda, Maryland and supported in part by Siemens Medical Solutions, Forchheim, Germany and General Electric Healthcare, Princeton, New Jersey. Dr. Ferencik, Dr. Rogers, Dr. Truong, and Dr. Ghoshhajra were supported by Grant T32 HL076136 from the National Institutes of Health. Dr. Hoffmann has received research grants from Siemens Medical Solutions and General Electric Healthcare. Dr. Nagurney is funded by Biosite, San Diego, California for a biomarker research study. NR 21 TC 27 Z9 28 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2012 VL 110 IS 2 BP 183 EP 189 DI 10.1016/j.amjcard.2012.02.066 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982FX UT WOS:000307029500004 PM 22481015 ER PT J AU Martin, SS Metkus, TS Horne, A Blaha, MJ Hasan, R Campbell, CY Yousuf, O Joshi, P Kaul, S Miller, M Michos, ED Jones, SR Gluckman, TJ Cannon, CP Sperling, LS Blumenthal, RS AF Martin, Seth S. Metkus, Thomas S. Horne, Aaron Blaha, Michael J. Hasan, Rani Campbell, Catherine Y. Yousuf, Omair Joshi, Parag Kaul, Sanjay Miller, Michael Michos, Erin D. Jones, Steven R. Gluckman, Ty J. Cannon, Christopher P. Sperling, Laurence S. Blumenthal, Roger S. TI Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the Meantime, Some Challenges and Recommendations SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Editorial Material ID LOW-DENSITY-LIPOPROTEIN; ELEVATION MYOCARDIAL-INFARCTION; ASSOCIATION TASK-FORCE; CARDIOVASCULAR RISK; LDL CHOLESTEROL; CONSENSUS CONFERENCE; APOLIPOPROTEIN-B; FOCUSED UPDATE; EXPERT PANEL; DISEASE AB The National Cholesterol Education Program Adult Treatment Panel (ATP) has provided education and guidance for decades on the management of hypercholesterolemia. Its third report (ATP III) was published 10 years ago, with a white paper update in 2004. There is a need for translation of more recent evidence into a revised guideline. To help address the significant challenges facing the ATP IV writing group, this statement aims to provide balanced recommendations that build on ATP III. The authors aim for simplicity to increase the likelihood of implementation in clinical practice. To move from ATP III to ATP IV, the authors recommend the following: (1) assess risk more accurately, (2) simplify the starting algorithm, (3) prioritize statin therapy, (4) relax the follow-up interval for repeat lipid testing, (5) designate <70 mg/di as an "ideal" low-density lipoprotein cholesterol target, (6) endorse targets beyond low-density lipoprotein cholesterol, (7) refine therapeutic target levels to the equivalent population percentile, (8) remove misleading descriptors such as "borderline high," and (9) make lifestyle messages simpler. In conclusion, the solutions offered in this statement represent ways to translate the totality of published reports into enhanced hyperlipidemia guidelines to better combat the devastating impact of hyperlipidemia on cardiovascular health. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:307-313) C1 [Martin, Seth S.; Metkus, Thomas S.; Horne, Aaron; Blaha, Michael J.; Hasan, Rani; Campbell, Catherine Y.; Yousuf, Omair; Joshi, Parag; Michos, Erin D.; Jones, Steven R.; Blumenthal, Roger S.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Kaul, Sanjay] Cedars Sinai Med Ctr, Div Cardiovasc, Los Angeles, CA 90048 USA. [Miller, Michael] Univ Maryland, Sch Med, Div Cardiovasc, Baltimore, MD 21201 USA. [Gluckman, Ty J.] Providence Heart & Vasc Inst, Portland, OR USA. [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Sperling, Laurence S.] Emory Univ, Sch Med, Div Cardiovasc, Atlanta, GA USA. RP Martin, SS (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. EM smart100@jhmi.edu NR 30 TC 22 Z9 22 U1 1 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2012 VL 110 IS 2 BP 307 EP 313 DI 10.1016/j.amjcard.2012.03.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982FX UT WOS:000307029500023 PM 22497674 ER PT J AU Liu, QL Rehman, H Krishnasamy, Y Ramshesh, VK Theruvath, TP Chavin, KD Schnellmann, RG Lemasters, JJ Zhong, Z AF Liu, Qinlong Rehman, Hasibur Krishnasamy, Yasodha Ramshesh, Venkat K. Theruvath, Tom P. Chavin, Kenneth D. Schnellmann, Rick G. Lemasters, John J. Zhong, Zhi TI Role of inducible nitric oxide synthase in mitochondrial depolarization and graft injury after transplantation of fatty livers SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE ALCOHOL; Inos; Liver; Transplantation; Mitochondrial; Depolarization; Steatosis ID N-TERMINAL KINASE; PERMEABILITY TRANSITION; REPERFUSION INJURY; HEPATIC STEATOSIS; MOUSE-LIVER; ISCHEMIA/REPERFUSION INJURY; STORAGE/REPERFUSION INJURY; UNCOUPLING PROTEIN-2; OXIDATIVE DAMAGE; RAT HEPATOCYTES AB This study investigated the role of inducible nitric oxide synthase (iNOS) in failure of ethanol-induced fatty liver grafts. Rat livers were explanted 20 h after gavaging with ethanol (5 g/kg) and storing in UW solution for 24 h before implantation. Hepatic oil red O staining-positive areas increased from similar to 2 to similar to 33% after ethanol treatment, indicating steatosis. iNOS expression increased similar to 8-fold after transplantation of lean grafts (LG) and 25-fold in fatty grafts (FG). Alanine aminotransferase release, total bilirubin, hepatic necrosis, TUNEL-positive cells, and cleaved caspase-3 were higher in FG than LG. A specific iNOS inhibitor 1400W (5 mu M in the cold-storage solution) blunted these alterations by > 42% and increased survival of fatty grafts from 25 to 88%. Serum nitrite/nitrate and hepatic nitrotyrosine adducts increased to a greater extent after transplantation of FG than LG, indicating reactive nitrogen species (RNS) overproduction. Phospho-c-Jun and phospho-c-Jun N-terminal kinase-1/2 (JNK1/2) were higher in FG than in LG, indicating more JNK activation in fatty grafts. RNS formation and JNK activation were blunted by 1400W. Mitochondrial polarization and cell death were visualized by intravital multiphoton microscopy of rhodamine 123 and propidium iodide, respectively. After implantation, viable cells with depolarized mitochondria were 3-fold higher in FG than in LG and 1400W decreased mitochondrial depolarization in FG to the levels of LG. Taken together, iNOS is upregulated after transplantation of FG, leading to excessive RNS formation, JNK activation, mitochondrial dysfunction, and severe graft injury. The iNOS inhibitor 1400W could be an effective therapy for primary nonfunction of fatty liver grafts. (C) 2012 Elsevier Inc. All rights reserved. C1 [Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Theruvath, Tom P.; Schnellmann, Rick G.; Lemasters, John J.; Zhong, Zhi] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Liu, Qinlong] Dalian Med Univ, Affiliated Hosp 2, Dept Gen Surg, Dalian, Peoples R China. [Ramshesh, Venkat K.; Schnellmann, Rick G.; Lemasters, John J.; Zhong, Zhi] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Chavin, Kenneth D.] Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson VA Med Ctr, Charleston, SC 29403 USA. [Lemasters, John J.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Zhong, Z (reprint author), Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. EM zhong@musc.edu RI Ji, Haofeng/G-6206-2012 FU National Institutes of Health [DK70844, DK70844S1, AA017756, DK84632, DK37034, 1P30 CA138313] FX This study was supported, in part, by Grants DK70844, DK70844S1, AA017756, DK84632, and DK37034 from the National Institutes of Health. We thank the Cell & Molecular Imaging Core of the Hollings Cancer Center at the Medical University of South Carolina supported by NIH Grant 1P30 CA138313 for providing instrumentation and assistance for confocal/multiphoton microscopy. NR 76 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL 15 PY 2012 VL 53 IS 2 BP 250 EP 259 DI 10.1016/j.freeradbiomed.2012.05.012 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 977PS UT WOS:000306677500008 PM 22609250 ER PT J AU Tsujino, K Takeda, Y Arai, T Shintani, Y Inagaki, R Saiga, H Iwasaki, T Tetsumoto, S Jin, YJ Ihara, S Minami, T Suzuki, M Nagatomo, I Inoue, K Kida, H Kijima, T Ito, M Kitaichi, M Inoue, Y Tachibana, I Takeda, K Okumura, M Hemler, ME Kumanogoh, A AF Tsujino, Kazuyuki Takeda, Yoshito Arai, Toru Shintani, Yasushi Inagaki, Ryosaku Saiga, Hiroyuki Iwasaki, Takeo Tetsumoto, Satoshi Jin, Yingji Ihara, Shoichi Minami, Toshiyuki Suzuki, Mayumi Nagatomo, Izumi Inoue, Koji Kida, Hiroshi Kijima, Takashi Ito, Mari Kitaichi, Masanori Inoue, Yoshikazu Tachibana, Isao Takeda, Kiyoshi Okumura, Meinoshin Hemler, Martin E. Kumanogoh, Atsushi TI Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE alveolar epithelial cell; adhesion strength; epithelial-to-mesenchymal transition; Smad2; CD9 ID GROWTH-FACTOR-BETA; MESENCHYMAL TRANSITION; MICE LACKING; BASEMENT-MEMBRANES; CELL-ADHESION; IN-VITRO; LUNG; DISEASE; ACTIVATION; DELETION AB Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. Methods: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wildtype mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. Measurements and Main Results: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased alpha-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. Conclusions: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases. C1 [Tsujino, Kazuyuki; Takeda, Yoshito; Iwasaki, Takeo; Tetsumoto, Satoshi; Jin, Yingji; Ihara, Shoichi; Minami, Toshiyuki; Suzuki, Mayumi; Nagatomo, Izumi; Inoue, Koji; Kida, Hiroshi; Kijima, Takashi; Tachibana, Isao; Kumanogoh, Atsushi] Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, Suita, Osaka 5650871, Japan. [Shintani, Yasushi; Okumura, Meinoshin] Osaka Univ, Grad Sch Med, Dept Thorac Surg, Suita, Osaka 5650871, Japan. [Saiga, Hiroyuki; Takeda, Kiyoshi] Osaka Univ, Grad Sch Med, Dept Microbiol & Immunol, Lab Immune Regulat, Suita, Osaka 5650871, Japan. [Arai, Toru; Kitaichi, Masanori; Inoue, Yoshikazu] Natl Hosp Org Kinki Chuo Chest Med Ctr, Dept Diffuse Lung Dis & Resp Failure, Sakai, Osaka, Japan. [Inagaki, Ryosaku; Ito, Mari] Dainippon Sumitomo Pharma Co Ltd, Drug Res Div, Osaka, Japan. [Hemler, Martin E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kumanogoh, Atsushi] Osaka Univ, Dept Immunol, Immunol Frontier Res Ctr IFrec, Suita, Osaka 5650871, Japan. RP Takeda, Y (reprint author), Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM yoshito@imed3.med.osaka-u.ac.jp FU Takeda Science Foundation; Okamoto Satoshi Memorial Fund for Pulmonary Fibrosis Research; Kato Memorial Trust For Nambyo Research; National Institutes of Health [CA42368]; Funding Program for Next Generation World-Leading Researchers (NEXT Program); Special Coordination Funds for Promoting Science and Technology; [21590992] FX Supported by a Grant-in-Aid for Scientific Research (C) No. 21590992, the Takeda Science Foundation, the Okamoto Satoshi Memorial Fund for Pulmonary Fibrosis Research, the Kato Memorial Trust For Nambyo Research (Y.T.), National Institutes of Health grant CA42368 (M.E.H.), the Funding Program for Next Generation World-Leading Researchers (NEXT Program), and Special Coordination Funds for Promoting Science and Technology (A.K.). NR 53 TC 15 Z9 16 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2012 VL 186 IS 2 BP 170 EP 180 DI 10.1164/rccm.201201-0117OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 974OH UT WOS:000306445300013 PM 22592804 ER PT J AU Liu, SZ Song, N Zou, L AF Liu, Shizhou Song, Na Zou, Lee TI The conserved C terminus of Claspin interacts with Rad9 and promotes rapid activation of Chk1 SO CELL CYCLE LA English DT Article DE Claspin; Chk1; Rad9; isoforms; splicing ID DNA-DAMAGE RESPONSE; REPLICATION CHECKPOINT RESPONSE; ATR; PROTEIN; PHOSPHORYLATION; COMPLEXES; DEGRADATION; RECRUITMENT; CHROMATIN; RECOVERY AB Claspin is a key mediator of the ATR-Chk1 checkpoint pathway. In response to DNA damage, Claspin interacts with Rad17 and Chk1 in a phosphorylation-dependent manner, enabling ATR to phosphorylate Chk1 efficiently. Claspin also interacts with Rad9, but how they interact and whether the interaction is functional remains unknown. Unexpectedly, our analysis of two splicing isoforms of Claspin provided an answer to these questions. The Claspin(1339) isoform contains an evolutionarily conserved C terminus, but the Claspin(1332) isoform does not. Although the transcripts encoding both Claspin isoforms coexist in HCT116 cells, Claspin(1339) is the predominant form responsible for Chk1 activation. When expressed in cells depleted of endogenous Claspin, both Claspin(1339) and Claspin(1332) are able to mediate Chk1 activation. However, the activation of Chk1 is delayed in Claspin(1332)-expressing cells compared with Claspin(1339)-expressing cells. Furthermore, only Claspin(1339) but not Claspin(1332) interacts with Rad9 efficiently. Together, these results suggest that the conserved C terminus of Claspin interacts with Rad9 and ensures timely activation of the ATR-Chk1 pathway. C1 [Liu, Shizhou; Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Charlestown, MA USA. [Zou, Lee] Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. [Liu, Shizhou; Song, Na] China Med Univ, Dept Med Oncol, Affiliated Hosp 1, Shenyang, Peoples R China. RP Zou, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Charlestown, MA USA. EM zou.lee@mgh.harvard.edu FU NIH [GM076388]; Federal Share of Proton Program Income FX We thank Drs. William Dunphy, Junjie Chen, Daniel Haber and Jiri Bartek for Claspin plasmids, and members of the Zou lab for helpful discussions. L.Z. is supported by the NIH grant GM076388 and a grant funded by the Federal Share of Proton Program Income. L.Z. is a Jim and Ann Orr MGH Research Scholar. NR 32 TC 9 Z9 9 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2012 VL 11 IS 14 BP 2711 EP 2716 DI 10.4161/cc.21041 PG 6 WC Cell Biology SC Cell Biology GA 974CE UT WOS:000306406600022 PM 22732499 ER PT J AU McClatchey, AI Cichowski, K AF McClatchey, Andrea I. Cichowski, Karen TI SPRED proteins provide a NF-ty link to Ras suppression SO GENES & DEVELOPMENT LA English DT Article DE Legius syndrome; NF1; signal transduction; Ras/MAPK; Sprouty ID NEUROFIBROMATOSIS TYPE-1 PROTEIN; TUMOR-SUPPRESSOR; LEGIUS SYNDROME; SPROUTY; PHENOTYPE; GAP; ACTIVATION; MUTATIONS; MECHANISM; GENOTYPE AB Mutations in the SPRED1 (Sprouty-related protein with an EVH [Ena/Vasp homology] domain 1) and NF1 (neurofibromatosis 1) genes underlie clinically related human disorders. The NF1-encoded protein neurofibromin is a Ras GTPase-activating protein (GAP) and can directly limit Ras activity. Spred proteins also negatively regulate Ras signaling, but the mechanism by which they do so is not clear. In the July 1, 2012, issue of Genes & Development, Stowe and colleagues (pp. 1421-1426) present evidence that Spred1 recruits neurofibromin to the membrane, where it dampens growth factor-induced Ras activity, providing a satisfying explanation for the overlapping features of two human diseases. C1 [McClatchey, Andrea I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Dept Pathol, Charlestown, MA 02129 USA. [Cichowski, Karen] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Cichowski, Karen] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cichowski, Karen] Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA 02115 USA. RP McClatchey, AI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Dept Pathol, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu; kcichowski@rics.bwh.harvard.edu NR 33 TC 1 Z9 1 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2012 VL 26 IS 14 BP 1515 EP 1519 DI 10.1101/gad.197434.112 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 974FS UT WOS:000306417000002 PM 22802525 ER PT J AU Utermark, T Rao, T Cheng, HL Wang, Q Lee, SH Wang, ZGC Iglehart, JD Roberts, TM Muller, WJ Zhao, JJ AF Utermark, Tamara Rao, Trisha Cheng, Hailing Wang, Qi Lee, Sang Hyun Wang, Zhigang C. Iglehart, J. Dirk Roberts, Thomas M. Muller, William J. Zhao, Jean J. TI The p110 alpha and p110 beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis SO GENES & DEVELOPMENT LA English DT Article DE PI3K; HER2; genetic mouse model; mammary tumorigenesis ID REGULATORY SUBUNIT P85-ALPHA; HUMAN BREAST-CANCER; PHOSPHOINOSITIDE 3-KINASE; METABOLIC-REGULATION; CATALYTIC SUBUNIT; TRANSGENIC MICE; T-ANTIGEN; KINASE; TRANSFORMATION; TUMORS AB Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110 alpha blocks tumor formation in both polyoma middle T antigen (MT) and HER2/Neu transgenic models of breast cancer. Surprisingly, p110 beta ablation results in both increased ductal branching and tumorigenesis. Biochemical analyses suggest a competition model in which the less active p110 beta competes with the more active p110 alpha for receptor binding sites, thereby modulating the level of PI3K activity associated with activated receptors. Our findings demonstrate a novel p110 beta-based regulatory role in receptor-mediated PI3K activity and identify p110 alpha as an important target for treatment of HER2-positive disease. C1 [Rao, Trisha; Muller, William J.] McGill Univ, Goodman Canc Res Ctr, Dept Biochem, Montreal, PQ H3A 1A3, Canada. [Utermark, Tamara; Cheng, Hailing; Wang, Qi; Lee, Sang Hyun; Wang, Zhigang C.; Iglehart, J. Dirk; Roberts, Thomas M.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Utermark, Tamara; Cheng, Hailing; Wang, Qi; Lee, Sang Hyun; Roberts, Thomas M.; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Cheng, Hailing; Wang, Zhigang C.; Iglehart, J. Dirk; Zhao, Jean J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02215 USA. RP Muller, WJ (reprint author), McGill Univ, Goodman Canc Res Ctr, Dept Biochem, Montreal, PQ H3A 1A3, Canada. EM william.muller@mcgill.ca; jean_zhao@dfci.harvard.edu FU NIH [CA030002, CA050661, CA134502, P50CA089393-08S1, CA148164-01]; Stand Up to Cancer Dream Team Translational Research Grant; Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Department of Defense [BC051565]; V Foundation; Claudia Adams Barr Program; CIHR [MOP 89751]; Terry Fox Team Grant [NCIC 02002]; CRC Chair in Molecular Oncology; DOD studentship [W81XWH-09-01-0079] FX We thank Dr. Linda K. Clayton for critical reading and suggestions. We thank Dr. Roderick Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for histopathological analyses. This work was supported by NIH grants CA030002 (to T. M. R.), CA050661 (to T. M. R.), CA134502 (to J.J.Z.), P50CA089393-08S1 (to J.J.Z.), and CA148164-01 (to T. M. R. and J.J.Z.); Stand Up to Cancer Dream Team Translational Research Grant; a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) (T. M. R. and J.J.Z.); the Department of Defense (BC051565 to J.J.Z.); the V Foundation (J.J.Z.); the Claudia Adams Barr Program (J.J.Z.); CIHR (MOP 89751 to W. M.); Terry Fox Team Grant (NCIC 02002 to W.J.M.); a CRC Chair in Molecular Oncology (W. M.); and a DOD studentship (W81XWH-09-01-0079 to T. R.). In compliance with Harvard Medical School guidelines, we disclose that T. M. R. and J.J.Z. are consultants for Novartis Pharmaceuticals, Inc. NR 45 TC 46 Z9 47 U1 1 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2012 VL 26 IS 14 BP 1573 EP 1586 DI 10.1101/gad.191973.112 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 974FS UT WOS:000306417000008 PM 22802530 ER PT J AU Huang, H Woo, AJ Waldon, Z Schindler, Y Moran, TB Zhu, HH Feng, GS Steen, H Cantor, AB AF Huang, Hui Woo, Andrew J. Waldon, Zachary Schindler, Yocheved Moran, Tyler B. Zhu, Helen H. Feng, Gen-Sheng Steen, Hanno Cantor, Alan B. TI A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation SO GENES & DEVELOPMENT LA English DT Article DE RUNX1; tyrosine phosphorylation; c-Src; Shp2; megakaryocyte; T cell ID HEMATOPOIETIC STEM-CELLS; SHP2 TYROSINE PHOSPHATASE; GENOME-WIDE ANALYSIS; TRANSCRIPTION FACTOR; ADULT HEMATOPOIESIS; HUMAN LEUKEMIA; MOUSE EMBRYO; BINDING; AML1; ACTIVATION AB Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly. C1 [Huang, Hui; Woo, Andrew J.; Schindler, Yocheved; Moran, Tyler B.; Cantor, Alan B.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Childrens Hosp Boston,Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Waldon, Zachary; Steen, Hanno] Harvard Univ, Sch Med, Dept Pathol, Childrens Hosp Boston, Boston, MA 02115 USA. [Zhu, Helen H.; Feng, Gen-Sheng] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA. [Cantor, Alan B.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Cantor, AB (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Childrens Hosp Boston,Dept Pediat Hematol Oncol, Boston, MA 02115 USA. EM alan.cantor@childrens.harvard.edu FU NIH [R01 HL082952, R01 HL096125]; Gabrielle's Angel Foundation FX We thank Benjamin Neel, Rebecca Chan, Alan Friedman, Gordon Chan, Huafeng Xie, Xi Wang, and Zhe Li for helpful advice, and Nancy Speck, Yotis Senis, Martha Sola-Visner, and Wei Tong for sharing reagents and/or unpublished data. We also thank Gary Gilliland for providing RUNX1fl/fl mice, Thomas Graf for Vav-Cre mice, and Radek Skoda for PF4-Cre mice. This work was supported by NIH grants R01 HL082952 (to A. B. C.) and R01 HL096125 (to G.-S.F.) and a grant from the Gabrielle's Angel Foundation (to A. B. C.). H. H., H. S., and A. B. C. designed the experiments. H. H. carried out all experiments, except as otherwise stated for the other contributors. A.J.W. performed vWF immunohistochemistry experiments. Z.W. contributed to mass spectrometry analysis of RUNX1 phosphorylation. Y.S. performed Shp2 immunofluorescence studies. T. B. M. contributed to RUNX1 multiprotein complex purification and characterization. H.H.Z. constructed Shp2 conditional knockout mice. G-S. F. contributed Shp2 conditional knockout mice and assisted with interpretation of data. H. S. performed mass spectrometry analysis of RUNX1 tyrosine phosphorylation. H. H. and A. B. C. wrote the manuscript. NR 57 TC 21 Z9 22 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2012 VL 26 IS 14 BP 1587 EP 1601 DI 10.1101/gad.192054.112 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 974FS UT WOS:000306417000009 PM 22759635 ER PT J AU Buys, E Raher, M Kirby, A Mohd, S Baron, D Hayton, S Tainsh, L Sips, P Rauwerdink, K Tainsh, R Shakartzi, H Stevens, C Decaluwe, K Rodrigues-Machado, MD Malhotra, R Van de Voorde, J Wang, T Brouckaert, P Daly, M Bloch, K AF Buys, Emmanuel Raher, Michael Kirby, Andrew Mohd, Shahid Baron, David Hayton, Sarah Tainsh, Laurel Sips, Patrick Rauwerdink, Kristen Tainsh, Robert Shakartzi, Hannah Stevens, Christine Decaluwe, Kelly Rodrigues-Machado, Maria da Gloria Malhotra, Rajeev Van de Voorde, Johan Wang, Tong Brouckaert, Peter Daly, Mark Bloch, Kenneth TI Identification of renin signaling as a blood pressure modifying mechanism in soluble guanylate cyclase alpha(1)-deficient mice SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 7th International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide CY JUL 22-26, 2012 CL Edinburgh, SCOTLAND C1 [Buys, Emmanuel; Raher, Michael; Mohd, Shahid; Baron, David; Hayton, Sarah; Tainsh, Laurel; Sips, Patrick; Rauwerdink, Kristen; Tainsh, Robert; Shakartzi, Hannah; Rodrigues-Machado, Maria da Gloria; Malhotra, Rajeev; Bloch, Kenneth] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Anesthesia Ctr Crit Care Res,Dept Anesthesia Crit, Boston, MA USA. [Kirby, Andrew; Stevens, Christine; Daly, Mark] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Dept Med, Boston, MA USA. [Wang, Tong] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Decaluwe, Kelly; Van de Voorde, Johan] Univ Ghent, Dept Pharmacol, B-9000 Ghent, Belgium. [Malhotra, Rajeev; Bloch, Kenneth] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Brouckaert, Peter] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. OI Sips, Patrick/0000-0001-9241-5980 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUL 15 PY 2012 VL 27 SU 1 BP S25 EP S26 DI 10.1016/j.niox.2012.04.093 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973UD UT WOS:000306384400082 ER PT J AU Buys, E Ko, YC Hayton, S Jones, A Tainsh, L Ren, RY Abernathy, E Tainsh, R Oh, DJ Malhotra, R Loomis, S Kang, JH Gong, HY Rhee, D Brouckaert, P Wiggs, J Gregory, M Pasquale, L Bloch, K Ksander, B AF Buys, Emmanuel Ko, Yu-Chieh Hayton, Sarah Jones, Alexander Tainsh, Laurel Ren, Ruiyi Abernathy, Emma Tainsh, Robert Oh, Dong-Jin Malhotra, Rajeev Loomis, Stephanie Kang, Jae-Hee Gong, Haiyan Rhee, Douglas Brouckaert, Peter Wiggs, Janey Gregory, Meredith Pasquale, Louis Bloch, Kenneth Ksander, Bruce TI Open angle glaucoma in soluble guanylate cyclase alpha(1)-deficient mice and its association with the GUCY1A3/GUCY1B3 locus in humans SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 7th International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide CY JUL 22-26, 2012 CL Edinburgh, SCOTLAND C1 [Buys, Emmanuel; Hayton, Sarah; Tainsh, Laurel; Tainsh, Robert; Malhotra, Rajeev; Bloch, Kenneth] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Ko, Yu-Chieh; Jones, Alexander; Abernathy, Emma; Gregory, Meredith; Ksander, Bruce] Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA USA. [Ren, Ruiyi; Gong, Haiyan] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Oh, Dong-Jin; Loomis, Stephanie; Rhee, Douglas; Wiggs, Janey; Gregory, Meredith; Pasquale, Louis; Ksander, Bruce] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Malhotra, Rajeev; Bloch, Kenneth] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Kang, Jae-Hee] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Brouckaert, Peter] Dept Biomed Mol Biol, Ghent, Belgium. 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUL 15 PY 2012 VL 27 SU 1 BP S26 EP S26 DI 10.1016/j.niox.2012.04.094 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973UD UT WOS:000306384400083 ER PT J AU Lukacs-Kornek, V Malhotra, D Turley, SJ AF Lukacs-Kornek, Veronika Malhotra, Deepali Turley, Shannon J. TI Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 7th International Conference on the Biology, Chemistry and Therapeutic Application of Nitric Oxide CY JUL 22-26, 2012 CL Edinburgh, SCOTLAND C1 [Lukacs-Kornek, Veronika; Malhotra, Deepali; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Malhotra, Deepali] Harvard Univ, Div Med Sci, Sch Med, Boston, MA 02115 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUL 15 PY 2012 VL 27 SU 1 BP S8 EP S8 DI 10.1016/j.niox.2012.04.032 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973UD UT WOS:000306384400026 ER PT J AU Deng, XM Zhou, WJ Weisberg, E Wang, JH Zhang, JM Sasaki, T Nelson, E Griffin, JD Janne, PA Gray, NS AF Deng, Xianming Zhou, Wenjun Weisberg, Ellen Wang, Jinhua Zhang, Jianming Sasaki, Takaaki Nelson, Erik Griffin, James D. Jaenne, Pasi A. Gray, Nathanael S. TI An amino-indazole scaffold with spectrum selective kinase inhibition of FLT3, PDGFR alpha and kit SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Amino-indazole; Type-II kinase inhibitor ID BCR-ABL; C-SRC; CANCER; CONFORMATIONS; RESISTANCE; DISCOVERY; MUTATION; MUTANT AB Here we describe the synthesis and characterization of a number of 3-amino-1H-indazol-6-yl-benzamides that were designed to target the 'DFG-out' conformation of the kinase activation loop. Several compounds such as 4 and 11 exhibit single-digit nanomolar EC(50)s against FLT3, c-Kit and the gatekeeper T674M mutant of PDGFR alpha. (C) 2012 Published by Elsevier Ltd. C1 [Deng, Xianming; Zhou, Wenjun; Wang, Jinhua; Zhang, Jianming; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Deng, Xianming; Zhou, Wenjun; Wang, Jinhua; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Weisberg, Ellen; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. [Sasaki, Takaaki; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu FU NIH [CA130876-02] FX This work was supported by the NIH Grant number CA130876-02. We thank Ambit Biosciences for technical support in the compound KINOMEscan profiling and Maria Nicolais for helping with Cell-Titer Glo experiments. The kinase dendrogram was adapted and reproduced with permission from Cell Signaling Technology, Inc. (http://www.cellsignal.com). NR 16 TC 6 Z9 6 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUL 15 PY 2012 VL 22 IS 14 BP 4579 EP 4584 DI 10.1016/j.bmcl.2012.05.107 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 970AU UT WOS:000306101300017 PM 22727638 ER PT J AU Biswas, A Meissner, TB Kawai, T Kobayashi, KS AF Biswas, Amlan Meissner, Torsten B. Kawai, Taro Kobayashi, Koichi S. TI Cutting Edge: Impaired MHC Class I Expression in Mice Deficient for Nlrc5/Class I Transactivator SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NUCLEOTIDE-BINDING DOMAIN; BARE LYMPHOCYTE SYNDROME; FAMILY-MEMBER NLRC5; CIITA; LACKING; INDUCTION; RESPONSES; PATHWAYS; COMPLEX AB MHC class I and class II are crucial for the adaptive immune system. Although regulation of MHC class II expression by CIITA has long been recognized, the mechanism of MHC class I transactivation has been largely unknown until the recent discovery of NLRC5/class I transactivator. In this study, we show using Nlrc5-deficient mice that NLRC5 is required for both constitutive and inducible MHC class I expression. Loss of Nlrc5 resulted in severe reduction in the expression of MHC class I and related genes such as beta(2)-microglobulin, Tap1, or Lmp2, but did not affect MHC class II levels. IFN-gamma stimulation could not overcome the impaired MHC class I expression in Nlrc5-deficient cells. Upon infection with Listeria monocyogenes, Nlrc5-deficient mice displayed impaired CD8(+) T cell activation, accompanied with increased bacterial loads. These findings illustrate critical roles of NLRC5/class I transactivator in MHC class I gene regulation and host defense by CD8(+) T cell responses. The Journal of Immunology, 2012, 189: 516-520. C1 [Biswas, Amlan; Meissner, Torsten B.; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Biswas, Amlan; Meissner, Torsten B.; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [Kawai, Taro] Osaka Univ, Host Def Lab, World Premier Int Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan. [Kawai, Taro] Osaka Univ, Dept Host Def, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan. RP Kobayashi, KS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dana 1420A,450 Brookline Ave, Boston, MA 02215 USA. EM Koichi_Kobayashi@dfci.harvard.edu FU National Institutes of Health; Crohn's and Colitis Foundation of America; Cancer Research Institute; Claudia Adams Barr Award; European Molecular Biology Organization Long-Term fellowship; Crohn's Colitis Foundation of America fellowship FX This work was supported by grants from the National Institutes of Health and the Crohn's and Colitis Foundation of America. K.S.K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award. T.B.M. has been a recipient of the European Molecular Biology Organization Long-Term fellowship, and A.B. is a recipient of Crohn's Colitis Foundation of America fellowship. NR 23 TC 31 Z9 32 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2012 VL 189 IS 2 BP 516 EP 520 DI 10.4049/jimmunol.1200064 PG 5 WC Immunology SC Immunology GA 970HU UT WOS:000306119800009 PM 22711889 ER PT J AU Moran, MD Wilson, AA Elmore, CS Parkes, J Ng, A Sadovski, O Graff, A Daskalakis, ZJ Houle, S Chapdelaine, MJ Vasdev, N AF Moran, Matthew D. Wilson, Alan A. Elmore, Charles S. Parkes, Jun Ng, Alvina Sadovski, Oleg Graff, Ariel Daskalakis, Zafiris J. Houle, Sylvain Chapdelaine, Marc J. Vasdev, Neil TI Development of new carbon-11 labelled radiotracers for imaging GABA(A)- and GABA(B)-benzodiazepine receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Radiopharmaceuticals; Positron emission tomography; GABA(A) receptors; GABA(B) receptors; Carbon-11 ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO EVALUATION; ALCOHOL-PREFERRING RATS; BENZODIAZEPINE-RECEPTORS; ALLOSTERIC MODULATORS; PET; PHARMACOLOGY; RADIOLIGAND; LIGANDS; RADIOSYNTHESIS AB Two quinolines identified as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors containing the alpha(2) subunit, 9-amino-2-cyclobutyl-5-(6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (4) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (5), were radiolabelled at the methoxy position with carbon-11 (half-life = 20.4 min). These quinolines represent a new class of potential radiotracers for imaging the benzodiazepine site of GABA(A) receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [C-11]CH3I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [C-11]CO2) with high specific activities (>70 GBq mu mol (1); >2 Ci mu mol(-1)) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [C-11]2-methoxypyridine moieties. Although both radiotracers demonstrated promising imaging characteristics based on preliminary ex vivo biodistribution studies in conscious rodents, higher brain uptake was observed with [C-11]5 and therefore this radiotracer was further evaluated. Carbon-11 labelled 5 readily penetrated the brain (>1 standard uptake value in cortical regions at 15 min post-injection of the radiotracer), had an appropriate regional brain distribution for GABA(A) receptors that appeared to be reversible, and did not show any appreciable radiometabolites in rat brain homogenates up to 15 min post-injection. Preadministration of flumazenil (1, 10mg kg (1)) or 5 (5 mg kg (1)) effectively blocked >50% of [C-11]5 binding to the GABA(A) receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABA(A) receptors. Additionally (R,S)-N-(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3-diphenylpropan-1-amine, 6, an allosteric modulator of GABA(B) receptors, was efficiently labelled in one step using [C-11]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABA(B). In conclusion, [C-11]5 is worthy of further evaluation in higher species for imaging GABA(A) receptors in the central nervous system. Published by Elsevier Ltd. C1 [Moran, Matthew D.; Wilson, Alan A.; Parkes, Jun; Ng, Alvina; Sadovski, Oleg; Graff, Ariel; Daskalakis, Zafiris J.; Houle, Sylvain; Vasdev, Neil] Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada. [Moran, Matthew D.; Wilson, Alan A.; Parkes, Jun; Ng, Alvina; Sadovski, Oleg; Graff, Ariel; Daskalakis, Zafiris J.; Houle, Sylvain; Vasdev, Neil] Univ Toronto, Toronto, ON M5T 1R8, Canada. [Elmore, Charles S.; Chapdelaine, Marc J.] AstraZeneca, Dept Chem, Wilmington, DE 19850 USA. [Elmore, Charles S.] AstraZeneca, Dept DMPK, Molndal, Sweden. RP Vasdev, N (reprint author), Massachusetts Gen Hosp, Dept Nucl Med & Mol Imaging, Boston, MA 02114 USA. EM vasdev.neil@mgh.harvard.edu RI Wilson, Alan/A-1788-2011; Graff, Ariel/G-6624-2012; Daskalakis, Zafiris/J-5503-2013 OI Daskalakis, Zafiris/0000-0001-9502-0538 FU CAMH FX The authors thank Armando Garcia, Winston Stableford and Min Wong for assistance with the radiochemisty, and Justin Hicks for assistance with the logD7.4 determinations. CAMH is gratefully acknowledged for support in the form of a post-doctoral fellowship (M.D.M.). NR 50 TC 10 Z9 10 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2012 VL 20 IS 14 BP 4482 EP 4488 DI 10.1016/j.bmc.2012.05.046 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 968BR UT WOS:000305952500035 PM 22717238 ER PT J AU Mak, RH Alexander, BM Asomaning, K Heist, RS Liu, CY Su, L Zhai, RH Ancukiewicz, M Napolitano, B Niemierko, A Willers, H Choi, NC Christiani, DC AF Mak, Raymond H. Alexander, Brian M. Asomaning, Kofi Heist, Rebecca S. Liu, Chen-yu Su, Li Zhai, Rihong Ancukiewicz, Marek Napolitano, Brian Niemierko, Andrzej Willers, Henning Choi, Noah C. Christiani, David C. TI A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy SO CANCER LA English DT Article DE radiation pneumonitis; single-nucleotide polymorphism; lung cancer; oxidative stress; MTHFR ID VOLUME HISTOGRAM ANALYSIS; CONCURRENT CHEMOTHERAPY; PHASE-III; RADIOTHERAPY; CISPLATIN; NSCLC AB BACKGROUND: This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer. METHODS: A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades =2 and =3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting. RESULTS: With a median follow-up of 21.4 months, the incidence of grade =2 RP was 29% and grade =3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade =2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade =3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP. CONCLUSIONS: This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP. Cancer 2012;36543665. (C) 2011 American Cancer Society. C1 [Asomaning, Kofi; Heist, Rebecca S.; Liu, Chen-yu; Su, Li; Zhai, Rihong; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Mak, Raymond H.] Harvard Radiat Oncol Program, Boston, MA USA. [Alexander, Brian M.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Heist, Rebecca S.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Liu, Chen-yu] Natl Taiwan Univ, Inst Environm Hlth, Taipei 10764, Taiwan. [Ancukiewicz, Marek; Napolitano, Brian; Niemierko, Andrzej; Willers, Henning; Choi, Noah C.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg 1,Room 1402, Boston, MA 02115 USA. EM dchristi@hsph.harvard.edu OI LIU, CHEN-YU/0000-0002-4693-5667 FU National Institutes of Health [CA 74386] FX Supported by the National Institutes of Health (grant CA 74386). NR 21 TC 11 Z9 13 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2012 VL 118 IS 14 BP 3654 EP 3665 DI 10.1002/cncr.26667 PG 12 WC Oncology SC Oncology GA 967FD UT WOS:000305890900026 PM 22144047 ER PT J AU Ellis, JW Chen, MH Foster, MC Liu, CT Larson, MG de Boer, I Kottgen, A Parsa, A Bochud, M Boger, CA Kao, L Fox, CS O'Seaghdha, CM AF Ellis, Jaclyn W. Chen, Ming-Huei Foster, Meredith C. Liu, Ching-Ti Larson, Martin G. de Boer, Ian Koettgen, Anna Parsa, Afshin Bochud, Murielle Boeger, Carsten A. Kao, Linda Fox, Caroline S. O'Seaghdha, Conall M. CA CKDGen Consortium CARe Renal Consortium TI Validated SNPs for eGFR and their associations with albuminuria SO HUMAN MOLECULAR GENETICS LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION; ALBUMIN/CREATININE RATIO; DIABETIC-NEPHROPATHY; BLOOD-PRESSURE; CYSTATIN-C; MICROALBUMINURIA; POPULATION; PREVALENCE AB Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR 25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta 0.034, P-value 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P 0.007. Although we found the genotype score to be associated with albuminuria (P 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits. C1 [Ellis, Jaclyn W.; Foster, Meredith C.; Fox, Caroline S.; O'Seaghdha, Conall M.] NHLBIs Framingham Heart Study, Chapel Hill, NC 27599 USA. [Ellis, Jaclyn W.; Foster, Meredith C.; Fox, Caroline S.; O'Seaghdha, Conall M.] Ctr Populat Studies, Chapel Hill, NC 27599 USA. [Ellis, Jaclyn W.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Liu, Ching-Ti] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02117 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [de Boer, Ian] Univ Washington, Div Nephrol, Seattle, WA 98104 USA. [de Boer, Ian] Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. [Koettgen, Anna] Freiburg Univ Clin, Div Renal, D-79110 Freiburg, Germany. [Koettgen, Anna; Kao, Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Deparment Epidemiol, Baltimore, MD 21205 USA. [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Bochud, Murielle] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1066 Epalinges, Switzerland. [Bochud, Murielle] Univ Lausanne, CH-1066 Epalinges, Switzerland. [Boeger, Carsten A.] Univ Med Ctr Regensburg, Dept Internal Med 2, D-93042 Regensburg, Germany. [Kao, Linda] Welch Ctr Prevent, Baltimore, MD 21287 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.; O'Seaghdha, Conall M.] Harvard Univ, Sch Med, Boston, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP O'Seaghdha, CM (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM conall.o'seaghdha@nih.gov RI Rudan, Igor/I-1467-2012; Colaus, PsyColaus/K-6607-2013; Gudnason, Vilmundur/K-6885-2015; Polasek, Ozren/B-6002-2011; Kronenberg, Florian/B-1736-2008; Bochud, Murielle/A-3981-2010; Smith, Albert Vernon/K-5150-2015 OI Rudan, Igor/0000-0001-6993-6884; Gudnason, Vilmundur/0000-0001-5696-0084; Polasek, Ozren/0000-0002-5765-1862; Kronenberg, Florian/0000-0003-2229-1120; Bochud, Murielle/0000-0002-5727-0218; Larson, Martin/0000-0002-9631-1254; Magi, Reedik/0000-0002-2964-6011; Fuchsberger, Christian/0000-0002-5918-8947; Smith, Albert Vernon/0000-0003-1942-5845 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195). NR 28 TC 11 Z9 11 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2012 VL 21 IS 14 BP 3293 EP 3298 DI 10.1093/hmg/dds138 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 966FI UT WOS:000305822700017 PM 22492995 ER PT J AU Linas, BP Wong, AY Schackman, BR Kim, AY Freedberg, KA AF Linas, Benjamin P. Wong, Angela Y. Schackman, Bruce R. Kim, Arthur Y. Freedberg, Kenneth A. TI Cost-effective Screening for Acute Hepatitis C Virus Infection in HIV-Infected Men Who Have Sex With Men SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUSTAINED VIROLOGICAL RESPONSE; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; ALPHA-2A PLUS RIBAVIRIN; HEALTH-STATE UTILITIES; NEW-YORK-CITY; HIV-1-INFECTED PATIENTS; NATURAL-HISTORY; UNITED-STATES AB Background. We used a Monte Carlo computer simulation to estimate the effectiveness and cost-effectiveness of screening for acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected men who have sex with men. Methods. One-time screening for prevalent HCV infection was performed at the time of enrollment in care, followed by either symptom-based screening, screening with liver function tests (LFTs), HCV antibody (Ab) screening, or HCV RNA screening in various combinations and intervals. We considered both treatment with pegylated interferon and ribavirin (PEG/RBV) alone and with an HCV protease inhibitor. Outcome measures were life expectancy, quality-adjusted life expectancy, direct medical costs, and cost-effectiveness, assuming a societal willingness to pay $100 000 per quality-adjusted life-year (QALY) gained. Results. All strategies increased life expectancy (from 0.49 to 0.94 life-months), quality-adjusted life expectancy (from 0.47 to 1.00 quality-adjusted life-months), and costs (from $1900 to $7600), compared with symptom-based screening. The incremental cost-effectiveness ratio of screening with 6-month LFTs and a 12-month HCV Ab test, compared with symptom-based screening, was $43 700/QALY (for PEG/RBV alone) and $57 800/QALY (for PEG/RBV plus HCV protease inhibitor). The incremental cost-effectiveness ratio of screening with 3-month LFTs, compared with 6-month LFTs plus a 12-month HCVAb test, was $129 700/QALY (for PEG/RBV alone) and $229 900/QALY (for PEG/RBV plus HCV protease inhibitor). With HCV protease inhibitor-based therapy, screening with 6-month LFTs and a 12-month HCV Ab test was the optimal strategy when the HCV infection incidence was <= 1.25 cases/100 person-years. The 3-month LFT strategy was optimal when the incidence was >1.25 cases/100 person-years. Conclusions. Screening for acute HCV infection in HIV-infected MSM prolongs life expectancy and is cost-effective. Depending on incidence, regular screening with LFTs, with or without an HCV Ab test, is the optimal strategy. C1 [Linas, Benjamin P.] Boston Med Ctr, Infect Dis Sect, HIV Epidemiol & Outcomes Res Unit, Boston, MA 02118 USA. [Linas, Benjamin P.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wong, Angela Y.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Kim, Arthur Y.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kim, Arthur Y.; Freedberg, Kenneth A.] Harvard Ctr AIDS Res, Boston, MA USA. [Schackman, Bruce R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. RP Linas, BP (reprint author), Boston Med Ctr, Infect Dis Sect, HIV Epidemiol & Outcomes Res Unit, 850 Harrison Ave,Dowling 3N,Rm 3205, Boston, MA 02118 USA. EM Benjamin.Linas@BMC.org OI Linas, Benjamin/0000-0001-9574-7075 FU National Institute of Allergy and Infectious Diseases [K01AI073193, K24AI062476, R37AI42006, R01 DA027379, U19 AI066345]; National Institute on Drug Abuse FX This work was supported by the National Institute of Allergy and Infectious Diseases (K01AI073193, K24AI062476, R37AI42006, R01 DA027379, and U19 AI066345). The project described was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute on Drug Abuse. NR 68 TC 29 Z9 29 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 15 PY 2012 VL 55 IS 2 BP 279 EP 290 DI 10.1093/cid/cis382 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 963IE UT WOS:000305612800023 PM 22491339 ER PT J AU Arvold, ND Niemierko, A Broussard, GP Adams, J Fullerton, B Loeffler, JS Shih, HA AF Arvold, Nils D. Niemierko, Andrzej Broussard, George P. Adams, Judith Fullerton, Barbara Loeffler, Jay S. Shih, Helen A. TI Projected Second Tumor Risk and Dose to Neurocognitive Structures After Proton Versus Photon Radiotherapy for Benign Meningioma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the Particle-Therapy-Co-Operative-Group CY MAY 08-14, 2011 CL Philadelphia, PA SP Particle Therapy Co-Operat Grp DE Second tumor risk; Proton radiotherapy; Photon radiotherapy; Benign meningioma; Neurocognitive ID CONFORMAL RADIOTHERAPY; INTRACRANIAL TUMORS; THERAPY; CANCER; MEDULLOBLASTOMA; DISTRIBUTIONS; IRRADIATION; SURVIVORS; OUTCOMES; BEAMS AB Purpose: To calculated projected second tumor rates and dose to organs at risk (OAR) in patients with benign intracranial meningioma (BM), according to dosimetric comparisons between proton radiotherapy (PRT) and photon radiotherapy (XRT) treatment plans. Methods and Materials: Ten patients with BM treated at Massachusetts General Hospital during 2006-2010 with PRT were replanned with XRT (intensity-modulated or three-dimensional conformal radiotherapy), optimizing dose to the tumor while sparing OAR. Total dose was 54 Gy in 1.8 Gy per fraction for all plans. We calculated equivalent uniform doses, normal tissue complication probabilities, and whole brain-based estimates of excess risk of radiation-associated intracranial second tumors. Results: Excess risk of second tumors was significantly lower among PRT compared with XRT plans (1.3 vs. 2.8 per 10,000 patients per year, p < 0.002). Mean equivalent uniform doses were lower among PRT plans for the whole brain (19.0 vs. 22.8 Gy, p < 0.0001), brainstem (23.8 vs. 35.2 Gy, p = 0.004), hippocampi (left, 13.5 vs. 25.6 Gy, p < 0.0001; right, 7.6 vs. 21.8 Gy, p = 0.001), temporal lobes (left, 25.8 vs. 34.6 Gy, p = 0.007; right, 25.8 vs. 32.9 Gy, p = 0.008), pituitary gland (29.2 vs. 37.0 Gy, p = 0.047), optic nerves (left, 28.5 vs. 33.8 Gy, p = 0.04; right, 25.1 vs. 31.1 Gy, p = 0.07), and cochleas (left, 12.2 vs. 15.8 Gy, p = 0.39; right, 1.5 vs. 8.8 Gy, p =0.01). Mean normal tissue complication probability was <1% for all structures and not significantly different between PRT and XRT plans. Conclusions: Compared with XRT, PRT for BM decreases the risk of RT-associated second tumors by half and delivers significantly lower doses to neurocognitive and critical structures of vision and hearing. (C) 2012 Elsevier Inc. C1 [Niemierko, Andrzej; Broussard, George P.; Adams, Judith; Fullerton, Barbara; Loeffler, Jay S.; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Arvold, Nils D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. RP Shih, HA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM hshih@partners.org NR 20 TC 11 Z9 11 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP E495 EP E500 DI 10.1016/j.ijrobp.2011.10.056 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400007 PM 22285662 ER PT J AU Chen, RC Mamon, HJ Ancukiewicz, M Killoran, JH Crowley, EM Blaszkowsky, LS Wo, JY Ryan, DP Hong, TS AF Chen, Ronald C. Mamon, Harvey J. Ancukiewicz, Marek Killoran, Joseph H. Crowley, Elizabeth M. Blaszkowsky, Lawrence S. Wo, Jennifer Y. Ryan, David P. Hong, Theodore S. TI Dose-Volume Effects on Patient-Reported Acute Gastrointestinal Symptoms During Chemoradiation Therapy for Rectal Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Rectal cancer; Chemoradiation therapy; Patient-reported outcomes; Quality of life; Dose-volume histogram ID SMALL-BOWEL TOXICITY; PREOPERATIVE CHEMORADIOTHERAPY; RADIOTHERAPY; OUTCOMES; ADJUVANT AB Purpose: Research on patient-reported outcomes (PROs) in rectal cancer is limited. We examined whether dose-volume parameters of the small bowel and large bowel were associated with patient-reported gastrointestinal (GI) symptoms during 5-fluorouracil (5-FU)-based chemoradiation treatment for rectal cancer. Methods and Materials: 66 patients treated at the Brigham & Women's Hospital or Massachusetts General Hospital between 2006 and 2008 were included. Weekly during treatment, patients completed a questionnaire assessing severity of diarrhea, urgency, pain, cramping, mucus, and tenesmus. The association between dosimetric parameters and changes in overall GI symptoms from baseline through treatment was examined by using Spearman's correlation. Potential associations between these parameters and individual GI symptoms were also explored. Results: The amount of small bowel receiving at least 15 Gy (V15) was significantly associated with acute symptoms (p = 0.01), and other dosimetric parameters ranging from V5 to V45 also trended toward association. For the large bowel, correlations between dosimetric parameters and overall GI symptoms at the higher dose levels from V25 to V45 did not reach statistical significance (p = 0.1), and a significant association was seen with rectal pain from V15 to V45 (p < 0.01). Other individual symptoms did not correlate with small bowel or large bowel dosimetric parameters. Conclusions: The results of this study using PROs are consistent with prior studies with physician-assessed acute toxicity, and they identify small bowel V15 as an important predictor of acute GI symptoms during 5-FU-based chemoradiation treatment. A better understanding of the relationship between radiation dosimetric parameters and PROs may allow physicians to improve radiation planning to optimize patient outcomes. (C) 2012 Elsevier Inc. C1 [Chen, Ronald C.; Ancukiewicz, Marek; Crowley, Elizabeth M.; Wo, Jennifer Y.; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Blaszkowsky, Lawrence S.; Ryan, David P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chen, Ronald C.; Mamon, Harvey J.; Killoran, Joseph H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Chen, Ronald C.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. [Chen, Ronald C.; Mamon, Harvey J.; Killoran, Joseph H.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM tshong1@partners.org NR 16 TC 5 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP E513 EP E517 DI 10.1016/j.ijrobp.2012.01.013 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400010 PM 22436781 ER PT J AU Dyer, MA Kelly, PJ Chen, YH Pinnell, NE Claus, EB Lee, EQ Weiss, SE Arvold, ND Lin, NU Alexander, BM AF Dyer, Michael A. Kelly, Paul J. Chen, Yu-Hui Pinnell, Nancy E. Claus, Elizabeth B. Lee, Eudocia Q. Weiss, Stephanie E. Arvold, Nils D. Lin, Nancy U. Alexander, Brian M. TI Importance of Extracranial Disease Status and Tumor Subtype for Patients Undergoing Radiosurgery for Breast Cancer Brain Metastases SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Breast cancer; Brain metastases; Tumor subtype; Extracranial disease; Radiosurgery ID PROGNOSTIC-FACTORS; STRATIFICATION SYSTEMS; CLINICAL-OUTCOMES; RADIOTHERAPY; INDEX; RPA AB Purpose: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases. Methods and Materials: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) <= 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS <= 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes. Conclusions: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS. (C) 2012 Elsevier Inc. C1 [Alexander, Brian M.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Yu-Hui] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Claus, Elizabeth B.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Claus, Elizabeth B.] Yale Univ, Sch Med, New Haven, CT USA. [Lee, Eudocia Q.] Dana Farber Brigham & Womens Ctr, Ctr Neurooncol, Boston, MA USA. [Arvold, Nils D.] Harvard Radiat Oncol Program, Boston, MA USA. [Lin, Nancy U.] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA. RP Alexander, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM bmalexander@lroc.harvard.edu FU Breast Cancer Research Foundation FX The authors acknowledge salary support (to N.U.L.) by the Breast Cancer Research Foundation for work in brain metastases. NR 20 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP E479 EP E486 DI 10.1016/j.ijrobp.2012.01.054 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400005 PM 22704705 ER PT J AU Wilder, RB Buyyounouski, MK Efstathiou, JA Beard, CJ AF Wilder, Richard B. Buyyounouski, Mark K. Efstathiou, Jason A. Beard, Clair J. TI Radiotherapy Treatment Planning for Testicular Seminoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review DE Radiotherapy; Field; Dose; Testicular; Seminoma ID STAGE-I SEMINOMA; GERM-CELL TUMORS; CONSENSUS-GROUP EGCCCG; LONG-TERM SURVIVORS; FOLLOW-UP; RANDOMIZED-TRIAL; PROSPECTIVE MULTICENTER; EUROPEAN CONSENSUS; RADIATION-THERAPY; TARGET VOLUME AB Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 x 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior-posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e. g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy). (C) 2012 Elsevier Inc. C1 [Wilder, Richard B.] H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, Tampa, FL 33612 USA. [Buyyounouski, Mark K.] Fox Chase Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19111 USA. [Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Beard, Clair J.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. RP Wilder, RB (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM richardbwilder@yahoo.com NR 67 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2012 VL 83 IS 4 BP E445 EP E452 DI 10.1016/j.ijrobp.2012.01.044 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 960WK UT WOS:000305423400001 PM 22436787 ER PT J AU Smith, MA Covington, MD Schnellmann, RG AF Smith, Matthew A. Covington, Marisa D. Schnellmann, Rick G. TI Loss of calpain 10 causes mitochondrial dysfunction during chronic hyperglycemia SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Calpain 10; Kidney; Hyperglycemia; siRNA; Mitochondria; Dysfunction ID TYPE-2 DIABETES-MELLITUS; OXIDATIVE STRESS; LON PROTEASE; BETA-CELLS; EXPRESSION; MECHANISM; PARKIN; KIDNEY; INJURY; RATS AB We showed that renal calpain 10, a mitochondrial and cytosolic Ca2+-regulated cysteine protease, is specifically decreased in kidneys of diabetic rats and mice, and is associated with diabetic nephropathy. The goals of this study were to examine renal calpain 10 and mitochondrial dysfunction in streptozotocin-induced hyperglycemic rats and determine the effects of siRNA-mediated knock down of renal calpain 10 on mitochondrial function. Four weeks after streptozotocin injection, calpain 10 protein and mRNA were decreased and calpain 10 substrates accumulated. We detected increased state 2 respiration in isolated renal mitochondria and increased markers of mitochondrial fission and mitophagy. All changes were prevented by daily insulin injection. Compared to scrambled siRNA, calpain 10 siRNA resulted in a marked decrease in renal calpain 10 at 2,5 and 7 days. In concert with the loss of renal calpain 10, calpain 10 substrates accumulated, mitochondrial fusion decreased, mitochondrial fission and mitophagy increased. In summary, insulin-sensitive hyperglycemia induced loss of renal calpain 10 is correlated with renal mitochondrial dysfunction, fission and mitophagy, and specific depletion of renal calpain 10 produces similar mitochondria! defects. These results provide evidence that diabetes-induced renal mitochondrial dysfunction and renal injury may directly result from the loss of renal calpain 10. Published by Elsevier Inc. C1 [Smith, Matthew A.; Covington, Marisa D.; Schnellmann, Rick G.] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Ctr Cell Death Injury & Regenerat, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Schnellmann, RG (reprint author), Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Ctr Cell Death Injury & Regenerat, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. EM schnell@musc.edu FU NIH [GM 084147, C06 RR-015455]; NIEHS [ES-012239]; NIH/NIEHS [T32ES012878HS] FX This study was supported by NIH Grant [GM 084147], the NIEHS Grant [ES-012239], the NIH/NIEHS Training Program in Environmental Stress Signaling [T32ES012878HS Training Program in Environmental Stress Sig and Development Program of the Department of Veterans Affairs. Animal facilities were funded by NIH grant [C06 RR-015455]. NR 42 TC 7 Z9 9 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUL 15 PY 2012 VL 523 IS 2 BP 161 EP 168 DI 10.1016/j.abb.2012.04.020 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 959HR UT WOS:000305304000004 PM 22568896 ER PT J AU Watkins, GR Wang, N Mazalouskas, MD Gomez, RJ Guthrie, CR Kraemer, BC Schweiger, S Spiller, BW Wadzinski, BE AF Watkins, Guy R. Wang, Ning Mazalouskas, Matthew D. Gomez, Rey J. Guthrie, Chris R. Kraemer, Brian C. Schweiger, Susann Spiller, Benjamin W. Wadzinski, Brian E. TI Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit alpha 4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID E3 UBIQUITIN LIGASE; OPITZ-SYNDROME; ALZHEIMERS-DISEASE; BINDING; TAU; ENZYME; MID1; DEGRADATION; PROTEOLYSIS; RESOLUTION AB Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. alpha 4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of alpha 4 triggers calpain-mediated cleavage and switches alpha 4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved alpha 4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of alpha 4, and dysregulation of alpha 4 cleavage may contribute to Opitz syndrome and Alzheimer disease. C1 [Watkins, Guy R.; Wang, Ning; Mazalouskas, Matthew D.; Gomez, Rey J.; Spiller, Benjamin W.; Wadzinski, Brian E.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Guthrie, Chris R.; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Kraemer, Brian C.] Univ Washington, Div Gerontol & Geriatr Med, Dept Med, Seattle, WA 98104 USA. [Schweiger, Susann] Univ Dundee, Sch Med, Med Res Inst, Div Neurosci, Dundee DD1 SY9, Scotland. RP Wadzinski, BE (reprint author), Vanderbilt Univ, Med Ctr, Dept Pharmacol, 424 RRB, Nashville, TN 37232 USA. EM brian.wadzinski@vanderbilt.edu FU National Institutes of Health [DK070787, GM051366, NS064131, T32 GM07628]; American Cancer Society [IRG-58-009-49]; Department of Veterans Affairs Merit Review Grant [114891]; Ataxia UK; Tenovus Scotland FX This work was supported by National Institutes of Health Grants DK070787 and GM051366 (to B. E. W.), NS064131 (to B. C. K.), and T32 GM07628 (to G. R. W.); American Cancer Society IRG-58-009-49 (to B. W. S.); Department of Veterans Affairs Merit Review Grant 114891 (to B. C. K.); and Ataxia UK and Tenovus Scotland (to S. S.). NR 36 TC 17 Z9 22 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2012 VL 287 IS 29 BP 24207 EP 24215 DI 10.1074/jbc.M112.368613 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100015 PM 22613722 ER PT J AU Lei, IL Gao, XL Sham, MH Wang, Z AF Lei, Ienglam Gao, Xiaolin Sham, Mai Har Wang, Zhong TI SWI/SNF Protein Component BAF250a Regulates Cardiac Progenitor Cell Differentiation by Modulating Chromatin Accessibility during Second Heart Field Development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REMODELING COMPLEX; NEUREGULIN RECEPTOR; MUSCLE DEVELOPMENT; OUTFLOW-TRACT; SUBUNIT; PLURIPOTENCY; REQUIREMENT; EXPRESSION; ORIGINS; DISEASE AB ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation. C1 [Lei, Ienglam; Sham, Mai Har] Univ Hong Kong, Dept Biochem, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China. [Lei, Ienglam; Gao, Xiaolin; Wang, Zhong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lei, Ienglam; Gao, Xiaolin; Wang, Zhong] Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Sham, MH (reprint author), Univ Hong Kong, Dept Biochem, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China. EM mhsham@hku.hk; zhwang@partners.org OI Sham, Mai Har/0000-0003-1179-7839 FU National Institutes of Health [R01 HL109054-01]; Harvard Stem Cell Institute; Massachusetts General Hospital; Stem Cell and Regenerative Medicine Consortium at Hong Kong University; Hong Kong University-Massachusetts General Hospital FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 HL109054-01 (to Z. W.). This work was also supported by a seed grant from the Harvard Stem Cell Institute (to Z. W.), an internal grant from Massachusetts General Hospital (to Z. W.), and the Stem Cell and Regenerative Medicine Consortium at Hong Kong University (to M. H. S.).; Supported by a Hong Kong University-Massachusetts General Hospital joint Ph.D. studentship. NR 35 TC 23 Z9 24 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2012 VL 287 IS 29 BP 24255 EP 24262 DI 10.1074/jbc.M112.365080 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100019 PM 22621927 ER PT J AU Bensing, BA Yen, YT Seepersaud, R Sullam, PM AF Bensing, Barbara A. Yen, Yihfen T. Seepersaud, Ravin Sullam, Paul M. TI A Specific Interaction between SecA2 and a Region of the Preprotein Adjacent to the Signal Peptide Occurs during Transport via the Accessory Sec System SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING PROTEIN-GSPB; STREPTOCOCCUS-PNEUMONIAE ADHESIN; SURFACE GLYCOPROTEIN GSPB; STAPHYLOCOCCUS-AUREUS; HUMAN PLATELETS; ATPASE SECA; GORDONII; EXPORT; GLYCOSYLATION; TRANSLOCATION AB The accessory Sec systems of streptococci and staphylococci mediate the transport of a family of large, serine-rich glycoproteins to the bacterial cell surface. These systems are comprised of SecA2, SecY2, and three core accessory Sec proteins (Asp1-3). In Streptococcus gordonii, transport of the serine-rich glycoprotein GspB requires both a unique 90-residue N-terminal signal peptide and an adjacent 24-residue segment (the AST domain). We used in vivo site-specific photo-cross-linking to identify proteins that interact with the AST domain during transport. To facilitate this analysis, the entire accessory Sec system of S. gordonii was expressed in Escherichia coli. The determinants of GspB trafficking to the accessory Sec system in E. coli matched those in S. gordonii, establishing the validity of this approach. When the photo-cross-linker was placed within the AST domain, the preprotein was found to cross-link to SecA2. Importantly, no cross-linking to SecA was detected. Cross-linking of the N-terminal end of the AST domain to SecA2 occurred regardless of whether Asp1-3 were present. However, cross-linking to the C-terminal end was dependent on the Asps. The combined results indicate that full engagement of the AST domain by SecA2 is modulated by one or more of the Asps, and suggest that this process is important for initiating transport. C1 San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94121 USA. RP Sullam, PM (reprint author), VA Med Ctr, Div Infect Dis, 111W,4150 Clement St, San Francisco, CA 94121 USA. EM paul.sullam@ucsf.edu FU National Institutes of Health [RO1AI41513]; Dept. of Veterans Affairs; VA Merit Review program; Northern California Institute for Research and Education; American Heart Association FX This work was supported, in whole or in part, by the National Institutes of Health Grant RO1AI41513 (to P. S.), the Dept. of Veterans Affairs, and the VA Merit Review program, the Northern California Institute for Research and Education, and by a Postdoctoral Fellowship Award from the American Heart Association (to Y. Y.). NR 42 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2012 VL 287 IS 29 BP 24438 EP 24447 DI 10.1074/jbc.M112.378059 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100037 PM 22654116 ER PT J AU Ramos, TN Darley, MM Weckbach, S Stahel, PF Tomlinson, S Barnum, SR AF Ramos, Theresa N. Darley, Meghan M. Weckbach, Sebastian Stahel, Philip F. Tomlinson, Stephen Barnum, Scott R. TI The C5 Convertase Is Not Required for Activation of the Terminal Complement Pathway in Murine Experimental Cerebral Malaria SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXPERIMENTAL SIMIAN MALARIA; C6 DEFICIENCY; TARGETED EXPRESSION; PLASMINOGEN-BINDING; FACTOR-B; MICE; COAGULATION; COMPONENT; C3; SUSCEPTIBILITY AB Cerebral malaria (CM) is the most severe manifestation of clinical malaria syndromes and has a high fatality rate especially in the developing world. Recent studies demonstrated that C5(-/-) mice are resistant to experimental CM (ECM) and that protection was due to the inability to form the membrane attack complex. Unexpectedly, we observed that C4(-/-) and factor B-/- mice were fully susceptible to disease, indicating that activation of the classical or alternative pathways is not required for ECM. C3(-/-) mice were also susceptible to ECM, indicating that the canonical C5 convertases are not required for ECM development and progression. Abrogation of ECM by treatment with anti-C9 antibody and detection of C5a in serum of C3(-/-) mice confirmed that C5 activation occurs in ECM independent of C5 convertases. Our data indicate that activation of C5 in ECM likely occurs via coagulation enzymes of the extrinsic protease pathway. C1 [Ramos, Theresa N.; Darley, Meghan M.; Barnum, Scott R.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Ramos, Theresa N.; Darley, Meghan M.; Barnum, Scott R.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Weckbach, Sebastian; Stahel, Philip F.] Univ Colorado, Dept Orthoped Surg, Denver, CO 80204 USA. [Weckbach, Sebastian; Stahel, Philip F.] Univ Colorado, Dept Neurosurg, Denver, CO 80204 USA. [Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Barnum, SR (reprint author), Univ Alabama Birmingham, Dept Microbiol, 845 19th St S,BBRB-842, Birmingham, AL 35294 USA. EM sbarnum@uab.edu FU National Institutes of Health [T32 AI07051, NS077811, AI08382, HL82485]; Veterans Affairs Grant [NURC-051-10F]; German Research Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants T32 AI07051 and NS077811 (to T. N. R.), AI08382 (to S. R. B.), and HL82485 (to S. T.). This work was also supported by Veterans Affairs Grant NURC-051-10F (to S. T.) and a research fellowship from the German Research Foundation (to S. W.). NR 44 TC 16 Z9 16 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2012 VL 287 IS 29 BP 24734 EP 24738 DI 10.1074/jbc.C112.378364 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 977IQ UT WOS:000306651100066 PM 22689574 ER PT J AU Kim, HG Kim, HT Leach, NT Lan, F Ullmann, R Silahtaroglu, A Kurth, I Nowka, A Seong, IS Shen, YP Talkowski, ME Ruderfer, D Lee, JH Glotzbach, C Ha, K Kjaergaard, S Levin, AV Romeike, BF Kleefstra, T Bartsch, O Elsea, SH Jabs, EW MacDonald, ME Harris, DJ Quade, BJ Ropers, HH Shaffer, LG Kutsche, K Layman, LC Tommerup, N Kalscheuer, VM Shi, Y Morton, CC Kim, CH Gusella, JF AF Kim, Hyung-Goo Kim, Hyun-Taek Leach, Natalia T. Lan, Fei Ullmann, Reinhard Silahtaroglu, Asli Kurth, Ingo Nowka, Anja Seong, Ihn Sik Shen, Yiping Talkowski, Michael E. Ruderfer, Douglas Lee, Ji-Hyun Glotzbach, Caron Ha, Kyungsoo Kjaergaard, Susanne Levin, Alex V. Romeike, Bernd F. Kleefstra, Tjitske Bartsch, Oliver Elsea, Sarah H. Jabs, Ethylin Wang MacDonald, Marcy E. Harris, David J. Quade, Bradley J. Ropers, Hans-Hilger Shaffer, Lisa G. Kutsche, Kerstin Layman, Lawrence C. Tommerup, Niels Kalscheuer, Vera M. Shi, Yang Morton, Cynthia C. Kim, Cheol-Hee Gusella, James F. TI Translocations Disrupting PHF21A in the Potocki-Shaffer-Syndrome Region Are Associated with Intellectual Disability and Craniofacial Anomalies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-DELETION SYNDROME; BALANCED CHROMOSOME REARRANGEMENTS; CHROMATIN-REMODELING COMPLEX; ENLARGED PARIETAL FORAMINA; LINKED MENTAL-RETARDATION; OF-FUNCTION MUTATIONS; COFFIN-SIRIS SYNDROME; BRAF-HDAC COMPLEX; MULTIPLE EXOSTOSES AB Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11 and is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs). Despite the identification of individual genes responsible for multiple exostoses and parietal foramina in PSS, the identity of the gene(s) associated with the ID and CFA phenotypes has remained elusive. Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2. PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis. Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription. In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A haploinsufficiency on transcriptional regulation. Our finding that disruption of PHF21A by translocations in the PSS region is associated with ID adds to the growing list of ID-associated genes that emphasize the critical role of transcriptional regulation and chromatin remodeling in normal brain development and cognitive function. C1 [Kim, Hyung-Goo; Seong, Ihn Sik; Shen, Yiping; Talkowski, Michael E.; Ruderfer, Douglas; Lee, Ji-Hyun; MacDonald, Marcy E.; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kim, Hyung-Goo; Layman, Lawrence C.] Georgia Hlth Sci Univ, Inst Mol Med & Genet, Dept Obstet & Gynecol, Augusta, GA 30912 USA. [Kim, Hyung-Goo; Ullmann, Reinhard; Ropers, Hans-Hilger; Kalscheuer, Vera M.] Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany. [Kim, Hyun-Taek; Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. [Leach, Natalia T.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Leach, Natalia T.; Quade, Bradley J.; Morton, Cynthia C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lan, Fei; Shen, Yiping; Shi, Yang] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lan, Fei] Constellat Pharmaceut, Dept Biol, Cambridge, MA 02142 USA. [Silahtaroglu, Asli; Tommerup, Niels] Univ Copenhagen, Dept Cellular & Mol Med, Wilhelm Johannsen Ctr Funct Genome Res, DK-2200 Copenhagen, Denmark. [Kurth, Ingo] Jena Univ Hosp, Inst Human Genet, D-07743 Jena, Germany. [Kurth, Ingo; Nowka, Anja; Kutsche, Kerstin] Univ Klinikum Hamburg Eppendorf, Inst Humangenet, D-20249 Hamburg, Germany. [Seong, Ihn Sik; Talkowski, Michael E.; MacDonald, Marcy E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Shen, Yiping] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China. [Talkowski, Michael E.; Ruderfer, Douglas; MacDonald, Marcy E.; Morton, Cynthia C.; Gusella, James F.] Program Med & Populat Genet, Cambridge, MA 02114 USA. [Glotzbach, Caron; Shaffer, Lisa G.] PerkinElmer, Signature Genom Labs, Spokane, WA 99207 USA. [Ha, Kyungsoo] Georgia Hlth Sci Univ, Ctr Canc, Augusta, GA 30912 USA. [Kjaergaard, Susanne] Rigshosp, Univ Hosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Levin, Alex V.] Thomas Jefferson Univ, Wills Eye Inst, Philadelphia, PA 19107 USA. [Romeike, Bernd F.] Univ Jena, Dept Neuropathol, D-07747 Jena, Germany. [Kleefstra, Tjitske] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 Nijmegen, Netherlands. [Bartsch, Oliver] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Human Genet, D-55101 Mainz, Germany. [Elsea, Sarah H.] Virginia Commonwealth Univ, Sch Med, Dept Pediat, Richmond, VA 23298 USA. [Elsea, Sarah H.] Virginia Commonwealth Univ, Sch Med, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Jabs, Ethylin Wang] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Jabs, Ethylin Wang] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD 21287 USA. [Harris, David J.] Childrens Hosp Boston, Div Genet, Boston, MA 02115 USA. [Quade, Bradley J.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Kim, HG (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM hkim@chgr.mgh.harvard.edu RI Kim, Cheol-Hee/F-6278-2013; Kleefstra, Tjitske/G-2619-2012; Ruderfer, Douglas/M-5795-2016; OI Jabs, Ethylin/0000-0001-8983-5466; Kalscheuer, Vera/0000-0001-6898-3259; Ruderfer, Douglas/0000-0002-2365-386X; Kurth, Ingo/0000-0002-5642-8378; Romeike, Bernd/0000-0002-9693-3870 FU Next-Generation BioGreen 21 Program, Republic of Korea [PJ00812701]; Deutsche Forschungsgemeinschaft [KU 1240/5-1]; Danish National Research Foundation; Lundbeck Foundation; National Institutes of Health [NCI118487, RO1 GM071004]; United States Public Health Service [GM061354, HD065286]; European Union [241995]; German Federal Ministry of Education and Research through the German Mental Retardation Network [01GS08161] FX We are grateful to DGAP012 and MCN1762, as well as their family members, for their cooperation and participation in this study. We are also indebted to Amy Bosco, Heather L. Ferguson, and Chantal Kelly for obtaining informed consent and clinical information; to Joanne Sutherland, genetic counselor at the Hospital for Sick Children, Toronto, for her assistance in obtaining samples; to Shigeki Iwase and Tadashi Baba for the PHF21A antibody; to Mary Anne Anderson and Tammy Gillis in the Center for Human Genetic Research Tissue Culture Facility and Genomics Resource for technical assistance; to Ian Krantz, Stephanie Seminara, and Simeon A. Boyadjiev for providing samples of affected individuals; and to Ines Muller and Corinna Menzel for technical assistance. This work was supported by a grant from the Next-Generation BioGreen 21 Program (PJ00812701 to C.H.K.), Republic of Korea, a grant from the Deutsche Forschungsgemeinschaft (KU 1240/5-1 to K.K.), the Danish National Research Foundation (N.T.), the Lundbeck Foundation (N.T. and A.S.), National Institutes of Health grants NCI118487 (to Y.S.) and RO1 GM071004 (to Y.S.), and United States Public Health Service grants GM061354 (Developmental Genome Anatomy Project to C.C.M. and J.F.G.) and HD065286 (to J.F.G.). Part of this work was financed by the European Union's Seventh Framework Program under grant agreement number 241995, project GENCODYS, and the German Federal Ministry of Education and Research through the German Mental Retardation Network (grant 01GS08161 to H.H.R.). NR 74 TC 19 Z9 19 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2012 VL 91 IS 1 BP 56 EP 72 DI 10.1016/j.ajhg.2012.05.005 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 974OE UT WOS:000306445000005 PM 22770980 ER PT J AU Staropoli, JF Karaa, A Lim, ET Kirby, A Elbalalesy, N Romansky, SG Leydiker, KB Coppel, SH Barone, R Xin, WN MacDonald, ME Abdenur, JE Daly, MJ Sims, KB Cotman, SL AF Staropoli, John F. Karaa, Amel Lim, Elaine T. Kirby, Andrew Elbalalesy, Naser Romansky, Stephen G. Leydiker, Karen B. Coppel, Scott H. Barone, Rosemary Xin, Winnie MacDonald, Marcy E. Abdenur, Jose E. Daly, Mark J. Sims, Katherine B. Cotman, Susan L. TI A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROGRESSIVE MYOCLONIC EPILEPSY; CHANNEL-RELATED GENE; KUFS-DISEASE; AUTOPHAGY; LIGASES; MATURATION; SUBUNITS; SPECTRUM; ADAPTER; FAMILY AB Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that similar to 8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14. C1 [Staropoli, John F.; Karaa, Amel; Lim, Elaine T.; Kirby, Andrew; Coppel, Scott H.; Barone, Rosemary; Xin, Winnie; MacDonald, Marcy E.; Daly, Mark J.; Sims, Katherine B.; Cotman, Susan L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Staropoli, John F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lim, Elaine T.; Kirby, Andrew; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Kirby, Andrew; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Elbalalesy, Naser] Childrens Hosp Orange Cty, Div Neurol, Orange, CA 92868 USA. [Romansky, Stephen G.] Miller Childrens Hosp, Long Beach, CA 90806 USA. [Leydiker, Karen B.; Abdenur, Jose E.] Childrens Hosp Orange Cty, Div Metab Disorders, Orange, CA 92868 USA. [Xin, Winnie; MacDonald, Marcy E.; Sims, Katherine B.; Cotman, Susan L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Cotman, SL (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM cotman@helix.mgh.harvard.edu OI Leydiker, MA, MS, LCGC, Karen/0000-0002-5988-8716; Karaa, Amel /0000-0001-5781-9824 FU National Institutes of Health National Institute of Neurological Disorders and Stroke [R01NS073813, R01NS33648]; Batten Disease Support and Research Association; Massachusetts General Hospital Executive Committee on Research Tosteson Award; Kirschstein National Research Service Award Training Program [GM007748-32] FX This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (R01NS073813 to S.L.C and R01NS33648 to M.E.M.) and the Batten Disease Support and Research Association (J.F.S.). J.F.S. is supported by a Massachusetts General Hospital Executive Committee on Research Tosteson Award. A.K. receives training support from the Kirschstein National Research Service Award Training Program T32 (grant GM007748-32). We would like to thank the National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and the following ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). Plasmids encoding Myc-Cullin-1 and Myc-Cullin-3 were gifts from Yue Xiong (plasmids 19896 and 19893, respectively; Addgene, Cambridge, MA). We thank Xin Feng and Yi Cao for expert technical support. S.L.C. and K.B.S. are members of the Batten Disease Support and Research Association scientific and medical advisory boards, respectively. NR 35 TC 36 Z9 41 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 13 PY 2012 VL 91 IS 1 BP 202 EP 208 DI 10.1016/j.ajhg.2012.05.023 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 974OE UT WOS:000306445000019 PM 22748208 ER PT J AU Burton, DR Poignard, P Stanfield, RL Wilson, IA AF Burton, Dennis R. Poignard, Pascal Stanfield, Robyn L. Wilson, Ian A. TI Broadly Neutralizing Antibodies Present New Prospects to Counter Highly Antigenically Diverse Viruses SO SCIENCE LA English DT Review ID HEPATITIS-C VIRUS; HUMAN MONOCLONAL-ANTIBODIES; INFLUENZA-A VIRUSES; MEMORY B-CELLS; STRUCTURAL BASIS; RATIONAL DESIGN; ENVELOPE GLYCOPROTEIN; E2 GLYCOPROTEIN; HIV-1; EPITOPE AB Certain human pathogens avoid elimination by our immune system by rapidly mutating the surface protein sites targeted by antibody responses, and consequently they tend to be problematic for vaccine development. The behavior described is prominent for a subset of viruses-the highly antigenically diverse viruses-which include HIV, influenza, and hepatitis C viruses. However, these viruses do harbor highly conserved exposed sites, usually associated with function, which can be targeted by broadly neutralizing antibodies. Until recently, not many such antibodies were known, but advances in the field have enabled increasing numbers to be identified. Molecular characterizations of the antibodies and, most importantly, of the sites of vulnerability that they recognize give hope for the discovery of new vaccines and drugs. C1 [Burton, Dennis R.; Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.; Poignard, Pascal] Scripps Res Inst, Int AIDS Vaccine Initiat IAVI Neutralizing Antibo, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Burton, Dennis R.] Harvard Univ, Boston, MA 02129 USA. [Stanfield, Robyn L.; Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Mol Biol, La Jolla, CA 92037 USA. [Stanfield, Robyn L.; Wilson, Ian A.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Poignard, Pascal] IAVI, New York, NY 10038 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu; wilson@scripps.edu RI poignard, pascal/N-6678-2013; Cheng, Yushao/E-6256-2011; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU NIH; IAVI; Ragon Institute FX We acknowledge the financial support of the NIH, the IAVI, and the Ragon Institute. We thank C. Corbaci for help in preparation of the manuscript and all of our past and present laboratory members for their many contributions to our research efforts. NR 79 TC 212 Z9 218 U1 4 U2 81 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 13 PY 2012 VL 337 IS 6091 BP 183 EP 186 DI 10.1126/science.1225416 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973AN UT WOS:000306323500046 PM 22798606 ER PT J AU Roth, M Will, B Simkin, G Narayanagari, S Barreyro, L Bartholdy, B Tamari, R Mitsiades, CS Verma, A Steidl, U AF Roth, Michael Will, Britta Simkin, Guillermo Narayanagari, Swathi Barreyro, Laura Bartholdy, Boris Tamari, Roni Mitsiades, Constantine S. Verma, Amit Steidl, Ulrich TI Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; THROMBOPOIETIN RECEPTOR AGONIST; MYELODYSPLASTIC SYNDROME; ANTITUMOR-ACTIVITY; STEM-CELLS; THROMBOCYTOPENIA; CHELATORS; SAFETY; PHARMACOKINETICS; NONPEPTIDYL AB Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates mega-karyopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G(1) phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia. (Blood. 2012; 120(2): 386-394) C1 [Roth, Michael; Will, Britta; Simkin, Guillermo; Narayanagari, Swathi; Barreyro, Laura; Bartholdy, Boris; Steidl, Ulrich] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Roth, Michael; Will, Britta; Simkin, Guillermo; Narayanagari, Swathi; Barreyro, Laura; Bartholdy, Boris; Verma, Amit; Steidl, Ulrich] Albert Einstein Canc Ctr, Bronx, NY USA. [Roth, Michael] Childrens Hosp Montefiore, Div Pediat Hematol Oncol, Bronx, NY USA. [Tamari, Roni; Verma, Amit; Steidl, Ulrich] Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10461 USA. [Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Verma, Amit] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA. RP Steidl, U (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Chanin Bldg 606,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM ulrich.steidl@einstein.yu.edu FU NYSTEM [C024172]; Albert Einstein Genomics Core Facility; American Cancer Society/J. T. Tai & Company postdoctoral fellowship; Howard Temin Award of the National Cancer Institute [R00CA131503]; Medical Research Award of the Gabrielle's Angel Foundation for Cancer Research FX The authors thank the staff of the Stem Cell FACS and Xenotrans-plantation Facility (supported by NYSTEM, C024172) and the Albert Einstein Genomics Core Facility.; This work was supported by an American Cancer Society/J. T. Tai & Company postdoctoral fellowship (to B.W). U.S. is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine and is the recipient of a Howard Temin Award of the National Cancer Institute (R00CA131503) and a Medical Research Award of the Gabrielle's Angel Foundation for Cancer Research. NR 39 TC 29 Z9 30 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 12 PY 2012 VL 120 IS 2 BP 386 EP 394 DI 10.1182/blood-2011-12-399667 PG 9 WC Hematology SC Hematology GA 987JG UT WOS:000307412400023 PM 22627766 ER PT J AU Zhou, YF Eng, ET Zhu, JQ Lu, CF Walz, T Springer, TA AF Zhou, Yan-Feng Eng, Edward T. Zhu, Jieqing Lu, Chafen Walz, Thomas Springer, Timothy A. TI Sequence and structure relationships within von Willebrand factorSequence and structure relationships within von Willebrand factor SO BLOOD LA English DT Article ID HUMAN VONWILLEBRAND-FACTOR; CRYSTAL-STRUCTURE; GROWTH-FACTOR; BINDING; DISEASE; INHIBITOR; DOMAINS; CELLS; REQUIREMENT; EXPRESSION AB In the present study, we re-annotated von Willebrand factor (VWF), assigned its entire sequence to specific modules, and related these modules to structure using electron microscopy (EM). The D domains are assemblies of smaller modules visible as lobes in EM. Modules in the D-domain assemblies include von Willebrand D, 8-cysteine, trypsin inhibitor-like, E or fibronectin type 1-like domains, and a unique D4N module in D4. The D1-D2 prodomain shows 2 large connected assemblies, each containing smaller lobes. The previous B and C regions of VWF are re-annotated as 6 tandem von Willebrand C (VWC) and VWC-like domains. These 6 VWC domains correspond to 6 elongated domains that associate in pairs at acidic pH in the stem region of VWF dimeric bouquets. This correspondence is demonstrated by binding of integrin alpha(IIb)beta(3) to the fourth module seen in EM, VWC4, which bears the VWF Arg-Gly-Asp motif. The C-terminal cystine knot domain dimerizes end-to-end in a manner predicted by homology to TGF-beta and orients approximately perpendicular to the VWC domains in dimeric bouquets. Homologies of domains in VWF to domains in other proteins allow many disulfide bonds to be tentatively assigned, which may have functional implications. (Blood. 2012;120(2):449-458) C1 [Zhou, Yan-Feng; Eng, Edward T.; Zhu, Jieqing; Lu, Chafen; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Immune Dis Inst, Boston, MA 02115 USA. [Zhou, Yan-Feng; Eng, Edward T.; Zhu, Jieqing; Lu, Chafen; Springer, Timothy A.] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Springer, TA (reprint author), 3 Blackfan Circle, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Zhou, Yanfeng/B-3792-2012 FU National Institutes of Health [HL-103526] FX This work was supported by the National Institutes of Health (grant HL-103526). NR 40 TC 63 Z9 66 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 12 PY 2012 VL 120 IS 2 BP 449 EP 458 DI 10.1182/blood-2012-01-405134 PG 10 WC Hematology SC Hematology GA 987JG UT WOS:000307412400030 PM 22490677 ER PT J AU Ishikawa, Y Nishiuchi, H Hayashi, H Viswanath, K AF Ishikawa, Yoshiki Nishiuchi, Hiromu Hayashi, Hana Viswanath, Kasisomayajula TI Socioeconomic Status and Health Communication Inequalities in Japan: A Nationwide Cross-Sectional Survey SO PLOS ONE LA English DT Article ID INFORMATION-SEEKING; SOCIAL DETERMINANTS AB Background: Considerable evidence suggests that communication inequality is one potential mechanism linking social determinants, particularly socioeconomic status, and health inequalities. This study aimed to examine how dimensions of health communication outcomes (health information seeking, self-efficacy, exposure, and trust) are patterned by socioeconomic status in Japan. Methods: Data of a nationally representative cross-sectional survey of 2,455 people aged 15-75 years in Japan were used for secondary analysis. Measures included socio-demographic characteristics, subjective health, recent health information seeking, self-efficacy in seeking health information, and exposure to and trust in health information from different media. Results: A total of 1,311 participants completed the questionnaire, giving a response rate of 53.6%. Multivariate logistic regression revealed that education and household income, but not employment, were significantly associated with health information seeking and self-efficacy. Socioeconomic status was not associated with exposure to and trust in health information from mass media, but was significantly associated with health information from healthcare providers and the Internet. Conclusion: Health communication outcomes were patterned by socioeconomic status in Japan thus demonstrating the prevalence of health communication inequalities. Providing customized exposure to and enhancing the quality of health information by considering social determinants may contribute to addressing social disparities in health in Japan. C1 [Ishikawa, Yoshiki] Jichi Med Univ, Dept Publ Hlth, Shimotuke, Tochigi, Japan. [Nishiuchi, Hiromu] Keio Univ, Sch Med, Dept Prevent Med & Publ Hlth, Shinjuku Ku, Tokyo, Japan. [Hayashi, Hana; Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Hayashi, Hana] McCann Healthcare Worldwide Japan Inc, Dept Publ Hlth, Minato Ku, Tokyo, Japan. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Ishikawa, Y (reprint author), Jichi Med Univ, Dept Publ Hlth, Shimotuke, Tochigi, Japan. EM ishikun@gmail.com FU Japanese Ministry of Health, Labour and Welfare FX The authors would like to acknowledge the financial support from Japanese Ministry of Health, Labour and Welfare (National Healthy Lifestyle Project 2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 15 TC 13 Z9 13 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2012 VL 7 IS 7 AR e40664 DI 10.1371/journal.pone.0040664 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973NH UT WOS:000306366400045 PM 22808229 ER PT J AU Rivara, MB Bajwa, EK Januzzi, JL Gong, MN Thompson, BT Christiani, DC AF Rivara, Matthew B. Bajwa, Ednan K. Januzzi, James L. Gong, Michelle N. Thompson, B. Taylor Christiani, David C. TI Prognostic Significance of Elevated Cardiac Troponin-T Levels in Acute Respiratory Distress Syndrome Patients SO PLOS ONE LA English DT Article ID ACUTE LUNG INJURY; CRITICALLY-ILL PATIENTS; ARTERY SYSTOLIC PRESSURE; ACUTE CORONARY SYNDROMES; INTENSIVE-CARE-UNIT; ACUTE COR-PULMONALE; TRANSTHORACIC ECHOCARDIOGRAPHY; MYOCARDIAL-INFARCTION; SEPTIC SHOCK; RISK-FACTOR AB Background: Elevated levels of biochemical markers of myocardial necrosis have been associated with worsened outcomes in Acute Respiratory Distress Syndrome (ARDS), but there are few prospective data on this relationship. We investigated elevated cardiac troponin T (cTnT) levels and their relationship with outcome in patients with ARDS. Methods: A prospective cohort study of patients with ARDS was conducted at a tertiary-care academic medical center. Patients had blood taken within 48 hours of ARDS onset and assayed for cTnT. Patients were followed for the outcomes of 60-day mortality, number of organ failures, and days free of mechanical ventilation. Echocardiographic and electrocardiographic (ECG) data were analyzed for signs of myocardial ischemia, infarction, or other myocardial dysfunction. Results: 177 patients were enrolled, 70 of whom died (40%). 119 patients had detectable cTnT levels (67%). Median cTnT level was 0.03 ng/mL, IQR 0-0.10 ng/mL, and levels were higher among non-survivors (P = .008). Increasing cTnT level was significantly associated with increasing mortality (P = .008). The association between increasing cTnT level and mortality remained significant after adjustment in a multivariate model (HRadj = 1.45, 95% CI 1.17-1.81, P = .001). Elevated cTnT level was also associated with increased number of organ failures (P = .002), decreased number of days free of mechanical ventilation (P = .03), echocardiographic wall motion abnormalities (P = 0.001), and severity of tricuspid regurgitation (P = .04). There was no association between ECG findings of myocardial ischemia or infarction and elevated cTnT. Conclusions: Elevated cTnT levels are common in patients with ARDS, and are associated with worsened clinical outcomes and certain echocardiographic abnormalities. No association was seen between cTnT levels and ECG evidence of coronary ischemia. C1 [Rivara, Matthew B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bajwa, Ednan K.; Thompson, B. Taylor; Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA USA. [Januzzi, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Unit, Boston, MA USA. [Gong, Michelle N.] Montefiore Med Ctr, Albert Einstein Coll Med, Crit Care Div, Bronx, NY 10467 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Rivara, MB (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM ebajwa@partners.org FU National Institutes of Health/National Heart, Lung, and Blood Institute [HL60710, HL67197, HL07874] FX This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grants HL60710, HL67197, and HL07874. Reagents for troponin assays were donated by Roche Diagnostics, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2012 VL 7 IS 7 AR e40515 DI 10.1371/journal.pone.0040515 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973NH UT WOS:000306366400030 PM 22808179 ER PT J AU Flaherty, KT Robert, C Hersey, P Nathan, P Garbe, C Milhem, M Demidov, LV Hassel, JC Rutkowski, P Mohr, P Dummer, R Trefzer, U Larkin, JMG Utikal, J Dreno, B Nyakas, M Middleton, MR Becker, JC Casey, M Sherman, LJ Wu, FS Ouellet, D Martin, AM Patel, K Schadendorf, D AF Flaherty, Keith T. Robert, Caroline Hersey, Peter Nathan, Paul Garbe, Claus Milhem, Mohammed Demidov, Lev V. Hassel, Jessica C. Rutkowski, Piotr Mohr, Peter Dummer, Reinhard Trefzer, Uwe Larkin, James M. G. Utikal, Jochen Dreno, Brigitte Nyakas, Marta Middleton, Mark R. Becker, Juergen C. Casey, Michelle Sherman, Laurie J. Wu, Frank S. Ouellet, Daniele Martin, Anne-Marie Patel, Kiran Schadendorf, Dirk CA METRIC Study Grp TI Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MUTATIONS; PATHWAY; CANCER; KINASE; RESISTANCE; CRITERIA AB BACKGROUND Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2: 1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.) C1 [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Robert, Caroline] Inst Gustave Roussy, INSERM, U981, F-94805 Villejuif, France. [Robert, Caroline] Inst Gustave Roussy, Dept Dermatol, Villejuif, France. [Hersey, Peter] Univ Sydney, Kolling Inst, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Nathan, Paul] Mt Vernon Canc Ctr, Northwood, Middx, England. [Nathan, Paul] Natl Inst Canc Res, Melanoma Clin Studies Grp, London, England. [Larkin, James M. G.] Royal Marsden Hosp, London SW3 6JJ, England. [Middleton, Mark R.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Dept Oncol, Oxford OX3 7LJ, England. [Garbe, Claus] Univ Tubingen Hosp, Tubingen, Germany. [Becker, Juergen C.] Univ Heidelberg Hosp, Dept Dermatol, Natl Ctr Tumor Dis, Heidelberg, Germany. [Mohr, Peter] Elbekliniken Buxtehude, Buxtehude, Germany. [Trefzer, Uwe] Charite, D-13353 Berlin, Germany. [Utikal, Jochen] German Canc Res Ctr, Skin Canc Unit, D-6900 Heidelberg, Germany. [Utikal, Jochen] Univ Med Ctr, Dept Dermatol Venereol & Allergol, Mannheim, Germany. [Utikal, Jochen] Univ Heidelberg, D-6800 Mannheim, Germany. [Schadendorf, Dirk] Univ Hosp Essen, Dept Dermatol, Essen, Germany. [Milhem, Mohammed] Univ Iowa Hosp & Clin, Dept Internal Med, Iowa City, IA 52242 USA. [Demidov, Lev V.] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Rutkowski, Piotr] Maria Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Rutkowski, Piotr] Inst Oncol, Warsaw, Poland. [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Nyakas, Marta] Oslo Univ Hosp, Dept Clin Canc Res, Oslo, Norway. [Becker, Juergen C.] Univ Klin Dermatol & Venerol, Graz, Austria. [Casey, Michelle; Sherman, Laurie J.; Wu, Frank S.; Ouellet, Daniele; Martin, Anne-Marie; Patel, Kiran] GlaxoSmithKline, Collegeville, PA USA. [Dreno, Brigitte] Hop Hotel Dieu, Dept Dermatooncol, CHU Nantes, Nantes, France. RP Flaherty, KT (reprint author), 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org RI Lorigan, Paul/J-6898-2015; Ottensmeier, Christian/E-8131-2012; Del Vecchio, Michele/K-1584-2016; OI Lorigan, Paul/0000-0002-8875-2164; Ottensmeier, Christian/0000-0003-3619-1657; Del Vecchio, Michele/0000-0001-9060-2512; Rutkowski, Piotr/0000-0002-8920-5429; Utikal, Jochen/0000-0001-5316-0241 FU GlaxoSmithKline FX Supported by GlaxoSmithKline. NR 23 TC 1013 Z9 1046 U1 8 U2 79 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 12 PY 2012 VL 367 IS 2 BP 107 EP 114 DI 10.1056/NEJMoa1203421 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 972IO UT WOS:000306270800007 PM 22663011 ER PT J AU Hunt, DP Becker, AE Guimaraes, AR Stemmer-Rachamimov, A Misdraji, J AF Hunt, Daniel P. Becker, Anne E. Guimaraes, Alexander R. Stemmer-Rachamimov, Anat Misdraji, Joseph TI Case 21-2012: A 27-Year-Old Man with Fatigue, Weakness, Weight Loss, and Decreased Libido SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OF-THE-LITERATURE; ANOREXIA-NERVOSA; EATING-DISORDERS; SPONTANEOUS PNEUMOMEDIASTINUM; PREVALENCE; STARVATION; NEUROPATHY; EMPHYSEMA; SURGERY; PATIENT C1 [Hunt, Daniel P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Becker, Anne E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Guimaraes, Alexander R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat; Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hunt, Daniel P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Becker, Anne E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Guimaraes, Alexander R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Stemmer-Rachamimov, Anat; Misdraji, Joseph] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hunt, DP (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 34 TC 6 Z9 6 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 12 PY 2012 VL 367 IS 2 BP 157 EP 169 DI 10.1056/NEJMcpc1110053 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 972IO UT WOS:000306270800013 PM 22784119 ER PT J AU Westra, SJ Goldstein, AM Allister, LM AF Westra, Sjirk J. Goldstein, Allan M. Allister, Lauren M. TI Case 12-2012: An Infant with Vomiting REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Westra, Sjirk J.; Goldstein, Allan M.; Allister, Lauren M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Westra, SJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 12 PY 2012 VL 367 IS 2 BP 186 EP 187 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 972IO UT WOS:000306270800033 ER PT J AU Shi, FX Kempfle, JS Edge, ASB AF Shi, Fuxin Kempfle, Judith S. Edge, Albert S. B. TI Wnt-Responsive Lgr5-Expressing Stem Cells Are Hair Cell Progenitors in the Cochlea SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INNER-EAR; SUPPORTING CELLS; SMALL-INTESTINE; IN-VITRO; EXPRESSION; REGENERATION; PROLIFERATION; RECEPTORS; LGR5; DIFFERENTIATION AB Auditory hair cells are surrounded on their basolateral aspects by supporting cells, and these two cell types together constitute the sensory epithelium of the organ of Corti, which is the hearing apparatus of the ear. We show here that Lgr5, a marker for adult stem cells, was expressed in a subset of supporting cells in the newborn and adult murine cochlea. Lgr5-expressing supporting cells, sorted by flow cytometry and cultured in a single-cell suspension, compared with unsorted cells, displayed an enhanced capacity for self-renewing neurosphere formation in response to Wnt and were converted to hair cells at a higher (> 10-fold) rate. The greater differentiation of hair cells in the neurosphere assay showed that Lgr5-positive cells had the capacity to act as cochlear progenitor cells, and lineage tracing confirmed that Lgr5-expressing cells accounted for the cells that formed neurospheres and differentiated to hair cells. The responsiveness to Wnt of cells with a capacity for division and sensory cell formation suggests a potential route to new hair cell generation in the adult cochlea. C1 [Shi, Fuxin; Kempfle, Judith S.; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Shi, Fuxin; Kempfle, Judith S.; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Edge, Albert S. B.] Harvard Univ, Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Edge, Albert S. B.] MIT, Cambridge, MA 02139 USA. RP Edge, ASB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM albert_edge@meei.harvard.edu FU National Institute on Deafness; Other Communicative Disorders [RO1 DC007174, P30 DC05209, RO3 DC010270]; Wiggins Fellowship in Inner Ear Biology FX This work was supported by grants from the National Institute on Deafness and Other Communicative Disorders (RO1 DC007174, P30 DC05209, and RO3 DC010270) and by a Wiggins Fellowship in Inner Ear Biology. NR 45 TC 83 Z9 84 U1 1 U2 14 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 JUL 11 PY 2012 VL 32 IS 28 BP 9639 EP 9648 DI 10.1523/JNEUROSCI.1064-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 975QU UT WOS:000306526800021 PM 22787049 ER PT J AU Lopes, C Liu, ZJ Xu, Y Ma, QF AF Lopes, Claudia Liu, Zijing Xu, Yi Ma, Qiufu TI Tlx3 and Runx1 Act in Combination to Coordinate the Development of a Cohort of Nociceptors, Thermoceptors, and Pruriceptors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DORSAL-ROOT GANGLIA; SENSORY NEURONS; SPINAL-CORD; GENE-EXPRESSION; TRIGEMINAL GANGLION; RECEPTOR EXPRESSION; NEUROPATHIC PAIN; DRG NEURONS; DIFFERENTIATION; BRN3A AB Neurons in the mouse dorsal root ganglia (DRGs) are composed of a variety of sensory modalities, such as pain-related nociceptors, itch-related pruriceptors, and thermoceptors. All these neurons are derived from late-born neurons that are initially marked by the expression of the nerve growth factor receptor TrkA. During perinatal and postnatal development, these TrkA lineage neurons are globally segregated into Ret-expressing and TrkA-expressing subtypes, and start to express a variety of sensory receptors and ion channels. The runt domain transcription factor Runx1 plays a pivotal role in controlling these developmental processes, but it remains unclear how it works. Here we showed that the homeodomain transcription factor Tlx3, expressed broadly in DRG neurons, is required to establish most Runx1-dependent phenotypes, including the segregation of TrkA-expressing versus Ret-expressing neurons and the expression of a dozen of sensory channels and receptors implicated in sensing pain, itch and temperature. Expression of Runx1 and Tlx3 is independent of each other at prenatal stages when they first establish the expression of these channels and receptors. Moreover, overexpression of Runx1 plus Tlx3 was able to induce ectopic expression of sensory channels and receptors. Collectively, these studies suggest that genetically Tlx3 acts in combination with Runx1 to control the development of a cohort of nociceptors, thermoceptors, and pruriceptors in mice. C1 [Lopes, Claudia; Liu, Zijing; Xu, Yi; Ma, Qiufu] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lopes, Claudia; Liu, Zijing; Xu, Yi; Ma, Qiufu] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Lopes, Claudia] Univ Porto, Mol Cell Biol Lab, P-4200319 Oporto, Portugal. RP Ma, QF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Qiufu_Ma@dfci.harvard.edu OI Liu, Zijing/0000-0001-7790-0590 FU NIH [P30-HD18655]; NIH from NIDCR [1R01DE018025]; NIH from NINDS [P01NS047572] FX We thank Drs. Nancy Speck and Gary Gilliland for the Runx1 conditional knock-out mice, Rohini Kuner for the Nav1.8-Cre mice, and David Rowitch for the Wnt1-Cre mice. We also thank Dr. Carmen Birchmeier, Tom Jessell, and Louis Reichardt for the Tlx3, Runx1, and TrkA antibodies, respectively. We also thank the Mouse Gene Manipulation Facility of the Children's Hospital Intellectual and Developmental Disabilities Research Center (IDDRC) supported by NIH Grant P30-HD18655. The work done in the Ma lab was supported by NIH grants from NIDCR (1R01DE018025) and NINDS (P01NS047572). NR 53 TC 19 Z9 20 U1 0 U2 10 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 JUL 11 PY 2012 VL 32 IS 28 BP 9706 EP 9715 DI 10.1523/JNEUROSCI.1109-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 975QU UT WOS:000306526800028 PM 22787056 ER PT J AU Hingtgen, S Kasmieh, R Elbayly, E Nesterenko, I Figueiredo, JL Dash, R Sarkar, D Hall, D Kozakov, D Vajda, S Fisher, PB Shah, K AF Hingtgen, Shawn Kasmieh, Randa Elbayly, Elizabeth Nesterenko, Irina Figueiredo, Jose-Luiz Dash, Rupesh Sarkar, Devanand Hall, David Kozakov, Dima Vajda, Sandor Fisher, Paul B. Shah, Khalid TI A First-Generation Multi-Functional Cytokine for Simultaneous Optical Tracking and Tumor Therapy SO PLOS ONE LA English DT Article ID APOPTOSIS-INDUCING CYTOKINE; CANCER-SPECIFIC APOPTOSIS; NEURAL PROGENITOR CELLS; STEM-CELLS; IN-VIVO; GENE-THERAPY; MELANOMA DIFFERENTIATION; GROWTH SUPPRESSION; MALIGNANT GLIOMAS; LENTIVIRUS VECTOR AB Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L. C1 [Hingtgen, Shawn; Kasmieh, Randa; Elbayly, Elizabeth; Nesterenko, Irina; Figueiredo, Jose-Luiz; Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02115 USA. [Hingtgen, Shawn; Kasmieh, Randa; Elbayly, Elizabeth; Nesterenko, Irina; Figueiredo, Jose-Luiz; Shah, Khalid] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shah, Khalid] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shah, Khalid] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Dash, Rupesh; Sarkar, Devanand; Fisher, Paul B.] Virginia Commonwealth Univ, Dept Human & Mol Genet, VCU Inst Mol Med, VCU Massey Canc Ctr,Sch Med, Richmond, VA USA. [Hall, David; Kozakov, Dima; Vajda, Sandor] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Hingtgen, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurotherapy & Imaging Lab, Boston, MA 02115 USA. EM kshah@mgh.harvard.edu OI dash, rupesh/0000-0001-5740-7053 FU American Brain Tumor Association; Alliance for Cancer Gene Therapy; American Cancer Society [R21 CA131980, 1R01CA138922-01A2, R01 CA097318, PO1 CA104177, R01 CA127641, R01 CA134721, GM061867]; Dana Foundation; James McDonnel Foundation FX This work was supported by the American Brain Tumor Association (K. S., S. H.), Alliance for Cancer Gene Therapy (K. S.), and American Cancer Society (K. S.), R21 CA131980 (K. S.), 1R01CA138922-01A2 (K. S.), R01 CA097318 (P. B. F.), PO1 CA104177 (P. B. F.), R01 CA127641 (P. B. F.), R01 CA134721 (P. B. F.), GM061867 (S. V.), the Dana Foundation (D. S.), and the James McDonnel Foundation (K. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 10 Z9 10 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 11 PY 2012 VL 7 IS 7 AR e40234 DI 10.1371/journal.pone.0040234 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973LU UT WOS:000306362400036 PM 22808125 ER PT J AU Kar, UK Jiang, JN Champion, CI Salehi, S Srivastava, M Sharma, S Rabizadeh, S Niazi, K Kickhoefer, V Rome, LH Kelly, KA AF Kar, Upendra K. Jiang, Janina Champion, Cheryl I. Salehi, Sahar Srivastava, Minu Sharma, Sherven Rabizadeh, Shahrooz Niazi, Kayvan Kickhoefer, Valerie Rome, Leonard H. Kelly, Kathleen A. TI Vault Nanocapsules as Adjuvants Favor Cell-Mediated over Antibody-Mediated Immune Responses following Immunization of Mice SO PLOS ONE LA English DT Article ID IN-VIVO; ANTIGEN PRESENTATION; CROSS-PRESENTATION; DELIVERY-SYSTEMS; DNA VACCINES; T-CELLS; PROTEIN; VIRUS; NANOPARTICLES; LOCALIZATION AB Background: Modifications of adjuvants that induce cell-mediated over antibody-mediated immunity is desired for development of vaccines. Nanocapsules have been found to be viable adjuvants and are amenable to engineering for desired immune responses. We previously showed that natural nanocapsules called vaults can be genetically engineered to elicit Th1 immunity and protection from a mucosal bacterial infection. The purpose of our study was to characterize immunity produced in response to OVA within vault nanoparticles and compare it to another nanocarrier. Methodology and Principal Findings: We characterized immunity resulting from immunization with the model antigen, ovalbumin (OVA) encased in vault nanocapsules and liposomes. We measured OVA responsive CD8(+) and CD4(+) memory T cell responses, cytokine production and antibody titers in vitro and in vivo. We found that immunization with OVA contain in vaults induced a greater number of anti-OVA CD8(+) memory T cells and production of IFN gamma plus CD4(+) memory T cells. Also, modification of the vault body could change the immune response compared to OVA encased in liposomes. Conclusions/Significance: These experiments show that vault nanocapsules induced strong anti-OVA CD8(+) and CD4(+) T cell memory responses and modest antibody production, which markedly differed from the immune response induced by liposomes. We also found that the vault nanocapsule could be modified to change antibody isotypes in vivo. Thus it is possible to create a vault nanocapsule vaccine that can result in the unique combination of immunogen-responsive CD8(+) and CD4(+) T cell immunity coupled with an IgG1 response for future development of vault nanocapsule-based vaccines against antigens for human pathogens and cancer. C1 [Kar, Upendra K.; Kickhoefer, Valerie; Rome, Leonard H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. [Jiang, Janina; Champion, Cheryl I.; Salehi, Sahar; Kelly, Kathleen A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Srivastava, Minu; Sharma, Sherven] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Med Lab, Los Angeles, CA USA. [Rabizadeh, Shahrooz; Niazi, Kayvan] Univ Calif Los Angeles, Samueli Sch Engn, Dept Bioengn, Los Angeles, CA USA. [Rabizadeh, Shahrooz; Niazi, Kayvan; Kickhoefer, Valerie; Rome, Leonard H.; Kelly, Kathleen A.] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA USA. RP Kar, UK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. EM kkelly@mednet.ucla.edu RI Rome, Leonard/E-8786-2016; OI Rome, Leonard/0000-0002-1236-2063; Kickhoefer, Valerie/0000-0002-0048-0580 FU National Institutes of Health [AI026328]; Abraxis Bioscience, Inc [20090918] FX These studies were supported by the National Institutes of Health, AI026328 (Dr. Kelly), sponsored research award from Abraxis Bioscience, Inc (Dr. Kelly) and 20090918. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 10 Z9 10 U1 0 U2 18 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 JUL 11 PY 2012 VL 7 IS 7 AR e38553 DI 10.1371/journal.pone.0038553 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973LU UT WOS:000306362400003 PM 22808011 ER PT J AU Bogoch, II Gandhi, RT Bibi, Y Dejsuphong, V Brown, CM Enis, D Cotsarelis, G Chernak, E Poretz, D Davidson, W Zhao, H Li, Y Bass, JM Tack, DM AF Bogoch, Isaac I. Gandhi, Rajesh T. Bibi, Yuval Dejsuphong, Voraphat Brown, Catherine M. Enis, David Cotsarelis, George Chernak, Esther Poretz, Donald Davidson, Whitni Zhao, Hui Li, Yu Bass, Jennifer M. Tack, Danielle M. TI Human Orf Virus Infection From Household Exposures-United States, 2009-2011 (Reprinted from MMWR, vol 61, pg 245-248, 2012) SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Reprint C1 [Bass, Jennifer M.] CDC Experience Appl Epidemiol, Atlanta, GA 30333 USA. [Bogoch, Isaac I.; Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bibi, Yuval] Harvard Vanguard Med Associates, Dept Dermatol, Boston, MA USA. [Dejsuphong, Voraphat] Boston Univ, Sch Med, Int Grad Dermatol Program, Boston, MA 02215 USA. [Brown, Catherine M.] Massachusetts Dept Publ Hlth, Boston, MA 02111 USA. [Enis, David; Cotsarelis, George] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Chernak, Esther] Philadelphia Dept Publ Hlth, Philadelphia, PA USA. [Poretz, Donald] Inova Fairfax Hosp, Falls Church, VA USA. [Davidson, Whitni; Zhao, Hui; Li, Yu] Natl Ctr Emerging & Zoonot Infect Dis, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Tack, Danielle M.] CDC, EIS, Atlanta, GA 30333 USA. RP Bass, JM (reprint author), CDC Experience Appl Epidemiol, Atlanta, GA 30333 USA. EM jbass@cdc.gov NR 1 TC 0 Z9 0 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 11 PY 2012 VL 308 IS 2 BP 126 EP 128 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 971QS UT WOS:000306219500009 ER PT J AU Kim, SZ Song, WJ Nyhan, WL Ficicioglu, C Mandell, R Shih, VE AF Kim, Sook Z. Song, Wung J. Nyhan, William L. Ficicioglu, Can Mandell, Roseann Shih, Vivian E. TI Long-term follow-up of four patients affected by HHH syndrome SO CLINICA CHIMICA ACTA LA English DT Article DE Hyperornithinemia; Hyperammonemia; Homocitrullinemia; HHH syndrome; Ornithine ID HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME; HYPERORNITHINEMIA-HYPERAMMONEMIA; ORNITHINE METABOLISM; MUTATIONS; SLC25A15; ACID; GENE AB Background: In hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, impaired ornithine transport across the mitochondrial membrane causes ornithine accumulation in cytoplasm. The resulting mitochondrial ornithine deficiency leads to reduced clearance of ammonia through the urea cycle. First described in 1969, no long-term follow-up has been reported. Methods: Four patients were followed up for 11 to 38 y. Diagnosis was made by plasma amino acid analysis using ion exchange chromatography, HPLC orotic acid measurement, and C-14-ornithine incorporation study using cultured fibroblasts. DNA from fibroblasts was amplified and sequenced. Blood ammonia was controlled by restriction of protein intake. Results: All patients had reduced C-14-ornithine incorporation. Mutation analysis revealed two novel mutations in the ORNT1 gene. Neurologic outcome included memory loss, low IQ tremor, spasticity of extremities, bladder incontinence, and abnormal gait. Neuroimaging revealed subcortical, cerebral and cerebellar atrophy, sparing the basal ganglia. Individual examination showed pyramidal signs, cerebellar signs, paraplegia, movement disorder, dystonia, and epilepsy. One patient had 3 pregnancies, one of which resulted in intrauterine growth retardation. Conclusions: Our patients expand the clinical phenotype of adults with HHH. Long-term follow-up showed serious neurologic outcomes in all patients; three patients clearly exhibited progression of neurologic dysfunction despite control of hyperammonemia. Intracellular ornithine deficiency may adversely affect brain functions. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kim, Sook Z.; Song, Wung J.] Korea Genet Res Ctr, Cheong Ju City 361841, South Korea. [Nyhan, William L.] UCSD, Biochem Genet Lab, La Jolla, CA USA. [Ficicioglu, Can; Mandell, Roseann; Shih, Vivian E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kim, SZ (reprint author), Korea Genet Res Ctr, Woon Cheon Dong 965, Cheong Ju City 361841, South Korea. EM kimgene@unitel.co.kr OI Ficicioglu, Can/0000-0002-8331-9804 FU Massachusetts General Hospital FX Supported in part by the Mary L Efron Fund, Massachusetts General Hospital. NR 22 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUL 11 PY 2012 VL 413 IS 13-14 BP 1151 EP 1155 DI 10.1016/j.cca.2012.03.015 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 949LR UT WOS:000304578200021 PM 22465082 ER PT J AU Bogoch, II Scully, EP Zachary, KC AF Bogoch, Isaac I. Scully, Eileen P. Zachary, Kimon C. TI Antiretroviral medication for preventing HIV infection in nonoccupational settings SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; POSTEXPOSURE PROPHYLAXIS; TENOFOVIR DF; TRANSMISSION; SEROCONVERSION; EMTRICITABINE; SEX C1 [Bogoch, Isaac I.] Sunnybrook Hlth Sci Ctr, Div Infect Dis, Toronto, ON M4N 3M5, Canada. [Bogoch, Isaac I.; Zachary, Kimon C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Scully, Eileen P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Bogoch, Isaac I.; Scully, Eileen P.; Zachary, Kimon C.] Harvard Univ, Sch Med, Boston, MA USA. RP Bogoch, II (reprint author), Sunnybrook Hlth Sci Ctr, Div Infect Dis, Toronto, ON M4N 3M5, Canada. EM Isaac.bogoch@utoronto.ca NR 20 TC 0 Z9 0 U1 1 U2 1 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JUL 10 PY 2012 VL 184 IS 10 BP 1153 EP 1157 DI 10.1503/cmaj.120267 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 979SG UT WOS:000306839500043 PM 22641683 ER PT J AU Kamel, H Johnston, SC Kirkham, JC Turner, CG Kizer, JR Devereux, RB Iadecola, C AF Kamel, Hooman Johnston, S. Claiborne Kirkham, John C. Turner, Christopher G. Kizer, Jorge R. Devereux, Richard B. Iadecola, Costantino TI Association Between Major Perioperative Hemorrhage and Stroke or Q-Wave Myocardial Infarction SO CIRCULATION LA English DT Article DE hemorrhage; myocardial infarction; risk factors; stroke; surgery ID BYPASS GRAFT-SURGERY; QUALITY IMPROVEMENT PROGRAM; NONCARDIAC SURGERY; RISK-FACTORS; ISCHEMIC-STROKE; ANTIPLATELET THERAPY; PRACTICE GUIDELINES; SURGICAL-PROCEDURES; BLOOD-TRANSFUSION; 30-DAY MORTALITY AB Background-Hemorrhage is associated with ischemic complications in cardiac patients. The nature of this relationship in surgical patients is unknown. Methods and Results-We examined the association between major perioperative hemorrhage and stroke or myocardial infarction among adults who underwent surgery from 2005 through 2009 at centers participating in the National Surgical Quality Improvement Program. We excluded patients with emergent, trauma-related, transplantation, cardiac, or neurological operations. Major hemorrhage was defined as bleeding necessitating transfusion of >4 U of packed red blood cells or whole blood. Stroke was defined as focal brain dysfunction lasting >= 24 hours from a vascular cause. A diagnosis of myocardial infarction required new ECG Q waves. Outcomes were assessed from surgery until 30 days afterward. Among 651 775 patients who underwent surgery, 5233 (0.80%) experienced major hemorrhage, 1575 (0.24%) developed Q-wave myocardial infarction, and 1321 (0.20%) suffered a stroke. In Cox proportional hazards analyses controlling for vascular risk factors, illness severity, and type of surgery, hemorrhage was independently associated with subsequent stroke (hazard ratio, 2.5; 95% confidence interval, 1.9-3.3) and subsequent Q-wave myocardial infarction (hazard ratio, 2.7; 95% confidence interval, 2.1-3.4). Interaction terms revealed no significant variation in these associations by age, sex, or type of surgery. Our results were robust across multiple sensitivity analyses. Conclusions-Major perioperative hemorrhage is associated with subsequent stroke and myocardial infarction in patients undergoing noncardiac, nonneurological surgery. This suggests the need for randomized trials to guide perioperative use of antiplatelet drugs, which affect the risk of both bleeding and vascular events. (Circulation. 2012; 126: 207-212.) C1 [Kamel, Hooman; Iadecola, Costantino] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. [Kizer, Jorge R.; Devereux, Richard B.] Weill Cornell Med Coll, Div Cardiol, New York, NY 10065 USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY 10065 USA. [Johnston, S. Claiborne] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Johnston, S. Claiborne] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kirkham, John C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Turner, Christopher G.] Suny Downstate Med Ctr, Dept Surg, New York, NY USA. RP Kamel, H (reprint author), Weill Cornell Med Coll, Dept Neurol & Neurosci, 525 E 68th St,F610, New York, NY 10065 USA. EM hok9010@med.cornell.edu FU NINDS NIH HHS [R01 NS034179, R01 NS073666] NR 37 TC 35 Z9 36 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 10 PY 2012 VL 126 IS 2 BP 207 EP 212 DI 10.1161/CIRCULATIONAHA.112.094326 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981SN UT WOS:000306991000015 PM 22679143 ER PT J AU Weinberg, I Jaff, MR AF Weinberg, Ido Jaff, Michael R. TI Nonatherosclerotic Arterial Disorders of the Lower Extremities SO CIRCULATION LA English DT Review DE atherosclerosis; peripheral arterial disease; lower extremity ID CYSTIC ADVENTITIAL DISEASE; OBLITERANS BUERGERS-DISEASE; EXTERNAL ILIAC ARTERY; OF-THE-LITERATURE; POPLITEAL VASCULAR ENTRAPMENT; LARGE-VESSEL VASCULITIS; MIDDLE AORTIC SYNDROME; GIANT-CELL ARTERITIS; TAKAYASU ARTERITIS; FIBROMUSCULAR DYSPLASIA C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Sect Vasc Med, Div Cardiovasc Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, Sect Vasc Med, Div Cardiovasc Med, 55 Fruit St, Boston, MA 02114 USA. EM mjaff@partners.org NR 87 TC 14 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 10 PY 2012 VL 126 IS 2 BP 213 EP 222 DI 10.1161/CIRCULATIONAHA.111.060335 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981SN UT WOS:000306991000016 PM 22777664 ER PT J AU Gruenbaum-Cohen, Y Harel, I Umansky, KB Tzahor, E Snapper, SB Shilo, BZ Schejter, ED AF Gruenbaum-Cohen, Yael Harel, Itamar Umansky, Kfir-Baruch Tzahor, Eldad Snapper, Scott B. Shilo, Ben-Zion Schejter, Eyal D. TI The actin regulator N-WASp is required for muscle-cell fusion in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin nucleation; myotube formation ID SYNDROME PROTEIN WASP; MYOBLAST FUSION; SKELETAL-MUSCLE; SATELLITE CELLS; PROGENITOR CELLS; BLOWN-FUSE; IN-VIVO; DROSOPHILA; MYOGENESIS; MOUSE AB A fundamental aspect of skeletal myogenesis involves extensive rounds of cell fusion, in which individualmyoblasts are incorporated into growing muscle fibers. Here we demonstrate that N-WASp, a ubiquitous nucleation-promoting factor of branched microfilament arrays, is an essential contributor to skeletal muscle-cell fusion in developing mouse embryos. Analysis both in vivo and in primary satellite-cell cultures, shows that disruption of N-WASp function does not interfere with the program of skeletal myogenic differentiation, and does not affect myoblast motility, morphogenesis and attachment capacity. N-WASp-deficient myoblasts, however, fail to fuse. Furthermore, our analysis suggests that myoblast fusion requires N-WASp activity in both partners of a fusing myoblast pair. These findings reveal a specific role for N-WASp during mammalian myogenesis. WASp-family elements appear therefore to act as universal mediators of the myogenic cell-cell fusion mechanism underlying formation of functional muscle fibers, in both vertebrate and invertebrate species. C1 [Gruenbaum-Cohen, Yael; Umansky, Kfir-Baruch; Shilo, Ben-Zion; Schejter, Eyal D.] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Harel, Itamar; Tzahor, Eldad] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. [Snapper, Scott B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med & Immunol, Boston, MA 02115 USA. RP Shilo, BZ (reprint author), Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. EM benny.shilo@weizmann.ac.il; eyal.schejter@weizmann.ac.il FU Israel Science Foundation (ISF); Muscular Dystrophy Association; MYORES; ISF Legacy Grant [1875/08] FX We thank Paul Knopp and Peter Zammit (King's College, London) for providing instruction and sharing their expertise on generation and handling of satellite cell cultures. We thank our colleagues Ari Elson, David Goldhamer, Yoram Groner, Eran Hornstein, Ronen Schweitzer, and Eli Zelzer for advice, reagents, and use of laboratory facilities; Margaret Buckingham for insightful discussions; Sagi Levy for instruction and help in quantifying myoblast motility; R'ada Massarwa, Ariel Rinon, and Natti Weinblum for their contributions to experiments performed in the course of this study; and all members of the B.-Z. S. laboratory for their help and support. This work was supported by research grants from the Israel Science Foundation (ISF) and the Muscular Dystrophy Association (to B-Z.S. and E. D. S.) and a MYORES travel grant (to Y.G-C.). K-B. U. was supported by ISF Legacy Grant 1875/08. B-Z.S. is an incumbent of the Hilda and Cecil Lewis Chair in Molecular Genetics. NR 39 TC 40 Z9 40 U1 0 U2 4 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 JUL 10 PY 2012 VL 109 IS 28 BP 11211 EP 11216 DI 10.1073/pnas.1116065109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100042 PM 22736793 ER PT J AU Grisanzio, C Werner, L Takeda, D Awoyemi, BC Pomerantz, MM Yamada, H Sooriakumaran, P Robinson, BD Leung, R Schinzel, AC Mills, I Ross-Adams, H Neal, DE Kido, M Yamamoto, T Petrozziello, G Stack, EC Lis, R Kantoff, PW Loda, M Sartor, O Egawa, S Tewari, AK Hahn, WC Freedman, ML AF Grisanzio, Chiara Werner, Lillian Takeda, David Awoyemi, Bisola C. Pomerantz, Mark M. Yamada, Hiroki Sooriakumaran, Prasanna Robinson, Brian D. Leung, Robert Schinzel, Anna C. Mills, Ian Ross-Adams, Helen Neal, David E. Kido, Masahito Yamamoto, Toshihiro Petrozziello, Gillian Stack, Edward C. Lis, Rosina Kantoff, Philip W. Loda, Massimo Sartor, Oliver Egawa, Shin Tewari, Ashutosh K. Hahn, William C. Freedman, Matthew L. TI Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE expression quantitative trait loci; prostate cancer risk SNPs; multi-ethnic ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; AFRICAN-AMERICANS; DNA VARIANTS; RISK LOCI; EXPRESSION; REPLICATION; MUTATIONS; DISEASE; TCF2 AB One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P <= 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis. C1 [Grisanzio, Chiara; Takeda, David; Awoyemi, Bisola C.; Pomerantz, Mark M.; Yamada, Hiroki; Petrozziello, Gillian; Stack, Edward C.; Lis, Rosina; Kantoff, Philip W.; Loda, Massimo; Hahn, William C.; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Schinzel, Anna C.; Hahn, William C.; Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Takeda, David; Hahn, William C.] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA. [Freedman, Matthew L.] Broad Inst Harvard & MIT, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Pomerantz, Mark M.; Loda, Massimo; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Lis, Rosina; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yamada, Hiroki; Kido, Masahito; Yamamoto, Toshihiro; Egawa, Shin] Jikei Univ, Sch Med, Dept Urol, Minato Ku, Tokyo 1058461, Japan. [Sooriakumaran, Prasanna; Robinson, Brian D.; Leung, Robert; Tewari, Ashutosh K.] Weill Cornell Med Coll, Lefrak Ctr Robot Surg, Dept Urol, New York, NY 10065 USA. [Sooriakumaran, Prasanna; Robinson, Brian D.; Leung, Robert; Tewari, Ashutosh K.] Weill Cornell Med Coll, Prostate Canc Inst, New York, NY 10065 USA. [Mills, Ian] Univ Oslo, Ctr Mol Med Norway NCMM, N-0349 Oslo, Norway. [Mills, Ian; Loda, Massimo] Oslo Univ Hosp, Dept Urol, N-0370 Oslo, Norway. [Mills, Ian] Oslo Univ Hosp, Dept Canc Prevent, N-0370 Oslo, Norway. [Ross-Adams, Helen; Neal, David E.] Canc Res United Kingdom, Cambridge Res Inst, Urooncol Res Grp, Cambridge CB2 0RE, England. [Sartor, Oliver] Tulane Univ, Sch Med, Tulane Canc Ctr, Dept Med & Urol, New Orleans, LA 70112 USA. RP Freedman, ML (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM freedman@broadinstitute.org OI Neal, David/0000-0002-6033-5086 FU US National Institutes of Health [R01 CA129435, U19 CA148537 (GAME-ON)]; Mayer Foundation; H. L. Snyder Medical Foundation; Dana-Farber/Harvard Cancer Center Prostate Cancer Specialized Program of Research Excellence (National Cancer Institute) [5P50CA90381]; Kohlberg Foundation; A. David Mazzone Awards Program; Emerald Foundation; Claudia Adams Barr award; Howard Hughes Medical Institute FX We thank the Center for Cancer Genome Discovery at the Dana-Farber Cancer Institute for technical assistance with genotyping. This work was supported by Grants R01 CA129435 and U19 CA148537 (GAME-ON) from the US National Institutes of Health; the Mayer Foundation (M. L. F.); the H. L. Snyder Medical Foundation (M. L. F.); the Dana-Farber/Harvard Cancer Center Prostate Cancer Specialized Program of Research Excellence (National Cancer Institute Grant 5P50CA90381); the Kohlberg Foundation; the A. David Mazzone Awards Program (M. L. F.); and the Emerald Foundation (M. L. F.). M. L. F. is a Howard Hughes Medical Institute Physician-Scientist Early Career Awardee (www.hhmi.org) and a recipient of a 2009 Claudia Adams Barr award (www.dana-farber.org). NR 39 TC 38 Z9 39 U1 2 U2 18 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 JUL 10 PY 2012 VL 109 IS 28 BP 11252 EP 11257 DI 10.1073/pnas.1200853109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100049 PM 22730461 ER PT J AU Sengupta, P Basu, S Soni, S Pandey, A Roy, B Oh, MS Chin, KT Paraskar, AS Sarangi, S Connor, Y Sabbisetti, VS Kopparam, J Kulkarni, A Muto, K Amarasiriwardena, C Jayawardene, I Lupoli, N Dinulescu, DM Bonventre, JV Mashelkar, RA Sengupta, S AF Sengupta, Poulomi Basu, Sudipta Soni, Shivani Pandey, Ambarish Roy, Bhaskar Oh, Michael S. Chin, Kenneth T. Paraskar, Abhimanyu S. Sarangi, Sasmit Connor, Yamicia Sabbisetti, Venkata S. Kopparam, Jawahar Kulkarni, Ashish Muto, Katherine Amarasiriwardena, Chitra Jayawardene, Innocent Lupoli, Nicola Dinulescu, Daniela M. Bonventre, Joseph V. Mashelkar, Raghunath A. Sengupta, Shiladitya TI Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; nanomedicine ID LIPOSOMAL-CISPLATIN; ANTICANCER AGENTS; K-RAS; CANCER; PHARMACOKINETICS; FORMULATIONS; TRANSPORT; DELIVERY; CARRIERS; TUMORS AB Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O -> Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+/)Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a nextgeneration platinum-based agent in the clinics. C1 [Sengupta, Poulomi; Basu, Sudipta; Soni, Shivani; Pandey, Ambarish; Roy, Bhaskar; Oh, Michael S.; Paraskar, Abhimanyu S.; Sarangi, Sasmit; Connor, Yamicia; Kopparam, Jawahar; Kulkarni, Ashish; Mashelkar, Raghunath A.; Sengupta, Shiladitya] Brigham & Womens Hosp, Dept Med, Lab Nanomed, Div Biomed Engn, Cambridge, MA 02139 USA. [Sengupta, Poulomi; Basu, Sudipta; Soni, Shivani; Pandey, Ambarish; Roy, Bhaskar; Oh, Michael S.; Paraskar, Abhimanyu S.; Sarangi, Sasmit; Connor, Yamicia; Kopparam, Jawahar; Kulkarni, Ashish; Mashelkar, Raghunath A.; Sengupta, Shiladitya] Brigham & Womens Hosp, Ctr Regenerat Therapeut, Cambridge, MA 02139 USA. [Sabbisetti, Venkata S.; Bonventre, Joseph V.] Brigham & Womens Hosp, Div Renal, Cambridge, MA 02139 USA. [Sabbisetti, Venkata S.; Bonventre, Joseph V.] Brigham & Womens Hosp, Div Biomed Engn, Cambridge, MA 02139 USA. [Chin, Kenneth T.; Muto, Katherine; Dinulescu, Daniela M.] Brigham & Womens Hosp, Dept Pathol, Cambridge, MA 02139 USA. [Amarasiriwardena, Chitra; Jayawardene, Innocent; Lupoli, Nicola] Brigham & Womens Hosp, Channing Lab, Cambridge, MA 02139 USA. [Sengupta, Poulomi; Basu, Sudipta; Soni, Shivani; Pandey, Ambarish; Roy, Bhaskar; Oh, Michael S.; Paraskar, Abhimanyu S.; Sarangi, Sasmit; Connor, Yamicia; Sabbisetti, Venkata S.; Kopparam, Jawahar; Kulkarni, Ashish; Dinulescu, Daniela M.; Bonventre, Joseph V.; Sengupta, Shiladitya] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Connor, Yamicia; Sengupta, Shiladitya] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Mashelkar, Raghunath A.] Natl Chem Labs, Pune 411021, Maharashtra, India. [Amarasiriwardena, Chitra; Jayawardene, Innocent; Lupoli, Nicola] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Sengupta, Shiladitya] Indo US Joint Ctr Nanobiotechnol, Cambridge, MA 02139 USA. [Sengupta, Shiladitya] Dana Farber Canc Inst, Brookline, MA 02445 USA. RP Basu, S (reprint author), Indian Inst Sci Educ & Res IISER Pune, Dept Chem, Pune 411021, Maharashtra, India. EM sudipta.basu@iiserpune.ac.in; ssengupta2@partners.org RI KOPPARAM, JAWAHAR/D-4338-2017; OI Oh, Michael/0000-0002-7206-771X FU US Department of Defense [W81XWH-07-1-0482]; Department of Defense; National Institutes of Health [R01 CA135242-01A2]; Charles A. King Trust Fellowship; Burroughs-Wellcome Foundation; Harvard Ovarian Cancer Spore Award; Canary Fund; Mary Kay Ash Foundation; V Foundation for Cancer Research Scholar Award FX This work is supported by US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award W81XWH-07-1-0482; a Department of Defense Collaborative Innovator Grant; National Institutes of Health Grant R01 CA135242-01A2; a Charles A. King Trust Fellowship; a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship Award; the Burroughs-Wellcome Foundation; a Harvard Ovarian Cancer Spore Award; the Canary Fund; the Mary Kay Ash Foundation; and a V Foundation for Cancer Research Scholar Award. NR 39 TC 58 Z9 59 U1 1 U2 50 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 JUL 10 PY 2012 VL 109 IS 28 BP 11294 EP 11299 DI 10.1073/pnas.1203129109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100056 PM 22733767 ER PT J AU Sunshine, SB Dallabrida, SM Durand, E Ismail, NS Bazinet, L Birsner, AE Sohn, R Ikeda, S Pu, WT Kulke, MH Javaherian, K Zurakowski, D Folkman, JM Rupnick, M AF Sunshine, Sarah B. Dallabrida, Susan M. Durand, Ellen Ismail, Nesreen S. Bazinet, Lauren Birsner, Amy E. Sohn, Regina Ikeda, Sadakatsu Pu, William T. Kulke, Matthew H. Javaherian, Kashi Zurakowski, David Folkman, Judah M. Rupnick, Maria TI Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; METASTATIC BREAST-CANCER; TYROSINE KINASE INHIBITOR; DOWNS-SYNDROME; COLLAGEN-XVIII; TUMOR-GROWTH; PHASE-II; ANGIOGENESIS; BEVACIZUMAB; MECHANISMS AB Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression. C1 [Sunshine, Sarah B.; Dallabrida, Susan M.; Durand, Ellen; Ismail, Nesreen S.; Bazinet, Lauren; Birsner, Amy E.; Javaherian, Kashi; Folkman, Judah M.; Rupnick, Maria] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Vasc Biol, Boston, MA 02115 USA. [Ikeda, Sadakatsu; Pu, William T.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Cardiol, Boston, MA 02115 USA. [Zurakowski, David] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Anesthesia, Boston, MA 02115 USA. [Zurakowski, David] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Surg, Boston, MA 02115 USA. [Sohn, Regina; Rupnick, Maria] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Kulke, Matthew H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Sunshine, SB (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Div Vasc Biol, Boston, MA 02115 USA. EM ssunshine@jhmi.edu FU NHLBI NIH HHS [R01 HL095712] NR 54 TC 17 Z9 18 U1 0 U2 8 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 JUL 10 PY 2012 VL 109 IS 28 BP 11306 EP 11311 DI 10.1073/pnas.1203275109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FP UT WOS:000306642100058 PM 22733742 ER PT J AU Moldovan, GL D'Andrea, AD AF Moldovan, George-Lucian D'Andrea, Alan D. TI To the Rescue: The Fanconi Anemia Genome Stability Pathway Salvages Replication Forks SO CANCER CELL LA English DT Editorial Material ID HOMOLOGOUS RECOMBINATION; RAD51; BRCA2; DNA AB DNA damage can arrest replication forks during S phase. Failure to stabilize and restart arrested forks results in fork collapse and genomic instability. In this issue of Cancer Cell, Schlacher et al. show that the Fanconi anemia and BRCA2 tumor suppressor pathways cooperate to protect stalled replication forks from degradation. C1 [Moldovan, George-Lucian; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu OI George-Lucian, Moldovan/0000-0003-3825-149X FU NHLBI NIH HHS [P01 HL048546, R37 HL052725]; NIDDK NIH HHS [R01 DK043889] NR 10 TC 10 Z9 11 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 10 PY 2012 VL 22 IS 1 BP 5 EP 6 DI 10.1016/j.ccr.2012.06.006 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 973YA UT WOS:000306395300003 PM 22789533 ER PT J AU Mione, M Zon, LI AF Mione, Marina Zon, Leonard I. TI Cancer and Inflammation: An Aspirin a Day Keeps the Cancer at Bay SO CURRENT BIOLOGY LA English DT Editorial Material ID STEM-CELLS; GROWTH C1 [Mione, Marina] Karlsruhe Inst Technol, Inst Toxicol & Genet, Karlsruhe, Germany. [Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Boston, MA USA. [Zon, Leonard I.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Mione, M (reprint author), Karlsruhe Inst Technol, Inst Toxicol & Genet, Karlsruhe, Germany. EM Maria.Mione@kit.edu; zon@enders.tch.harvard.edu RI Mione, Maria Caterina /I-3073-2013 FU NCI NIH HHS [R01 CA103846] NR 18 TC 6 Z9 6 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUL 10 PY 2012 VL 22 IS 13 BP R522 EP R525 DI 10.1016/j.cub.2012.05.037 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973SH UT WOS:000306379600009 PM 22789999 ER PT J AU Polireddy, K Khan, MMT Chavan, H Young, S Ma, XC Waller, A Garcia, M Perez, D Chavez, S Strouse, JJ Haynes, MK Bologa, CG Oprea, TI Tegos, GP Sklar, LA Krishnamurthy, P AF Polireddy, Kishore Khan, Mohiuddin Md Taimur Chavan, Hemantkumar Young, Susan Ma, Xiaochao Waller, Anna Garcia, Matthew Perez, Dominique Chavez, Stephanie Strouse, Jacob J. Haynes, Mark K. Bologa, Cristian G. Oprea, Tudor I. Tegos, George P. Sklar, Larry A. Krishnamurthy, Partha TI A Novel Flow Cytometric HTS Assay Reveals Functional Modulators of ATP Binding Cassette Transporter ABCB6 SO PLOS ONE LA English DT Article ID CANCER-CELLS; DRUG-BINDING; IDENTIFICATION; RESISTANCE; EXPRESSION; MECHANISM; PROTEINS; SURVIVAL; STRESS; GENES AB ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6's ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity. C1 [Polireddy, Kishore; Chavan, Hemantkumar; Ma, Xiaochao; Krishnamurthy, Partha] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Khan, Mohiuddin Md Taimur; Young, Susan; Waller, Anna; Garcia, Matthew; Perez, Dominique; Chavez, Stephanie; Strouse, Jacob J.; Haynes, Mark K.; Bologa, Cristian G.; Oprea, Tudor I.; Tegos, George P.; Sklar, Larry A.] Univ New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USA. [Khan, Mohiuddin Md Taimur; Tegos, George P.; Sklar, Larry A.] Univ New Mexico, Div Biocomp, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Khan, Mohiuddin Md Taimur; Tegos, George P.; Sklar, Larry A.] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Tegos, George P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tegos, George P.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Polireddy, K (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. EM gtegos@salud.unm.edu; lsklar@salud.unm.edu; pkrishnamurthy@kumc.edu RI Oprea, Tudor/A-5746-2011; Bologa, Cristian/A-7952-2010; OI Oprea, Tudor/0000-0002-6195-6976; Bologa, Cristian/0000-0003-2232-4244; Chavan, Hemantkumar/0000-0002-9963-6230 FU National Institutes of Health (NIH) [5U54MH084690-02, R03MH093193] FX Funding for GPT and LAS was provided by the National Institutes of Health (NIH, 5U54MH084690-02, Center Driven Initiative 1) and PK by R03MH093193. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 42 TC 5 Z9 5 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2012 VL 7 IS 7 AR e40005 DI 10.1371/journal.pone.0040005 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973JD UT WOS:000306355500020 PM 22808084 ER PT J AU Wang, Q Dai, XQ Li, Q Wang, ZC Cantero, MD Li, S Shen, J Tu, JC Cantiello, H Chen, XZ AF Wang, Qian Dai, Xiao-Qing Li, Qiang Wang, Zuocheng del Rocio Cantero, Maria Li, Shu Shen, Ji Tu, Jian-Cheng Cantiello, Horacio Chen, Xing-Zhen TI Structural Interaction and Functional Regulation of Polycystin-2 by Filamin SO PLOS ONE LA English DT Article ID ACTIN-BINDING PROTEIN; KIDNEY-DISEASE PROTEIN; ALPHA-ACTININ; CHANNEL ACTIVITY; INTRACELLULAR TRAFFICKING; HUMAN SYNCYTIOTROPHOBLAST; CD2-ASSOCIATED PROTEIN; SURFACE EXPRESSION; CATION CHANNEL; NMDA RECEPTOR AB Filamins are important actin cross-linking proteins implicated in scaffolding, membrane stabilization and signal transduction, through interaction with ion channels, receptors and signaling proteins. Here we report the physical and functional interaction between filamins and polycystin-2, a TRP-type cation channel mutated in 10-15% patients with autosomal dominant polycystic kidney disease. Yeast two-hybrid and GST pull-down experiments demonstrated that the C-termini of filamin isoforms A, B and C directly bind to both the intracellular N- and C-termini of polycystin-2. Reciprocal co-immunoprecipitation experiments showed that endogenous polycystin-2 and filamins are in the same complexes in renal epithelial cells and human melanoma A7 cells. We then examined the effect of filamin on polycystin-2 channel function by electrophysiology studies with a lipid bilayer reconstitution system and found that filamin-A substantially inhibits polycystin-2 channel activity. Our study indicates that filamins are important regulators of polycystin-2 channel function, and further links actin cytoskeletal dynamics to the regulation of this channel protein. C1 [Wang, Qian; Dai, Xiao-Qing; Li, Qiang; Wang, Zuocheng; Li, Shu; Chen, Xing-Zhen] Univ Alberta, Dept Physiol, Membrane Prot Dis Res Grp, Edmonton, AB, Canada. [del Rocio Cantero, Maria; Cantiello, Horacio] Univ Buenos Aires, Fac Odontol, Catedra Biofis, Buenos Aires, DF, Argentina. [Shen, Ji; Tu, Jian-Cheng] Wuhan Univ, Zhongnan Hosp, Wuhan 430072, Hubei, Peoples R China. [Cantiello, Horacio] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Charlestown, MA USA. [Cantiello, Horacio] Harvard Univ, Sch Med, Charlestown, MA USA. RP Wang, Q (reprint author), Univ Alberta, Dept Physiol, Membrane Prot Dis Res Grp, Edmonton, AB, Canada. EM cantiello@helix.mgh.harvard.edu; xzchen@ualberta.ca FU Canadian Institutes of Health Research; Kidney Foundation of Canada; National Science Foundation of China [30770658]; National Institutes of Health ARRA [DK077079] FX This work was supported by grants from the Canadian Institutes of Health Research and the Kidney Foundation of Canada (to XZC), and the National Science Foundation of China (to JCT, grant# 30770658). XZC is a Senior Scholar of the Alberta Heritage Foundation for Medical Research. MRC and HC are members of the Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) de Argentina. HC gratefully acknowledges partial support of this study by National Institutes of Health ARRA Award DK077079. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 12 Z9 12 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2012 VL 7 IS 7 AR e40448 DI 10.1371/journal.pone.0040448 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973JD UT WOS:000306355500043 PM 22802962 ER PT J AU Kindler, HL Karrison, TG Gandara, DR Lu, C Krug, LM Stevenson, JP Janne, PA Quinn, DI Koczywas, MN Brahmer, JR Albain, KS Taber, DA Armato, SG Vogelzang, NJ Chen, HX Stadler, WM Vokes, EE AF Kindler, Hedy L. Karrison, Theodore G. Gandara, David R. Lu, Charles Krug, Lee M. Stevenson, James P. Jaenne, Pasi A. Quinn, David I. Koczywas, Marianna N. Brahmer, Julie R. Albain, Kathy S. Taber, David A. Armato, Samuel G., III Vogelzang, Nicholas J. Chen, Helen X. Stadler, Walter M. Vokes, Everett E. TI Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LEUKEMIA GROUP-B; ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; PLEURAL MESOTHELIOMA; CISPLATIN; SURVIVAL; VEGF; CHEMOTHERAPY; COMBINATION; PACLITAXEL AB Purpose Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. Patients and Methods Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. Results One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. Conclusion The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM. C1 [Kindler, Hedy L.] Univ Chicago, Ctr Comprehens Canc, Hematol Oncol Sect, Chicago, IL 60637 USA. [Albain, Kathy S.] Loyola Univ, Maywood, IL 60153 USA. [Gandara, David R.] Univ Calif Davis, Sacramento, CA 95817 USA. [Quinn, David I.] Univ So Calif, Los Angeles, CA USA. [Koczywas, Marianna N.] City Hope Med Ctr, Duarte, CA USA. [Lu, Charles] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Krug, Lee M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Stevenson, James P.] Univ Penn, Philadelphia, PA 19104 USA. [Jaenne, Pasi A.] Dana Farber Canc Ctr, Boston, MA USA. [Brahmer, Julie R.] Johns Hopkins Univ, Baltimore, MD USA. [Chen, Helen X.] NCI, Bethesda, MD 20892 USA. [Taber, David A.] No Indiana Canc Res Consortium, South Bend, IN USA. RP Kindler, HL (reprint author), Univ Chicago, Ctr Comprehens Canc, Hematol Oncol Sect, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM hkindler@medicine.bsd.uchicago.edu RI Quinn, David/F-4343-2015 OI Quinn, David/0000-0002-1411-0417 FU National Cancer Institute [N01-CM-17102, N01-CM-62209]; Genentech; Eli Lilly; Genentech/Roche FX Supported by National Cancer Institute Grants No. N01-CM-17102 and N01-CM-62209.; Research Funding: Hedy L. Kindler, Genentech, Eli Lilly; David R. Gandara, Genentech/Roche, Eli Lilly; Lee M. Krug, Eli Lilly; James P. Stevenson, Genentech, Eli Lilly; Kathy S. Albain, Eli Lilly; Nicholas J. Vogelzang, Genentech/Roche, Eli Lilly; Walter M. Stadler, Genentech NR 42 TC 79 Z9 80 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2012 VL 30 IS 20 BP 2509 EP 2515 DI 10.1200/JCO.2011.41.5869 PG 7 WC Oncology SC Oncology GA 971YU UT WOS:000306244300017 PM 22665541 ER PT J AU Phelps, AC Lauderdale, KE Alcorn, S Dillinger, J Balboni, MT Van Wert, M VanderWeele, TJ Balboni, TA AF Phelps, Andrea C. Lauderdale, Katharine E. Alcorn, Sara Dillinger, Jennifer Balboni, Michael T. Van Wert, Michael VanderWeele, Tyler J. Balboni, Tracy A. TI Addressing Spirituality Within the Care of Patients at the End of Life: Perspectives of Patients With Advanced Cancer, Oncologists, and Oncology Nurses SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; TREATMENT PREFERENCES; FAMILY MEDICINE; NEAR-DEATH; PHYSICIANS; NEEDS; QUESTIONNAIRE; ASSOCIATIONS; SATISFACTION; INPATIENTS AB Purpose Attention to patients' religious and spiritual needs is included in national guidelines for quality end-of-life care, but little data exist to guide spiritual care. Patients and Methods The Religion and Spirituality in Cancer Care Study is a multi-institution, quantitative-qualitative study of 75 patients with advanced cancer and 339 cancer physicians and nurses. Patients underwent semistructured interviews, and care providers completed a Web-based survey exploring their perspectives on the routine provision of spiritual care by physicians and nurses. Theme extraction was performed following triangulated procedures of interdisciplinary analysis. Multivariable ordinal logistic regression models assessed relationships between participants' characteristics and attitudes toward spiritual care. Results The majority of patients (77.9%), physicians (71.6%), and nurses (85.1%) believed that routine spiritual care would have a positive impact on patients. Only 25% of patients had previously received spiritual care. Among patients, prior spiritual care (adjusted odds ratio [AOR], 14.65; 95% CI, 1.51 to 142.23), increasing education (AOR, 1.26; 95% CI, 1.06 to 1.49), and religious coping (AOR, 4.79; 95% CI, 1.40 to 16.42) were associated with favorable perceptions of spiritual care. Physicians held more negative perceptions of spiritual care than patients (P < .001) and nurses (P = .008). Qualitative analysis identified benefits of spiritual care, including supporting patients' emotional well-being and strengthening patient-provider relationships. Objections to spiritual care frequently related to professional role conflicts. Participants described ideal spiritual care to be individualized, voluntary, inclusive of chaplains/clergy, and based on assessing and supporting patient spirituality. Conclusion Most patients with advanced cancer, oncologists, and oncology nurses value spiritual care. Themes described provide an empirical basis for engaging spiritual issues within clinical care. C1 [Phelps, Andrea C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lauderdale, Katharine E.] RAND Corp, Santa Monica, CA USA. [Alcorn, Sara] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Van Wert, Michael] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Phelps, AC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM andrea_phelps@dfci.harvard.edu FU NCI NIH HHS [T32 CA009172, L30 CA166015] NR 37 TC 46 Z9 47 U1 0 U2 21 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2012 VL 30 IS 20 BP 2538 EP 2544 DI 10.1200/JCO.2011.40.3766 PG 7 WC Oncology SC Oncology GA 971YU UT WOS:000306244300021 PM 22614979 ER PT J AU Ebb, D Meyers, P Grier, H Bernstein, M Gorlick, R Lipshultz, SE Krailo, M Devidas, M Barkauskas, DA Siegal, GP Ferguson, WS Letson, GD Marcus, K Goorin, A Beardsley, P Marina, N AF Ebb, David Meyers, Paul Grier, Holcombe Bernstein, Mark Gorlick, Richard Lipshultz, Steven E. Krailo, Mark Devidas, Meenakshi Barkauskas, Donald A. Siegal, Gene P. Ferguson, William Shay Letson, George Douglas Marcus, Karen Goorin, Allen Beardsley, Peter Marina, Neyssa TI Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HER2-POSITIVE BREAST-CANCER; STUDY-GROUP PROTOCOLS; CARDIAC TROPONIN-T; MONOCLONAL-ANTIBODY; ADJUVANT CHEMOTHERAPY; NATRIURETIC PEPTIDE; PEDIATRIC-PATIENTS; MYOCARDIAL INJURY; RANDOMIZED-TRIAL; PREDICTIVE-VALUE AB Purpose Despite efforts to intensify chemotherapy, survival for patients with metastatic osteosarcoma remains poor. Overexpression of human epidermal growth factor receptor 2 (HER2) in osteosarcoma has been shown to predict poor therapeutic response and decreased survival. This study tests the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 overexpression. Patients and Methods Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry. All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide. Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline. Only patients with HER2 overexpression received concurrent therapy with trastuzumab given for 34 consecutive weeks. Results The 30-month event-free and overall survival rates for patients with HER2 overexpression treated with chemotherapy and trastuzumab were 32% and 59%, respectively. For patients without HER2 overexpression, treated with chemotherapy alone, the 30-month event-free and overall survival rates were 32% and 50%, respectively. There was no clinically significant short-term cardiotoxicity in patients treated with trastuzumab and doxorubicin. Conclusion Despite intensive chemotherapy plus trastuzumab for patients with HER2-positive disease, the outcome for all patients was poor, with no significant difference between the HER2-positive and HER2-negative groups. Although our findings suggest that trastuzumab can be safely delivered in combination with anthracycline-based chemotherapy and dexrazoxane, its therapeutic benefit remains uncertain. Definitive assessment of trastuzumab's potential role in treating osteosarcoma would require a randomized study of patients with HER2-positive disease. C1 [Ebb, David] Massachusetts Gen Hosp, Dept Pediat Hematol Oncol, Boston, MA 02114 USA. [Grier, Holcombe; Marcus, Karen; Goorin, Allen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Meyers, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Gorlick, Richard] Montefiore Med Ctr, New York, NY USA. [Lipshultz, Steven E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Devidas, Meenakshi] Childrens Oncol Grp, Gainesville, FL USA. [Letson, George Douglas] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Krailo, Mark; Barkauskas, Donald A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Marina, Neyssa] Stanford Univ, Lucile Packard Childrens Hosp, Palo Alto, CA 94304 USA. [Siegal, Gene P.] Univ Alabama, Tuscaloosa, AL USA. [Ferguson, William Shay] St Louis Univ, Cardinal Glennon Childrens Hosp, St Louis, MO USA. [Beardsley, Peter] Yale Univ, New Haven, CT USA. [Bernstein, Mark] IWK Hlth Ctr, Halifax, NS, Canada. RP Ebb, D (reprint author), Massachusetts Gen Hosp, Dept Pediat Hematol Oncol, Yawkey 8B,55 Fruit St, Boston, MA 02114 USA. EM debb@partners.org OI Meyers, Paul/0000-0001-6146-6101 FU Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD [U10 CA98543, U24 CA114766]; WWWW (QuadW) Foundation; National Institutes of Health; Haley's Hope Memorial Support Fund for Osteosarcoma; Thomas Logan RAID Fund for Ewing's Sarcoma Research FX Supported by the Chair's Grant No. U10 CA98543 and Human Specimen Banking Grant No. U24 CA114766 of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD. Additional support for research was provided by a grant from the WWWW (QuadW) Foundation to the Children's Oncology Group; Research Funding: Gene P. Siegal, National Institutes of Health, Haley's Hope Memorial Support Fund for Osteosarcoma, Thomas Logan RAID Fund for Ewing's Sarcoma Research NR 42 TC 56 Z9 57 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2012 VL 30 IS 20 BP 2545 EP 2551 DI 10.1200/JCO.2011.37.4546 PG 7 WC Oncology SC Oncology GA 971YU UT WOS:000306244300022 PM 22665540 ER PT J AU Saboo, SS Fennessy, F Benajiba, L Laubach, J Anderson, KC Richardson, PG AF Saboo, Sachin S. Fennessy, Fiona Benajiba, Lina Laubach, Jacob Anderson, Kenneth C. Richardson, Paul G. TI Imaging Features of Extramedullary, Relapsed, and Refractory Multiple Myeloma involving the Liver Across Treatment With Cyclophosphamide, Lenalidomide, Bortezomib, and Dexamethasone SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID DISEASE; PLASMACYTOMAS; MANAGEMENT; LESIONS C1 [Saboo, Sachin S.; Fennessy, Fiona; Benajiba, Lina; Laubach, Jacob; Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Saboo, SS (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA050947, P50 CA100707, P01 CA155258, P01 CA078378] NR 18 TC 2 Z9 2 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2012 VL 30 IS 20 BP E175 EP E179 DI 10.1200/JCO.2011.41.1413 PG 5 WC Oncology SC Oncology GA 971YU UT WOS:000306244300003 PM 22689802 ER PT J AU Williams, SB Hirsch, MS Kantoff, PW Richie, JP AF Williams, Stephen B. Hirsch, Michelle S. Kantoff, Philip W. Richie, Jerome P. TI Neuroepithelial Tumor Arising in a Testicular Teratoma With Retroperitoneal Metastasis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID GERM-CELL TUMORS; NEUROECTODERMAL TUMOR; TESTIS C1 [Williams, Stephen B.; Hirsch, Michelle S.; Richie, Jerome P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Williams, SB (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2012 VL 30 IS 20 BP E172 EP E174 DI 10.1200/JCO.2011.40.1166 PG 3 WC Oncology SC Oncology GA 971YU UT WOS:000306244300002 PM 22689796 ER PT J AU O'Donoghue, ML Vaidya, A Afsal, R Alfredsson, J Boden, WE Braunwald, E Cannon, CP Clayton, TC de Winter, RJ Fox, KAA Lagerqvist, B McCullough, PA Murphy, SA Spacek, R Swahn, E Windhausen, F Sabatine, MS AF O'Donoghue, Michelle L. Vaidya, Ajay Afsal, Rizwan Alfredsson, Joakim Boden, William E. Braunwald, Eugene Cannon, Christopher P. Clayton, Tim C. de Winter, Robbert J. Fox, Keith A. A. Lagerqvist, Bo McCullough, Peter A. Murphy, Sabina A. Spacek, Rudolf Swahn, Eva Windhausen, Fons Sabatine, Marc S. TI An Invasive or Conservative Strategy in Patients With Diabetes Mellitus and Non-ST-Segment Elevation Acute Coronary Syndromes A Collaborative Meta-Analysis of Randomized Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE conservative strategy; diabetes mellitus; invasive strategy; meta-analysis ID MANAGEMENT; REGISTRY AB Objectives The purpose of this study was to conduct a meta-analysis to examine an invasive or conservative strategy in diabetic versus nondiabetic patients. Background Diabetic patients are at increased risk of cardiovascular events after an acute coronary syndrome, yet it remains unknown whether they derive enhanced benefit from an invasive strategy. Methods Randomized trials comparing an invasive versus conservative treatment strategy were identified. The prevalence of cardiovascular events through 12 months was reported for each trial, stratified by diabetes mellitus status and randomized treatment strategy. Relative risk (RR) ratios and absolute risk reductions were combined using random-effects models. Results Data were combined across 9 trials comprising 9,904 subjects of whom 1,789 (18.1%) had diabetes mellitus. The RRs for death, nonfatal myocardial infarction (MI), or rehospitalization with an acute coronary syndrome for an invasive versus conservative strategy were similar between diabetic patients (RR: 0.87; 95% confidence interval [CI]: 0.73 to 1.03) and nondiabetic patients (RR: 0.86; 95% CI: 0.70 to 1.06; p interaction = 0.83). An invasive strategy reduced nonfatal MI in diabetic patients (RR: 0.71; 95% CI: 0.55 to 0.92), but not in nondiabetic patients (RR: 0.98; 95% CI: 0.74 to 1.29; p interaction = 0.09). The absolute risk reduction in MI with an invasive strategy was greater in diabetic than nondiabetic patients (absolute risk reduction: 3.7% vs. 0.1%; p interaction = 0.02). There were no differences in death or stroke between groups (p interactions 0.68 and 0.20, respectively). Conclusions An early invasive strategy yielded similar RR reductions in overall cardiovascular events in diabetic and nondiabetic patients. However, an invasive strategy appeared to reduce recurrent nonfatal MI to a greater extent in diabetic patients. These data support the updated guidelines that recommend an invasive strategy for patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes. (J Am Coll Cardiol 2012; 60:106-11) (C) 2012 by the American College of Cardiology Foundation C1 [O'Donoghue, Michelle L.; Braunwald, Eugene; Cannon, Christopher P.; Murphy, Sabina A.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Vaidya, Ajay] Univ Calif San Francisco, Div Cardiovasc, San Francisco, CA 94143 USA. [Afsal, Rizwan] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Alfredsson, Joakim; Swahn, Eva] Linkoping Univ, Fac Hlth Sci, Dept Med & Hlth Sci, Dept Cardiol,Univ Hosp, Linkoping, Sweden. [Boden, William E.] Albany Stratton VA Med Ctr, Dept Med, Albany, NY USA. [Clayton, Tim C.] London Sch Hyg & Trop Med, London WC1, England. [de Winter, Robbert J.; Windhausen, Fons] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Lagerqvist, Bo] Univ Uppsala Hosp, Uppsala, Sweden. [McCullough, Peter A.] St John Providence Hlth Syst Providence Pk Heart, Novi, MI USA. [Spacek, Rudolf] 3rd Med Fac Prague, Prague, Czech Republic. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM modonoghue@partners.org FU Medicines Company; Merck; AstraZeneca; Johnson Johnson; Beckman Coulter; Eli Lilly; Roche Diagnostics; sanofi-aventis; Daiichi Sankyo; GlaxoSmithKline; Bristol-Myers Squibb; Merck Co.; Gilead; Menarini International; Pfizer; Abbott; Roche; Takeda; Nanosphere; Bristol-Myers Squibb/sanofi-aventis; Accumetrics FX Mr. Clayton has received research grant support and consultant's fees from The Medicines Company. Dr. Braunwald has received grant support from Merck, AstraZeneca, Johnson & Johnson, Beckman Coulter, Eli Lilly, Roche Diagnostics, sanofi-aventis, Daiichi Sankyo, GlaxoSmithKline, and Bristol-Myers Squibb. Dr. Braunwald is a consultant to Amorcyte, Ikaria, sanofi-aventis, CVRx, The Medicines Company, and Daiichi Sankyo; and has received lecture fees from Eli Lilly, Merck & Co., CV Therapeutics (now Gilead), Daiichi Sankyo, and Menarini International. Dr. Sabatine has received research grants from AstraZeneca, Pfizer, Abbott, Roche, Takeda, Nanosphere, Bristol-Myers Squibb/sanofi-aventis, and AstraZeneca; and has received honoraria from Bristol-Myers Squibb/sanofi-aventis, GlaxoSmithKline, Merck, and Pfizer. Dr. Cannon has received grant support from Accumetrics, AstraZeneca, GlaxoSmithKline, Merck & Co., and Takeda; honoraria for the development of educational symposia from Pfizer and AstraZeneca; and is a clinical advisor for, with equity in, Automedics Medical Systems. Dr. Fox is a consultant to Bayer, Eli Lilly, Boehringer-Ingelheim, and sanofi-aventis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 10 TC 24 Z9 25 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 10 PY 2012 VL 60 IS 2 BP 106 EP 111 DI 10.1016/j.jacc.2012.02.059 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 969VT UT WOS:000306088200004 PM 22766336 ER PT J AU Jin, CN Rajabi, H Pitroda, S Li, AL Kharbanda, A Weichselbaum, R Kufe, D AF Jin, Caining Rajabi, Hasan Pitroda, Sean Li, Ailing Kharbanda, Akriti Weichselbaum, Ralph Kufe, Donald TI Cooperative Interaction between the MUC1-C Oncoprotein and the Rab31 GTPase in Estrogen Receptor-Positive Breast Cancer Cells SO PLOS ONE LA English DT Article ID GENE-EXPRESSION SIGNATURE; MAMMARY-GLAND; LUNG-CANCER; PREDICT; DIFFERENTIATION; TUMORIGENESIS; TRAFFICKING; CARCINOMAS; ACTIVATION; SURVIVAL AB Rab31 is a member of the Ras superfamily of small GTPases that has been linked to poor outcomes in patients with breast cancer. The MUC1-C oncoprotein is aberrantly overexpressed in most human breast cancers and also confers a poor prognosis. The present results demonstrate that MUC1-C induces Rab31 expression in estrogen receptor positive (ER+) breast cancer cells. We show that MUC1-C forms a complex with estrogen receptor alpha (ER alpha) on the Rab31 promoter and activates Rab31 gene transcription in an estrogen-dependent manner. In turn, Rab31 contributes to the upregulation of MUC1-C abundance in breast cancer cells by attenuating degradation of MUC1-C in lysosomes. Expression of an inactive Rab31(S20N) mutant in nonmalignant breast epithelial cells confirmed that Rab31 regulates MUC1-C expression. The functional significance of the MUC1-C/Rab31 interaction is supported by the demonstration that Rab31 confers the formation of mammospheres by a MUC1-C-dependent mechanism. Analysis of microarray databases further showed that (i) Rab31 is expressed at higher levels in breast cancers as compared to that in normal breast tissues, (ii) MUC1+ and ER+ breast cancers have increased levels of Rab31 expression, and (iii) patients with Rab31-positive breast tumors have a significantly decreased ten-year overall survival as compared to those with Rab31-negative tumors. These findings indicate that MUC1-C and Rab31 function in an autoinductive loop that contributes to overexpression of MUC1-C in breast cancer cells. C1 [Jin, Caining; Rajabi, Hasan; Kharbanda, Akriti; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pitroda, Sean; Weichselbaum, Ralph] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Li, Ailing] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Jin, CN (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA42802, CA100707] FX This work was supported by grants CA97098, CA42802 and CA100707 awarded by the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 13 Z9 14 U1 0 U2 10 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 JUL 9 PY 2012 VL 7 IS 7 AR e39432 DI 10.1371/journal.pone.0039432 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 973IV UT WOS:000306354700011 PM 22792175 ER PT J AU Venkatesh, AK Kline, JA Courtney, M Camargo, CA Plewa, MC Nordenholz, KE Moore, CL Richman, PB Smithline, HA Beam, DM Kabrhel, C AF Venkatesh, Arjun K. Kline, Jeffrey A. Courtney, Mark Camargo, Carlos A., Jr. Plewa, Michael C. Nordenholz, Kristen E. Moore, Christopher L. Richman, Peter B. Smithline, Howard A. Beam, Daren M. Kabrhel, Christopher TI Evaluation of Pulmonary Embolism in the Emergency Department and Consistency With a National Quality Measure Quantifying the Opportunity for Improvement SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SIMPLE CLINICAL-MODEL; D-DIMER; COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; ANGIOGRAPHY; MANAGEMENT; MULTICENTER; DIAGNOSIS; CT AB Background: The National Quality Forum (NQF) has endorsed a performance measure designed to increase imaging efficiency for the evaluation of pulmonary embolism (PE) in the emergency department (ED). To our knowledge, no published data have examined the effect of patient-level predictors on performance. Methods: To quantify the prevalence of avoidable imaging in ED patients with suspected PE, we performed a prospective, multicenter observational study of ED patients evaluated for PE from 2004 through 2007 at 11 US EDs. Adult patients tested for PE were enrolled, with data collected in a standardized instrument. The primary outcome was the proportion of imaging that was potentially avoidable according to the NQF measure. Avoidable imaging was defined as imaging in a patient with low pretest probability for PE, who either did not have a D-dimer test ordered or who had a negative D-dimer test result. We performed subanalyses testing alternative pretest probability cutoffs and imaging definitions on measure performance as well as a secondary analysis to identify factors associated with inappropriate imaging. chi(2) Test was used for bivariate analysis of categorical variables and multivariable logistic regression for the secondary analysis. Results: We enrolled 5940 patients, of whom 4113 (69%) had low pretest probability of PE. Imaging was performed in 2238 low-risk patients (38%), of whom 811 had no D-dimer testing, and 394 had negative D-dimer test results. Imaging was avoidable, according to the NQF measure, in 1205 patients (32%; 95% CI, 31%-34%). Avoidable imaging owing to not ordering a D-dimer test was associated with age (odds ratio [OR], 1.15 per decade; 95% CI, 1.10-1.21). Avoidable imaging owing to imaging after a negative D-dimer test result was associated with inactive malignant disease (OR, 1.66; 95% CI, 1.11-2.49). Conclusions: One-third of imaging performed for suspected PE may be categorized as avoidable. Improving adherence to established diagnostic protocols is likely to result in significantly fewer patients receiving unnecessary irradiation and substantial savings. C1 [Venkatesh, Arjun K.; Camargo, Carlos A., Jr.; Kabrhel, Christopher] Massachusetts Gen Hosp, Dept Emergency Med, Brigham & Womens Hosp, Boston, MA 02114 USA. [Venkatesh, Arjun K.; Camargo, Carlos A., Jr.; Kabrhel, Christopher] Harvard Univ, Sch Med, Boston, MA USA. [Kline, Jeffrey A.; Beam, Daren M.] Carolinas Med Ctr, Dept Emergency Med, Charlotte, NC 28203 USA. [Courtney, Mark] Northwestern Univ, Dept Emergency Med, Chicago, IL 60611 USA. [Plewa, Michael C.] Mercy St Vincent Med Ctr, Dept Emergency Med, Toledo, OH USA. [Nordenholz, Kristen E.] Univ Colorado, Dept Emergency Med, Denver, CO 80202 USA. [Moore, Christopher L.] Yale Univ, Dept Emergency Med, Med Ctr, New Haven, CT USA. [Richman, Peter B.] Mayo Clin Arizona, Dept Emergency Med, Scottsdale, AZ USA. [Smithline, Howard A.] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. RP Kabrhel, C (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Brigham & Womens Hosp, 0 Emerson Pl,Ste 3B, Boston, MA 02114 USA. EM ckabrhel@partners.org OI Kabrhel, Christopher/0000-0002-8699-7176 FU National Institutes of Health [2R42HL074415] FX This study was funded by the National Institutes of Health grant No. 2R42HL074415. NR 22 TC 31 Z9 31 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 9 PY 2012 VL 172 IS 13 BP 1028 EP 1032 DI 10.1001/archinternmed.2012.1804 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 971FP UT WOS:000306189500012 PM 22664742 ER PT J AU Kupersmith, J Eisen, S AF Kupersmith, Joel Eisen, Seth TI A New Approach to Health Services Research SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Kupersmith, Joel; Eisen, Seth] US Dept Vet Affairs, Off Res & Dev, Washington, DC 20420 USA. [Eisen, Seth] US Dept Vet Affairs, Hlth Serv Res & Dev Serv, Washington, DC 20420 USA. RP Kupersmith, J (reprint author), US Dept Vet Affairs, Off Res & Dev, 810 Vermont Ave NW, Washington, DC 20420 USA. EM Joel.Kupersmith@va.gov NR 3 TC 5 Z9 5 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 9 PY 2012 VL 172 IS 13 BP 1033 EP 1034 DI 10.1001/archinternmed.2012.2004 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 971FP UT WOS:000306189500013 PM 22664894 ER PT J AU Stickrath, C Druck, J Hensley, N Maddox, TM Richlie, D AF Stickrath, Chad Druck, Jeffrey Hensley, Nathan Maddox, Thomas M. Richlie, Daniel TI Patient and Health Care Provider Discussions About the Risks of Medical Imaging: Not Ready for Prime Time SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID INCIDENTAL FINDINGS; RADIATION; BENEFITS C1 [Stickrath, Chad; Richlie, Daniel] Univ Colorado, Div Gen Internal Med, Denver Sch Med, Denver, CO 80202 USA. [Maddox, Thomas M.] Univ Colorado, Div Cardiol, Denver Sch Med, Denver, CO 80202 USA. [Druck, Jeffrey] Univ Colorado, Dept Med, Dept Emergency Med, Denver Sch Med, Denver, CO 80202 USA. [Hensley, Nathan] Univ Colorado, Dept Radiol, Denver Sch Med, Denver, CO 80202 USA. [Stickrath, Chad; Hensley, Nathan; Maddox, Thomas M.; Richlie, Daniel] Denver VA Med Ctr, Denver, CO 80220 USA. RP Stickrath, C (reprint author), Denver VA Med Ctr, 1055 Clermont St 111, Denver, CO 80220 USA. EM Chad.stickrath@va.gov NR 6 TC 7 Z9 7 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 9 PY 2012 VL 172 IS 13 BP 1037 EP 1038 DI 10.1001/archinternmed.2012.1791 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 971FP UT WOS:000306189500015 PM 22664652 ER PT J AU Steininger, P Neuner, M Weichenberger, H Sharp, GC Winey, B Kametriser, G Sedlmayer, F Deutschmann, H AF Steininger, P. Neuner, M. Weichenberger, H. Sharp, G. C. Winey, B. Kametriser, G. Sedlmayer, F. Deutschmann, H. TI Auto-masked 2D/3D image registration and its validation with clinical cone-beam computed tomography SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID GUIDED RADIATION-THERAPY; 2D-3D REGISTRATION; DIGITAL TOMOSYNTHESIS; CT; RADIOTHERAPY; RECONSTRUCTION; IMPLEMENTATION; GUIDANCE; SYSTEMS AB Image-guided alignment procedures in radiotherapy aim at minimizing discrepancies between the planned and the real patient setup. For that purpose, we developed a 2D/3D approach which rigidly registers a computed tomography (CT) with two x-rays by maximizing the agreement in pixel intensity between the x-rays and the corresponding reconstructed radiographs from the CT. Moreover, the algorithm selects regions of interest (masks) in the x-rays based on 3D segmentations from the pre-planning stage. For validation, orthogonal x-ray pairs from different viewing directions of 80 pelvic cone-beam CT (CBCT) raw data sets were used. The 2D/3D results were compared to corresponding standard 3D/3D CBCT-to-CT alignments. Outcome over 8400 2D/3D experiments showed that parametric errors in root mean square were <0.18 degrees (rotations) and <0.73 mm (translations), respectively, using rank correlation as intensity metric. This corresponds to a mean target registration error, related to the voxels of the lesser pelvis, of <2mm in 94.1% of the cases. From the results we conclude that 2D/3D registration based on sequentially acquired orthogonal x-rays of the pelvis is a viable alternative to CBCT-based approaches if rigid alignment on bony anatomy is sufficient, no volumetric intra-interventional data set is required and the expected error range fits the individual treatment prescription. C1 [Steininger, P.; Neuner, M.; Weichenberger, H.; Sedlmayer, F.; Deutschmann, H.] Paracelsus Med Univ, Inst Res & Dev Adv Radiat Technol radART, A-5020 Salzburg, Austria. [Weichenberger, H.; Kametriser, G.; Sedlmayer, F.; Deutschmann, H.] Paracelsus Med Univ, Univ Clin Radiotherapy & Radiooncol, A-5020 Salzburg, Austria. [Sharp, G. C.; Winey, B.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Steininger, P (reprint author), Paracelsus Med Univ, Inst Res & Dev Adv Radiat Technol radART, Muellner Hauptstr 48, A-5020 Salzburg, Austria. EM philipp.steininger@pmu.ac.at OI Sedlmayer, Felix/0000-0002-1181-0178 FU PMU Research Fund (PMU-FFF) [R-10/04/018-STE]; ELEKTA (Crawley, UK) FX The authors wish to thank the radiation therapy technologists of the University Clinic for Radiotherapy and Radio-Oncology Salzburg for their complaisance and assistance during CBCT acquisition. The study was supported by the PMU Research Fund (PMU-FFF) under grant R-10/04/018-STE and by ELEKTA (Crawley, UK). NR 29 TC 10 Z9 11 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2012 VL 57 IS 13 BP 4277 EP 4292 DI 10.1088/0031-9155/57/13/4277 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 965YL UT WOS:000305803600014 PM 22705709 ER PT J AU Glass, K Ott, E Losert, W Girvan, M AF Glass, Kimberly Ott, Edward Losert, Wolfgang Girvan, Michelle TI Implications of functional similarity for gene regulatory interactions SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE Gene Ontology; functional similarity; gene regulatory networks ID SEMANTIC SIMILARITY; SACCHAROMYCES-CEREVISIAE; COMPLEX NETWORKS; ONTOLOGY; RECONSTRUCTION; ANNOTATION; EXPRESSION; YEAST; INTEGRATION; ALGORITHM AB If one gene regulates another, those two genes are likely to be involved in many of the same biological functions. Conversely, shared biological function may be suggestive of the existence and nature of a regulatory interaction. With this in mind, we develop a measure of functional similarity between genes based on annotations made to the Gene Ontology in which the magnitude of their functional relationship is also indicative of a regulatory relationship. In contrast to other measures that have previously been used to quantify the functional similarity between genes, our measure scales the strength of any shared functional annotation by the frequency of that function's appearance across the entire set of annotations. We apply our method to both Escherichia coli and Saccharomyces cerevisiae gene annotations and find that the strength of our scaled similarity measure is more predictive of known regulatory interactions than previously published measures of functional similarity. In addition, we observe that the strength of the scaled similarity measure is correlated with the structural importance of links in the known regulatory network. By contrast, other measures of functional similarity are not indicative of any structural importance in the regulatory network. We therefore conclude that adequately adjusting for the frequency of shared biological functions is important in the construction of a functional similarity measure aimed at elucidating the existence and nature of regulatory interactions. We also compare the performance of the scaled similarity with a high-throughput method for determining regulatory interactions from gene expression data and observe that the ontology-based approach identifies a different subset of regulatory interactions compared with the gene expression approach. We show that combining predictions from the scaled similarity with those from the reconstruction algorithm leads to a significant improvement in the accuracy of the reconstructed network. C1 [Glass, Kimberly] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Glass, Kimberly; Ott, Edward; Losert, Wolfgang; Girvan, Michelle] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Losert, Wolfgang; Girvan, Michelle] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Glass, K (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM kglass@jimmy.harvard.edu RI O, E/F-1630-2015 NR 39 TC 5 Z9 5 U1 0 U2 5 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JUL 7 PY 2012 VL 9 IS 72 BP 1625 EP 1636 DI 10.1098/rsif.2011.0585 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 947NT UT WOS:000304437400019 PM 22298814 ER PT J AU Ceccaldi, R Parmar, K Mouly, E Delord, M Kim, JM Regairaz, M Pla, M Vasquez, N Zhang, QS Pondarre, C de Latour, RP Gluckman, E Cavazzana-Calvo, M Leblanc, T Larghero, J Grompe, M Socie, G D'Andrea, AD Soulier, J AF Ceccaldi, Raphael Parmar, Kalindi Mouly, Enguerran Delord, Marc Kim, Jung Min Regairaz, Marie Pla, Marika Vasquez, Nadia Zhang, Qing-Shuo Pondarre, Corinne de Latour, Regis Peffault Gluckman, Eliane Cavazzana-Calvo, Marina Leblanc, Thierry Larghero, Jerome Grompe, Markus Socie, Gerard D'Andrea, Alan D. Soulier, Jean TI Bone Marrow Failure in Fanconi Anemia Is Triggered by an Exacerbated p53/p21 DNA Damage Response that Impairs Hematopoietic Stem and Progenitor Cells SO CELL STEM CELL LA English DT Article ID FANCD2 KNOCKOUT MICE; TNF-ALPHA; P53; CANCER; PATHWAY; REPAIR; SENESCENCE; CYCLE; DYSFUNCTION; FIBROBLASTS AB Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21(Cdkn1a)-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 "physiological" response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care. C1 [Ceccaldi, Raphael; Mouly, Enguerran; Delord, Marc; Regairaz, Marie; Pla, Marika; Larghero, Jerome; Socie, Gerard; Soulier, Jean] Univ Paris Diderot, Sorbonne Paris Cite, Inst Hematol IUH, Paris 75010, France. [Ceccaldi, Raphael; Regairaz, Marie; Soulier, Jean] St Louis Hosp, INSERM, U944, F-75010 Paris, France. [Ceccaldi, Raphael; Regairaz, Marie; Soulier, Jean] St Louis Hosp, CNRS, UMR7212, F-75010 Paris, France. [Ceccaldi, Raphael; Vasquez, Nadia; Soulier, Jean] St Louis Hosp, APHP, Hematol Lab, F-75010 Paris, France. [Pla, Marika; Larghero, Jerome] St Louis Hosp, INSERM, UMRS 940, F-75010 Paris, France. [de Latour, Regis Peffault; Gluckman, Eliane; Socie, Gerard] St Louis Hosp, APHP, Hematol Transplantat Dept, F-75010 Paris, France. [Socie, Gerard] St Louis Hosp, INSERM, U728, F-75010 Paris, France. [Larghero, Jerome] St Louis Hosp, APHP, Cell Therapy Unit, F-75010 Paris, France. [Larghero, Jerome] St Louis Hosp, APHP, CIC BT501, F-75010 Paris, France. [Parmar, Kalindi; Kim, Jung Min; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Zhang, Qing-Shuo; Grompe, Markus] Oregon Hlth & Sci Univ, Oregon Stem Cell Ctr, Portland, OR 97239 USA. [Pondarre, Corinne] Hosp Civils Lyon, Inst Pediat Hematol & Oncol, F-69008 Lyon, France. [Cavazzana-Calvo, Marina] Hop Necker Enfants Malad, INSERM, U768, F-75015 Paris, France. [Leblanc, Thierry] Robert Debre Hosp, Dept Pediat Hematol, F-75019 Paris, France. RP Soulier, J (reprint author), Univ Paris Diderot, Sorbonne Paris Cite, Inst Hematol IUH, Paris 75010, France. EM jean.soulier@sls.aphp.fr OI Zhang, Qing-shuo/0000-0002-4407-6053 FU AFMF (Association Francaise de la Maladie de Fanconi); FARF (Fanconi Anemia Research Fund); Agence Nationale de la Recherche (ANR) "Genopath"; National Institutes of Health (NIH) [P01HL048546, RC4DK090913, R01DK43889]; NIH/NHLB [P01HL048546-16]; Association pour la Recherche contre le Cancer (ARC); Association Laurette Fugain FX We are grateful to William Vainchenker, Jean-Claude Gluckman, and Hugues de The for helpful discussion. We thank Lucie Hernandez (Genomic facility, IUH), Niclas Setterblad (Plateau technique, IUH), Abigail Hamilton (DFCI), and Aurelie Coquin (APHP, Saint-Louis Hospital) for their technical assistance; Eric Benedetti (OHSU) for maintaining the Fancd2/p53 mouse colony; Daniela Geromin at the Cellulotheque of Saint-Louis Hospital; and Patrizia Vinciguerra (DFCI) for her initial observations on the role of p53 in the cytokinesis failure of HSCs. We thank the patients and their families, and the AFMF (Association Francaise de la Maladie de Fanconi) and FARF (Fanconi Anemia Research Fund) for their support to J.S. and A.D.D., respectively, and the physicians and nurses from French pediatric, genetic, and/or hematological centers who have taken care of the patients. We also thank Joelle Roume, Laurence Loeuillet, Christine Francannet, and Anne-Marie Beaufrere, who referred FA fetus samples to our laboratory. Our center is supported by the French Government (Direction de l'Hospitalisation et de l'Organisation des Solos) as Centre de Reference Maladies Rares "Aplasies Medullaires Constitutionnelles" (coordination: G. Socie), and by the "Reseau INCa des Maladies Cassantes de l'AND" (coordination: D. Stoppa-Lyonnet and A. Sarasin). This work was supported by a grant from the Agence Nationale de la Recherche (ANR) "Genopath" to J.S., and by grants of the National Institutes of Health (NIH) (P01HL048546, RC4DK090913, and R01DK43889 to A.D.D.) and NIH/NHLB (P01HL048546-16 to M.G.). R.C. was supported by a fellowship of the Association pour la Recherche contre le Cancer (ARC) and by the Association Laurette Fugain. NR 68 TC 97 Z9 98 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 6 PY 2012 VL 11 IS 1 BP 36 EP 49 DI 10.1016/j.stem.2012.05.013 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 975SS UT WOS:000306532400008 PM 22683204 ER PT J AU Anguera, MC Sadreyev, R Zhang, ZQ Szanto, A Payer, B Sheridan, SD Kwok, S Haggarty, SJ Sur, M Alvarez, J Gimelbrant, A Mitalipova, M Kirby, JE Lee, JT AF Anguera, Montserrat C. Sadreyev, Ruslan Zhang, Zhaoqing Szanto, Attila Payer, Bernhard Sheridan, Steven D. Kwok, Showming Haggarty, Stephen J. Sur, Mriganka Alvarez, Jason Gimelbrant, Alexander Mitalipova, Maisam Kirby, James E. Lee, Jeannie T. TI Molecular Signatures of Human Induced Pluripotent Stem Cells Highlight Sex Differences and Cancer Genes SO CELL STEM CELL LA English DT Article ID X-CHROMOSOME INACTIVATION; HUMAN SOMATIC-CELLS; DOSAGE COMPENSATION; IPS CELLS; IN-VITRO; LINES; MOUSE; RNA; ES; DIFFERENTIATION AB Although human induced pluripotent stem cells (hiPSCs) have enormous potential in regenerative medicine, their epigenetic variability suggests that some lines may not be suitable for human therapy. There are currently few benchmarks for assessing quality. Here we show that X-inactivation markers can be used to separate hiPSC lines into distinct epigenetic classes and that the classes are phenotypically distinct. Loss of XIST expression is strongly correlated with upregulation of X-linked oncogenes, accelerated growth rate in vitro, and poorer differentiation in vivo. Whereas differences in X-inactivation potential result in epigenetic variability of female hiPSC lines, male hiPSC lines generally resemble each other and do not overexpress the oncogenes. Neither physiological oxygen levels nor HDAC inhibitors offer advantages to culturing female hiPSC lines. We conclude that female hiPSCs may be epigenetically less stable in culture and caution that loss of XIST may result in qualitatively less desirable stem cell lines. C1 [Anguera, Montserrat C.; Sadreyev, Ruslan; Szanto, Attila; Payer, Bernhard; Lee, Jeannie T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. [Anguera, Montserrat C.; Sadreyev, Ruslan; Szanto, Attila; Payer, Bernhard; Lee, Jeannie T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Anguera, Montserrat C.; Sadreyev, Ruslan; Szanto, Attila; Payer, Bernhard; Alvarez, Jason; Gimelbrant, Alexander; Lee, Jeannie T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Genet, Boston, MA 02114 USA. [Sheridan, Steven D.; Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Zhang, Zhaoqing] Qiagen, SAB Biosci, Frederick, MD 21703 USA. [Sheridan, Steven D.; Kwok, Showming; Sur, Mriganka] MIT, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Alvarez, Jason; Gimelbrant, Alexander] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Mitalipova, Maisam] Whitehead Inst Biomed Sci, Cambridge, MA 02142 USA. [Kirby, James E.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Lee, JT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu RI Payer, Bernhard/F-7353-2010; OI Payer, Bernhard/0000-0002-4694-2082; Haggarty, Stephen J./0000-0002-7872-168X FU NIH [RO1-GM58839, R21MH087896]; ARRA supplement; Stanley Medical Research Institute FX We thank members of the J.T.L. laboratory for critical insight and discussion; G. Daley for pEYK, HD 12D-1, and JDM 6C-1; G. Mostoslovasky for STEMCCA lentiviral cassette; H. Willard and J. Lawrence for PGK1 probe; L. Daheron, T. Ahfeldt, and R. Alagappan for technical assistance; and C. Ware for advice on HDACi. This work was funded by NIH RO1-GM58839 and ARRA supplement to J.T.L. and NIH R21MH087896 and a Stanley Medical Research Institute award to S.J.H. J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 63 TC 48 Z9 49 U1 0 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 6 PY 2012 VL 11 IS 1 BP 75 EP 90 DI 10.1016/j.stem.2012.03.008 PG 16 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 975SS UT WOS:000306532400011 PM 22770242 ER PT J AU Kono, K Saeki, Y Yoshida, S Tanaka, K Pellman, D AF Kono, Keiko Saeki, Yasushi Yoshida, Satoshi Tanaka, Keiji Pellman, David TI Proteasomal Degradation Resolves Competition between Cell Polarization and Cellular Wound Healing SO CELL LA English DT Article ID RSP5 UBIQUITIN LIGASE; PROTEIN-KINASE-C; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; PLASMA-MEMBRANE; ACTIN CABLES; SECRETORY VESICLES; SINGLE-CELL; YEAST; POLARITY AB Cellular wound healing, enabling the repair of membrane damage, is ubiquitous in eukaryotes. One aspect of the wound healing response is the redirection of a polarized cytoskeleton and the secretory machinery to the damage site. Although there has been recent progress in identifying conserved proteins involved in wound healing, the mechanisms linking these components into a coherent response are not defined. Using laser damage in budding yeast, we demonstrate that local cell wall/membrane damage triggers the dispersal of proteins from the site of polarized growth, enabling their accumulation at the wound. We define a protein-kinase-C-dependent mechanism that mediates the destruction of the formin Bni1 and the exocyst component Sec3. This degradation is essential to prevent competition between the site of polarized growth and the wound. Mechanisms to overcome competition from a preexisting polarized cytoskeleton may be a general feature of effective wound healing in polarized cells. C1 [Kono, Keiko; Yoshida, Satoshi; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kono, Keiko; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Saeki, Yasushi; Tanaka, Keiji] Tokyo Metropolitan Inst Med Sci, Lab Prot Metab, Setagaya Ku, Tokyo 1568506, Japan. [Yoshida, Satoshi] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Yoshida, Satoshi] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Pellman, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU NIH [RO1 GM061345] FX We thank D. Finley and M. Springer for critical reading of the manuscript; C. Mann, W. Guo, M. Cyert, L. Hicke, and D. Lew for reagents; Z. Shi for pilot experiments; S. Gygi and R. Tomaino for mass spectrometry analysis; L. Cameron for advice on microscopy; members of the Pellman lab, especially S. Buttery and B. Atkins, for helpful discussions; and C. Kuroda for strain construction. This work was supported by NIH grant RO1 GM061345. NR 52 TC 30 Z9 30 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 6 PY 2012 VL 150 IS 1 BP 151 EP 164 DI 10.1016/j.cell.2012.05.030 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 970GB UT WOS:000306115000014 PM 22727045 ER PT J AU Truog, RD Kesselheim, AS Joffe, S AF Truog, Robert D. Kesselheim, Aaron S. Joffe, Steven TI Paying Patients for Their Tissue: The Legacy of Henrietta Lacks SO SCIENCE LA English DT Editorial Material C1 [Truog, Robert D.] Childrens Hosp Boston, Boston, MA 02115 USA. [Kesselheim, Aaron S.] Brigham & Womens Hosp, Boston, MA 02120 USA. [Joffe, Steven] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Truog, RD (reprint author), Childrens Hosp Boston, Boston, MA 02115 USA. EM robert.truog@childrens.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU AHRQ HHS [K08 HS018465, K08HS18465-01]; NCRR NIH HHS [1 UL1 RR025758-01, UL1 RR025758] NR 6 TC 9 Z9 11 U1 2 U2 41 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 6 PY 2012 VL 337 IS 6090 BP 37 EP 38 DI 10.1126/science.1216888 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KC UT WOS:000306053100032 PM 22767914 ER PT J AU Tennessen, JA Bigham, AW O'Connor, TD Fu, WQ Kenny, EE Gravel, S McGee, S Do, R Liu, XM Jun, G Kang, HM Jordan, D Leal, SM Gabriel, S Rieder, MJ Abecasis, G Altshuler, D Nickerson, DA Boerwinkle, E Sunyaev, S Bustamante, CD Bamshad, MJ Akey, JM AF Tennessen, Jacob A. Bigham, Abigail W. O'Connor, Timothy D. Fu, Wenqing Kenny, Eimear E. Gravel, Simon McGee, Sean Do, Ron Liu, Xiaoming Jun, Goo Kang, Hyun Min Jordan, Daniel Leal, Suzanne M. Gabriel, Stacey Rieder, Mark J. Abecasis, Goncalo Altshuler, David Nickerson, Deborah A. Boerwinkle, Eric Sunyaev, Shamil Bustamante, Carlos D. Bamshad, Michael J. Akey, Joshua M. CA Broad GO Seattle GO NHLBI Exome Sequencing Project TI Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes SO SCIENCE LA English DT Article ID POSITIVE SELECTION; HAPLOTYPE MAP; DISCOVERY; POPULATIONS; MUTATIONS; SPECTRUM; DISEASE; GENOME AB As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111x in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of similar to 313 genes per genome, and similar to 95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits. C1 [Tennessen, Jacob A.; O'Connor, Timothy D.; Fu, Wenqing; McGee, Sean; Rieder, Mark J.; Nickerson, Deborah A.; Bamshad, Michael J.; Akey, Joshua M.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Bigham, Abigail W.; Bamshad, Michael J.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Kenny, Eimear E.; Gravel, Simon] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Do, Ron; Gabriel, Stacey; Altshuler, David; Sunyaev, Shamil] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Do, Ron] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Liu, Xiaoming; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Jun, Goo; Kang, Hyun Min; Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jordan, Daniel; Sunyaev, Shamil] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Bamshad, MJ (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM mbamshad@u.washington.edu; akeyj@uw.edu RI Abecasis, Goncalo/B-7840-2010; Liu, Xiaoming/C-2743-2008; Altshuler, David/A-4476-2009; Jun, Goo/M-5235-2016; Jun, Goo/F-1941-2017; OI Liu, Xiaoming/0000-0001-8285-5528; Altshuler, David/0000-0002-7250-4107; Jun, Goo/0000-0003-0891-0204; Jun, Goo/0000-0003-0891-0204; Tennessen, Jacob/0000-0002-5015-4740; Abecasis, Goncalo/0000-0003-1509-1825; Jordan, Daniel/0000-0002-5318-8225 FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926] FX We acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research; and the Population Genetics Project Team. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (Women's Health Initiative Exome Sequencing Project, WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Filtered sets of annotated variants and their allele frequencies are available at http://evs.gs.washington.edu/EVS/ and have been deposited in dbSNP (www.ncbi.nlm.nih.gov/snp; local batch ID, ESP2500). Genotypes and phenotypes from a large subset of individuals are also available via dbGaP (www.ncbi.nlm.nih.gov/gap) using the following accession information: NHLBI GO-ESP: Women's Health Initiative Exome Sequencing Project (WHI) - WHISP, WHISP_Subject_Phenotypes, pht002246.v2. p2, phs000281.v2.p2; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (JHS), ESP_HeartGO_JHS_LDLandEOMI_Subject_Phenotypes, pht002539.v1.p1, phs000402.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (FHS), HeartGO_FHS_LDLandEOMI_PhenotypeDataFile, pht002476.v1.p1, phs000401.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CHS), HeartGO_CHS_LDL_PhenotypeDataFile, pht002536.v1.p1, phs000400.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (ARIC), ESP_ARIC_LDLandEOMI_Sample, pht002466.v1.p1, phs000398.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Cystic Fibrosis), ESP_LungGO_CF_PA_Culture_Data, pht002227. v1.p1, phs000254.v1.p1; NHLBI GO-ESP: Early-Onset Myocardial Infarction (Broad EOMI), ESP_Broad_EOMI_Subject_Phenotypes, pht001437.v1.p1, phs000279.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension), PAH_Subject_Phenotypes_Baseline_Measures, pht002277.v1.p1, phs000290.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Lung Health Study of Chronic Obstructive Pulmonary Disease), LHS_COPD_Subject_Phenotypes_Baseline_Measures, pht002272.v1.p1, phs000291. v1.p1. C. D. B. is on the scientific advisory board for Personalis, Incorporated; Mubadala Medical Holding Company; 23andme "Roots into the future" project; and Ancestry. com. M.J.R. owns stock in Illumina. NR 28 TC 712 Z9 722 U1 6 U2 82 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 6 PY 2012 VL 337 IS 6090 BP 64 EP 69 DI 10.1126/science.1219240 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KC UT WOS:000306053100043 PM 22604720 ER PT J AU Solimini, NL Xu, QK Mermel, CH Liang, AC Schlabach, MR Luo, J Burrows, AE Anselmo, AN Bredemeyer, AL Li, MZ Beroukhim, R Meyerson, M Elledge, SJ AF Solimini, Nicole L. Xu, Qikai Mermel, Craig H. Liang, Anthony C. Schlabach, Michael R. Luo, Ji Burrows, Anna E. Anselmo, Anthony N. Bredemeyer, Andrea L. Li, Mamie Z. Beroukhim, Rameen Meyerson, Matthew Elledge, Stephen J. TI Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential SO SCIENCE LA English DT Article ID LINEAGE-SURVIVAL ONCOGENE; TUMOR SUPPRESSION; LIVER-CANCER; IDENTIFICATION; GENES; PRINCIPLES; MUTATIONS; GENOMES AB Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes. Analysis of their chromosomal distribution revealed that recurring deletions preferentially overrepresent STOP genes and underrepresent GO genes. We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies. Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types. C1 [Solimini, Nicole L.; Xu, Qikai; Liang, Anthony C.; Schlabach, Michael R.; Luo, Ji; Burrows, Anna E.; Anselmo, Anthony N.; Bredemeyer, Andrea L.; Li, Mamie Z.; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Solimini, Nicole L.; Xu, Qikai; Liang, Anthony C.; Schlabach, Michael R.; Luo, Ji; Burrows, Anna E.; Anselmo, Anthony N.; Bredemeyer, Andrea L.; Li, Mamie Z.; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02115 USA. [Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Mermel, Craig H.; Beroukhim, Rameen; Meyerson, Matthew] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02141 USA. [Beroukhim, Rameen] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu RI Meyerson, Matthew/E-7123-2012; OI Bredemeyer, Andrea/0000-0003-2970-5998 FU National Human Genome Research Institute; NIH [U54CA143798]; U.S. Department of Defense; Susan G. Komen for the Cure Foundation [KG080087]; American Cancer Society [116410-PF-09-078-01-MGO]; National Institute of General Medical Sciences Medical Scientist Training Program [T32GM07753]; NIH, Stand Up to Cancer FX We thank S. Forbes, A. Futreal, and M. Stratton for generously providing the whole-genome sequencing data from the COSMIC database, and C. Shaw, D. MacPherson, M. Emanuele, C. Thoma, T. Westbrook, and members of the Elledge lab for helpful discussions and critical reading of this manuscript. Supported by grants from the National Human Genome Research Institute-funded Cancer Genome Atlas project (M. M.); NIH grant U54CA143798 (R. B.); NIH, Stand Up to Cancer, and the U.S. Department of Defense (S.J.E.); Susan G. Komen for the Cure Foundation postdoctoral fellowship KG080087 (N.L.S.); American Cancer Society postdoctoral fellowship 116410-PF-09-078-01-MGO (Q. X.); and National Institute of General Medical Sciences Medical Scientist Training Program award T32GM07753 (C. H. M.). S.J.E. is an investigator of the Howard Hughes Medical Institute. NR 25 TC 75 Z9 75 U1 0 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 6 PY 2012 VL 337 IS 6090 BP 104 EP 109 DI 10.1126/science.1219580 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 969KC UT WOS:000306053100054 PM 22628553 ER PT J AU Ghobrial, IM AF Ghobrial, Irene M. TI Myeloma as a model for the process of metastasis: implications for therapy SO BLOOD LA English DT Article ID BONE-MARROW MICROENVIRONMENT; EPITHELIAL-MESENCHYMAL TRANSITION; HEMATOPOIETIC STEM/PROGENITOR CELLS; UNDETERMINED SIGNIFICANCE MGUS; SMOLDERING MULTIPLE-MYELOMA; BREAST-CANCER METASTASIS; CIRCULATING PLASMA-CELLS; RESISTANCE CAM-DR; STEM-CELL; MONOCLONAL GAMMOPATHY AB Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed. (Blood. 2012;120(1):20-30) C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Mayer 1B, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu FU National Institutes of Health [R01CA133799, R01CA125690, R01CA154648]; Millennium; Bristol-Myers Squibb; Noxxon; Novartis; Onyx; Genzyme FX This work was supported in part by the National Institutes of Health (R01CA133799, R01CA125690, and R01CA154648).; I.M.G. is on the advisory board of Millennium, Novartis, Onyx, and Bristol-Myers Squibb and has research support from Millennium, Bristol-Myers Squibb, Noxxon, Novartis, Onyx, and Genzyme. NR 151 TC 47 Z9 51 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 5 PY 2012 VL 120 IS 1 BP 20 EP 30 DI 10.1182/blood-2012-01-379024 PG 11 WC Hematology SC Hematology GA 987IT UT WOS:000307411100009 PM 22535658 ER PT J AU Detre, C Keszei, M Garrido-Mesa, N Kis-Toth, K Castro, W Agyemang, AF Veerapen, N Besra, GS Carroll, MC Tsokos, GC Wang, NH Leadbetter, EA Terhorst, C AF Detre, Cynthia Keszei, Marton Garrido-Mesa, Natividad Kis-Toth, Katalin Castro, Wilson Agyemang, Amma F. Veerapen, Natacha Besra, Gurdyal S. Carroll, Michael C. Tsokos, George C. Wang, Ninghai Leadbetter, Elizabeth A. Terhorst, Cox TI SAP expression in invariant NKT cells is required for cognate help to support B-cell responses SO BLOOD LA English DT Article ID KILLER T-CELLS; LINKED LYMPHOPROLIFERATIVE-DISEASE; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; DENDRITIC CELLS; LIPID ANTIGEN; GENE-PRODUCT; IN-VIVO; ACTIVATION; RECEPTORS AB One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that alpha-galactosylceramide (alpha GalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-). B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-). BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2. B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgam-maglobulinemia. (Blood. 2012;120(1):122-129) C1 [Detre, Cynthia; Keszei, Marton; Garrido-Mesa, Natividad; Castro, Wilson; Wang, Ninghai; Terhorst, Cox] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol,Dept Med, Boston, MA 02115 USA. [Kis-Toth, Katalin; Tsokos, George C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Rheumatol,Dept Med, Boston, MA 02115 USA. [Agyemang, Amma F.; Carroll, Michael C.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Agyemang, Amma F.; Carroll, Michael C.] Childrens Hosp, Program Mol & Cellular Med, Boston, MA 02115 USA. [Veerapen, Natacha; Besra, Gurdyal S.] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. [Leadbetter, Elizabeth A.] Trudeau Inst Inc, Saranac Lake, NY 12983 USA. RP Detre, C (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol,Dept Med, 3 Blackfan Cir,CLS 928, Boston, MA 02115 USA. EM cdetre@bidmc.harvard.edu RI Keszei, Marton/F-3295-2014; OI Keszei, Marton/0000-0002-1158-2179; Besra, Gurdyal/0000-0002-5605-0395; Garrido Mesa, Natividad/0000-0002-3374-0270 FU National Institutes of Health [PO1 AI 35714, RO1 AI 065687] FX This study was supported by grants from the National Institutes of Health (PO1 AI 35714 and RO1 AI 065687 to C.T.). NR 36 TC 18 Z9 18 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 JUL 5 PY 2012 VL 120 IS 1 BP 122 EP 129 DI 10.1182/blood-2011-11-395913 PG 8 WC Hematology SC Hematology GA 987IT UT WOS:000307411100020 PM 22613797 ER PT J AU Peters, CG Michelson, AD Flaumenhaft, R AF Peters, Christian G. Michelson, Alan D. Flaumenhaft, Robert TI Granule exocytosis is required for platelet spreading: differential sorting of alpha-granules expressing VAMP-7 SO BLOOD LA English DT Article ID EPITHELIAL-CELL MIGRATION; TI-VAMP; RELEASE REACTION; PLASMA-MEMBRANE; SNARE; PROTEINS; SECRETION; FUSION; MECHANISM; DISTINCT AB There has been recent controversy as to whether platelet alpha-granules represent a single granule population or are composed of different subpopulations that serve discrete functions. To address this question, we evaluated the localization of vesicle-associated membrane proteins (VAMPs) in spread platelets to determine whether platelets actively sort a specific subpopulation of alpha-granules to the periphery during spreading. Immunofluorescence microscopy demonstrated that granules expressing VAMP-3 and VAMP-8 localized to the central granulomere of spread platelets along with the granule cargos von Willebrand factor and serotonin. In contrast, alpha-granules expressing VAMP-7 translocated to the periphery of spread platelets along with the granule cargos TIMP2 and VEFG. Time-lapse microscopy demonstrated that alpha-granules expressing VAMP-7 actively moved from the granulomere to the periphery during spreading. Platelets from a patient with gray platelet syndrome lacked alpha-granules and demonstrated only minimal spreading. Similarly, spreading was impaired in platelets obtained from Unc13d(Jinx) mice, which are deficient in Munc13-4 and have an exocytosis defect. These studies identify a new alpha-granule subtype expressing VAMP-7 that moves to the periphery during spreading, supporting the premise that alpha-granules are heterogeneous and demonstrating that granule exocytosis is required for platelet spreading. (Blood. 2012;120(1):199-206) C1 [Flaumenhaft, Robert] Harvard Univ, Ctr Life Sci, Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis,Dept Med,Med Sch, Boston, MA 02215 USA. [Michelson, Alan D.] Harvard Univ, Childrens Hosp Boston, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol,Med Sc, Boston, MA 02215 USA. RP Flaumenhaft, R (reprint author), Harvard Univ, Ctr Life Sci, Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis,Dept Med,Med Sch, Rm 939,3 Blackfan Cir, Boston, MA 02215 USA. EM rflaumen@bidmc.harvard.edu FU National Institutes of Health [HL087203]; American Heart Association; [T32 HL07917] FX This work was supported by National Institutes of Health grant HL087203 (R.F.). C.G.P. was supported by T32 HL07917. R.F. is a recipient of an Established Investigator Award from the American Heart Association. NR 46 TC 26 Z9 26 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 5 PY 2012 VL 120 IS 1 BP 199 EP 206 DI 10.1182/blood-2011-10-389247 PG 8 WC Hematology SC Hematology GA 987IT UT WOS:000307411100028 PM 22589474 ER PT J AU Asch, DA Muller, RW Volpp, KG AF Asch, David A. Muller, Ralph W. Volpp, Kevin G. TI Automated Hovering in Health Care - Watching Over the 5000 Hours SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID FINANCIAL INCENTIVES C1 [Asch, David A.; Volpp, Kevin G.] Univ Penn, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Asch, David A.; Muller, Ralph W.; Volpp, Kevin G.] Univ Penn, Hlth Syst Ctr Innovat Hlth Care Financing, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] Univ Penn, Penn CMU Roybal Ctr Behav Econ & Hlth P30, Philadelphia, PA 19104 USA. [Asch, David A.; Muller, Ralph W.; Volpp, Kevin G.] Univ Penn, Ctr Hlth Incent & Behav Econ, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] Univ Penn, Perelman Sch, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. RP Asch, DA (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. OI Asch, David/0000-0002-7970-286X NR 5 TC 46 Z9 46 U1 2 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 5 PY 2012 VL 367 IS 1 BP 1 EP 3 DI 10.1056/NEJMp1203869 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 968KJ UT WOS:000305979400014 PM 22716935 ER PT J AU Morrow, M Harris, JR Schnitt, SJ AF Morrow, Monica Harris, Jay R. Schnitt, Stuart J. TI Surgical Margins in Lumpectomy for Breast Cancer - Bigger Is Not Better SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID 20-YEAR FOLLOW-UP; CONSERVING THERAPY; ESTROGEN-RECEPTOR; RANDOMIZED-TRIAL; PROGESTERONE-RECEPTOR; RADICAL-MASTECTOMY; RADIATION-THERAPY; ADJUVANT BREAST; SURGERY; RECURRENCE C1 [Morrow, Monica] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Harris, Jay R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Harris, Jay R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schnitt, Stuart J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Harris, Jay R.; Schnitt, Stuart J.] Harvard Univ, Sch Med, Boston, MA USA. RP Morrow, M (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 35 TC 73 Z9 74 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 5 PY 2012 VL 367 IS 1 BP 79 EP 82 DI 10.1056/NEJMsb1202521 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 968KJ UT WOS:000305979400013 PM 22762325 ER PT J AU Eccles, MP Grimshaw, JM Shekelle, P Schunemann, HJ Woolf, S AF Eccles, Martin P. Grimshaw, Jeremy M. Shekelle, Paul Schuenemann, Holger J. Woolf, Steven TI Developing clinical practice guidelines: target audiences, identifying topics for guidelines, guideline group composition and functioning and conflicts of interest SO IMPLEMENTATION SCIENCE LA English DT Article ID RAPID ADVICE GUIDELINES; INDUSTRY; QUALITY; POLICY; INVOLVEMENT; SOCIETIES; APPRAISAL AB Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this first paper we discuss: the target audience(s) for guidelines and their use of guidelines; identifying topics for guidelines; guideline group composition (including consumer involvement) and the processes by which guideline groups function and the important procedural issue of managing conflicts of interest in guideline development. C1 [Eccles, Martin P.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. [Grimshaw, Jeremy M.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Grimshaw, Jeremy M.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Shekelle, Paul] RAND Corp, Santa Monica, CA 90407 USA. [Shekelle, Paul] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Schuenemann, Holger J.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Woolf, Steven] Virginia Commonwealth Univ, Dept Family Med, Richmond, VA USA. [Woolf, Steven] Virginia Commonwealth Univ, Ctr Human Needs, Richmond, VA USA. RP Shekelle, P (reprint author), RAND Corp, Santa Monica, CA 90407 USA. EM shekelle@rand.org RI Grimshaw, Jeremy/D-8726-2013; OI Grimshaw, Jeremy/0000-0001-8015-8243 NR 47 TC 53 Z9 57 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 4 PY 2012 VL 7 AR 60 DI 10.1186/1748-5908-7-60 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 066EZ UT WOS:000313204500001 PM 22762776 ER PT J AU Shekelle, P Woolf, S Grimshaw, JM Schunemann, HJ Eccles, MP AF Shekelle, Paul Woolf, Steven Grimshaw, Jeremy M. Schuenemann, Holger J. Eccles, Martin P. TI Developing clinical practice guidelines: reviewing, reporting, and publishing guidelines; updating guidelines; and the emerging issues of enhancing guideline implementability and accounting for comorbid conditions in guideline development SO IMPLEMENTATION SCIENCE LA English DT Article ID QUALITY; CARE; FRAMEWORK AB Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this third paper we discuss the issues of: reviewing, reporting, and publishing guidelines; updating guidelines; and the two emerging issues of enhancing guideline implementability and how guideline developers should approach dealing with the issue of patients who will be the subject of guidelines having co-morbid conditions. C1 [Shekelle, Paul] RAND Corp, Santa Monica, CA 90407 USA. [Shekelle, Paul] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Woolf, Steven] Virginia Commonwealth Univ, Dept Family Med, Richmond, VA USA. [Woolf, Steven] Virginia Commonwealth Univ, Ctr Human Needs, Richmond, VA USA. [Grimshaw, Jeremy M.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Grimshaw, Jeremy M.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Schuenemann, Holger J.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Eccles, Martin P.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. RP Shekelle, P (reprint author), RAND Corp, Santa Monica, CA 90407 USA. EM shekelle@rand.org RI Grimshaw, Jeremy/D-8726-2013; OI Grimshaw, Jeremy/0000-0001-8015-8243 NR 23 TC 58 Z9 60 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 4 PY 2012 VL 7 AR 62 DI 10.1186/1748-5908-7-62 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 044MJ UT WOS:000311623400001 PM 22762242 ER PT J AU Budd, SJ Aris, RM Medaiyese, AA Tilley, SL Neuringer, IP AF Budd, Steven J. Aris, Robert M. Medaiyese, Ayorinde A. Tilley, Stephen L. Neuringer, Isabel P. TI Increased plasma mannose binding lectin levels are associated with bronchiolitis obliterans after lung transplantation SO RESPIRATORY RESEARCH LA English DT Article DE Mannose binding lectin; Lung transplantation; Bronchiolitis obliterans syndrome ID BRONCHOALVEOLAR LAVAGE FLUID; ISCHEMIA-REPERFUSION INJURY; SURFACTANT PROTEIN-A; ALLOGRAFT-REJECTION; SERINE-PROTEASE; GRAFT-SURVIVAL; KIDNEY-TRANSPLANTATION; COMPLEMENT ACTIVATION; PATTERN-RECOGNITION; GENE POLYMORPHISMS AB Background: Long-term lung allograft survival is limited by bronchiolitis obliterans syndrome (BOS). Mannose binding lectin (MBL) belongs to the innate immune system, participates in complement activation, and may predispose to graft rejection. We investigated mannose binding (MBL) during cold ischemia and in tissue samples from explanted lungs with BOS, and assessed MBL and complement proteins in plasma post-lung transplantation relative to BOS staging. Methods: MBL was detected by immunohistochemistry lung tissue at the time of cold ischemia and in samples with BOS. MBL was assayed in the peripheral blood of 66 lung transplant patients transplanted between 1990-2007. Results: MBL localized to vasculature and basement membrane during cold ischemia and BOS. Patients further out post-lung transplant > 5 years (n = 33), had significantly lower levels of MBL in the blood compared to lung transplant patients < 5 years with BOS Op-3 (n = 17), 1738 +/- 250 ng/ml vs 3198 +/- 370 ng/ml, p = 0.027, and similar levels to lung transplant patients < 5 years with BOS 0 (n = 16), 1738 +/- 250 ng/ml vs 1808 +/- 345 ng/ml. MBL levels in all BOS 0 (n = 30) vs. all BOS Op-3 (n = 36) were 1378 +/- 275 ng/ml vs. 2578 +/- 390 ng/ml, p = 0.001, respectively. C3 plasma levels in BOS 0 (n = 30) vs. BOS Op-3 (n = 36) were 101 +/- 19.8 mg/ml vs. 114 +/- 25.2 mg/ml, p = 0.024, respectively. Conclusions: MBL localizes within the lung during graft ischemia and BOS, higher levels of plasma MBL are associated with BOS Op-3 and < 5 years post-transplant, and higher level of plasma complement protein C3 was associated with BOS Op-3 clinical status. MBL may serve as a biomarker for poorer outcome post-lung transplantation. C1 [Neuringer, Isabel P.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Budd, Steven J.] Protochips, Raleigh, NC USA. [Aris, Robert M.; Tilley, Stephen L.] Univ N Carolina, Div Pulm & Crit Care Med, Chapel Hill, NC USA. [Medaiyese, Ayorinde A.] Pikeville Med Cen, Pikeville, KY USA. RP Neuringer, IP (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, 148 Bulfinch Bldg,55 Fruit St, Boston, MA 02114 USA. EM INeuringer@Partners.org FU American Society of Transplantation Clinical Science Faculty Development Grant FX SJB participated in performance of research, RMA participated in the writing of the paper and data analysis, AAM participated in performance of the research, SLT participated in the writing of the paper, IPN participated in research design, writing of the paper, and data analysis. Support for this study granted by the American Society of Transplantation Clinical Science Faculty Development Grant. All authors read and approved the final manuscript. NR 56 TC 5 Z9 5 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X J9 RESP RES JI Respir. Res. PD JUL 4 PY 2012 VL 13 AR 56 DI 10.1186/1465-9921-13-56 PG 9 WC Respiratory System SC Respiratory System GA 004BJ UT WOS:000308654800001 PM 22762710 ER PT J AU Woolf, S Schunemann, HJ Eccles, MP Grimshaw, JM Shekelle, P AF Woolf, Steven Schuenemann, Holger J. Eccles, Martin P. Grimshaw, Jeremy M. Shekelle, Paul TI Developing clinical practice guidelines: types of evidence and outcomes; values and economics, synthesis, grading, and presentation and deriving recommendations SO IMPLEMENTATION SCIENCE LA English DT Article ID SERVICES TASK-FORCE; SHARED DECISION-MAKING; HEALTH-CARE CONSUMERS; QUALITY; STRENGTH; MEDICINE; PREFERENCES; CONSENSUS; NUMBERS; SYMBOLS AB Clinical practice guidelines are one of the foundations of efforts to improve healthcare. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearinghouses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this second paper, we discuss issues of identifying and synthesizing evidence: deciding what type of evidence and outcomes to include in guidelines; integrating values into a guideline; incorporating economic considerations; synthesis, grading, and presentation of evidence; and moving from evidence to recommendations. C1 [Shekelle, Paul] RAND Corp, Santa Monica, CA 90407 USA. [Shekelle, Paul] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Woolf, Steven] Virginia Commonwealth Univ, Dept Family Med, Richmond, VA USA. [Woolf, Steven] Virginia Commonwealth Univ, Ctr Human Needs, Richmond, VA USA. [Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Schuenemann, Holger J.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Eccles, Martin P.] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. [Grimshaw, Jeremy M.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Grimshaw, Jeremy M.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. RP Shekelle, P (reprint author), RAND Corp, Santa Monica, CA 90407 USA. EM shekelle@rand.org RI Grimshaw, Jeremy/D-8726-2013; OI Grimshaw, Jeremy/0000-0001-8015-8243 NR 64 TC 35 Z9 39 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 4 PY 2012 VL 7 AR 61 DI 10.1186/1748-5908-7-61 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 001NG UT WOS:000308466800001 PM 22762158 ER PT J AU Guo, W Chambers, AR Darrow, KN Hancock, KE Shinn-Cunningham, BG Polley, DB AF Guo, Wei Chambers, Anna R. Darrow, Keith N. Hancock, Kenneth E. Shinn-Cunningham, Barbara G. Polley, Daniel B. TI Robustness of Cortical Topography across Fields, Laminae, Anesthetic States, and Neurophysiological Signal Types SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PRIMARY AUDITORY-CORTEX; CAT PRIMARY; IN-VIVO; FUNCTIONAL-ORGANIZATION; TONOTOPIC ORGANIZATION; EVOKED POTENTIALS; SPECTRAL INTEGRATION; BALANCED INHIBITION; RECEPTIVE-FIELDS; CRITICAL PERIOD AB Topographically organized maps of the sensory receptor epithelia are regarded as cornerstones of cortical organization as well as valuable readouts of diverse biological processes ranging from evolution to neural plasticity. However, maps are most often derived from multi-unit activity recorded in the thalamic input layers of anesthetized animals using near-threshold stimuli. Less distinct topography has been described by studies that deviated from the formula above, which brings into question the generality of the principle. Here, we explicitly compared the strength of tonotopic organization at various depths within core and belt regions of the auditory cortex using electrophysiological measurements ranging from single units to delta-band local field potentials (LFP) in the awake and anesthetized mouse. Unit recordings in the middle cortical layers revealed a precise tonotopic organization in core, but not belt, regions of auditory cortex that was similarly robust in awake and anesthetized conditions. In core fields, tonotopy was degraded outside the middle layers or when LFP signals were substituted for unit activity, due to an increasing proportion of recording sites with irregular tuning for pure tones. However, restricting our analysis to clearly defined receptive fields revealed an equivalent tonotopic organization in all layers of the cortical column and for LFP activity ranging from gamma to theta bands. Thus, core fields represent a transition between topographically organized simple receptive field arrangements that extend throughout all layers of the cortical column and the emergence of nontonotopic representations outside the input layers that are further elaborated in the belt fields. C1 [Guo, Wei; Chambers, Anna R.; Darrow, Keith N.; Hancock, Kenneth E.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Guo, Wei; Shinn-Cunningham, Barbara G.] Boston Univ, Ctr Computat Neurosci & Neural Technol, Boston, MA 02215 USA. [Chambers, Anna R.; Polley, Daniel B.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Darrow, Keith N.] Worcester State Univ, Dept Commun Sci & Disorders, Worcester, MA 01602 USA. [Hancock, Kenneth E.; Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Shinn-Cunningham, Barbara G.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Polley, DB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM Daniel_polley@meei.harvard.edu OI Polley, Daniel/0000-0002-5120-2409 FU Howard Hughes Medical Institute International Student Research Fellowship; National Institutes of Health Grants [DC009836, DC009477, P30 DC5029] FX This work was supported by a Howard Hughes Medical Institute International Student Research Fellowship (W.G.) and National Institutes of Health Grants DC009836 (D.B.P.), DC009477 (B.G.S.-C.), and P30 DC5029. We thank Dr. J. Fritz for critical comments on an earlier version of this manuscript. NR 70 TC 58 Z9 58 U1 3 U2 18 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 JUL 4 PY 2012 VL 32 IS 27 BP 9159 EP 9172 DI 10.1523/JNEUROSCI.0065-12.2012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 971HH UT WOS:000306193900006 PM 22764225 ER PT J AU McGinley, MJ Liberman, MC Bal, R Oertel, D AF McGinley, Matthew J. Liberman, M. Charles Bal, Ramazan Oertel, Donata TI Generating Synchrony from the Asynchronous: Compensation for Cochlear Traveling Wave Delays by the Dendrites of Individual Brainstem Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AUDITORY-NERVE FIBERS; OCTOPUS CELLS; POTASSIUM CURRENTS; PYRAMIDAL NEURONS; FREQUENCY MAP; CBA/J MOUSE; NUCLEUS; CAT; CONDUCTANCES; INPUT AB Broadband transient sounds, such as clicks and consonants, activate a traveling wave in the cochlea. This wave evokes firing in auditory nerve fibers that are tuned to high frequencies several milliseconds earlier than in fibers tuned to low frequencies. Despite this substantial traveling wave delay, octopus cells in the brainstem receive broadband input and respond to clicks with submillisecond temporal precision. The dendrites of octopus cells lie perpendicular to the tonotopically organized array of auditory nerve fibers, placing the earliest arriving inputs most distally and the latest arriving closest to the soma. Here, we test the hypothesis that the topographic arrangement of synaptic inputs on dendrites of octopus cells allows octopus cells to compensate the traveling wave delay. We show that in mice the full cochlear traveling wave delay is 1.6 ms. Because the dendrites of each octopus cell spread across approximately one-third of the tonotopic axis, a click evokes a soma-directed sweep of synaptic input lasting 0.5 ms in individual octopus cells. Morphologically and biophysically realistic, computational models of octopus cells show that soma-directed sweeps with durations matching in vivo measurements result in the largest and sharpest somatic EPSPs. A low input resistance and activation of a low-voltage-activated potassium conductance that are characteristic of octopus cells are important determinants of sweep sensitivity. We conclude that octopus cells have dendritic morphologies and biophysics tailored to accomplish the precise encoding of broadband transient sounds. C1 [McGinley, Matthew J.; Bal, Ramazan; Oertel, Donata] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurosci, Madison, WI 53706 USA. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP McGinley, MJ (reprint author), Yale Univ, Dept Neurobiol, New Haven, CT 06510 USA. EM matthew.mcginley@yale.edu FU NIH Grant [DC00176] FX This work was supported by NIH Grant DC00176. We thank Inge Siggelkow for histology, Yaniv Lazimy for Neurolucida reconstructions, Andrew Davison for simulated annealing code, Bill Kath for help learning NEURON, John Rinzel and Michiel Remme for NEURON code for potassium channels, Michael Migliore for NEURON code for HCN channels, and Meyer Jackson, Larry Trussell, Kevin Bender, Megan Hagenauer, and Flavio Frohlich for helpful comments on this manuscript. NR 50 TC 18 Z9 18 U1 1 U2 6 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 JUL 4 PY 2012 VL 32 IS 27 BP 9301 EP 9311 DI 10.1523/JNEUROSCI.0272-12.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 971HH UT WOS:000306193900018 PM 22764237 ER PT J AU Zhu, JM Zhang, X Xu, YH Spencer, TJ Biederman, J Bhide, PG AF Zhu, Jinmin Zhang, Xuan Xu, Yuehang Spencer, Thomas J. Biederman, Joseph Bhide, Pradeep G. TI Prenatal Nicotine Exposure Mouse Model Showing Hyperactivity, Reduced Cingulate Cortex Volume, Reduced Dopamine Turnover, and Responsiveness to Oral Methylphenidate Treatment SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MATERNAL SMOKING; BEHAVIORAL TERATOGENICITY; THERAPEUTIC ACTIONS; LOCOMOTOR-ACTIVITY; ADOLESCENT RATS; BRAIN DOPAMINE; C57B1/6 MICE; RISK-FACTOR; PREGNANCY AB Cigarette smoking, nicotine replacement therapy, and smokeless tobacco use during pregnancy are associated with cognitive disabilities later in life in children exposed prenatally to nicotine. The disabilities include attention deficit hyperactivity disorder (ADHD) and conduct disorder. However, the structural and neurochemical bases of these cognitive deficits remain unclear. Using a mouse model we show that prenatal nicotine exposure produces hyperactivity, selective decreases in cingulate cortical volume, and radial thickness, as well as decreased dopamine turnover in the frontal cortex. The hyperactivity occurs in both male and female offspring and peaks during the "active" or dark phase of the light/dark cycle. These features of the mouse model closely parallel the human ADHD phenotype, whether or not the ADHD is associated with prenatal nicotine exposure. A single oral, but not intraperitoneal, administration of a therapeutic equivalent dose (0.75 mg/kg) of methylphenidate decreases the hyperactivity and increases the dopamine turnover in the frontal cortex of the prenatally nicotine exposed mice, once again paralleling the therapeutic effects of this compound in ADHD subjects. Collectively, our data suggest that the prenatal nicotine exposure mouse model has striking parallels to the ADHD phenotype not only in behavioral, neuroanatomical, and neurochemical features, but also with respect to responsiveness of the behavioral phenotype to methylphenidate treatment. The behavioral, neurochemical, and anatomical biomarkers in the mouse model could be valuable for evaluating new therapies for ADHD and mechanistic investigations into its etiology. C1 [Zhu, Jinmin; Bhide, Pradeep G.] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL 32311 USA. [Zhang, Xuan; Xu, Yuehang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Spencer, Thomas J.; Biederman, Joseph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. RP Bhide, PG (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM pradeep.bhide@med.fsu.edu OI Bhide, Pradeep/0000-0003-4236-9415 FU United States Public Health Service [R01DA020796, P30NS045776, R21DA027358] FX This work was supported by United States Public Health Service Grants R01DA020796, P30NS045776, and R21DA027358. We are grateful to Dr. Michael Schwarzschild for access to equipment and resources in his laboratory at the Massachusetts General Hospital, Thomas C. Burdett and Cody A. Desjardins in Dr. Schwarzschild's laboratory for assistance with high-performance liquid chromatography, Enric Navas Peres for help with histology and stereology, and the staff of the Massachusetts General Hospital's Center for Comparative Medicine for expert assistance with mouse colony management. NR 51 TC 28 Z9 28 U1 2 U2 13 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 JUL 4 PY 2012 VL 32 IS 27 BP 9410 EP 9418 DI 10.1523/JNEUROSCI.1041-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 971HH UT WOS:000306193900030 PM 22764249 ER PT J AU Cooper, O Seo, H Andrabi, S Guardia-Laguarta, C Graziotto, J Sundberg, M McLean, JR Carrillo-Reid, L Xie, Z Osborn, T Hargus, G Deleidi, M Lawson, T Bogetofte, H Perez-Torres, E Clark, L Moskowitz, C Mazzulli, J Chen, L Volpicelli-Daley, L Romero, N Jiang, HB Uitti, RJ Huang, ZG Opala, G Scarffe, LA Dawson, VL Klein, C Feng, J Ross, OA Trojanowski, JQ Lee, VMY Marder, K Surmeier, DJ Wszolek, ZK Przedborski, S Krainc, D Dawson, TM Isacson, O AF Cooper, Oliver Seo, Hyemyung Andrabi, Shaida Guardia-Laguarta, Cristina Graziotto, John Sundberg, Maria McLean, Jesse R. Carrillo-Reid, Luis Xie, Zhong Osborn, Teresia Hargus, Gunnar Deleidi, Michela Lawson, Tristan Bogetofte, Helle Perez-Torres, Eduardo Clark, Lorraine Moskowitz, Carol Mazzulli, Joseph Chen, Li Volpicelli-Daley, Laura Romero, Norma Jiang, Houbo Uitti, Ryan J. Huang, Zhigao Opala, Grzegorz Scarffe, Leslie A. Dawson, Valina L. Klein, Christine Feng, Jian Ross, Owen A. Trojanowski, John Q. Lee, Virginia M. -Y. Marder, Karen Surmeier, D. James Wszolek, Zbigniew K. Przedborski, Serge Krainc, Dimitri Dawson, Ted M. Isacson, Ole CA NINDS PD iPS Cell Res Consortium TI Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson's Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PLURIPOTENT STEM-CELLS; EARLY-ONSET PARKINSONISM; AUTOSOMAL-DOMINANT PARKINSONISM; SUBSTANTIA-NIGRA NEURONS; DOPAMINERGIC-NEURONS; AXONAL-TRANSPORT; CLINICAL-FEATURES; GENETIC-ANALYSIS; PINK1 MUTATIONS; BAFILOMYCIN A1 AB Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease. C1 [Cooper, Oliver; Seo, Hyemyung; Sundberg, Maria; McLean, Jesse R.; Osborn, Teresia; Hargus, Gunnar; Deleidi, Michela; Lawson, Tristan; Bogetofte, Helle; Perez-Torres, Eduardo; Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Inst, Belmont, MA 02478 USA. [Andrabi, Shaida; Chen, Li; Scarffe, Leslie A.; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Neuroregenerat Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Andrabi, Shaida; Chen, Li; Scarffe, Leslie A.; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Andrabi, Shaida; Chen, Li; Scarffe, Leslie A.; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Andrabi, Shaida; Chen, Li; Scarffe, Leslie A.; Dawson, Valina L.; Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Guardia-Laguarta, Cristina; Clark, Lorraine; Moskowitz, Carol; Romero, Norma; Marder, Karen; Przedborski, Serge] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Neurol, New York, NY 10032 USA. [Guardia-Laguarta, Cristina; Clark, Lorraine; Moskowitz, Carol; Romero, Norma; Marder, Karen; Przedborski, Serge] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Psychiat, New York, NY 10032 USA. [Guardia-Laguarta, Cristina; Clark, Lorraine; Moskowitz, Carol; Romero, Norma; Marder, Karen; Przedborski, Serge] Columbia Univ, Sergievsky Ctr, Taub Inst, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Guardia-Laguarta, Cristina; Clark, Lorraine; Moskowitz, Carol; Romero, Norma; Marder, Karen; Przedborski, Serge] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. [Graziotto, John; Mazzulli, Joseph; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Carrillo-Reid, Luis; Xie, Zhong; Surmeier, D. James] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA. [Volpicelli-Daley, Laura; Trojanowski, John Q.; Lee, Virginia M. -Y.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging, Philadelphia, PA 19104 USA. [Volpicelli-Daley, Laura; Trojanowski, John Q.; Lee, Virginia M. -Y.] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Jiang, Houbo; Feng, Jian] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14214 USA. [Uitti, Ryan J.; Ross, Owen A.; Wszolek, Zbigniew K.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Uitti, Ryan J.; Ross, Owen A.; Wszolek, Zbigniew K.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Huang, Zhigao] Univ Florida Shands, Jacksonville, FL 32209 USA. [Opala, Grzegorz] Med Univ Silesia, Dept Neurol, PL-40055 Katowice, Poland. [Klein, Christine] Med Univ Lubeck, Sect Clin & Mol Neurogenet, Dept Neurol, D-23562 Lubeck, Germany. RP Isacson, O (reprint author), Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Inst, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu RI Andrabi, Shaida/I-6167-2012; Ross, Owen/D-7573-2013; Xie, Zhong/B-6829-2011; Bogetofte, Helle/Q-9303-2016; OI Andrabi, Shaida/0000-0002-3305-2638; Xie, Zhong/0000-0002-8348-4455; Cooper, Oliver/0000-0001-6567-7491; Guardia-Laguarta, Cristina/0000-0003-0811-9068; Dawson, Valina/0000-0002-2915-3970; Carrillo-Reid, Luis/0000-0002-0511-2533 FU American Recovery and Reinvestment Act-NIH/National Institute of Neurological Disorders and Stroke (NINDS) [1RC2NS070276]; NIH [1U24NS078338-01]; Michael J. Fox Foundation; Harvard Stem Cell Institute; Miller Consortium for the Development of Nervous System Therapies; Orchard Foundation; Harold and Ronna Cooper family; Consolidated Anti-Aging Foundation; Poul Hansen family; NIH/NINDS [NS057567, P50NS072187, NS38377]; Mayo Clinic Florida (MCF) Research Committee CR [90052030]; Dystonia Medical Research Foundation; Maryland Stem Cell Research Foundation [2007-MSCRFI-0420-00]; Hermann and Lilly Schilling Foundation FX Funding: This work was supported by a grant from the American Recovery and Reinvestment Act-NIH/National Institute of Neurological Disorders and Stroke (NINDS) (1RC2NS070276) and the NIH U24 grant (1U24NS078338-01) awarded to the PDiPS Cell Research Consortium. O.I., O.C., H. S., M. S., J.M., T.O., G. H., M. D., T. L., H. B. and E.P.-T. were supported by the Michael J. Fox Foundation, the Harvard Stem Cell Institute and the Miller Consortium for the Development of Nervous System Therapies, the Orchard Foundation, the Harold and Ronna Cooper family, the Consolidated Anti-Aging Foundation, and the Poul Hansen family. Z.K.W. was partially supported by the NIH/NINDS NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch Jr. and Susan Bass Bolch (MCF 90052031/PAU 90052). S. A., L. Chen, L. A. S., V. L. D., and T. M. D. were supported by NIH/NINDS NS38377 and the Maryland Stem Cell Research Foundation 2007-MSCRFI-0420-00 and acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation's Parkinson's Disease Program No. M-1. C. K. was supported by a career development award from the Hermann and Lilly Schilling Foundation. NR 70 TC 46 Z9 49 U1 7 U2 25 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 4 PY 2012 VL 4 IS 141 AR 141ra90 DI 10.1126/scitranslmed.3003985 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 970DR UT WOS:000306108800004 PM 22764206 ER PT J AU Issadore, D Chung, J Shao, HL Liong, M Ghazani, AA Castro, CM Weissleder, R Lee, H AF Issadore, David Chung, Jaehoon Shao, Huilin Liong, Monty Ghazani, Arezou A. Castro, Cesar M. Weissleder, Ralph Lee, Hakho TI Ultrasensitive Clinical Enumeration of Rare Cells ex Vivo Using a Micro-Hall Detector SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CIRCULATING TUMOR-CELLS; CANCER-PATIENTS; BIOSENSORS; ASSAYS; BLOOD; FIELD AB The ability to detect rare cells (<100 cells/ml whole blood) and obtain quantitative measurements of specific biomarkers on single cells is increasingly important in basic biomedical research. Implementing such methodology for widespread use in the clinic, however, has been hampered by low cell density, small sample sizes, and requisite sample purification. To overcome these challenges, we have developed a microfluidic chip-based micro-Hall detector (mu HD), which can directly measure single, immunomagnetically tagged cells in whole blood. The mu HD can detect single cells even in the presence of vast numbers of blood cells and unbound reactants, and does not require any washing or purification steps. In addition, the high bandwidth and sensitivity of the semiconductor technology used in the mu HD enables high-throughput screening (currently similar to 10(7) cells/min). The clinical use of the mu HD chip was demonstrated by detecting circulating tumor cells in whole blood of 20 ovarian cancer patients at higher sensitivity than currently possible with clinical standards. Furthermore, the use of a panel of magnetic nanoparticles, distinguished with unique magnetization properties and bio-orthogonal chemistry, allowed simultaneous detection of the biomarkers epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2)/neu, and epidermal growth factor receptor (EGFR) on individual cells. This cost-effective, single-cell analytical technique is well suited to perform molecular and cellular diagnosis of rare cells in the clinic. C1 [Issadore, David; Chung, Jaehoon; Shao, Huilin; Liong, Monty; Ghazani, Arezou A.; Castro, Cesar M.; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Castro, Cesar M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; hlee@mgh.harvard.edu RI Issadore, David/L-8451-2014 FU NIH [2R01-EB004626, U01-HL080731, HHSN 268201000044C, U54-CA119349, T32-CA79443 K12CA087723-10S2] FX Funding: This work was supported in part by NIH grants 2R01-EB004626, U01-HL080731, HHSN 268201000044C, U54-CA119349, and T32-CA79443 K12CA087723-10S2. NR 31 TC 60 Z9 62 U1 2 U2 65 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 4 PY 2012 VL 4 IS 141 AR 141ra92 DI 10.1126/scitranslmed.3003747 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 970DR UT WOS:000306108800007 PM 22764208 ER PT J AU Zhang, J Xie, FL Delzell, E Chen, L Winthrop, KL Lewis, JD Saag, KG Baddley, JW Curtis, JR AF Zhang, Jie Xie, Fenglong Delzell, Elizabeth Chen, Lang Winthrop, Kevin L. Lewis, James D. Saag, Kenneth G. Baddley, John W. Curtis, Jeffrey R. TI Association Between Vaccination for Herpes Zoster and Risk of Herpes Zoster Infection Among Older Patients With Selected Immune-Mediated Diseases SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RHEUMATOID-ARTHRITIS; UNITED-STATES; ADMINISTRATIVE DATABASE; VARICELLA; RECOMMENDATIONS; CHILDREN; THERAPY; SAFETY; AGENTS; ADULTS AB Context Based on limited data, the live attenuated herpes zoster (HZ) vaccine is contraindicated in patients taking anti-tumor necrosis factor (anti-TNF) therapies or other biologics commonly used to treat immune-mediated diseases. The safety and effectiveness of the vaccine are unclear for these patients. Objective To examine the association between HZ vaccination and HZ incidence within and beyond 42 days after vaccination in patients with selected immune-mediated diseases and in relation to biologics and other therapies used to treat these conditions. Design, Setting, and Patients Retrospective cohort study of 463 541 Medicare beneficiaries 60 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease using Medicare claims data from January 1, 2006, through December 31, 2009. Main Outcome Measures Herpes zoster incidence rate within 42 days after vaccination (a safety concern) and beyond 42 days; hazard ratios estimated using Cox proportional hazards models for HZ comparing vaccinated vs unvaccinated patients. Results Median duration of follow-up was 2.0 years (interquartile range, 0.8-3.0); 4.0% of patients received HZ vaccine. The overall crude HZ incidence rate was 7.8 cases per 1000 person-years (95% CI, 3.7-16.5) within 42 days after vaccination. The rate among the unvaccinated was 11.6 cases per 1000 person-years (95% CI, 11.4-11.9). Among 633 patients exposed to biologics at the time of vaccination or within the subsequent 42 days, no case of HZ or varicella occurred. After multivariable adjustment, HZ vaccination was associated with a hazard ratio of 0.61 (95% CI, 0.52-0.71) for HZ risk after 42 days. Conclusions Receipt of HZ vaccine was not associated with a short-term increase in HZ incidence among Medicare beneficiaries with selected immune-mediated diseases, including those exposed to biologics. The vaccine was associated with a lower HZ incidence over a median of 2 years of follow-up. JAMA. 2012; 308(1):43-49 www.jama.com C1 [Zhang, Jie; Delzell, Elizabeth; Curtis, Jeffrey R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Xie, Fenglong; Chen, Lang; Saag, Kenneth G.; Curtis, Jeffrey R.] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Baddley, John W.] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL 35294 USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Dept Med, Div Infect Dis, Portland, OR 97201 USA. [Lewis, James D.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Curtis, JR (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, FOT 805D,510 20th St S, Birmingham, AL 35294 USA. EM jcurtis@uab.edu FU Amgen; Pfizer; UCB; Abbott; Centocor; Takeda; Shire; Merck; Genentech/Roche; BMS; Agency for Healthcare Research and Quality (AHRQ) [R01 HS018517, T32HS013852]; National Institutes of Health [AR 053351] FX Dr Zhang reported having received research support from Amgen. Dr Delzell reported having received research support from Amgen. Dr Winthrop reported having received consulting fees from Pfizer, Amgen, UCB, and Abbott and grants from Pfizer. Dr Lewis reported having received research grants from Centocor, Takeda, and Shire and having served as a consultant for Amgen, Abbott, Pfizer, and Millennium Pharmaceuticals. Dr Saag is the chair of the American College of Rheumatology Quality of Care Committee and reported having received consulting fees from Merck. Dr Baddley reported having received consulting fees from Abbott and Merck. Dr Curtis reported having received research grants and consulting fees from Amgen, UCB, Abbott, Genentech/Roche, Centocor, BMS, and Merck. No other disclosures were reported.; This project was supported by the Agency for Healthcare Research and Quality (AHRQ) (R01 HS018517). Dr Zhang received support from the AHRQ (T32HS013852), and Dr Curtis received support from the National Institutes of Health (AR 053351). NR 23 TC 110 Z9 111 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 4 PY 2012 VL 308 IS 1 BP 43 EP 49 DI 10.1001/jama.2012.7304 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 971DD UT WOS:000306183000022 PM 22760290 ER PT J AU Uppal, R Ciesienski, KL Chonde, DB Loving, GS Caravan, P AF Uppal, Ritika Ciesienski, Kate L. Chonde, Daniel B. Loving, Galen S. Caravan, Peter TI Discrete Bimodal Probes for Thrombus Imaging SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MRI CONTRAST AGENTS; MOLECULAR MRI; FIBRIN; TOMOGRAPHY; PEPTIDES AB Here we report a generalizable solid/solution-phase strategy for the synthesis of discrete bimodal fibrin-targeted imaging probes. A fibrin-specific peptide was conjugated with two distinct imaging reporters at the C- and N-termini. In vitro studies demonstrated retention of fibrin affinity and specificity. Imaging studies showed that these probes could detect fibrin over a wide range of probe concentrations by optical, magnetic resonance, and positron emission tomography imaging. C1 [Uppal, Ritika; Ciesienski, Kate L.; Chonde, Daniel B.; Loving, Galen S.; Caravan, Peter] Harvard Univ, AA Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Harvard Univ, AA Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Sch Med, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU National Institutes of Health [R01HL109448, R01EB009062, T32CA009502, P41RR14075] FX Thomas Benner and Zdravka Medarova are thanked for assistance in the MRI and OI studies. This work was supported in part by Awards R01HL109448, R01EB009062, T32CA009502, and P41RR14075 from the National Institutes of Health. NR 29 TC 16 Z9 16 U1 2 U2 29 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 JUL 4 PY 2012 VL 134 IS 26 BP 10799 EP 10802 DI 10.1021/ja3045635 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 966UW UT WOS:000305863900022 PM 22698259 ER PT J AU Qaseem, A Humphrey, LL Shekelle, P AF Qaseem, Amir Humphrey, Linda L. Shekelle, Paul TI Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. [Humphrey, Linda L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Shekelle, Paul] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Qaseem, A (reprint author), Amer Coll Physicians, Philadelphia, PA 19106 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 3 PY 2012 VL 157 IS 1 BP 76 EP 77 DI 10.7326/0003-4819-157-1-201207030-00019 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 992NS UT WOS:000307784900013 ER PT J AU Haaf, P Drexler, B Reichlin, T Twerenbold, R Reiter, M Meissner, J Schaub, N Stelzig, C Freese, M Heinzelmann, A Meune, C Balmelli, C Freidank, H Winkler, K Denhaerynck, K Hochholzer, W Osswald, S Mueller, C AF Haaf, Philip Drexler, Beatrice Reichlin, Tobias Twerenbold, Raphael Reiter, Miriam Meissner, Julia Schaub, Nora Stelzig, Claudia Freese, Michael Heinzelmann, Amely Meune, Christophe Balmelli, Cathrin Freidank, Heike Winkler, Katrin Denhaerynck, Kris Hochholzer, Willibald Osswald, Stefan Mueller, Christian TI High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease SO CIRCULATION LA English DT Article DE coronary angiography; decision support techniques; heart diseases; myocardial infarction; troponin ID ACUTE CORONARY SYNDROME; EARLY-DIAGNOSIS; EMERGENCY-DEPARTMENT; PREDICTION MODELS; OF-CARDIOLOGY; I ASSAY; T ASSAY; RECOMMENDATIONS; GUIDELINES; ABSOLUTE AB Background-We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease. Methods and Results-In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 mu g/L [interquartile range, 0.049-0.246 mu g/L] versus 0.012 mu g/L [interquartile range, 0.006-0.034 mu g/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 mu g/L [interquartile range, 0.007-0.067 mu g/L] versus 0.001 mu g/L [interquartile range, 0-0.003 mu g/L]; P<0.001) than patients with cardiac noncoronary artery disease. Similar findings were obtained with the hs-cTnI assays. Adding changes of hs-cTn in the first hour to its presentation value yielded a diagnostic accuracy for AMI as quantified by the area under the receiver-operating characteristics curve of 0.94 for hs-cTnT (0.92 for both hs-cTnI assays). Algorithms using ST-elevation, presentation values, and changes in hs-cTn in the first hour accurately separated patients with AMI and those with cardiac noncoronary artery disease. These findings were confirmed when the final diagnosis was readjudicated with the use of hs-cTnT values and validated in an independent validation cohort. Conclusion-The combined use of hs-cTn at presentation and its early absolute change excellently discriminates between patients with AMI and those with cardiac noncoronary artery disease. C1 [Reichlin, Tobias; Osswald, Stefan; Mueller, Christian] Univ Basel Hosp, Dept Cardiol, CH-4031 Basel, Switzerland. [Haaf, Philip; Drexler, Beatrice; Reichlin, Tobias; Twerenbold, Raphael; Reiter, Miriam; Meissner, Julia; Schaub, Nora; Stelzig, Claudia; Freese, Michael; Heinzelmann, Amely; Meune, Christophe; Balmelli, Cathrin; Denhaerynck, Kris; Hochholzer, Willibald; Mueller, Christian] Univ Basel Hosp, Dept Internal Med, CH-4031 Basel, Switzerland. [Freidank, Heike] Univ Basel Hosp, Dept Lab Med, CH-4031 Basel, Switzerland. [Meune, Christophe] Paris Descartes Univ, Cochin Hosp, APHP, Dept Cardiol, Paris, France. [Winkler, Katrin] UPF, Serv Urgencias, Hosp del Mar, IMIM,CIBERES,ISC III, Barcelona, Spain. [Hochholzer, Willibald] Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Div,Dept Med,Med Sch, Boston, MA 02115 USA. RP Mueller, C (reprint author), Univ Basel Hosp, Dept Cardiol, Petersgraben 4, CH-4031 Basel, Switzerland. EM chmueller@uhbs.ch OI Twerenbold, Raphael/0000-0003-3814-6542 FU Swiss National Science Foundation [PP00B-102853]; Swiss Heart Foundation; Abbott; Beckman-Coulter; Roche; Nanosphere; Siemens; Department of Internal Medicine, University Hospital Basel; Stanley Thomas Johnson Foundation; ALERE; Brahms; University of Basel; Freie Akademische Gesellschaft Basel FX This study was supported by research grants from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, Abbott, Beckman-Coulter, Roche, Nanosphere, Siemens, and the Department of Internal Medicine, University Hospital Basel.; Dr Mueller has received research support from the Swiss National Science Foundation (PP00B-102853), the Swiss Heart Foundation, the Stanley Thomas Johnson Foundation, Abbott, ALERE, Beckman-Coulter, Brahms, Nanosphere, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Brahms, Roche, and Siemens. Dr Reichlin has received research grants from the University of Basel and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria from Brahms and Roche. Dr Meune was supported by a grant from the Freie Akademische Gesellschaft Basel. The other authors report no conflicts. NR 28 TC 80 Z9 80 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 31 EP + DI 10.1161/CIRCULATIONAHA.112.100867 PG 24 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100021 PM 22623715 ER PT J AU Piccini, JP White, JA Mehta, RH Lokhnygina, Y Al-Khatib, SM Tricoci, P Pollack, CV Montalescot, G Van de Werf, F Gibson, CM Giugliano, RP Califf, RM Harrington, RA Newby, LK AF Piccini, Jonathan P. White, Jennifer A. Mehta, Rajendra H. Lokhnygina, Yuliya Al-Khatib, Sana M. Tricoci, Pierluigi Pollack, Charles V., Jr. Montalescot, Gilles Van de Werf, Frans Gibson, C. Michael Giugliano, Robert P. Califf, Robert M. Harrington, Robert A. Newby, L. Kristin TI Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non-ST-Segment-Elevation Acute Coronary Syndromes SO CIRCULATION LA English DT Article DE acute coronary syndrome; mortality; tachycardia, ventricular; ventricular fibrillation ID ACUTE MYOCARDIAL-INFARCTION; GLYCOPROTEIN IIB/IIIA INHIBITION; CARDIOVERTER-DEFIBRILLATOR; CONTROLLED-TRIAL; RISK SCORE; INTERVENTION; OUTCOMES; ARRHYTHMIAS; MORTALITY; FAILURE AB Background-Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non-ST-segment-elevation (NSTE) ACS populations are not well described. Methods and Results-We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n = 141); 0.6% (n = 55) had VT/VF <= 48 hours after enrollment, and 0.9% (n = 86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (<= 48 versus >48 hours). Patients with VT/VF <= 48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF <= 48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68-16.9). The increased risk of death associated with VT/VF <= 48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF <= 48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39-27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60-12.08; P = 0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%). Conclusions-Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients. C1 [Piccini, Jonathan P.] Duke Univ, Div Cardiol, Duke Clin Res Inst, Med Ctr, Durham, NC 27705 USA. [Pollack, Charles V., Jr.] Penn Hosp, Dept Emergency Med, Philadelphia, PA 19107 USA. [Montalescot, Gilles] Grp Hosp Pitie Salpetriere, Inst Cardiol, F-75634 Paris, France. [Van de Werf, Frans] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Van de Werf, Frans] Leuven Coordinating Ctr, Louvain, Belgium. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Giugliano, Robert P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Piccini, JP (reprint author), Duke Univ, Div Cardiol, Duke Clin Res Inst, Med Ctr, POB 17969, Durham, NC 27705 USA. EM jonathan.piccini@duke.edu OI Van de Werf, Frans/0000-0001-9479-7767 FU Schering-Plough Corporation; Merck Co, Inc.; Boston Scientific; Johnson Johnson; Bayer Healthcare; Janssen Pharmaceuticals, Inc; Forest Laboratories; Sanofi-Aventis; Medtronic; Biotronik; Merck Co, Inc; Schering-Plough; Bristol Myers Squibb; Centocor; Cordis; Eli-Lilly; Federation Franaise de Cardiologie; Fondation de France; Guerbet Medical; INSERM; ITC Edison; Pfizer; Sanofi-Aventis Group; Societe Franaise de Cardiologie; Accumetrics; AstraZeneca; Bayer; Boehringer-Ingelheim; Bristol-Myers Squibb; Daichi-Sankyo; Eisai; Menarini; MSD; Novartis; Portola; Merck; Roche; Daiichi-Sankyo FX The EARLY ACS trial was funded by Schering-Plough Corporation. These analyses were funded by research grant support from Merck & Co, Inc.; Dr Piccini receives grants for clinical research (to the institution) from Boston Scientific, Johnson & Johnson, and Bayer Healthcare, as well as consulting fees from Janssen Pharmaceuticals, Inc, Forest Laboratories, and Sanofi-Aventis. Dr Al-Khatib receives research funding and speaking fees from Medtronic and speaking fees from Biotronik. Dr Tricoci receives a research grant from Merck & Co, Inc and is on the advisory board for Merck & Co, Inc. Dr Pollack receives research support from Schering-Plough and Sanofi-Aventis. Dr Montalescot receives research grants (to the institution) from Bristol Myers Squibb, Boston Scientific, Centocor, Cordis, Eli-Lilly, Federation Franaise de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, Sanofi-Aventis Group, and Societe Franaise de Cardiologie, as well as consulting or lecture fees from Accumetrics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daichi-Sankyo, Eisai, Eli-Lilly, Menarini, MSD, Novartis, Portola, Sanofi-Aventis Group, Schering-Plough, and The Medicines Company. Dr Van de Werf receives research grants from Schering-Plough (now Merck) and Roche and advisory board and speaker fees from Schering-Plough, Merck & Co, Inc, and Roche. Dr Gibson receives research support from Schering-Plough and Merck & Co, Inc. Dr Giugliano receives research grant support, advisory board fees, and honoraria for lectures from Schering-Plough, Inc and Merck & Co, Inc; research grant support from Daiichi-Sankyo; and consultant fees/honoraria for lectures from Bristol Myers Squibb and Sanofi-Aventis. Dr Califf receives research funding and consulting fees from Schering-Plough, now Merck & Co, Inc (all consulting funds donated to not-for-profit organizations). A complete listing of Dr Califf's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. Dr Harrington receives research funding and consulting fees from Schering-Plough, now Merck & Co, Inc. A complete listing of Dr Harrington's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. Dr Newby receives research grants from Schering Plough and Merck & Co, Inc through the Duke Clinical Research Institute and consulting honoraria from Schering-Plough. A complete listing of Dr Newby's relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. The other authors report no conflicts. NR 25 TC 24 Z9 24 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 41 EP 49 DI 10.1161/CIRCULATIONAHA.111.071860 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100022 PM 22645292 ER PT J AU Steinberg, BA Zhao, X Heidenreich, PA Peterson, ED Bhatt, DL Cannon, CP Hernandez, AF Fonarow, GC AF Steinberg, Benjamin A. Zhao, Xin Heidenreich, Paul A. Peterson, Eric D. Bhatt, Deepak L. Cannon, Christopher P. Hernandez, Adrian F. Fonarow, Gregg C. CA Guidelines Sci Advisory Comm Invst TI Trends in Patients Hospitalized With Heart Failure and Preserved Left Ventricular Ejection Fraction Prevalence, Therapies, and Outcomes SO CIRCULATION LA English DT Article DE cardiomyopathies; epidemiology; heart failure; outcome assessment (health care) ID NATIONAL REGISTRY ADHERE; SYSTOLIC FUNCTION; CLINICAL CHARACTERISTICS; OF-CARDIOLOGY; DIAGNOSIS; MANAGEMENT; MORTALITY; ASSOCIATION; GUIDELINES; UPDATE AB Background-Heart failure with preserved ejection fraction (EF) is a common syndrome, but trends in treatments and outcomes are lacking. Methods and Results-We analyzed data from 275 hospitals in Get With the Guidelines-Heart Failure from January 2005 to October 2010. Patients were stratified by EF as reduced EF (EF <40% [HF-reduced EF]), borderline EF (40%<= EF<50% [HF-borderline EF]), or preserved (EF >= 50% [HF-preserved EF]). Using multivariable models, we examined trends in therapies and outcomes. Among 110 621 patients, 50% (55 083) had HF-reduced EF, 14% (15 184) had HF-borderline EF, and 36% (40 354) had HF-preserved EF. From 2005 to 2010, the proportion of hospitalizations for HF-preserved EF increased from 33% to 39% (P < 0.0001). In multivariable analyses, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers at discharge decreased in all EF groups, and beta-blocker use increased. Patients with HF-preserved EF less frequently achieved blood pressure control (adjusted odds ratio, 0.44 versus HF-reduced EF; P < 0.001) and were more likely discharged to skilled nursing (adjusted odds ratio, 1.16 versus HF-reduced EF; P < 0.001). In-hospital mortality for HF-preserved EF decreased from 3.32% in 2005 to 2.35% in 2010 (adjusted odds ratio, 0.89 per year; P = 0.01) but was stable for patients with HF-reduced EF (3.03%-2.83%; adjusted odds ratio, 0.93 per year; P = 0.10). Conclusions-Hospitalization for HF-preserved EF is increasing relative to HF-reduced EF. Although in-hospital mortality for patients with HF-preserved EF declined over the study period, an important opportunity remains for identifying evidence-based therapies in patients with HF-preserved EF. (Circulation. 2012; 126: 65-75.) C1 [Steinberg, Benjamin A.] Duke Univ, Med Ctr, Durham, NC USA. [Zhao, Xin; Peterson, Eric D.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Heidenreich, Paul A.] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.; Cannon, Christopher P.] Harvard Univ, Sch Med, Boston, MA USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA 90095 USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room 47-123 CHS, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Hernandez, Adrian F./A-7818-2016 OI Heidenreich, Paul/0000-0001-7730-8490; Hernandez, Adrian F./0000-0003-3387-9616 FU American Heart Association; Medtronic; GlaxoSmithKline; Ortho-McNeil; American Heart Association Pharmaceutical Roundtable; Amarin; AstraZeneca; Bristol-Myers Squibb; Eisai; Ethicon; Sanofi Aventis; The Medicines Company; FlowCo; PLx Pharma; Takeda; Accumetrics; Intekrin Therapeutics; Merck; Johnson Johnson; Amylin; Proventys; National Heart, Lung, and Blood Institute; Novartis; Pfizer FX The GWTG-HF program is provided by the American Heart Association. GWTG-HF has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. Support for the current analysis was provided by the American Heart Association Council on Clinical Cardiology via a Young Investigator Database Research Seed Grant to Dr Steinberg.; Dr Bhatt reports serving on the Advisory Board for Medscape Cardiology; being on the Board of Directors for Boston VA Research Institute, Society of Chest Pain Centers; and serving as Chair for the American Heart Association Get With The Guidelines Science Subcommittee. Dr Bhatt has received honoraria from the American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; and performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr Cannon reports receiving research support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda; participating in advisory board activities (but donating funds to charity) with Bristol-Myers Squibb/Sanofi, Novartis, and Alnylam; receiving honoraria for the development of independent educational symposia from Pfizer and AstraZeneca; and being a clinical advisor to and holding equity in Automedics Medical Systems. Dr Hernandez reports receiving research support from Johnson & Johnson, Amylin, and Proventys. Dr Fonarow reports research support from the National Heart, Lung, and Blood Institute; consultant fees from Novartis and Pfizer; and honoraria from Medtronic. The other authors report no conflicts. NR 25 TC 159 Z9 170 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 65 EP + DI 10.1161/CIRCULATIONAHA.111.080770 PG 26 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100025 PM 22615345 ER PT J AU Beaudoin, J Levine, RA Yosefy, C Beeri, R Neary, JH Morgan, NV Passeri, JJ AF Beaudoin, Jonathan Levine, Robert A. Yosefy, Chaim Beeri, Ronen Neary, Jennifer H. Morgan, Nina V. Passeri, Jonathan J. TI Severe Ischemic Mitral Regurgitation Despite Normally Contracting Subpapillary Myocardium SO CIRCULATION LA English DT Editorial Material ID INFARCTION C1 [Passeri, Jonathan J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Ultrasound Lab,Div Cardiol, Boston, MA 02114 USA. RP Passeri, JJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Ultrasound Lab,Div Cardiol, 55 Fruit St,Yawkey 5A, Boston, MA 02114 USA. EM jpasseri@partners.org FU NHLBI NIH HHS [K24 HL067434, R01 HL072265, R01 HL109506] NR 4 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2012 VL 126 IS 1 BP 138 EP 141 DI 10.1161/CIRCULATIONAHA.111.064253 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 981OG UT WOS:000306977100036 PM 22753536 ER PT J AU Yang, MH Nickerson, S Kim, ET Liot, C Laurent, G Spang, R Philips, MR Shan, Y Shaw, DE Bar-Sagi, D Haigis, MC Haigis, KM AF Yang, Moon Hee Nickerson, Seth Kim, Eric T. Liot, Caroline Laurent, Gaelle Spang, Robert Philips, Mark R. Shan, Yibing Shaw, David E. Bar-Sagi, Dafna Haigis, Marcia C. Haigis, Kevin M. TI Regulation of RAS oncogenicity by acetylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR SWITCH; FORCE-FIELD; PROTEIN; BINDING; SOS; ACTIVATION; DYNAMICS; UBIQUITINATION; PARAMETERS; EFFECTORS AB Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach. C1 [Yang, Moon Hee; Haigis, Kevin M.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Yang, Moon Hee; Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Yang, Moon Hee; Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA 02129 USA. [Yang, Moon Hee; Haigis, Kevin M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Laurent, Gaelle; Spang, Robert; Haigis, Marcia C.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Nickerson, Seth; Bar-Sagi, Dafna] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. [Liot, Caroline; Philips, Mark R.] NYU, Sch Med, Dept Med, New York, NY 10016 USA. [Liot, Caroline; Philips, Mark R.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Liot, Caroline; Philips, Mark R.] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Kim, Eric T.; Shan, Yibing; Shaw, David E.] DE Shaw Res, New York, NY 10036 USA. [Shaw, David E.] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. RP Haigis, KM (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. EM khaigis@partners.org FU American Cancer Society Research Scholar [MGO-114877] FX This work was supported by American Cancer Society Research Scholar Grant MGO-114877 (to K.M.H.). NR 35 TC 27 Z9 28 U1 4 U2 22 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 JUL 3 PY 2012 VL 109 IS 27 BP 10843 EP 10848 DI 10.1073/pnas.1201487109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FF UT WOS:000306641100032 PM 22711838 ER PT J AU Kopco, N Huang, S Belliveau, JW Raij, T Tengshe, C Ahveninen, J AF Kopco, Norbert Huang, Samantha Belliveau, John W. Raij, Tommi Tengshe, Chinmayi Ahveninen, Jyrki TI Neuronal representations of distance in human auditory cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE computational modeling; psychophysics; spatial hearing; what and where pathways; neuronal adaptation ID REVERBERANT ENERGY RATIO; HUMAN BRAIN; SOUND LOCALIZATION; COMPLEX SOUNDS; NEARBY SOURCES; COORDINATE SYSTEM; CORTICAL-NEURONS; RHESUS-MONKEYS; RATE CODE; PERCEPTION AB Neuronal mechanisms of auditory distance perception are poorly understood, largely because contributions of intensity and distance processing are difficult to differentiate. Typically, the received intensity increases when sound sources approach us. However, we can also distinguish between soft-but-nearby and loud-but-distant sounds, indicating that distance processing can also be based on intensity-independent cues. Here, we combined behavioral experiments, fMRI measurements, and computational analyses to identify the neural representation of distance independent of intensity. In a virtual reverberant environment, we simulated sound sources at varying distances (15-100 cm) along the right-side interaural axis. Our acoustic analysis suggested that, of the individual intensity-independent depth cues available for these stimuli, direct-to-reverberant ratio (D/R) is more reliable and robust than interaural level difference (ILD). However, on the basis of our behavioral results, subjects' discrimination performance was more consistent with complex intensity-independent distance representations, combining both available cues, than with representations on the basis of either D/R or ILD individually. fMRI activations to sounds varying in distance (containing all cues, including intensity), compared with activations to sounds varying in intensity only, were significantly increased in the planum temporale and posterior superior temporal gyrus contralateral to the direction of stimulation. This fMRI result suggests that neurons in posterior nonprimary auditory cortices, in or near the areas processing other auditory spatial features, are sensitive to intensity-independent sound properties relevant for auditory distance perception. C1 [Kopco, Norbert; Huang, Samantha; Belliveau, John W.; Raij, Tommi; Tengshe, Chinmayi; Ahveninen, Jyrki] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. [Kopco, Norbert] Safarik Univ, Inst Comp Sci, Kosice 04001, Slovakia. [Kopco, Norbert] Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA. [Belliveau, John W.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Kopco, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. EM kopco@bu.edu RI Kopco, Norbert/S-1447-2016 FU National Institutes of Health (NIH) [R21DC010060, R01MH083744, R01HD040712, R01NS037462]; NIH/National Center for Research Resources (NCRR) [P41RR14075]; European Community [PIRSES-GA-2009-247543]; Slovak Scientific Grant Agency [1/0492/12]; NCRR [S10RR023401, S10RR019307, S10RR023043]; NIH [P30DC004663] FX This work was supported by National Institutes of Health (NIH) Awards R21DC010060, R01MH083744, R01HD040712, and R01NS037462, and NIH/National Center for Research Resources (NCRR) Award P41RR14075. N.K. was also supported by the European Community's 7FP/2007-13 Grant PIRSES-GA-2009-247543 and by Slovak Scientific Grant Agency Grant VEGA 1/0492/12. The research environment was supported by NCRR Shared Instrumentation Grants S10RR023401, S10RR019307, and S10RR023043. Acoustic measurements performed at the Boston University Hearing Research Center used resources supported by NIH Award P30DC004663. NR 58 TC 17 Z9 17 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 3 PY 2012 VL 109 IS 27 BP 11019 EP 11024 DI 10.1073/pnas.1119496109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FF UT WOS:000306641100062 PM 22699495 ER PT J AU Fukuda, D Aikawa, E Swirski, FK Novobrantseva, TI Kotelianski, V Gorgun, CZ Chudnovskiy, A Yamazaki, H Croce, K Weissleder, R Aster, JC Hotamisligil, GS Yagita, H Aikawa, M AF Fukuda, Daiju Aikawa, Elena Swirski, Filip K. Novobrantseva, Tatiana I. Kotelianski, Victor Gorgun, Cem Z. Chudnovskiy, Aleksey Yamazaki, Hiroyuki Croce, Kevin Weissleder, Ralph Aster, Jon C. Hotamisligil, Goekhan S. Yagita, Hideo Aikawa, Masanori TI Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biotherapy; cardiovascular diseases; collagen; diabetes mellitus; obesity ID NF-KAPPA-B; AORTIC-VALVE CALCIFICATION; INHIBITS TUMOR-GROWTH; INSULIN-RESISTANCE; ADIPOSE-TISSUE; MACROPHAGE ACTIVATION; OSTEOGENIC DIFFERENTIATION; NONPRODUCTIVE ANGIOGENESIS; DENDRITIC CELLS; IMMUNE-SYSTEM AB Atherosclerosis and insulin resistance are major components of the cardiometabolic syndrome, a global health threat associated with a systemic inflammatory state. Notch signaling regulates tissue development and participates in innate and adaptive immunity in adults. The role of Notch signaling in cardiometabolic inflammation, however, remains obscure. We noted that a high-fat, high-cholesterol diet increased expression of the Notch ligand Delta-like 4 (Dll4) in atheromata and fat tissue in LDL-receptor-deficient mice. Blockade of Dll4-Notch signaling using neutralizing anti-Dll4 antibody attenuated the development of atherosclerosis, diminished plaque calcification, improved insulin resistance, and decreased fat accumulation. These changes were accompanied by decreased macrophage accumulation, diminished expression of monocyte chemoattractant protein-1 (MCP-1), and lower levels of nuclear factor-kappa B (NF-kappa B) activation. In vitro cell culture experiments revealed that Dll4-mediated Notch signaling increases MCP-1 expression via NF-kappa B, providing a possible mechanism for in vivo effects. Furthermore, Dll4 skewed macrophages toward a proinflammatory phenotype ("M1"). These results suggest that Dll4-Notch signaling plays a central role in the shared mechanism for the pathogenesis of cardiometabolic disorders. C1 [Fukuda, Daiju; Aikawa, Elena; Yamazaki, Hiroyuki; Croce, Kevin; Aikawa, Masanori] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Aster, Jon C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Swirski, Filip K.; Chudnovskiy, Aleksey; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Novobrantseva, Tatiana I.; Kotelianski, Victor] Alnylam Pharmaceut, Dept Res, Cambridge, MA 02142 USA. [Gorgun, Cem Z.; Hotamisligil, Goekhan S.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Yagita, Hideo] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. RP Aikawa, M (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. EM maikawa@rics.bwh.harvard.edu FU National Institutes of Health [R01HL107550]; American Heart Association [0655878T, 0835460N]; Japanese Heart Foundation; Japan Society for the Promotion of Science; Uehara Memorial Foundation FX We thank Jose-Luiz Figueiredo, Eugenia Shvartz, Yevgenia Tesmenitsky, Jacob Aaron, and Mohammad Zafari for technical assistance, and Sara Karwacki for her editorial expertise. This study was supported in part by National Institutes of Health Grant R01HL107550 (to M. A.) and American Heart Association Grants 0655878T (to M. A.) and 0835460N (to E. A.), Postdoctoral Fellowship Awards for Research Abroad from the Japanese Heart Foundation, the Japan Society for the Promotion of Science, and the Uehara Memorial Foundation (D.F.). NR 69 TC 49 Z9 53 U1 0 U2 10 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 JUL 3 PY 2012 VL 109 IS 27 BP E1868 EP E1877 DI 10.1073/pnas.1116889109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 977FF UT WOS:000306641100011 PM 22699504 ER PT J AU Haslinger, R Pipa, G Lima, B Singer, W Brown, EN Neuenschwander, S AF Haslinger, Robert Pipa, Gordon Lima, Bruss Singer, Wolf Brown, Emery N. Neuenschwander, Sergio TI Context Matters: The Illusive Simplicity of Macaque V1 Receptive Fields SO PLOS ONE LA English DT Article ID PRIMARY VISUAL-CORTEX; GAMMA-BAND SYNCHRONIZATION; STRIATE CORTICAL-NEURONS; TIME-RESCALING THEOREM; NATURAL SCENES; RESPONSE VARIABILITY; LOGISTIC-REGRESSION; STIMULUS CONTRAST; CELL PROPERTIES; NEURAL SPIKING AB Even in V1, where neurons have well characterized classical receptive fields (CRFs), it has been difficult to deduce which features of natural scenes stimuli they actually respond to. Forward models based upon CRF stimuli have had limited success in predicting the response of V1 neurons to natural scenes. As natural scenes exhibit complex spatial and temporal correlations, this could be due to surround effects that modulate the sensitivity of the CRF. Here, instead of attempting a forward model, we quantify the importance of the natural scenes surround for awake macaque monkeys by modeling it non-parametrically. We also quantify the influence of two forms of trial to trial variability. The first is related to the neuron's own spike history. The second is related to ongoing mean field population activity reflected by the local field potential (LFP). We find that the surround produces strong temporal modulations in the firing rate that can be both suppressive and facilitative. Further, the LFP is found to induce a precise timing in spikes, which tend to be temporally localized on sharp LFP transients in the gamma frequency range. Using the pseudo R 2 as a measure of model fit, we find that during natural scene viewing the CRF dominates, accounting for 60% of the fit, but that taken collectively the surround, spike history and LFP are almost as important, accounting for 40%. However, overall only a small proportion of V1 spiking statistics could be explained (R-2 similar to 5%), even when the full stimulus, spike history and LFP were taken into account. This suggests that under natural scene conditions, the dominant influence on V1 neurons is not the stimulus, nor the mean field dynamics of the LFP, but the complex, incoherent dynamics of the network in which neurons are embedded. C1 [Haslinger, Robert] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Haslinger, Robert; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Pipa, Gordon] Univ Osnabruck, Dept Neuroinformat, Osnabruck, Germany. [Pipa, Gordon; Lima, Bruss; Singer, Wolf; Neuenschwander, Sergio] Max Planck Inst Brain Res, Dept Neurophysiol, D-60496 Frankfurt, Germany. [Pipa, Gordon] Frankfurt Inst Adv Studies, Frankfurt, Germany. [Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Neuenschwander, Sergio] Univ Fed Rio Grande do Norte, Inst Brain, BR-59072970 Natal, RN, Brazil. RP Haslinger, R (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM robhh@nmr.mgh.harvard.edu RI Pipa, Gordon/M-1813-2014; Singer, Wolf/D-6874-2012; Lima, Bruss/I-9164-2016 OI Pipa, Gordon/0000-0002-3416-2652; Lima, Bruss/0000-0001-6865-2900 FU National Institutes of Health [K25 NS052422-02, DP1 ODOO3646]; European Union [FP6-2005-NEST-Path-043309]; EC Project Phocus [240763]; Max Planck Society FX This work was supported by National Institutes of Health grants K25 NS052422-02 (RH), and DP1 ODOO3646 (EB), as well as European Union Grant FP6-2005-NEST-Path-043309 (GP), EC Project Phocus Grant 240763 (GP) and the Max Planck Society (GP, BL, WS, SN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 95 TC 12 Z9 12 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 JUL 3 PY 2012 VL 7 IS 7 AR e39699 DI 10.1371/journal.pone.0039699 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 971EQ UT WOS:000306186900014 PM 22802940 ER PT J AU Roh, M Zhang, Y Murakami, Y Thanos, A Lee, SC Vavvas, DG Benowitz, LI Miller, JW AF Roh, Miin Zhang, Yan Murakami, Yusuke Thanos, Aristomenis Lee, Sung Chul Vavvas, Demetrios G. Benowitz, Larry I. Miller, Joan W. TI Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-alpha (TNF-alpha), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma SO PLOS ONE LA English DT Article ID OPTIC-NERVE HEAD; OPEN-ANGLE GLAUCOMA; ELEVATED INTRAOCULAR-PRESSURE; CHRONIC OCULAR HYPERTENSION; ALZHEIMERS-DISEASE; MOUSE MODEL; RHEUMATOID-ARTHRITIS; FLUORESCEIN LEAKAGE; ACTIVATED MICROGLIA; NEURONAL DEATH AB Background: Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) as a link between elevated IOP and RGC death, but the cellular source of TNF-alpha and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-alpha and examined whether Etanercept, a TNF-alpha blocker that is in common clinical use for other indications, is protective against RGC death. Methodology/Principal Findings: Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-alpha levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-alpha in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-alpha levels, axon degeneration in the optic nerve, and the loss of RGCs. Conclusions/Significance: Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-alpha. Blocking TNF-alpha activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-alpha antagonists or suppressors of inflammation. C1 [Roh, Miin; Zhang, Yan; Murakami, Yusuke; Thanos, Aristomenis; Vavvas, Demetrios G.; Miller, Joan W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02215 USA. [Roh, Miin; Zhang, Yan; Murakami, Yusuke; Thanos, Aristomenis; Vavvas, Demetrios G.; Miller, Joan W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA USA. [Roh, Miin; Lee, Sung Chul] Yonsei Univ, Coll Med, Inst Vis Res, Dept Ophthalmol, Seoul, South Korea. [Benowitz, Larry I.] Harvard Univ, Sch Med, Labs Neurosci Res Neurosurg, Boston, MA USA. [Benowitz, Larry I.] Harvard Univ, Sch Med, Dept Surg, FM Kirby Neurobiol Ctr,Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, FM Kirby Neurobiol Ctr,Childrens Hosp, Boston, MA USA. [Benowitz, Larry I.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Roh, M (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02215 USA. EM larry.benowitz@childrens.harvard.edu; joan_miller@meei.harvard.edu FU Neovascular Research Fund; Bacardi Fund; Research to Prevent Blindness Foundation; Lions Eye Research Fund; Onassis Foundation; Fight For Sight; Harvard Ophthalmology Department; National Eye Institute [EY014104, EY05690] FX This work was supported by the Neovascular Research Fund (JM, MR), the Bacardi Fund (DV), the Research to Prevent Blindness Foundation (DV), the Lions Eye Research Fund (DV), the Onassis Foundation (DV), a Fight For Sight Grant-in-Aid (DV), the Harvard Ophthalmology Department (DV), and National Eye Institute grants EY014104 (JM) and EY05690 (LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 73 Z9 76 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 JUL 3 PY 2012 VL 7 IS 7 AR e40065 DI 10.1371/journal.pone.0040065 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 971EQ UT WOS:000306186900025 PM 22802951 ER PT J AU Selby, JV Schmittdiel, JA Fireman, B Jaffe, M Ransom, LJ Dyer, W Uratsu, CS Reed, ME Kerr, EA Hsu, J AF Selby, Joe V. Schmittdiel, Julie A. Fireman, Bruce Jaffe, Marc Ransom, Laura J. Dyer, Wendy Uratsu, Connie S. Reed, Mary E. Kerr, Eve A. Hsu, John TI Improving treatment intensification to reduce cardiovascular disease risk: a cluster randomized trial SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Diabetes mellitus; Hypertension; Hyperlipidemia; Cardiovascular diseases; Clinical inertia ID QUALITY IMPROVEMENT STRATEGIES; BLOOD-PRESSURE CONTROL; DIABETES-MELLITUS; GLYCEMIC CONTROL; HYPERTENSION MANAGEMENT; DECISION-SUPPORT; CLINICAL INERTIA; PRIMARY-CARE; ADHERENCE; THERAPY AB Background: Blood pressure, lipid, and glycemic control are essential for reducing cardiovascular disease (CVD) risk. Many health care systems have successfully shifted aspects of chronic disease management, including population-based outreach programs designed to address CVD risk factor control, to non-physicians. The purpose of this study is to evaluate provision of new information to non-physician outreach teams on need for treatment intensification in patients with increased CVD risk. Methods: Cluster randomized trial (July 1-December 31, 2008) in Kaiser Permanente Northern California registry of members with diabetes mellitus, prior CVD diagnoses and/or chronic kidney disease who were high-priority for treatment intensification: blood pressure >= 140 mmHg systolic, LDL-cholesterol >= 130 mg/dl, or hemoglobin A1c >= 9%; adherent to current medications; no recent treatment intensification). Randomization units were medical center-based outreach teams (4 intervention; 4 control). For intervention teams, priority flags for intensification were added monthly to the registry database with recommended next pharmacotherapeutic steps for each eligible patient. Control teams used the same database without this information. Outcomes included 3-month rates of treatment intensification and risk factor levels during follow-up. Results: Baseline risk factor control rates were high (82-90%). In eligible patients, the intervention was associated with significantly greater 3-month intensification rates for blood pressure (34.1 vs. 30.6%) and LDL-cholesterol (28.0 vs 22.7%), but not A1c. No effects on risk factors were observed at 3 months or 12 months follow-up. Intervention teams initiated outreach for only 45-47% of high-priority patients, but also for 27-30% of lower-priority patients. Teams reported difficulties adapting prior outreach strategies to incorporate the new information. Conclusions: Information enhancement did not improve risk factor control compared to existing outreach strategies at control centers. Familiarity with prior, relatively successful strategies likely reduced uptake of the innovation and its potential for success at intervention centers. C1 [Schmittdiel, Julie A.; Fireman, Bruce; Dyer, Wendy; Uratsu, Connie S.; Reed, Mary E.] Permanente Med Grp Inc, Div Res, Oakland, CA USA. [Schmittdiel, Julie A.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Selby, Joe V.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Jaffe, Marc] Permanente Med Grp Inc, Dept Med & Endocrinol, San Francisco, CA USA. [Kerr, Eve A.] VA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI USA. [Kerr, Eve A.] Univ Michigan, Sch Med, Div Gen Med, Ann Arbor, MI USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Schmittdiel, JA (reprint author), Permanente Med Grp Inc, Div Res, Oakland, CA USA. EM julie.a.schmittdiel@kp.org RI Kerr, Eve/I-3330-2013 FU AHRQ Grant [R18 HS17031-01]; Health Delivery Systems Center for Diabetes Translational Research (CDTR) [NIDDK] [1P30-DK092924] FX This study was supported by AHRQ Grant No. R18 HS17031-01. Dr. Schmittdiel receives additional support from the Health Delivery Systems Center for Diabetes Translational Research (CDTR) [NIDDK grant 1P30-DK092924]. The authors acknowledge and thank the following leaders of medical center-based PHASE outreach teams: Lisa Bell, Linda Carnes, Laura Chan, Svasti Patel, and Kathleen Wolf. NR 38 TC 6 Z9 6 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 2 PY 2012 VL 12 AR 183 DI 10.1186/1472-6963-12-183 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 003LL UT WOS:000308612900001 PM 22747998 ER PT J AU Shaik, S Nucera, C Inuzuka, H Gao, DM Garnaas, M Frechette, G Harris, L Wan, LX Fukushima, H Husain, A Nose, V Fadda, G Sadow, PM Goessling, W North, T Lawler, J Wei, WY AF Shaik, Shavali Nucera, Carmelo Inuzuka, Hiroyuki Gao, Daming Garnaas, Maija Frechette, Gregory Harris, Lauren Wan, Lixin Fukushima, Hidefumi Husain, Amjad Nose, Vania Fadda, Guido Sadow, Peter M. Goessling, Wolfram North, Trista Lawler, Jack Wei, Wenyi TI SCF beta-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; PHASE-II TRIAL; F-BOX PROTEINS; TUMOR ANGIOGENESIS; CARBOXYL-TERMINUS; DOWN-REGULATION; BREAST-CANCER; IN-VIVO; EXPRESSION AB The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCF beta-TRCP promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)-dependent manner. beta-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. beta-TRCP-depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, beta-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between beta-TRCP protein levels and angiogenesis in PTC. We also show that beta-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC. C1 [Shaik, Shavali; Nucera, Carmelo; Inuzuka, Hiroyuki; Gao, Daming; Frechette, Gregory; Harris, Lauren; Wan, Lixin; Fukushima, Hidefumi; Husain, Amjad; North, Trista; Lawler, Jack; Wei, Wenyi] Harvard Univ, Sch Med, Dept Pathol, Div Canc Biol & Angiogenesis, Boston, MA 02115 USA. [Nucera, Carmelo; Husain, Amjad; Lawler, Jack] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02115 USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol,Endocrine Serv, Boston, MA 02115 USA. [Garnaas, Maija; Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Garnaas, Maija; Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Univ, Sch Med, Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. [Nose, Vania] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Fadda, Guido] Catholic Univ Policlin A Gemelli, I-00168 Rome, Italy. [Goessling, Wolfram; North, Trista] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Wei, WY (reprint author), Harvard Univ, Sch Med, Dept Pathol, Div Canc Biol & Angiogenesis, Boston, MA 02115 USA. EM wwei2@bidmc.harvard.edu RI Wan, Lixin/F-2124-2011; Fadda, Guido/J-3621-2012 FU National Institutes of Health (NIH) [GM089763, GM094777, CA130895]; NRSA T-32 training grant; K01 grant from NIH [AG041218]; JSPS Postdoctoral Fellowship; Ph.D. fellowship from the Italian Ministry of Education, Universities and Research (MIUR); American Thyroid Association for a Thyroid Cancer Grant FX W. Wei is a DOD Prostate Research Program New Investigator and American Cancer Society Scholar. This work was supported in part by the National Institutes of Health (NIH) grants to W. Wei (GM089763 and GM094777) and J. Lawler (CA130895). S. Shaik is supported by a NRSA T-32 training grant, H. Inuzuka was awarded a K01 grant (AG041218) from NIH, and H. Fukushima is supported by a JSPS Postdoctoral Fellowship. C. Nucera was the recipient of a Ph.D. fellowship from the Italian Ministry of Education, Universities and Research (MIUR). C. Nucera is also funded by the American Thyroid Association for a Thyroid Cancer Grant. NR 75 TC 36 Z9 37 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 2 PY 2012 VL 209 IS 7 BP 1289 EP 1307 DI 10.1084/jem.20112446 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 971AP UT WOS:000306174300006 PM 22711876 ER PT J AU de Groot, M Evans, CL de Boer, JF AF de Groot, Mattijs Evans, Conor L. de Boer, Johannes F. TI Self-interference fluorescence microscopy: three dimensional fluorescence imaging without depth scanning SO OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY; GROWTH-FACTOR; CANCER; ANTIBODIES; HEART AB We present a new method for high-resolution, three-dimensional fluorescence imaging. In contrast to beam-scanning confocal microscopy, where the laser focus must be scanned both laterally and axially to collect a volume, we obtain depth information without the necessity of depth scanning. In this method, the emitted fluorescence is collected in the backward direction and is sent through a phase plate that encodes the depth information into the phase of a spectrally resolved interference pattern. We demonstrate that decoding this phase information allows for depth localization accuracy better than 4 mu m over a 500 mu m depth-of-field. In a high numerical aperture configuration with a much smaller depth of field, a localization accuracy of tens of nanometers can be achieved. This approach is ideally suited for miniature endoscopes, where space limitations at the endoscope tip render depth scanning difficult. We illustrate the potential for 3D visualization of complex biological samples by constructing a three-dimensional volume of the microvasculature of ex vivo murine heart tissue from a single 2D scan. (C)2012 Optical Society of America C1 [de Groot, Mattijs; de Boer, Johannes F.] Vrije Univ Amsterdam, Dept Phys & Astron, Inst Lasers Life & Biophoton Amsterdam, NL-1081 HV Amsterdam, Netherlands. [Evans, Conor L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP de Groot, M (reprint author), Vrije Univ Amsterdam, Dept Phys & Astron, Inst Lasers Life & Biophoton Amsterdam, de Boelelaan 1081, NL-1081 HV Amsterdam, Netherlands. EM m.de.groot@vu.nl RI de Boer, Johannes/B-7590-2012; de Groot , Mattijs/D-8470-2014 OI de Boer, Johannes/0000-0003-1253-4950; FU National Institutes of Health [R21 RR023139]; Netherlands Organization for Scientific Research (NWO) FX We would like to thank Joke Wortel and Ruud Toonen from the Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam for their help with the animal experiments. This work was supported by the National Institutes of Health (project R21 RR023139). This work is part of the research program Vernieuwingsimpuls which is (partly) financed by the Netherlands Organization for Scientific Research (NWO). NR 13 TC 6 Z9 6 U1 1 U2 14 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 2 PY 2012 VL 20 IS 14 BP 15253 EP 15262 DI 10.1364/OE.20.015253 PG 10 WC Optics SC Optics GA 971BF UT WOS:000306176100065 PM 22772223 ER PT J AU Liao, SY Liu, YQ Tan, YD Gan, L Mei, J Song, WZ Chi, S Dong, XJ Chen, XJ Deng, SP AF Liao, Shunyao Liu, Yunqiang Tan, Yuande Gan, Lu Mei, Jie Song, Wenzhong Chi, Shu Dong, Xianjue Chen, Xiaojuan Deng, Shaoping TI Association of Genetic Variants of Melatonin Receptor 1B with Gestational Plasma Glucose Level and Risk of Glucose Intolerance in Pregnant Chinese Women SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; DIABETES-MELLITUS; COMMON VARIANT; MTNR1B; POPULATION; GLYCEMIA AB Background: This study aimed to explore the association of MTNR1B genetic variants with gestational plasma glucose homeostasis in pregnant Chinese women. Methods: A total of 1,985 pregnant Han Chinese women were recruited and evaluated for gestational glucose tolerance status with a two-step approach. The four MTNR1B variants rs10830963, rs1387153, rs1447352, and rs2166706 which had been reported to associate with glucose levels in general non-pregnant populations, were genotyped in these women. Using an additive model adjusted for age and body mass index (BMI), association of these variants with gestational fasting and postprandial plasma glucose (FPG and PPG) levels were analyzed by multiple linear regression; relative risk of developing gestational glucose intolerance was calculated by logistic regression. Hardy-Weinberg Equilibrium was tested by Chi-square and linkage disequilibrium (LD) between these variants was estimated by measures of D' and r(2). Results: In the pregnant Chinese women, the MTNR1B variant rs10830963, rs1387153, rs2166706 and rs1447352 were shown to be associated with the increased 1 hour PPG level (p = 8.04 x 10(-10), 5.49 x 10(-6), 1.89 x 10(-5) and 0.02, respectively). The alleles were also shown to be associated with gestational glucose intolerance with odds ratios (OR) of 1.64 (p = 8.03 x 10(-11)), 1.43 (p = 1.94 x 10(-6)), 1.38 (p = 1.63 x 10(-5)) and 1.24 (p = 0.007), respectively. MTNR1B rs1387153, rs2166706 were shown to be associated with gestational FPG levels (p = 0.04). Our data also suggested that, the LD pattern of these variants in the studied women conformed to that in the general populations: rs1387153 and rs2166706 were in high LD, they linked moderately with rs10830963, but might not linked with rs1447352; rs10830963 might not link with rs1447352, either. In addition, the MTNR1B variants were not found to be associated with any other traits tested. Conclusions: The MTNR1B is likely to be involved in the regulation of glucose homeostasis during pregnancy. C1 [Liao, Shunyao; Gan, Lu; Deng, Shaoping] Sichuan Acad Med Sci, Ctr Diabet, Chengdu, Peoples R China. [Mei, Jie] Sichuan Prov Peoples Hosp, Sichuan Acad Med Sci, Dept Obstet & Gynecol, Chengdu, Peoples R China. [Liu, Yunqiang] Sichuan Univ, W China Hosp, Dept Med Genet, Chengdu 610064, Peoples R China. [Liu, Yunqiang] Sichuan Univ, W China Hosp, Div Morbid Genom, State Key Lab Biotherapy, Chengdu 610064, Peoples R China. [Tan, Yuande] Hunan Normal Univ, Coll Life Sci, Changsha, Hunan, Peoples R China. [Song, Wenzhong; Chi, Shu] Sichuan Prov Peoples Hosp, Sichuan Acad Med Sci, Clin Isotop Lab, Chengdu, Peoples R China. [Dong, Xianjue] Chongqing Med Univ, Dept Endocrinol, Chongqing, Peoples R China. [Chen, Xiaojuan] NW Univ Hosp, Dept Surg, Chicago, IL USA. [Deng, Shaoping] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Human Islet Lab, Boston, MA USA. RP Liao, SY (reprint author), Sichuan Acad Med Sci, Ctr Diabet, Chengdu, Peoples R China. EM shunyaol@yahoo.com; sdeng1@partner.com FU Key Project of Sichuan Province [416001004085]; Sichuan Academy of Medical Science and Sichuan Provincial Hospital [303005002153008, 303005002271027] FX This study was supported by the research grant (to Shaoping Deng) from the Key Project of Sichuan Province (416001004085) and by grants (to Shaoping Deng and to Shunyao Liao) from Sichuan Academy of Medical Science and Sichuan Provincial Hospital (303005002153008 & 303005002271027). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 16 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2012 VL 7 IS 7 AR e40113 DI 10.1371/journal.pone.0040113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 968GX UT WOS:000305966500046 PM 22768333 ER PT J AU Chung, J Shao, HL Reiner, T Issadore, D Weissleder, R Lee, H AF Chung, Jaehoon Shao, Huilin Reiner, Thomas Issadore, David Weissleder, Ralph Lee, Hakho TI Microfluidic Cell Sorter (mu FCS) for On-chip Capture and Analysis of Single Cells SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID CIRCULATING TUMOR-CELLS; TYROSINASE MESSENGER-RNA; MELANOMA-CELLS; PERIPHERAL-BLOOD; CANCER-CELLS; MICRODEVICE; MARKERS C1 [Chung, Jaehoon; Shao, Huilin; Reiner, Thomas; Issadore, David; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Shao, Huilin] Harvard Univ, Harvard Biophys Program, Sch Med, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; hlee@mgh.harvard.edu RI Issadore, David/L-8451-2014 FU B.S.-Ph.D. National Science Scholarship; Agency for Science, Technology and Research, Singapore; National Institute of Health [R01-EB0044626, R01-EB010011]; P50 grant [P50CA86355]; CCNE [U54CA151884]; TPEN [HHSN268201000044C] FX The authors thank Gregory Wojtkiewicz for his assistance in CT imaging; Y. Fisher-Jeffes for critical reading of the manuscript. H. Shao acknowledges financial support from the B.S.-Ph.D. National Science Scholarship awarded by the Agency for Science, Technology and Research, Singapore. This work was supported in part by National Institute of Health Grants R01-EB0044626, R01-EB010011, P50 grant P50CA86355, CCNE contract U54CA151884, and TPEN contract HHSN268201000044C. NR 28 TC 21 Z9 22 U1 2 U2 44 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD JUL PY 2012 VL 1 IS 4 BP 432 EP 436 DI 10.1002/adhm.201200046 PG 5 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA 092IE UT WOS:000315113100004 PM 23184773 ER PT J AU Ellis, HL Shioda, K Rosenthal, NF Coser, KR Shioda, T AF Ellis, Haley L. Shioda, Keiko Rosenthal, Noel F. Coser, Kathryn R. Shioda, Toshi TI Masculine Epigenetic Sex Marks of the CYP19A1/Aromatase Promoter in Genetically Male Chicken Embryonic Gonads Are Resistant to Estrogen-Induced Phenotypic Sex Conversion SO BIOLOGY OF REPRODUCTION LA English DT Article DE embryo; endocrine disruptors; epigenetics; gene regulation; sex determination ID PRIMORDIAL GERM-CELLS; BREAST-CANCER CELLS; BISPHENOL-A; DNA METHYLATION; TRANSGENERATIONAL ACTIONS; OVARIAN DEVELOPMENT; VITELLOGENIN GENE; ORGAN DEVELOPMENT; FEMALE CHICKENS; AROMATASE GENES AB Sex of birds is genetically determined through inheritance of the ZW sex chromosomes (ZZ males and ZW females). Although the mechanisms of avian sex determination remains unknown, the genetic sex is experimentally reversible by in ovo exposure to exogenous estrogens (ZZ-male feminization) or aromatase inhibitors (ZW-female masculinization). Expression of various testis-and ovary-specific marker genes during the normal and reversed gonadal sex differentiation in chicken embryos has been extensively studied, but the roles of sex-specific epigenetic marks in sex differentiation are unknown. In this study, we show that a 170-nt region in the promoter of CYP19A1/aromatase, a key gene required for ovarian estrogen biosynthesis and feminization of chicken embryonic gonads, contains highly quantitative, nucleotide base-level epigenetic marks that reflect phenotypic gonadal sex differentiation. We developed a protocol to feminize ZZ-male chicken embryonic gonads in a highly quantitative manner by direct injection of emulsified ethynylestradiol into yolk at various developmental stages. Taking advantage of this experimental sex reversal model, we show that the epigenetic sex marks in the CYP19A1/aromatase promoter involving DNA methylation and histone lysine methylation are feminized significantly but only partially in sex-converted gonads even when morphological and transcriptional marks of sex differentiation show complete feminization, being indistinguishable from gonads of normal ZW females. Our study suggests that the epigenetic sex of chicken embryonic gonads is more stable than the morphologically or transcriptionally characterized sex differentiation, suggesting the importance of the nucleotide base-level epigenetic sex in gonadal sex differentiation. C1 [Shioda, Toshi] Massachusetts Gen Hosp, Mol Profiling Lab, Ctr Canc Res, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Shioda, T (reprint author), Massachusetts Gen Hosp, Mol Profiling Lab, Ctr Canc Res, Charlestown, MA USA. EM tshioda@partners.org FU NIH National Cancer Institute (NCI) Federal Share/Program Income Grant [R7963]; Friends of Mels grant FX Supported by the NIH National Cancer Institute (NCI) Federal Share/Program Income Grant (R7963) and the Friends of Mels grant to T.S. NR 64 TC 5 Z9 5 U1 0 U2 16 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUL PY 2012 VL 87 IS 1 AR 23 DI 10.1095/biolreprod.112.099747 PG 12 WC Reproductive Biology SC Reproductive Biology GA 080EN UT WOS:000314224200004 PM 22539680 ER PT J AU Biederman, J Petty, CR Woodworth, KY Lomedico, A Hyder, LL Faraone, SV AF Biederman, Joseph Petty, Carter R. Woodworth, K. Yvonne Lomedico, Alexandra Hyder, Laran L. Faraone, Stephen V. TI Adult Outcome of Attention-Deficit/Hyperactivity Disorder: A Controlled 16-Year Follow-Up Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; SUBTHRESHOLD DIAGNOSES; LATE-ONSET; PSYCHIATRIC STATUS; ADHD; CHILDREN; BOYS; COMORBIDITY; CRIMINALITY; SYMPTOMS AB Objective: To estimate the risks for psychopathology and functional impairments in adulthood among a longitudinal sample of youth with and without attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood. Method: This was a case-controlled, 16-year (15-19 years) prospective follow-up study of ADHD. 140 boys with and 120 without DSM-III-R ADHD were recruited from pediatric and psychiatric settings. The main outcome measures were structured diagnostic interviews and measures of psychosocial, educational, and neuropsychological functioning. Data were collected from 1988 to 2006. Results: At the 16-year follow-up, subjects with ADHD continued to significantly differ from controls in lifetime rates of antisocial, mood, anxiety, and addictive disorders, but with the exception of a higher interval prevalence of anxiety disorders (20% vs 8%; z = 2.32, P = .02) and smoking dependence (27% vs 11%; z = 2.30, P = .02), the incidence of individual disorders in the 6-year interval between the current and prior follow-up did not differ significantly from controls. At follow-up, the ADHD subjects compared with controls were significantly (P < .05) more impaired in psychosocial, educational, and neuropsychological functioning, differences that could not be accounted for by other active psychopathology. Conclusions: These long-term prospective findings provide further evidence for the high morbidity associated with ADHD across the life cycle, stressing the importance of early recognition of this disorder for prevention and early intervention strategies. These findings also indicate that, in adulthood, ADHD confers significant risks for impairment that cannot be accounted for by other psychopathology. J Clin Psychiatry 2012;73(7):941-950 (c) Copyright 2012 Physicians Postgraduate Press, Inc. C1 [Biederman, Joseph; Petty, Carter R.; Woodworth, K. Yvonne; Lomedico, Alexandra; Hyder, Laran L.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Biederman, Joseph; Petty, Carter R.; Woodworth, K. Yvonne; Lomedico, Alexandra; Hyder, Laran L.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Programs Adult ADHD, Boston, MA 02114 USA. [Biederman, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 6A, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Elminda; Janssen; McNeil; Shire; Fundacion Dr Manuel Camelo A.C. in Monterrey, Mexico; Abbott; Alza; AstraZeneca; Boston University; Bristol-Myers Squibb; Celltech; Cephalon; Eli Lilly; Esai; Fundacion Areces (Spain); Forest; Glaxo; Gliatech; Hastings Center; Medice Pharmaceuticals (Germany); Merck; MMC Pediatric; National Alliance for Research on Schizophrenia and Depression; National Institute on Drug Abuse; National Institute of Child Health and Human Development; National Institute of Mental Health; Novartis; Noven; Neurosearch; Organon; Otsuka; Pfizer; Pharmacia; Phase V Communications; Physicians Academy; Prechter Foundation; Quantia Communications; Reed Exhibitions; Spanish Child Psychiatry Association; Stanley Foundation; UCB Pharma; Veritas; Wyeth; Alcobra; National Institutes of Health; Lilly Foundation; Pediatric Psychopharmacology Council Fund of the Massachusetts General Hospital, Boston; New River FX Dr Biederman is currently receiving research support from Elminda, Janssen, McNeil, and Shire. In 2011, he gave a single unpaid talk for Juste Pharmaceutical Spain; received honoraria from the Massachusetts General Hospital (MGH) Psychiatry Academy for a tuition-funded continuing medical education (CME) course; received an honorarium for presenting at an international scientific conference on ADHD; received an honorarium from Cambridge University Press for a chapter publication; and received departmental royalties from a copyrighted rating scale used for ADHD diagnoses that were paid by Eli Lilly, Shire, and AstraZeneca to the Department of Psychiatry at MGH. In 2010, he received a speaker's fee from a single talk given at Fundacion Dr Manuel Camelo A.C. in Monterrey, Mexico; received honoraria, paid to the Department of Psychiatry at MGH, for providing single consultations for Shionogi Pharma and Cipher Pharmaceuticals; and received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. In previous years, he received research support, consultation fees, or speaker's fees for/from Abbott, Alza, AstraZeneca, Boston University, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Esai, Fundacion Areces (Spain), Forest, Glaxo, Gliatech, Hastings Center, Janssen, McNeil, Medice Pharmaceuticals (Germany), Merck, MMC Pediatric, the National Alliance for Research on Schizophrenia and Depression, the National Institute on Drug Abuse, New River, the National Institute of Child Health and Human Development, the National Institute of Mental Health, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, Prechter Foundation, Quantia Communications, Reed Exhibitions, Shire, Spanish Child Psychiatry Association, Stanley Foundation, UCB Pharma, Veritas, and Wyeth. In 2011, Dr Faraone received consulting income and research support from Shire and Alcobra and research support from the National Institutes of Health. In previous years, he received consulting fees or was on advisory boards or participated in CME programs sponsored by Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. He receives royalties from books published by Guilford Press (Straight Talk About Your Child's Mental Health) and by Oxford University Press (Schizophrenia: The Facts). Mr Petty and Mss Woodworth, Lomedico, and Hyder have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.; This work was supported, in part, by a grant from the Lilly Foundation and the Pediatric Psychopharmacology Council Fund of the Massachusetts General Hospital, Boston. NR 54 TC 78 Z9 78 U1 2 U2 27 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2012 VL 73 IS 7 BP 941 EP 950 DI 10.4088/JCP.11m07529 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SL UT WOS:000315000200005 PM 22901345 ER PT J AU Sung, SC Haley, CL Wisniewski, SR Fava, M Nierenberg, AA Warden, D Morris, DW Kurian, BT Trivedi, MH Rush, AJ AF Sung, Sharon C. Haley, Charlotte L. Wisniewski, Stephen R. Fava, Maurizio Nierenberg, Andrew A. Warden, Diane Morris, David W. Kurian, Benji T. Trivedi, Madhukar H. Rush, A. John CA CO-MED Study Team TI The Impact of Chronic Depression on Acute and Long-Term Outcomes in a Randomized Trial Comparing Selective Serotonin Reuptake Inhibitor Monotherapy Versus Each of 2 Different Antidepressant Medication Combinations SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DIAGNOSTIC SCREENING QUESTIONNAIRE; BEHAVIORAL-ANALYSIS SYSTEM; STAR-ASTERISK-D; REPORT QIDS-SR; SELF-REPORT; PSYCHOMETRIC EVALUATION; MAJOR DEPRESSION; QUICK INVENTORY; SCALE; PSYCHOTHERAPY AB Objective: To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. Method: 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score >= 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. Results: Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AGR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR16 scores and smaller overall percent changes in QIDS-SR16 from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. Conclusion: Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. C1 [Sung, Sharon C.; Haley, Charlotte L.; Rush, A. John] Duke NUS Grad Med Sch Singapore, Singapore 169857, Singapore. [Wisniewski, Stephen R.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Fava, Maurizio; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Warden, Diane; Morris, David W.; Kurian, Benji T.; Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. RP Sung, SC (reprint author), Duke NUS Grad Med Sch Singapore, Off Clin Sci, 8 Coll Rd, Singapore 169857, Singapore. EM sharon.sung@duke-nus.edu.sg RI McGrath, Patrick/I-6410-2013; Preskorn, Sheldon/L-9839-2016; Howland, Robert/K-6937-2015; OI McGrath, Patrick/0000-0001-7217-7321; Howland, Robert/0000-0002-6533-6010; Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU Abbott; lkermes; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells; Bristol-Myers Squibb; Cephalon; CeNeRx BioPharma; Clinical Trials Solutions; Clintara; Covidien; Eli Lilly; EnVivo; Euthymics Bioscience; Forest; Ganeden; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson Johnson PRD; Lichtwer; Lorex; NARSAD; National Center for Complementary and Alternative Medicine; National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Novartis; Organon; PamLab; Pfizer; Pharmavite; Photothera; Roche; RCT Logic; Sanofi-Aventis US; Shire; Solvay; Synthelabo; Wyeth-Ayerst; MGH from NIMH; PamLabs; Agency for Healthcare Research and Quality; Corcept; Cyberonics; Merck; NIMH [N01MH90003]; NIDA; Pharmacia Upjohn; Predix (EPIX); Targacept; Abdi Ibrahim; Akzo (Organon); Axon; CME Institute of Physicians Postgraduate Press; Evotec; Fabre-Kramer; Janssen; Lundbeck; Mead Johnson; MedAvante; Medtronic; Neuronetics; Otsuka; Parke-Davis; PGx Health; Rexahn; Sepracor; Shire Development; Takeda; VantagePoint; University of Michigan; Brain Resource FX Dr Wisniewski has been a consultant for Cyberonics, ImaRx Therapeutics, Bristol-Myers Squibb, Organon, Case-Western University, Singapore Clinical Research Institute, Dey, and Venebio. Dr Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, Cephalon, CeNeRx BioPharma, Clinical Trials Solutions, Clintara, Covidien, Eli Lilly, EnVivo, Euthymics Bioscience, Forest, Ganeden, GlaxoSmithKline, Icon Clinical Research, i3 Innovus/Ingenix, Johnson & Johnson PRD, Lichtwer, Lorex, NARSAD, the National Center for Complementary and Alternative Medicine, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), Novartis, Organon, PamLab, Pfizer, Pharmavite, Photothera, Roche, RCT Logic, Sanofi-Aventis US, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; has advised/consulted with Abbott, Affectis, Alkermes, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Bayer, Best Practice Project Management, BioMarin, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, CNS Response, Compellis, Cypress, DiagnoSearch Life Sciences, Dainippon Sumitomo, Dov, Edgemont, Eisai, Eli Lilly, ePharmaSolutions, EPIX, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal, i3 Innovus/Ingenis, Janssen, Jazz, Johnson & Johnson PRD, Knoll, Labopharm, Lorex, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuronetics, NextWave, Novartis, Nutrition 21, Orexigen, Organon, Otsuka, PamLab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics; Precision Human Biolaboratory, Prexa, Puretech, PsychoGenics, Psylin Neurosciences, Rexahn, Ridge Diagnostics, Roche, RCT Logic, Sanofi-Aventis US, Sepracor, Servier, Schering-Plough, Solvay, Somaxon, Somerset, Sunovion, Synthelabo, Takeda, Tal Medical, Tetragenex, TransForm, Transcept, and Vanda; has had speaking/publishing relationships with Adamed, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press, Eli Lilly, Forest, GlaxoSmithKline, Imedex, Massachusetts General Hospital (MGH) Psychiatry Academy/PRIMEDIA Healthcare, MGH Psychiatry Academy/Reed Elsevier, Novartis, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; holds equity in Compellis; holds a patent for Sequential Parallel Comparison Design (SPCD); holds a patent for research and licensing of SPCD with RCT Logic, Lippincott Williams & Wilkins, and World Scientific Publishing; has a patent application for a combination of azapirones and bupropion in major depressive disorder; and has received copyright royalties for the MGH Cognitive and Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms scale, and SAFER Criteria Interview diagnostic instruments.; Dr Nierenberg has consulted for Appliance Computing (Mindsite), Brandeis University, and, through the MGH Clinical Trials Network and Institute, AstraZeneca, BrainCells, Dainippon Sumitomo/Sepracor, Johnson & Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept, and Takeda-Lundbeck; has received grant/research support through MGH from NIMH, PamLabs, Pfizer, and Shire; has received honoraria from Belvior Publishing, Hillside Hospital, American Professional Society of ADHD and Related Disorders, American Society for Clinical Psychopharmacology, Columbia University, Imedex, International Society for Bipolar Disorders, MJ Consulting, New York State, MBL Publishing, Physicians Postgraduate Press, SciMed, State University of New York at Buffalo, University of Wisconsin, and the University of Pisa; has been a presenter for the MGH Psychiatry Academy (the education programs of the academy were supported through independent medical education grants from AstraZeneca, Eli Lilly, and Janssen in 2008 and AstraZeneca, Eli Lilly, and Bristol-Myers Squibb in 2009); has been on the advisory boards of Appliance Computing, BrainCells, Eli Lilly, Johnson & Johnson, Takeda-Lundbeck, and Targacept; owns stock options in Appliance Computing and BrainCells; and, through MGH, is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-Asberg Depression Rating Scale exclusively licensed to the MGH Clinical Trials Network and Institute. Dr Warden has received grant/research support from NARSAD and for the last 5 years has been a stock shareholder in Pfizer and Bristol-Myers Squibb. Dr Kurian has received grant/research support from Pfizer, Targacept, and Evotec. Dr Trivedi has received research support from the Agency for Healthcare Research and Quality, Corcept, Cyberonics, Merck, NARSAD, NIMH, NIDA, Novartis, Pharmacia & Upjohn, Predix (EPIX), Solvay, and Targacept and has received consulting and speaker fees from Abbott, Abdi Ibrahim, Akzo (Organon), AstraZeneca, Axon, Bristol-Myers Squibb, Cephalon, CME Institute of Physicians Postgraduate Press, Eli Lilly, Evotec, Fabre-Kramer, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson PRD, Lundbeck, Mead Johnson, MedAvante, Medtronic, Neuronetics, Otsuka, PamLab, Parke-Davis, Pfizer, PGx Health, Rexahn, Sepracor, Shire Development, Takeda, VantagePoint, and Wyeth-Ayerst. Dr Rush has received consulting fees from the University of Michigan and Brain Resource; has received grant/research support from NIMH; has received speaker fees from Otsuka; and has received author royalties from Guilford Publications and the University of Texas Southwestern Medical Center. Drs Sung, Haley, and Morris have no financial or other relationships that might pose a conflict of interest.; This project was funded by NIMH under grant N01MH90003 to The University of Texas Southwestern Medical Center at Dallas (Principal Investigators: Drs Rush and Trivedi). NR 31 TC 8 Z9 8 U1 1 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2012 VL 73 IS 7 BP 967 EP 976 DI 10.4088/JCP.11m07043 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SL UT WOS:000315000200008 PM 22687487 ER PT J AU Zhang, XY Chen, DC Xiu, MH Yang, FD Haile, CN Kosten, TA Kosten, TR AF Zhang, Xiang Yang Chen, Da Chun Xiu, Mei Hong Yang, Fu De Haile, Colin N. Kosten, Therese A. Kosten, Thomas R. TI Gender Differences in Never-Medicated First-Episode Schizophrenia and Medicated Chronic Schizophrenia Patients SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID 1ST EPISODE PSYCHOSIS; SEX-DIFFERENCES; CHINESE SCHIZOPHRENIA; VERBAL MEMORY; ONSET; AGE; SMOKING; PREVALENCE; DISORDERS; ILLNESS AB Background: Schizophrenia shows gender differences in patients' clinical presentation, neurocognitive impairment, course, and treatment outcome. The aims of this study were to compare gender differences in clinical features and cognitive functioning in first-episode and chronic schizophrenia among Han Chinese inpatients. Method: We compared gender differences in 262 unmedicated first-episode schizophrenia and 960 chronic schizophrenia inpatients (diagnosed according to DSM-IV) to 804 matched healthy controls on sociodemographic characteristics, smoking behavior, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients were also rated on the Positive and Negative Syndrome Scale. The study was conducted from December 2006 to May 2008. Results: Schizophrenia first occurred in both first-episode and chronic schizophrenia patients at a significantly earlier age in male than female patients (P < .05 and P < .001, respectively). The paranoid subtype of schizophrenia was more common in female patients only in chronic schizophrenia, not first-episode patients. Further, cigarette smoking was more common in male than female patients from both patient groups, and, among men, more chronic schizophrenia patients than controls smoked, while among women, fewer chronic schizophrenia patients than controls smoked. Female chronic schizophrenia patients had more severe positive and general psychopathological symptoms, whereas male patients had more severe negative symptoms. By contrast, first-episode schizophrenia patients showed no gender differences in symptoms and severity. Both first-episode and chronic schizophrenia patients performed worse than controls on most of the cognitive tasks. RBANS attention, delayed memory, and immediate memory were less impaired in female than male chronic schizophrenia patients, and first-episode schizophrenia patients showed no gender differences. Conclusions: Chronic schizophrenia patients have notable gender differences in the age at onset, smoking, symptom severity, and cognitive function favoring women, but first-episode schizophrenia patients show few gender differences. J Clin Psychiatry 2012;73(7):1025-1033 (c) Copyright 2012 Physicians Postgraduate Press, Inc. C1 [Zhang, Xiang Yang; Haile, Colin N.; Kosten, Therese A.; Kosten, Thomas R.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Chen, Da Chun; Xiu, Mei Hong; Yang, Fu De] Beijing HuiLongGuan Hosp, Ctr Psychiat Res, Beijing, Peoples R China. RP Zhang, XY (reprint author), VA Med Ctr, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu OI Haile, Colin/0000-0001-8293-7291 FU Stanley Medical Research Institute [03T-459, 05T-726]; Department of Veterans Affairs, VISN 16, Mental Illness Research, Education, and Clinical Center (MIRECC); United States National Institutes of Health [K05-DA0454, P50-DA18827, U01-MH79639] FX This study was funded by the Stanley Medical Research Institute (03T-459 and 05T-726); the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education, and Clinical Center (MIRECC); and United States National Institutes of Health (K05-DA0454, P50-DA18827, and U01-MH79639). NR 42 TC 33 Z9 34 U1 3 U2 33 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2012 VL 73 IS 7 BP 1025 EP 1033 DI 10.4088/JCP.11m07422 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SL UT WOS:000315000200017 PM 22901352 ER PT J AU Gray, ST Holbrook, EH Najm, MH Sadow, PM Curry, WT Lin, DT AF Gray, Stacey T. Holbrook, Eric H. Najm, Mohammed H. Sadow, Peter M. Curry, William T. Lin, Derrick T. TI Syndrome of Inappropriate Antidiuretic Hormone Secretion in Patients with Olfactory Neuroblastoma SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE olfactory neuroblastoma; syndrome of inappropriate antidiuretic hormone ID NEUROENDOCRINE CARCINOMA; ARGININE VASOPRESSIN; ESTHESIONEUROBLASTOMA; SIADH AB Objective. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported as a paraneoplastic syndrome in many different types of malignancies. Several case reports of SIADH have been reported in patients with olfactory neuroblastoma (ONB), but the exact incidence is unknown. The purpose of this study was to review our experience with olfactory neuroblastoma and to identify all patients who had a history of SIADH prior to the diagnosis of ONB. Study Design. Case series and chart review Setting. Tertiary care university-affiliated medical center. Subjects and Methods. A total of 21 patients presented to our institution with ONB between 1997 and 2009. All records were reviewed for a history of preoperative hyponatremia or SIADH. Results. Three patients were identified who had a history of SIADH prior to the diagnosis of ONB. Immunohistochemical staining of the tumor specimens from the 3 patients with SIADH was positive for arginine vasopressin. SIADH resolved in all 3 patients after successful treatment of ONB. Conclusion. Although uncommon, SIADH can be the presenting symptom of ONB and should be considered during the workup for idiopathic SIADH. C1 [Gray, Stacey T.; Holbrook, Eric H.; Sadow, Peter M.; Lin, Derrick T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Gray, Stacey T.; Holbrook, Eric H.; Sadow, Peter M.; Curry, William T.] Harvard Univ, Sch Med, Boston, MA USA. [Najm, Mohammed H.] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Curry, William T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Gray, ST (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Stacey_gray@meei.harvard.edu NR 28 TC 4 Z9 6 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2012 VL 147 IS 1 BP 147 EP 151 DI 10.1177/0194599812438842 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 080TZ UT WOS:000314267600025 PM 22368044 ER PT J AU Holowka, DW Wolf, EJ Marx, BP Foley, KM Kaloupek, DG Keane, TM AF Holowka, Darren W. Wolf, Erika J. Marx, Brian P. Foley, Kristen M. Kaloupek, Danny G. Keane, Terence M. TI Associations Among Personality, Combat Exposure and Wartime Atrocities SO PSYCHOLOGY OF VIOLENCE LA English DT Article DE personality; combat exposure; aggression; abusive violence; atrocities ID POSTTRAUMATIC-STRESS-DISORDER; VETERANS; VIOLENCE; AGGRESSION; VIETNAM; PTSD; SEVERITY; BEHAVIOR; TRAUMA; PREVALENCE AB Objective: The commission of wartime atrocities is a phenomenon known to occur among military personnel deployed to war zones. Although some research has examined the psychological sequelae to these events, there is virtually no research on the causes or correlates of such behavior. The present study examined associations among personality variables, combat exposure, and witnessing or participating in wartime atrocities during the Vietnam War. Method: One thousand one hundred and four Army and Marine veterans of the Vietnam War completed self-report measures that assessed personality, combat exposure, and participation in atrocities. Structural equation modeling was used to test a model in which combat exposure mediated the association between personality and participation in atrocities. Results: Combat exposure was strongly associated with self-reported participation in atrocities and fully mediated the association between trait aggression and participation in atrocities. Combat exposure was also shown to partially mediate the association between trait neuroticism and atrocities but evidenced no relationship with trait disconstraint. Disconstraint showed only a direct association with participation in atrocities. Conclusions: Personality and exposure to heavy combat should be considered not only risk factors for physical or mental illness, but also important risk factors for the commission of atrocities. Longitudinal research on risk factors for the commission of atrocities is needed, with a focus on those service members tasked with more dangerous assignments. Military commanders may wish to pay close attention to units under greater combat stress and to continue to devote resources to screening and treatment of members of these units. C1 [Holowka, Darren W.; Wolf, Erika J.; Marx, Brian P.; Foley, Kristen M.; Kaloupek, Danny G.; Keane, Terence M.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Boston, MA 02130 USA. [Holowka, Darren W.; Wolf, Erika J.; Marx, Brian P.; Kaloupek, Danny G.; Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 4, Boston, MA 02130 USA. EM brian.marx@va.gov OI Kaloupek, Danny/0000-0002-0795-593X; Wolf, Erika/0000-0003-2666-2435 NR 45 TC 4 Z9 4 U1 0 U2 9 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 2152-0828 J9 PSYCHOL VIOLENCE JI Psychol. Violence PD JUL PY 2012 VL 2 IS 3 BP 260 EP 272 DI 10.1037/a0026903 PG 13 WC Psychology, Clinical; Criminology & Penology; Family Studies SC Psychology; Criminology & Penology; Family Studies GA 087EY UT WOS:000314745300004 ER PT J AU Manchikanti, L Abdi, S Atluri, S Balog, CC Benyamin, RM Boswell, MV Brown, KR Bruel, BM Bryce, DA Burks, PA Burton, AW Calodney, AK Caraway, DL Cash, KA Christo, PJ Damron, KS Datta, S Deer, TR Diwan, S Eriator, I Falco, FJE Fellows, B Geffert, S Gharibo, CG Glaser, SE Grider, JS Hameed, H Hameed, M Hansen, H Harned, ME Hayek, SM Helm, S Hirsch, JA Janata, JW Kaye, AM Kaye, AD Kloth, DS Koyyalagunta, D Lee, M Malla, Y Manchikanti, KN McManus, CD Pampati, V Parr, AT Pasupuleti, R Patel, VB Sehgal, N Silverman, SM Singh, V Smith, HS Snook, LT Solanki, DR Tracy, DH Vallejo, R Wargo, BW AF Manchikanti, Laxmaiah Abdi, Salahadin Atluri, Sairam Balog, Carl C. Benyamin, Ramsin M. Boswell, Mark V. Brown, Keith R. Bruel, Brian M. Bryce, David A. Burks, Patricia A. Burton, Allen W. Calodney, Aaron K. Caraway, David L. Cash, Kimberly A. Christo, Paul J. Damron, Kim S. Datta, Sukdeb Deer, Timothy R. Diwan, Sudhir Eriator, Ike Falco, Frank J. E. Fellows, Bert Geffert, Stephanie Gharibo, Christopher G. Glaser, Scott E. Grider, Jay S. Hameed, Haroon Hameed, Mariam Hansen, Hans Harned, Michael E. Hayek, Salim M. Helm, Standiford, II Hirsch, Joshua A. Janata, Jeffrey W. Kaye, Adam M. Kaye, Alan D. Kloth, David S. Koyyalagunta, Dhanalakshmi Lee, Marion Malla, Yogesh Manchikanti, Kavita N. McManus, Carla D. Pampati, Vidyasagar Parr, Allan T. Pasupuleti, Ramarao Patel, Vikram B. Sehgal, Nalini Silverman, Sanford M. Singh, Vijay Smith, Howard S. Snook, Lee T. Solanki, Daneshvari R. Tracy, Deborah H. Vallejo, Ricardo Wargo, Bradley W. CA Amer Soc Interventional Pain Phys TI American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part I - Evidence Assessment SO PAIN PHYSICIAN LA English DT Article DE Chronic pain; persistent pain; non-cancer pain; controlled substances; substance abuse; prescription drug abuse; dependency; opioids; prescription monitoring; drug testing; adherence monitoring; diversion ID LOW-BACK-PAIN; CHRONIC NONMALIGNANT PAIN; CONTROLLED-RELEASE OXYCODONE; PLACEBO-CONTROLLED-TRIAL; ACTIVE-CONTROLLED-TRIAL; EVIDENCE-BASED MEDICINE; QUALITY-OF-LIFE; INTERLAMINAR EPIDURAL INJECTIONS; RANDOMIZED CONTROLLED-TRIAL; DRUG-MONITORING PROGRAMS AB Background: Opioid abuse has continued to increase at an alarming rate since the 1990s. As documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration, available evidence suggests a wide variance in chronic opioid therapy of 90 days or longer in chronic non-cancer pain. Part 1 describes evidence assessment. Objectives: The objectives of opioid guidelines as issued by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to produce consistency in the application of an opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. The focus of these guidelines is to curtail the abuse of opioids without jeopardizing non-cancer pain management with opioids. Results: 1) There is good evidence that non-medical use of opioids is extensive; one-third of chronic pain patients may not use prescribed opioids as prescribed or may abuse them, and illicit drug use is significantly higher in these patients. 2) There is good evidence that opioid prescriptions are increasing rapidly, as the majority of prescriptions are from non-pain physicians, many patients are on long-acting opioids, and many patients are provided with combinations of long-acting and short-acting opioids. 3) There is good evidence that the increased supply of opioids, use of high dose opioids, doctor shoppers, and patients with multiple comorbid factors contribute to the majority of the fatalities. 4) There is fair evidence that long-acting opioids and a combination of long-acting and short-acting opioids contribute to increasing fatalities and that even low-doses of 40 mg or 50 mg of daily morphine equivalent doses may be responsible for emergency room admissions with overdoses and deaths. 5) There is good evidence that approximately 60% of fatalities originate from opioids prescribed within the guidelines, with approximately 40% of fatalities occurring in 10% of drug abusers. 6) The short-term effectiveness of opioids is fair, whereas the long-term effectiveness of opioids is limited due to a lack of long-term (>3 months) high quality studies, with fair evidence with no significant difference between long-acting and short-acting opioids. 7) Among the individual drugs, most opioids have fair evidence for short-term and limited evidence for long-term due to a lack of quality studies. 8) The evidence for the effectiveness and safety of chronic opioid therapy in the elderly for chronic non-cancer pain is fair for short-term and limited for long-term due to lack of high quality studies; limited in children and adolescents and patients with comorbid psychological disorders due to lack of quality studies; and the evidence is poor in pregnant women. 9) There is limited evidence for reliability and accuracy of screening tests for opioid abuse due to lack of high quality studies. 10) There is fair evidence to support the identification of patients who are non-compliant or abusing prescription drugs or illicit drugs through urine drug testing and prescription drug monitoring programs, both of which can reduce prescription drug abuse or doctor shopping. Disclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care." C1 [Manchikanti, Laxmaiah; Burks, Patricia A.; Cash, Kimberly A.; Damron, Kim S.; Malla, Yogesh; McManus, Carla D.; Pampati, Vidyasagar] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Abdi, Salahadin] Beth Israel Deaconess Med Ctr, Div Pain Med, Brookline, MA USA. [Abdi, Salahadin; Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Atluri, Sairam] Tristate Spine Care Inst, Cincinnati, OH USA. [Balog, Carl C.] Oregon Pain Associates, Portland, OR USA. [Benyamin, Ramsin M.; Vallejo, Ricardo] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Coll Med, Urbana, IL 61801 USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Brown, Keith R.] Murray Calloway Cty Hosp, Murray, KY USA. [Bruel, Brian M.] Univ Texas SW Med Ctr Dallas, UTSW Spine Ctr, McDermott Ctr Pain Management, Dept Phys Med & Rehabil, Dallas, TX 75390 USA. [Bruel, Brian M.] Univ Texas SW Med Ctr Dallas, UTSW Spine Ctr, McDermott Ctr Pain Management, Dept Anesthesiol & Pain Management, Dallas, TX 75390 USA. [Bryce, David A.] Adv Pain Management, Madison, WI USA. [Burton, Allen W.] Univ Texas MD Anderson Canc Ctr, Dept Pain Med, Houston, TX 77030 USA. [Calodney, Aaron K.] NeuroCare Network, Tyler, TX USA. [Caraway, David L.] St Marys Pain Relief Ctr, Huntington, WV USA. [Christo, Paul J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Christo, Paul J.] Blaustein Pain Treatment Ctr, Div Pain Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Datta, Sukdeb] Laser Spine & Pain Inst, New York, NY USA. [Deer, Timothy R.] Ctr Pain Relief, Charleston, WV USA. [Diwan, Sudhir] Spine & Pain Inst New York, New York, NY USA. [Eriator, Ike] Jackson State Univ, Jackson, MS USA. [Eriator, Ike] Univ Mississippi, Med Ctr, Pain Program, Jackson, MS 39216 USA. [Falco, Frank J. E.; Geffert, Stephanie] Mid Atlantic Spine & Pain Phys Newark, Newark, DE USA. [Falco, Frank J. E.; Geffert, Stephanie] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Falco, Frank J. E.] Temple Univ, Sch Med, Dept PM&R, Philadelphia, PA 19122 USA. [Fellows, Bert] Pain Management Ctr Paducah, Psychol Serv, Paducah, KY USA. [Gharibo, Christopher G.] NYU Sch Med, NYU Langone Hosp Joint Dis, Dept Anesthesiol, New York, NY USA. [Glaser, Scott E.] Pain Specialists Greater Chicago, Burr Ridge, IL USA. [Grider, Jay S.] UK Healthcare Pain Serv, Lexington, KY USA. [Grider, Jay S.] Univ Kentucky, Dept Anesthesiol, Lexington, KY USA. [Hameed, Haroon; Hameed, Mariam] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. [Hansen, Hans] Pain Relief Ctr, Conover, NC USA. [Harned, Michael E.] Univ Kentucky, Div Pain Med, Dept Anesthesiol, Lexington, KY USA. [Hayek, Salim M.] Univ Hosp Cleveland, Dept Anesthesiol, Cleveland, OH 44106 USA. [Hayek, Salim M.] Univ Hosp Cleveland, Div Pain Med, Cleveland, OH 44106 USA. [Helm, Standiford, II] Helm Ctr Pain Management, Laguna Hills, CA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Janata, Jeffrey W.] Case Western Reserve Univ, Univ Hosp Cleveland, Behav Med Program, Cleveland, OH 44106 USA. [Kaye, Adam M.] Univ Pacific, Thomas J Long Sch Pharm & Hlth Sci, Stockton, CA 95211 USA. [Kaye, Alan D.] LSU Hlth Sci Ctr, Dept Anesthesia, New Orleans, LA USA. [Kloth, David S.] Connecticut Pain Care, Danbury, CT USA. [Koyyalagunta, Dhanalakshmi] Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol & Pain Med, Pain Management Ctr, Houston, TX 77030 USA. [Lee, Marion] Ctr Pain Management, Tifton, GA USA. [Manchikanti, Kavita N.] Univ Kentucky, Lexington, KY USA. [Parr, Allan T.] Premier Pain Ctr, Covington, LA USA. [Pasupuleti, Ramarao] Ctr Pain Management, Bowling Green, KY USA. [Patel, Vikram B.] ACMI Pain Care, Algonquin, IL USA. [Sehgal, Nalini] Univ Wisconsin, Sch Med & Publ Hlth, Intervent Pain Program, Madison, WI USA. [Sehgal, Nalini] Dept Orthoped & Rehabil Med, Madison, WI USA. [Silverman, Sanford M.] Comprehens Pain Med, Pompano Beach, FL USA. [Singh, Vijay] Spine Pain Diagnost Associates, Niagara, WI USA. [Smith, Howard S.] Albany Med Coll, Dept Anesthesiol, Albany, NY 12208 USA. [Snook, Lee T.] Metropolitan Pain Management Consultants Inc, Sacramento, CA USA. [Solanki, Daneshvari R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Tracy, Deborah H.] Inst Intervent Pain Management, Brooksville, FL USA. [Vallejo, Ricardo] Illinois State Univ, Normal, IL 61761 USA. [Wargo, Bradley W.] Mary Greeley Med Ctr, McFarland Clin, Ames, IA USA. [Deer, Timothy R.] W Virginia Univ, Sch Med, Charleston, WV 25304 USA. RP Manchikanti, L (reprint author), ASIPP, 81 Lakeview Dr, Paducah, KY 42003 USA. EM drm@asipp.org; sabdi@bidmc.harvard.edu; saiatluri@gmail.com; drcsaba@com-cast.net; ramsin-benyamin@yahoo.com; mark.boswell@louis-ville.edu; krbrownrph@aol.com; bbru-el@mdanderson.org; tonys09@gmail.com; clinicaldirector@thepainmd.com; awburton@houstonpainassociates.com; aaroncalodney@me.com; carawaymd@aol.com; kcash@thepainmd.com; pchristo@jhmi.edu; kim@thepainmd.com; sdattamd@gmail.com; doctdeer@aol.com; sudhir.diwan63@gmail.com; ikeijen@yahoo.com; cssm01@aol.com; bert@thepainmd.com; sgeffert@midatlanticspine.com; Cgharibo@usa.net; sglaser@painchicago.com; jsgrid2@email.uky.edu; hha-meed1@jhmi.edu; mha-meed1@jhmi.edu; hans@hippocrates.org; mharned@me.com; Salim.hayek@uhhospitals.org; drhelm@thehelmcenter.com; hirsch@snisonline.org; jeffrey.janata@case.edu; akaye@pacific.edu; alankaye44@hotmail.com; dkmd@ctpaincare.com; dkoyyala@mdanderson.org; painanswers@aol.com; Yogesh@thepainmd.com; kavita.manchikanti@gmail.com; carla@thepainmd.com; sagar@thepainmd.com; alparr@alparr.com; rampasu-puleti@yahoo.com; vikpatel1@yahoo.com; Sehgal@rehab.wisc.edu; san-fordsilverman@cpmedicine.com; vj@wmpnet.net; lsnook@pain-mpmc.com; dsolanki@utmb.edu; tracypain@tampabay.rr.com; vallejo1019@yahoo.com; bwargo@pol.net FU American Society of Interventional Pain Physicians; Cephalon/Teva; BioDelivery Sciences International, Inc.; Mundipharma Research GmbH Co.; AstraZeneca; Theravance; Sucampo Pharmaceuticals; Purdue Pharma, LP FX There was no external funding in the preparation of this manuscript. Internal funding provided by the American Society of Interventional Pain Physicians was limited to travel and lodging expenses of the authors.; Dr. Benyamin is a clinical investigator with Epimed and receives research support from Cephalon/Teva, BioDelivery Sciences International, Inc., Mundipharma Research GmbH & Co., AstraZeneca, Purdue Pharma, LP, and Theravance.; Dr. Datta receives research support from Sucampo Pharmaceuticals and an honorarium from Smith and Nephew. NR 680 TC 86 Z9 87 U1 7 U2 42 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL PY 2012 VL 15 IS 3 SU S SI SI BP S1 EP S65 PG 65 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 083KD UT WOS:000314461300018 PM 22786448 ER PT J AU Manchikanti, L Abdi, S Atluri, S Balog, CC Benyamin, RM Boswell, MV Brown, KR Bruel, BM Bryce, DA Burks, PA Burton, AW Calodney, AK Caraway, DL Cash, KA Christo, PJ Damron, KS Datta, S Deer, TR Diwan, S Eriator, I Falco, FJE Fellows, B Geffert, S Gharibo, CG Glaser, SE Grider, JS Hameed, H Hameed, M Hansen, H Harned, ME Hayek, SM Helm, S Hirsch, JA Janata, JW Kaye, AM Kaye, AD Kloth, DS Koyyalagunta, D Lee, M Malla, Y Manchikanti, KN McManus, CD Pampati, V Parr, AT Pasupuleti, R Patel, VB Sehgal, N Silverman, SM Singh, V Smith, HS Snook, LT Solanki, DR Tracy, DH Vallejo, R Wargo, BW AF Manchikanti, Laxmaiah Abdi, Salahadin Atluri, Sairam Balog, Carl C. Benyamin, Ramsin M. Boswell, Mark V. Brown, Keith R. Bruel, Brian M. Bryce, David A. Burks, Patricia A. Burton, Allen W. Calodney, Aaron K. Caraway, David L. Cash, Kimberly A. Christo, Paul J. Damron, Kim S. Datta, Sukdeb Deer, Timothy R. Diwan, Sudhir Eriator, Ike Falco, Frank J. E. Fellows, Bert Geffert, Stephanie Gharibo, Christopher G. Glaser, Scott E. Grider, Jay S. Hameed, Haroon Hameed, Mariam Hansen, Hans Harned, Michael E. Hayek, Salim M. Helm, Standiford, II Hirsch, Joshua A. Janata, Jeffrey W. Kaye, Adam M. Kaye, Alan D. Kloth, David S. Koyyalagunta, Dhanalakshmi Lee, Marion Malla, Yogesh Manchikanti, Kavita N. McManus, Carla D. Pampati, Vidyasagar Parr, Allan T. Pasupuleti, Ramarao Patel, Vikram B. Sehgal, Nalini Silverman, Sanford M. Singh, Vijay Smith, Howard S. Snook, Lee T. Solanki, Daneshvari R. Tracy, Deborah H. Vallejo, Ricardo Wargo, Bradley W. CA Amer Soc Interventional Pain Phys TI American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part 2-Guidance SO PAIN PHYSICIAN LA English DT Article DE Chronic pain; persistent pain; non-cancer pain; controlled substances; substance abuse; prescription drug abuse; dependency; opioids; prescription monitoring; drug testing; adherence monitoring; diversion ID LOW-BACK-PAIN; CAUDAL EPIDURAL INJECTIONS; CHRONIC NONMALIGNANT PAIN; ACTIVE-CONTROLLED-TRIAL; CHRONIC SPINAL PAIN; PRESCRIPTION MONITORING PROGRAMS; CLINICAL-PRACTICE GUIDELINE; RANDOMIZED CONTROLLED-TRIAL; TANDEM MASS-SPECTROMETRY; JOINT NERVE BLOCKS AB Results: Part 2 of the guidelines on responsible opioid prescribing provides the following recommendations for initiating and maintaining chronic opioid therapy of 90 days or longer. 1. A) Comprehensive assessment and documentation is recommended before initiating opioid therapy, including documentation of comprehensive history, general medical condition, psychosocial history, psychiatric status, and substance use history. (Evidence: good) B) Despite limited evidence for reliability and accuracy, screening for opioid use is recommended, as it will identify opioid abusers and reduce opioid abuse. (Evidence: limited) C) Prescription monitoring programs must be implemented, as they provide data on patterns of prescription usage, reduce prescription drug abuse or doctor shopping. (Evidence: good to fair) D) Urine drug testing (UDT) must be implemented from initiation along with subsequent adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. (Evidence: good) 2. A) Establish appropriate physical diagnosis and psychological diagnosis if available prior to initiating opioid therapy. (Evidence: good) B) Caution must be exercised in ordering various imaging and other evaluations, interpretation and communication with the patient; to avoid increased fear, activity restriction, requests for increased opioids, and maladaptive behaviors. (Evidence: good) C) Stratify patients into one of the 3 risk categories - low, medium, or high risk. D) A pain management consultation, may assist non-pain physicians, if high-dose opioid therapy is utilized. (Evidence: fair) 3. Essential to establish medical necessity prior to initiation or maintenance of opioid therapy. (Evidence: good) 4. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: good) 5. A) Long-acting opioids in high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids, as there is no significant difference between long-acting and short-acting opioids for their effectiveness or adverse effects. (Evidence: fair) B) The relative and absolute contraindications to opioid use in chronic non-cancer pain must be evaluated including respiratory instability, acute psychiatric instability, uncontrolled suicide risk, active or history of alcohol or substance abuse, confirmed allergy to opioid agents, coadministration of drugs capable of inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of controlled substances, and concomitant use of heavy doses of central nervous system depressants. (Evidence: fair to limited) 6. A robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion. (Evidence: fair) 7. A) Once medical necessity is established, opioid therapy may be initiated with low doses and short-acting drugs with appropriate monitoring to provide effective relief and avoid side effects. (Evidence: fair for short-term effectiveness, limited for long-term effectiveness) B) Up to 40 mg of morphine equivalent is considered as low dose, 41 to 90 mg of morphine equivalent as a moderate dose, and greater than 91 mg of morphine equivalence as high dose. (Evidence: fair) C) In reference to long-acting opioids, titration must be carried out with caution and overdose and misuse must be avoided. (Evidence: good) 8. A) Methadone is recommended for use in late stages after failure of other opioid therapy and only by clinicians with specific training in the risks and uses. (Evidence: limited) B) Monitoring recommendation for methadone prescription is that an electrocardiogram should be obtained prior to initiation, at 30 days and yearly thereafter. (Evidence: fair) 9. In order to reduce prescription drug abuse and doctor shopping, adherence monitoring by UDT and PMDPs provide evidence that is essential to the identification of those patients who are non-compliant or abusing prescription drugs or illicit drugs. (Evidence: fair) 10. Constipation must be closely monitored and a bowel regimen be initiated as soon as deemed necessary. (Evidence: good) 11. Chronic opioid therapy may be continued, with continuous adherence monitoring, in well-selected populations, in conjunction with or after failure of other modalities of treatments with improvement in physical and functional status and minimal adverse effects. (Evidence: fair) Disclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care." C1 [Manchikanti, Laxmaiah; Burks, Patricia A.; Cash, Kimberly A.; Damron, Kim S.; Malla, Yogesh; McManus, Carla D.; Pampati, Vidyasagar] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Abdi, Salahadin] Beth Israel Deaconess Med Ctr, Div Pain Med, Brookline, MA USA. [Abdi, Salahadin; Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Atluri, Sairam] Tristate Spine Care Inst, Cincinnati, OH USA. [Balog, Carl C.] Oregon Pain Associates, Portland, OR USA. [Benyamin, Ramsin M.; Vallejo, Ricardo] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Coll Med, Urbana, IL 61801 USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Brown, Keith R.] Murray Calloway Cty Hosp, Murray, KY USA. [Bruel, Brian M.] Univ Texas SW Med Ctr Dallas, UTSW Spine Ctr, McDermott Ctr Pain Management, Dept Phys Med & Rehabil, Dallas, TX 75390 USA. [Bruel, Brian M.] Univ Texas SW Med Ctr Dallas, UTSW Spine Ctr, McDermott Ctr Pain Management, Dept Anesthesiol & Pain Management, Dallas, TX 75390 USA. [Bryce, David A.] Adv Pain Management, Madison, WI USA. [Burton, Allen W.] Univ Texas MD Anderson Canc Ctr, Dept Pain Med, Houston, TX 77030 USA. [Calodney, Aaron K.] NeuroCare Network, Tyler, TX USA. [Caraway, David L.] St Marys Pain Relief Ctr, Huntington, WV USA. [Christo, Paul J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Christo, Paul J.] Blaustein Pain Treatment Ctr, Div Pain Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Datta, Sukdeb] Laser Spine & Pain Inst, New York, NY USA. [Deer, Timothy R.] Ctr Pain Relief, Charleston, WV USA. [Diwan, Sudhir] Spine & Pain Inst New York, New York, NY USA. [Eriator, Ike] Jackson State Univ, Jackson, MS USA. [Eriator, Ike] Univ Mississippi, Med Ctr, Pain Program, Jackson, MS 39216 USA. [Falco, Frank J. E.; Geffert, Stephanie] Mid Atlantic Spine & Pain Phys Newark, Newark, DE USA. [Falco, Frank J. E.; Geffert, Stephanie] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Falco, Frank J. E.] Temple Univ, Sch Med, Dept PM&R, Philadelphia, PA 19122 USA. [Fellows, Bert] Pain Management Ctr Paducah, Psychol Serv, Paducah, KY USA. [Gharibo, Christopher G.] NYU Sch Med, NYU Langone Hosp Joint Dis, Dept Anesthesiol, New York, NY USA. [Glaser, Scott E.] Pain Specialists Greater Chicago, Burr Ridge, IL USA. [Grider, Jay S.] UK Healthcare Pain Serv, Lexington, KY USA. [Grider, Jay S.] Univ Kentucky, Dept Anesthesiol, Lexington, KY USA. [Hameed, Haroon; Hameed, Mariam] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. [Hansen, Hans] Pain Relief Ctr, Conover, NC USA. [Harned, Michael E.] Univ Kentucky, Dept Anesthesiol, Div Pain Med, Lexington, KY USA. [Hayek, Salim M.] Univ Hosp Cleveland, Dept Anesthesiol, Cleveland, OH 44106 USA. [Hayek, Salim M.] Univ Hosp Cleveland, Div Pain Med, Cleveland, OH 44106 USA. [Helm, Standiford, II] Helm Ctr Pain Management, Laguna Hills, CA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Janata, Jeffrey W.] Case Western Reserve Univ, Univ Hosp Cleveland, Behav Med Program, Cleveland, OH 44106 USA. [Kaye, Adam M.] Univ Pacific, Thomas J Long Sch Pharm & Hlth Sci, Stockton, CA 95211 USA. [Kaye, Alan D.] LSU Hlth Sci Ctr, Dept Anesthesia, New Orleans, LA USA. [Kloth, David S.] Connecticut Pain Care, Danbury, CT USA. [Koyyalagunta, Dhanalakshmi] Univ Texas MD Anderson Canc Ctr, Pain Management Ctr, Dept Anesthesiol & Pain Med, Houston, TX 77030 USA. [Lee, Marion] Ctr Pain Management, Tifton, GA USA. [Manchikanti, Kavita N.] Univ Kentucky, Lexington, KY USA. [Parr, Allan T.] Premier Pain Ctr, Covington, LA USA. [Pasupuleti, Ramarao] Ctr Pain Management, Bowling Green, KY USA. [Patel, Vikram B.] ACMI Pain Care, Algonquin, IL USA. [Sehgal, Nalini] Univ Wisconsin, Sch Med & Publ Hlth, Intervent Pain Program, Madison, WI USA. [Sehgal, Nalini] Dept Orthoped & Rehabil Med, Madison, WI USA. [Silverman, Sanford M.] Comprehens Pain Med, Pompano Beach, FL USA. [Singh, Vijay] Spine Pain Diagnost Associates, Niagara, WI USA. [Smith, Howard S.] Albany Med Coll, Dept Anesthesiol, Albany, NY 12208 USA. [Snook, Lee T.] Metropolitan Pain Management Consultants Inc, Sacramento, CA USA. [Solanki, Daneshvari R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Tracy, Deborah H.] Inst Intervent Pain Management, Brooksville, FL USA. [Vallejo, Ricardo] Illinois State Univ, Normal, IL 61761 USA. [Wargo, Bradley W.] Mary Greeley Med Ctr, McFarland Clin, Ames, IA USA. [Deer, Timothy R.] W Virginia Univ, Sch Med, Charleston, WV 25304 USA. RP Manchikanti, L (reprint author), ASIPP, 81 Lakeview Dr, Paducah, KY 42003 USA. EM drm@asipp.org; sabdi@bidmc.harvard.edu; saiatluri@gmail.com; drcsaba@com-cast.net; ramsin-benyamin@yahoo.com; mark.boswell@louis-ville.edu; krbrownrph@aol.com; bbru-el@mdanderson.org; tonys09@gmail.com; clinicaldirector@thepainmd.com; awburton@houstonpainassociates.com; aaroncalodney@me.com; carawaymd@aol.com; kcash@thepainmd.com; pchristo@jhmi.edu; kim@thepainmd.com; sdattamd@gmail.com; doctdeer@aol.com; sudhir.diwan63@gmail.com; ikeijen@yahoo.com; cssm01@aol.com; bert@thepainmd.com; sgeffert@midatlanticspine.com; Cgharibo@usa.net; sglaser@painchicago.com; jsgrid2@email.uky.edu; hha-meed1@jhmi.edu; mha-meed1@jhmi.edu; hans@hippocrates.org; mharned@me.com; Salim.hayek@uh-hospitals.org; drhelm@thehelmcenter.com; hirsch@snisonline.org; jeffrey.janata@case.edu; akaye@pacific.edu; alankaye44@hotmail.com; dkmd@ctpaincare.com; dkoyyala@mdanderson.org; painanswers@aol.com; Yogesh@thepainmd.com; kavita.manchikanti@gmail.com; carla@thepainmd.com; sagar@thepainmd.com; alparr@alparr.com; rampasu-puleti@yahoo.com; vikpatel1@yahoo.com; Sehgal@rehab.wisc.edu; san-fordsilverman@cpmedicine.com; vj@wmpnet.net; lsnook@pain-mpmc.com; dsolanki@utmb.edu; tracypain@tampabay.rr.com; vallejo1019@yahoo.com; bwargo@pol.net FU American Society of Interventional Pain Physicians; Cephalon/Teva; BioDelivery Sciences International, Inc.; Mundipharma Research GmbH Co.; AstraZeneca; Purdue Pharma, LP; Theravance; Sucampo Pharmaceuticals FX There was no external funding in the preparation of this manuscript. Internal funding provided by the American Society of Interventional Pain Physicians was limited to travel and lodging expenses of the authors.; Dr. Benyamin is a clinical investigator with Epimed and receives research support from Cephalon/Teva, BioDelivery Sciences International, Inc., Mundipharma Research GmbH & Co., AstraZeneca, Purdue Pharma, LP, and Theravance.; Dr. Datta receives research support from Sucampo Pharmaceuticals and an honorarium from Smith and Nephew. NR 484 TC 150 Z9 153 U1 7 U2 40 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL PY 2012 VL 15 IS 3 SU S SI SI BP S67 EP S116 PG 50 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 083KD UT WOS:000314461300019 PM 22786449 ER PT J AU Kato, K Yonetsu, T Kim, SJ Xing, L Lee, H McNulty, I Yeh, RW Sakhuja, R Zhang, SS Uemura, S Yu, B Mizuno, K Jang, IK AF Kato, Koji Yonetsu, Taishi Kim, Soo-Joong Xing, Lei Lee, Hang McNulty, Iris Yeh, Robert W. Sakhuja, Rahul Zhang, Shaosong Uemura, Shiro Yu, Bo Mizuno, Kyoichi Jang, Ik-Kyung TI Nonculprit Plaques in Patients With Acute Coronary Syndromes Have More Vulnerable Features Compared With Those With Non-Acute Coronary Syndromes A 3-Vessel Optical Coherence Tomography Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerosis; coronary disease; imaging; plaque ID ACUTE MYOCARDIAL-INFARCTION; INTRAVASCULAR ULTRASOUND ANALYSIS; ELUTING STENT IMPLANTATION; THIN-CAP FIBROATHEROMA; TREATMENT PANEL-III; ATHEROSCLEROTIC PLAQUES; ARTERY-DISEASE; STABLE ANGINA; RUPTURE; NEOVASCULARIZATION AB Background-Patients with acute coronary syndrome (ACS) have a higher incidence of recurrent ischemic events. The aim of this study was to compare the plaque characteristics of nonculprit lesions between ACS and non-ACS patients using optical coherence tomography (OCT) imaging. Methods and Results-Patients who had 3-vessel OCT imaging were selected from the Massachusetts General Hospital (MGH) OCT Registry. MGH registry is a multicenter registry of patients undergoing OCT. The prevalence and characteristics of nonculprit plaques were compared between ACS and non-ACS patients. A total of 248 nonculprit plaques were found in 104 patients: 45 plaques in 17 ACS patients and 203 plaques in 87 non-ACS patients. Compared with plaques of non-ACS patients, plaques of ACS patients had a wider lipid arc (147.3 +/- 29.5 degrees versus 116.2 +/- 33.7, P< 0.001), a longer lipid length (10.7 +/- 5.9 mm versus 7.0 +/- 3.7 mm, P= 0.002), a larger lipid volume index [ averaged lipid arcxlipid length] (1605.5 +/- 1013.1 versus 853.4 +/- 570.8, P< 0.001), and a thinner fibrous cap (70.2 +/- 20.2 mu m versus 103.3 +/- 46.8 mu m, P< 0.001). Moreover, thin-cap fibroatheroma (64.7% versus 14.9%, P< 0.001), macrophage (82.4% versus 37.9%, P= 0.001), and thrombus (29.4% versus 1.1%, P< 0.001) were more frequent in ACS patients. Although the prevalence of microchannel did not differ between the groups, the closest distance from the lumen to microchannel was shorter in ACS subjects than in non-ACS (104.6 +/- 67.0 mu m versus 198.3 +/- 133.0 mu m, P= 0.027). Conclusions-Nonculprit lesions in patients with ACS have more vulnerable plaque characteristics compared with those with non-ACS. Neovascularization was more frequently located close to the lumen in patients with ACS. (Circ Cardiovasc Imaging. 2012; 5: 433-440.) C1 [Kato, Koji; Yonetsu, Taishi; Xing, Lei; McNulty, Iris; Yeh, Robert W.; Jang, Ik-Kyung] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lee, Hang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Kim, Soo-Joong] Kyung Hee Univ, Coll Med, Dept Cardiol, Seoul, South Korea. [Sakhuja, Rahul] Wellmont CVA Heart Inst, Kingsport, TN USA. [Zhang, Shaosong] LightLab Imaging Inc, St Jude Med, Westford, MA USA. [Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Educ Minist Myocardial Ischemia Mech & Treatment, Dept Cardiol,Key Labs, Harbin 150086, Peoples R China. [Mizuno, Kyoichi] Nippon Med Sch, Dept Med, Div Cardiol Hepatol Geriatr & Integrated Med, Tokyo 113, Japan. RP Jang, IK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM ijang@partners.org FU LightLab Imaging/St Jude Medical; St Jude Medical; Cardiology Division of Massachusetts General Hospital; Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad FX Dr Jang received a research grant and consulting fee from LightLab Imaging/St Jude Medical. This study was supported by research grants from St Jude Medical, the Cardiology Division of Massachusetts General Hospital, and the Dr John Nam fellowship grant. Dr Kato received a grant from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad. NR 43 TC 63 Z9 69 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JUL PY 2012 VL 5 IS 4 BP 433 EP 440 DI 10.1161/CIRCIMAGING.112.973701 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 071FK UT WOS:000313573500008 PM 22679059 ER PT J AU Riegel, B Lee, CS Ratcliffe, SJ De Geest, S Potashnik, S Patey, M Sayers, SL Goldberg, LR Weintraub, WS AF Riegel, Barbara Lee, Christopher S. Ratcliffe, Sarah J. De Geest, Sabina Potashnik, Sheryl Patey, Megan Sayers, Steven L. Goldberg, Lee R. Weintraub, William S. TI Predictors of Objectively Measured Medication Nonadherence in Adults With Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; medication adherence; patient compliance; self-care; sleep; World Health Organization ID SELF-CARE; ADHERENCE; ASSOCIATION; MIXTURE; HEALTH; QUESTIONNAIRE; SLEEPINESS; REGIMENS; NUMBER; TRIAL AB Background-Medication nonadherence rates are high. The factors predicting nonadherence in heart failure remain unclear. Methods and Results-A sample of 202 adults with heart failure was enrolled from the northeastern United States and followed for 6 months. Specific aims were to describe the types of objectively measured medication adherence (eg, taking, timing, dosing, drug holidays) and to identify contributors to nonadherence 6 months after enrollment. Latent growth mixture modeling was used to identify distinct trajectories of adherence. Indicators of the 5 World Health Organization dimensions of adherence (socioeconomic, condition, therapy, patient, and healthcare system) were tested to identify contributors to nonadherence. Two distinct trajectories were identified and labeled persistent adherence (77.8%) and steep decline (22.3%). Three contributors to the steep decline in adherence were identified. Participants with lapses in attention (adjusted OR, 2.65; P=0.023), those with excessive daytime sleepiness (OR, 2.51; P=0.037), and those with >= 2 medication dosings per day (OR, 2.59; P=0.016) were more likely to have a steep decline in adherence over time than to have persistent adherence. Conclusions-Two distinct patterns of adherence were identified. Three potentially modifiable contributors to nonadherence have been identified. (Circ Heart Fail. 2012; 5: 430-436.) C1 [Riegel, Barbara] Univ Penn, Sch Nursing, Biobehav Res Ctr, Philadelphia, PA 19104 USA. [Lee, Christopher S.] Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97201 USA. [Ratcliffe, Sarah J.; Goldberg, Lee R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [De Geest, Sabina] Univ Basel, Inst Nursing Sci, Basel, Switzerland. [Sayers, Steven L.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Weintraub, William S.] Christiana Care Hlth Syst, Dept Cardiol, Newark, DE USA. RP Riegel, B (reprint author), Univ Penn, Sch Nursing, Biobehav Res Ctr, Claire M Fagin Hall,418 Curie Blvd, Philadelphia, PA 19104 USA. EM briegel@nursing.upenn.edu OI Goldberg, Lee/0000-0002-7906-9638 FU National Heart, Lung & Blood Institute [RO1 HL084394-01A1]; Philadelphia Veterans Affairs Medical Center, VISN 4 Mental Illness Research, Education, and Clinical Center (MIREC) FX This work was funded by the National Heart, Lung & Blood Institute (RO1 HL084394-01A1) and by the Philadelphia Veterans Affairs Medical Center, VISN 4 Mental Illness Research, Education, and Clinical Center (MIREC). NR 41 TC 24 Z9 25 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2012 VL 5 IS 4 BP 430 EP 436 DI 10.1161/CIRCHEARTFAILURE.111.965152 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071GJ UT WOS:000313578100012 PM 22647773 ER PT J AU Ambrogio, C Carmona, FJ Santamaria, D Gomez, G Lozano, M Mainardi, S Nieto, P Kocher, O Esteller, M Barbacid, M AF Ambrogio, C. Carmona, F. J. Santamaria, D. Gomez, G. Lozano, M. Mainardi, S. Nieto, P. Kocher, O. Esteller, M. Barbacid, M. TI Proffered Paper: Involvement of Epigenetics in the Early Stages of NSCLC Development SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Carmona, F. J.; Esteller, M.] IDIBELL, Barcelona, Spain. [Gomez, G.] CNIO, Struct Biol & Biocomp Programme, Madrid, Spain. [Lozano, M.] CNIO, Biotechnol Programme, Madrid, Spain. [Kocher, O.] BIDMC, Dept Pathol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 25 BP S6 EP S6 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500022 ER PT J AU Barretina, J Caponigro, G Stransky, N Venkatesan, K Margolin, AA Kim, S Wilson, CJ Lehar, J Kryukov, GV Murray, L Morrissey, MP Sellers, WR Schlegel, R Garraway, LA AF Barretina, J. Caponigro, G. Stransky, N. Venkatesan, K. Margolin, A. A. Kim, S. Wilson, C. J. Lehar, J. Kryukov, G. V. Murray, L. Morrissey, M. P. Sellers, W. R. Schlegel, R. Garraway, L. A. TI The Cancer Cell Line Encyclopedia - Using Preclinical Models to Predict Anticancer Drug Sensitivity SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Barretina, J.; Caponigro, G.; Venkatesan, K.; Wilson, C. J.; Lehar, J.; Morrissey, M. P.; Sellers, W. R.; Schlegel, R.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Stransky, N.; Margolin, A. A.; Kryukov, G. V.; Murray, L.; Garraway, L. A.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kim, S.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Garraway, L. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RI Morrissey, Michael/C-6792-2013 NR 0 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 22 BP S5 EP S6 PG 2 WC Oncology SC Oncology GA 063XX UT WOS:000313036500020 ER PT J AU Carracedo, A Leliaert, A Bhasin, M Ito, K Puigserver, P Haigis, M Maratos-Flier, E Richardson, A Schafer, ZT Pandolfi, PP AF Carracedo, A. Leliaert, A. Bhasin, M. Ito, K. Puigserver, P. Haigis, M. Maratos-Flier, E. Richardson, A. Schafer, Z. T. Pandolfi, P. P. TI Proffered Paper: Regulation of Cellular Metabolism by Cancer Genes - Implications in Breast Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Carracedo, A.] CIC BioGUNE, Bilbao, Spain. [Leliaert, A.; Schafer, Z. T.] Notre Dame Univ, Indiana, PA USA. [Bhasin, M.; Ito, K.; Maratos-Flier, E.; Pandolfi, P. P.] BIDMC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 81 BP S19 EP S19 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500073 ER PT J AU Costa, C Ebi, H Engelman, J AF Costa, C. Ebi, H. Engelman, J. TI Investigation of Role of Different PI3K Isoforms in Breast Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Costa, C.; Ebi, H.; Engelman, J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 647 BP S153 EP S153 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501139 ER PT J AU Dastur, A Benes, C AF Dastur, A. Benes, C. TI Study of the Response of Melanoma Lines to BRAF Inhibitors SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Dastur, A.; Benes, C.] Massachusetts Gen Hosp, Signal Transduct Canc Ctr, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 823 BP S197 EP S197 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501300 ER PT J AU Dinu, I Wang, X Pyne, S AF Dinu, I. Wang, X. Pyne, S. TI Linear Combination Test for Gene Set Analysis of a Continuous Phenotype SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Dinu, I.; Wang, X.] Univ Alberta, Edmonton, AB, Canada. [Pyne, S.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 1147 BP S275 EP S276 PG 2 WC Oncology SC Oncology GA 063XX UT WOS:000313036501587 ER PT J AU Garcia-Garcia, C Ibrahim, YH Serra, V Calvo, MT Aura, C Perez, J Rommel, C Tabernero, J Baselga, J Scaltriti, M AF Garcia-Garcia, C. Ibrahim, Y. H. Serra, V. Calvo, M. T. Aura, C. Perez, J. Rommel, C. Tabernero, J. Baselga, J. Scaltriti, M. TI Dual MTORC1/2 and HER2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-HER2 Therapy SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Garcia-Garcia, C.; Ibrahim, Y. H.; Serra, V.; Calvo, M. T.; Aura, C.; Perez, J.; Tabernero, J.] Vall dHebron Inst Oncol, Barcelona, Spain. [Rommel, C.] Intellikine Inc, La Jolla, CA USA. [Baselga, J.; Scaltriti, M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 804 BP S192 EP S192 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501281 ER PT J AU Garnett, M McDermott, U Heidorn, S Benes, C Edelman, E Futreal, A Ramaswamy, S Haber, D Stratton, M AF Garnett, M. McDermott, U. Heidorn, S. Benes, C. Edelman, E. Futreal, A. Ramaswamy, S. Haber, D. Stratton, M. TI Pharmacogenomic Profiling of Drugs in Cancer Cells Identifies Novel Biomarkers of Sensitivity SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Garnett, M.; McDermott, U.; Heidorn, S.; Futreal, A.; Stratton, M.] Wellcome Trust Sanger Inst, Cambridge, England. [Benes, C.; Edelman, E.; Ramaswamy, S.; Haber, D.] Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 853 BP S205 EP S205 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501330 ER PT J AU Ibrahim, Y Garcia, CG He, L Serra, V Anton, P Guzman, M Cozar, P Ellison, L Scaltriti, M Baslega, J AF Ibrahim, Y. Garcia Garcia, C. He, L. Serra, V. Anton, P. Guzman, M. Cozar, P. Ellison, L. Scaltriti, M. Baslega, J. TI PI3K Inhibition Sensitizes Patient-derived Tumor Graft Models of Triple Negative Breast Cancer to PARP Inhibition SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Ibrahim, Y.; Garcia Garcia, C.; Serra, V.; Anton, P.; Guzman, M.; Cozar, P.] Vall Hebron Inst Oncol, Barcelona, Spain. [He, L.; Ellison, L.; Scaltriti, M.; Baslega, J.] Mass Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 1044 BP S251 EP S252 PG 2 WC Oncology SC Oncology GA 063XX UT WOS:000313036501499 ER PT J AU Serra, V Rodon, J Aura, C Vivancos, A Stemke-Hale, K Hibshoosh, H Wang, Y Cajal, SRY Tabernero, J Baselga, J AF Serra, V. Rodon, J. Aura, C. Vivancos, A. Stemke-Hale, K. Hibshoosh, H. Wang, Y. Ramon y Cajal, S. Tabernero, J. Baselga, J. TI Evaluation of PTEN and PIK3Ca Status in Breast Cancer for Patient Selection - Cross-validation Between Institutions SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Serra, V.; Rodon, J.; Tabernero, J.] Vall dHebron Inst Oncol, Expt Therapeut Grp, Barcelona, Spain. [Aura, C.; Ramon y Cajal, S.] Vall dHebron Inst Oncol, Mol Pathol Lab, Barcelona, Spain. [Vivancos, A.] Vall dHebron Inst Oncol, Canc Genom Grp, Barcelona, Spain. [Stemke-Hale, K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hibshoosh, H.] Columbia Univ, New York, NY USA. [Wang, Y.] Affymetrix Inc, Assay Applicat & Prod Dev MIP, Santa Clara, CA USA. [Baselga, J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RI Stemke-Hale, Katherine/K-9113-2013 OI Stemke-Hale, Katherine/0000-0002-1231-4192 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 531 BP S126 EP S126 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501034 ER PT J AU Stratton, M Garnett, M Edelman, EJ Heidorn, S Futreal, PA Haber, D Ramaswamy, S McDermott, U Benes, C AF Stratton, M. Garnett, M. Edelman, E. J. Heidorn, S. Futreal, P. A. Haber, D. Ramaswamy, S. McDermott, U. Benes, C. TI The Genomics of Drug Sensitivity in Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Stratton, M.; Garnett, M.; Heidorn, S.; Futreal, P. A.; McDermott, U.] Wellcome Trust Sanger Inst, Canc Genome Project, Cambridge, England. [Edelman, E. J.; Haber, D.; Ramaswamy, S.; Benes, C.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Charlestown, MA USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 35 BP S8 EP S8 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036500031 ER PT J AU Tenbaum, SP Ordonez-Moran, P Puig, I Chicote, I Arques, O Vivancos, A Baselga, J Tabernero, J Munoz, A Palmer, HG AF Tenbaum, S. P. Ordonez-Moran, P. Puig, I. Chicote, I. Arques, O. Vivancos, A. Baselga, J. Tabernero, J. Munoz, A. Palmer, H. G. TI Beta-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 22nd Biennial Congress of the European-Association-for-Cancer-Research CY JUL 07-10, 2012 CL Barcelona, SPAIN SP European Assoc Canc Res C1 [Tenbaum, S. P.; Puig, I.; Chicote, I.; Arques, O.; Palmer, H. G.] Vall dHebron Inst Oncol VHIO, Stem Cells & Canc Lab, Barcelona, Spain. [Ordonez-Moran, P.] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, Lausanne, Switzerland. [Vivancos, A.] Vall dHebron Inst Oncol VHIO, Genom Canc Grp, Barcelona, Spain. [Baselga, J.] Harvard Univ, Sch Med, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA USA. [Tabernero, J.] Hosp Univ Vall dHebron, Dept Med Oncol, Barcelona, Spain. [Munoz, A.] Univ Autonoma Madrid, Consejo Super Invest Cient, Inst Invest Biomed Alberto Sols, Madrid, Spain. NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2012 VL 48 SU 5 MA 687 BP S162 EP S162 PG 1 WC Oncology SC Oncology GA 063XX UT WOS:000313036501174 ER PT J AU Suvak, MK Sege, CT Sloan, DM Shea, MT Yen, S Litz, BT AF Suvak, Michael K. Sege, Christopher T. Sloan, Denise M. Shea, M. Tracie Yen, Shirley Litz, Brett T. TI Emotional Processing in Borderline Personality Disorder SO PERSONALITY DISORDERS-THEORY RESEARCH AND TREATMENT LA English DT Article DE borderline personality disorder; emotion responding; psychophysiology; heart rate; electromyography AB This study examines whether individuals with borderline personality disorder (BPD) would exhibit augmented emotional responses to picture stimuli after being challenged with an ideographic interpersonal conflict script. Participants were 24 adults diagnosed with BPD, 23 adults diagnosed with obsessive-compulsive personality disorder (OCPD), and 28 normal controls. Participants viewed emotionally evocative pictures before and after listening to the interpersonal script while a variety of physiological measures were recorded. Findings indicated that the interpersonal script was effective in eliciting enduring emotional responses from the BPD group relative to the control groups. However, despite the effectiveness of the interpersonal challenge task, there were no group differences in emotional responding to the affect eliciting stimuli. The findings underscore the complexities involved in examining emotional dysregulation in BPD in a laboratory setting. C1 [Suvak, Michael K.; Sege, Christopher T.; Sloan, Denise M.; Litz, Brett T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Suvak, Michael K.] Suffolk Univ, Dept Psychol, Boston, MA 02108 USA. [Sloan, Denise M.; Litz, Brett T.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Shea, M. Tracie] Vet Affairs Med Ctr, Providence, RI USA. [Shea, M. Tracie; Yen, Shirley] Brown Univ, Sch Med, Dept Psychiat & Human Behav, Providence, RI 02912 USA. RP Sloan, DM (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-2,150 S Huntington Ave, Boston, MA 02130 USA. EM Denise.Sloan@va.gov OI Sloan, Denise/0000-0002-0962-478X FU NIMH NIH HHS [R21MH069444-03, R21 MH069444, R01 MH050850] NR 23 TC 6 Z9 6 U1 2 U2 9 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1949-2715 J9 PERSONAL DISORD JI Personal. Disord. PD JUL PY 2012 VL 3 IS 3 BP 273 EP 282 DI 10.1037/a0027331 PG 10 WC Psychology, Clinical SC Psychology GA 051ZJ UT WOS:000312167200005 PM 22449065 ER PT J AU Scalea, JR Cooper, M AF Scalea, Joseph R. Cooper, Matthew TI Surgical strategies for type II diabetes SO TRANSPLANTATION REVIEWS LA English DT Article ID ISLET-CELL TRANSPLANTATION; SUPER-OBESE PATIENTS; PANCREAS TRANSPLANTATION; BARIATRIC SURGERY; MINIATURE SWINE; KIDNEY TRANSPLANTATION; DUODENAL SWITCH; GASTRIC BYPASS; MELLITUS; DISEASE AB Diabetes mellitus type II (or type 2 diabetes; DM2) has multiple definitions but is generally considered to be a disease marked by insulin resistance and loss of beta cell function that develops in adulthood. Today, greater than 90% of patients with diabetes have DM2. When uncontrolled, DM2 may result in comorbidities such as cardiovascular disease, retinopathy, neuropathy, immune system dysfunction, and renal failure. Classically, treatment of type 2 diabetes has included dietary and lifestyle changes. Even with behavior modification and oral hypoglycemics, many patients are unable to maintain glycemic control. With a growing understanding of the hormonal signals involved in the pathogenesis of type 2 diabetes, there has been a shift in the therapeutic approach to this growing epidemic. Bariatric surgery has been shown to decrease the progression and potentially reverse the effects of diabetes in 80% to 90% of patients. In addition, bariatric operations are associated with sustained weight loss in contrast to nonsurgical options. The antidiabetic effect of batiatric operations is likely due to the improvement in the hormonal dysregulation associated with the development of diabetes. Many patients with diabetes, however, have irreparably damaged insulin production capabilities as well. In addition, it is well recognized that transplantation may be required for patients with severe loss of islet cell function. Surgery for type 2 diabetes, via bariatric procedures and transplantation, has become an important treatment modality for patients with advanced disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Scalea, Joseph R.; Cooper, Matthew] Univ Maryland, Dept Surg, Div Transplantat, Baltimore, MD 21201 USA. [Scalea, Joseph R.] Massachusetts Gen Hosp, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Scalea, JR (reprint author), Univ Maryland, Dept Surg, Div Transplantat, Baltimore, MD 21201 USA. EM jscalea@tbrc.mgh.harvard.edu NR 53 TC 4 Z9 4 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-470X J9 TRANSPLANT REV-ORLAN JI Transplant. Rev. PD JUL PY 2012 VL 26 IS 3 BP 177 EP 182 DI 10.1016/j.trre.2011.07.002 PG 6 WC Immunology; Transplantation SC Immunology; Transplantation GA 045NW UT WOS:000311704500001 PM 22115951 ER PT J AU Becker, SJE Makanji, HS Ring, D AF Becker, Stephanie J. E. Makanji, Heeren S. Ring, David TI Expected and Actual Improvement of Symptoms With Carpal Tunnel Release SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Disability; expectations; improvement after carpal tunnel release; satisfaction ID PATIENT PREOPERATIVE EXPECTATIONS; FUNCTIONAL OUTCOMES; SURGERY; SATISFACTION; ARTHROPLASTY; VALIDATION; LUMBAR; SCALE AB Purpose This study tested the null hypothesis that there is no difference between expected improvement and actual improvement of symptoms with carpal tunnel release (CTR). Secondary analyses addressed factors associated with both expected relief and actual relief of symptoms with carpal tunnel syndrome surgical release, predictors of arm-specific disability, and satisfaction with surgery. Methods Sixty-six employed, English-speaking adult patients requesting limited-incision open CTR for electrodiagnostically confirmed carpal tunnel syndrome completed questionnaires before and after surgery. Before surgery, patients completed a survey regarding demographic data, expected improvement of symptoms with surgery, expected return to work after surgery, and validated questionnaires assessing arm-specific disability, job burnout, depressive symptoms, catastrophic thinking, and pain anxiety. An average of 6 +/- 5 months (range, 40 d to 19 mo) after surgery, participants completed questionnaires regarding actual improvement of symptoms with surgery, actual return to work, satisfaction with surgery, and arm-specific disability. Results Patients' actual and expected improvements with CTR were similar, with the exception of sleep disturbance, which was an average 0.3 points better than patients expected on a 5-point Likert scale. Lower postoperative disability was associated with men, less catastrophic thinking, and greater actual improvement of weakness with CTR. Fifty-three percent of the variation in satisfaction with treatment was associated with single status, more education, and relief of pain, sleep disturbance, and tingling. Conclusions Actual relief of symptoms with CTR matched patients' expectations in an employed population. Satisfaction with treatment correlated with relief of symptoms. (J Hand Surg 2012;37A:1324-1329. Copyright (c) 2012 by the American Society for Surgery of the Hand. All rights reserved.) C1 [Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI Becker, Stephanie/N-5761-2014 NR 22 TC 6 Z9 6 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1324 EP 1329 DI 10.1016/j.jhsa.2012.03.039 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700004 PM 22721456 ER PT J AU Buijze, GA Jorgsholm, P Thomsen, NOB Bjorkman, A Besjakov, J Ring, D AF Buijze, Geert A. Jorgsholm, Peter Thomsen, Niels O. B. Bjoerkman, Anders Besjakov, Jack Ring, David TI Factors Associated With Arthroscopically Determined Scaphoid Fracture Displacement and Instability SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Scaphoid fracture; diagnosis of displacement; instability; computed tomography; wrist arthroscopy ID PERCUTANEOUS SCREW FIXATION; 3-DIMENSIONAL ANALYSIS; NONUNION; PATTERNS; IMMOBILIZATION; DEFORMITY; INJURIES; ANATOMY; WAIST; BONE AB Purpose To identify factors associated with arthroscopically diagnosed scaphoid fracture displacement and instability. Methods This was a secondary use of data from 2 prospective cohort studies. The studies included 58 consecutive adult patients with a scaphoid fracture who elected arthroscopy-assisted operative fracture treatment: some for displacement, some as part of a prospective protocol, and others to avoid a cast. All patients had preoperative computed tomography with reconstructions in planes defined by the long axis of the scaphoid. Results Arthroscopy revealed 38 unstable fractures (movement between fracture fragments; 66%), 27 of which were also displaced. All arthroscopically determined displaced fractures were unstable, and 11 of the 31 arthroscopically determined, nondisplaced fractures were unstable. There was a significant correlation between radiographic comminution (more than 2 fracture fragments) and arthroscopically determined displacement and instability. Conclusions Radiographic comminution is associated with displacement and instability as determined by arthroscopy. (J Hand Surg 2012;37A:1405-1410. Copyright (c) 2012 by the American Society for Surgery of the Hand. All rights reserved.) C1 [Ring, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Boston, MA 02114 USA. Lund Univ, Dept Hand Surg, Skane Univ Hosp, Malmo, Sweden. Lund Univ, Dept Radiol, Skane Univ Hosp, Malmo, Sweden. RP Ring, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 24 TC 2 Z9 2 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1405 EP 1410 DI 10.1016/j.jhsa.2012.04.005 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700016 PM 22633223 ER PT J AU Kaas, L Struijs, PAA Ring, D van Dijk, CN Eygendaal, D AF Kaas, Laurens Struijs, Peter A. A. Ring, David van Dijk, C. Niek Eygendaal, Denise TI Treatment of Mason Type II Radial Head Fractures Without Associated Fractures or Elbow Dislocation: A Systematic Review SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Review DE Elbow; fracture; radial head; review; trauma ID PARTIAL ARTICULAR FRACTURES; TERM-FOLLOW-UP; INTERNAL-FIXATION; OPEN REDUCTION; RELIABILITY; EXCISION; NECK AB Purpose There is no consensus as to the best treatment of Mason type II fractures without concomitant elbow fractures or dislocation. The aim of this systematic review was to compare the results of operative and nonoperative treatment of these injuries. Methods We systematically screened the databases of PubMed, EMBASE, and Cochrane Library until September 2011 for studies on nonoperative or operative treatment of Mason type II fractures. We defined successful treatment as an excellent or good result according to the Broberg and Morrey score, Mayo Elbow Performance Score, or Radin score. Exclusion criteria were duration of follow-up of less than 6 months, an improperly described therapy or combination of therapies, skeletal immaturity, and articles written in languages other than English. Results Among 717 studies, 9 retrospective case series (level IV) describing 224 patients satisfied our inclusion criteria. Nonoperative treatment was successful in 114 of 142 patients (80%) pooled from the studies (42% to 96% success in individual studies). Open reduction and internal fixation was successful in 76 of 82 patients (93%) (81% to 100% success in individual studies). Conclusions Only a few studies with a low level of evidence address the treatment of isolated, displaced, partial articular fractures. There is a need for sufficiently powered randomized, controlled trials. C1 Amphia Hosp, Dept Orthopaed Surg, Breda, Netherlands. Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1105 AZ Amsterdam, Netherlands. Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Kaas, L (reprint author), Bethaniepl 10, NL-3701 EM Zeist, Netherlands. EM laurenskaas@hotmail.com NR 27 TC 11 Z9 11 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1416 EP 1421 DI 10.1016/j.jhsa.2012.03.042 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700018 PM 22622090 ER PT J AU Bauer, AS Lawson, BK Bliss, RL Dyer, GSM AF Bauer, Andrea S. Lawson, Bryan K. Bliss, Robin L. Dyer, George S. M. TI Risk Factors for Posttraumatic Heterotopic Ossification of the Elbow: Case-Control Study SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Elbow fracture; heterotopic ossification ID FLOATING ELBOW; BONE; OUTCOMES; INJURY AB Purpose Heterotopic ossification (HO) is well-known after surgical repair of elbow fractures, but little is known about risk factors for its development in these patients. The purpose of this study was to define factors associated with development of HO. Methods We used a prospective fracture registry collected in 2 Level I trauma centers and medical chart review to examine all elbow fractures treated surgically between 2002 and 2009. We determined which of these patients developed HO with an impact on range of motion (Hastings class II and III). We conducted a matched case-control study to examine factors associated with risk of HO. We used conditional logistic regression to compare occurrences of risk factors between cases and controls, matched by fracture type, age, and sex. Results Our database contained 786 elbow fractures treated surgically. Of these, 55 developed clinically relevant HO. The risk of HO varied among types of elbow fractures, with combined olecranon and radial head fractures having no HO and floating elbows (fractures on both sides of the elbow joint) having the highest incidence of HO at 36%. In multiple conditional logistic regression, risk factors for the development of HO were days to surgery, with subjects waiting 8 or more days having 12 times the odds of HO than subjects having surgery within a day of injury, and time to postoperative mobilization, with subjects who had at least 15 days to mobilization having greater odds of HO than those who had less than 7 days to mobilization. Conclusions Heterotopic ossification of the elbow occurs frequently after surgical repair of elbow fractures, with an incidence of 7% in this registry. In the case-control sample, conditions associated with development of HO included longer time to surgery and longer time to mobilization after surgery. (J Hand Surg 2012;37A:1422-1429. Copyright (c) 2012 by the American Society for Surgery of the Hand. All rights reserved.) C1 [Dyer, George S. M.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02140 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Dyer, GSM (reprint author), Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02140 USA. EM gdyer@partners.org FU Brigham & Women's Hospital Department of Orthopaedic Surgery PRIDE program FX The authors would like to acknowledge the Brigham & Women's Hospital Department of Orthopaedic Surgery PRIDE program for funding statistical analysis of this project. NR 25 TC 18 Z9 21 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1422 EP 1429 DI 10.1016/j.jhsa.2012.03.013 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700019 PM 22551954 ER PT J AU Jupiter, JB Gruber, JS AF Jupiter, Jesse B. Gruber, Jillian S. TI Innovation and Innovators: Does It Take 10,000 Hours? SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID EXPERT PERFORMANCE; PLATE FIXATION; SURGERY; FRACTURES; CAPSULORRHAPHY; COMPLICATIONS; ACQUISITION; DEVICE C1 [Jupiter, Jesse B.; Gruber, Jillian S.] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Gruber, JS (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM jsgruber@partners.org NR 48 TC 0 Z9 0 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1447 EP 1452 DI 10.1016/j.jhsa.2012.03.041 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700022 PM 22652180 ER PT J AU Ring, D AF Ring, David TI Letter Regarding "Painful Corticosteroid Injections for Idiopathic Trigger Finger" Reply SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD JUL PY 2012 VL 37A IS 7 BP 1513 EP 1513 DI 10.1016/j.jhsa.2012.05.038 PG 1 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 031VN UT WOS:000310670700040 ER PT J AU Chacon, E Estruga, A Murias, G Sales, B Montanya, J Lucangelo, U Garcia-Esquirol, O Villagra, A Villar, J Kacmarek, RM Burgueno, MJ Blanch, L Jam, R AF Chacon, Encarna Estruga, Anna Murias, Gaston Sales, Bernat Montanya, Jaume Lucangelo, Umberto Garcia-Esquirol, Oscar Villagra, Ana Villar, Jesus Kacmarek, Robert M. Burgueno, Maria Jose Blanch, Lluis Jam, Rosa TI NURSES' DETECTION OF INEFFECTIVE INSPIRATORY EFFORTS DURING MECHANICAL VENTILATION SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID ASYNCHRONY AB Background Patient-ventilator dyssynchrony is common and may influence patients' outcomes. Detection of such dyssynchronies relies on careful observation of patients and airway flow and pressure measurements. Given the shortage of specialists, critical care nurses could be trained to identify dyssynchronies. Objective To evaluate the accuracy of specifically trained critical care nurses in detecting ineffective inspiratory efforts during expiration. Methods We compared 2 nurses' evaluations of measurements from 1007 breaths in 8 patients with the evaluations of experienced critical care physicians. Sensitivity, specificity, positive predictive value, negative predictive value, and the Cohen kappa for interobserver agreement were calculated. Results For the first nurse, sensitivity was 92.5%, specificity was 98.3%, positive predictive value was 95.4%, negative predictive value was 97.1%, and kappa was 0.92 (95% CI, 0.89-0.94). For the second nurse, sensitivity was 98.5%, specificity was 84.7%, positive predictive value was 70.7%, negative predictive value was 99.3%, and kappa was 0.74 (95% CI, 0.70-0.78). Conclusion Specifically trained nurses can reliably detect ineffective inspiratory efforts during expiration. (American Journal of Critical Care. 2012;21:e89-e93) C1 [Chacon, Encarna; Estruga, Anna; Garcia-Esquirol, Oscar; Villagra, Ana; Burgueno, Maria Jose; Blanch, Lluis; Jam, Rosa] Univ Autonoma Barcelona, Hosp Sabadell, Crit Care Ctr, Sabadell 08208, Spain. [Murias, Gaston] Clin Bazterrica, Buenos Aires, DF, Argentina. [Murias, Gaston] Clin Santa Isabel, Buenos Aires, DF, Argentina. [Sales, Bernat; Villagra, Ana; Blanch, Lluis] ISCIII, CIBER Enfermedades Resp, Madrid, Spain. [Sales, Bernat; Montanya, Jaume; Garcia-Esquirol, Oscar] Fundacio Parc Tauli, Sabadell, Spain. [Lucangelo, Umberto] Univ Trieste, Osped Cattinara, Dipartimento Med Perioperatoria Terapia Intens &, I-34127 Trieste, Italy. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. [Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Chacon, E (reprint author), Univ Autonoma Barcelona, Hosp Sabadell, Crit Care Ctr, Corporacio Sanitaria Univ Parc Tauli,Parc Tauli 1, Sabadell 08208, Spain. EM EChacon@tauli.cat FU Fundacio Parc Tauli; Caixa Sabadell; ISCIII [PI09/91074]; CIBERes; Plan Avanza [TSI-020302-2008-38]; MCYIN; MITYC (Spain) FX This work was partially funded by Fundacio Parc Tauli, Caixa Sabadell, ISCIII PI09/91074, CIBERes, Plan Avanza TSI-020302-2008-38, MCYIN and MITYC (Spain). Lluis Blanch, Bernat Sales, Oscar Garcia-Esquirol and Gaston Murias own actions of BetterCare S.L. NR 16 TC 5 Z9 5 U1 1 U2 4 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 J9 AM J CRIT CARE JI Am. J. Crit. Care PD JUL 1 PY 2012 VL 21 IS 4 BP E89 EP E93 DI 10.4037/ajcc2012108 PG 5 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 031LL UT WOS:000310641800001 PM 22751376 ER PT J AU Ackerman, KG Vargas, SO Wilson, JA Jennings, RW Kozakewich, HPW Pober, BR AF Ackerman, Kate G. Vargas, Sara O. Wilson, Jay A. Jennings, Russell W. Kozakewich, Harry P. W. Pober, Barbara R. TI Congenital Diaphragmatic Defects: Proposal for a New Classification Based on Observations in 234 Patients SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE Bochdalek; CDH; diaphragm; hernia; pulmonary hypoplasia; sac hernia ID HERNIA; MODELS; SIZE; FOG2 AB Congenital diaphragmatic defects (CDDs) are a common group of birth defects, yet we presently know little about their pathogenesis. No systematic study documenting the detailed morphology of CDD has been performed, and current classification schemata of diaphragm phenotypes incompletely capture the location and extent of diaphragmatic involvement. To define the range of CDD anatomy, diaphragmatic pathology was reviewed from an examination of 181 autopsy records of children with CDDs at Children's Hospital Boston between 1927 and 2006. Defects were classified according to several parameters, including type (communicating versus noncommunicating) and location (anterior, posterior, etc.). The information permitted development of a phenotyping worksheet for prospective use on patients undergoing diaphragmatic repair at Children's Hospital Boston or MassGeneral Hospital for Children. Fifty-three patients who died between 1990 and 2006 had a total of 63 defects. Thirty-nine had a "classic'' CDD phenotype (64% posterolateral, 18% hemidiaphragmatic aplasia, and 18% anterior). The remaining 19 defects, not fitting classical descriptions, were located in the posteromedial, anterolateral, or lateral regions of the diaphragm. Prospective data collected during surgical repair revealed posterolateral defects in 34 of 41 cases that demonstrated wide phenotypic variability in size, location, shape, type, and extent of organ displacement. Congenital diaphragmatic defects display significant phenotypic variation. Because rigorous anatomic evaluation and documentation are important steps towards elucidating the developmental biology of these disorders, we suggest establishment of a new and more precise classification using the model presented herein. C1 [Ackerman, Kate G.] Univ Rochester, Ctr Pediat Biomed Res, Rochester, NY 14627 USA. [Ackerman, Kate G.] Univ Rochester, Dept Biomed Genet, Rochester, NY USA. [Ackerman, Kate G.] Univ Rochester, Dept Pediat, Div Crit Care, Rochester, NY USA. [Vargas, Sara O.; Wilson, Jay A.; Jennings, Russell W.; Kozakewich, Harry P. W.; Pober, Barbara R.] Harvard Univ, Sch Med, Boston, MA USA. [Vargas, Sara O.; Kozakewich, Harry P. W.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wilson, Jay A.; Jennings, Russell W.; Pober, Barbara R.] Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Pober, Barbara R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Pober, Barbara R.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. RP Ackerman, KG (reprint author), Univ Rochester, Ctr Pediat Biomed Res, Rochester, NY 14627 USA. EM kate_ackerman@urmc.rochester.edu FU NHLBI NIH HHS [K08 HL076286, R01 HL085459]; NICHD NIH HHS [P01 HD068250] NR 21 TC 10 Z9 10 U1 1 U2 4 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD JUL-AUG PY 2012 VL 15 IS 4 BP 265 EP 274 DI 10.2350/11-05-1041-OA.1 PG 10 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 025TG UT WOS:000310216800002 PM 22257294 ER PT J AU Hoogerwerf, JJ van der Windt, GJW Blok, DC Hoogendijk, AJ de Vos, AF van 't Veer, C Florquin, S Kobayashi, KS Flavell, RA van der Poll, T AF Hoogerwerf, Jacobien J. van der Windt, Gerritje J. W. Blok, Dana C. Hoogendijk, Arie J. de Vos, Alex F. van 't Veer, Cornelis Florquin, Sandrine Kobayashi, Koichi S. Flavell, Richard A. van der Poll, Tom TI Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia SO MOLECULAR MEDICINE LA English DT Article ID TOLL-LIKE RECEPTOR-4; IRAK-M; INNATE IMMUNITY; PNEUMOCOCCAL PNEUMONIA; KLEBSIELLA-PNEUMONIAE; BACTERIAL PNEUMONIA; UP-REGULATION; LUNG; INFLAMMATION; INFECTION AB Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M-/-) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M-/- alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M-/- mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M-/- mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00450 C1 [Hoogerwerf, Jacobien J.; van der Windt, Gerritje J. W.; Blok, Dana C.; Hoogendijk, Arie J.; de Vos, Alex F.; van 't Veer, Cornelis; van der Poll, Tom] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, NL-1105 AZ Amsterdam, Netherlands. [Hoogerwerf, Jacobien J.; van der Windt, Gerritje J. W.; Blok, Dana C.; Hoogendijk, Arie J.; de Vos, Alex F.; van 't Veer, Cornelis; van der Poll, Tom] Univ Amsterdam, Acad Med Ctr, Ctr Expt & Mol Med, NL-1105 AZ Amsterdam, Netherlands. [Florquin, Sandrine] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands. [Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kobayashi, Koichi S.] Harvard Univ, Sch Med, Boston, MA USA. [Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. RP van der Poll, T (reprint author), Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Meibergdreef 9,Room G2-129, NL-1105 AZ Amsterdam, Netherlands. EM t.vanderpoll@amc.uva.nl RI Hoogendijk, Arie/G-3179-2015 FU Academic Medical Center, Amsterdam FX We thank Joost Daalhuisen, Marieke ten Brink and Regina de Beer for expert technical assistance. JJ Hoogerwerf, GJW van der Windt, DC Blok and AJ Hoogendijk were supported by institutional research grants from the Academic Medical Center, Amsterdam. RA Flavell is an Investigator of the Howard Hughes Medical Institute. NR 42 TC 14 Z9 14 U1 0 U2 0 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 EI 1528-3658 J9 MOL MED JI Mol. Med. PD JUL PY 2012 VL 18 IS 7 BP 1067 EP 1075 DI 10.2119/molmed.2011.00450 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 022GT UT WOS:000309946500003 PM 22729155 ER PT J AU Lv, HJ Lipes, MA AF Lv, HuiJuan Lipes, Myra A. TI Role of Impaired Central Tolerance to alpha-Myosin in Inflammatory Heart Disease SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID IDIOPATHIC DILATED CARDIOMYOPATHY; CARDIAC-MYOSIN; AUTOIMMUNE-DISEASE; CHAGAS-DISEASE; MYOCARDIAL-INFARCTION; TRYPANOSOMA-CRUZI; HUMAN THYMUS; MICE; EXPRESSION; CELLS AB For more than a half century, autoimmunity has been linked to a diverse array of heart diseases, including rheumatic carditis, myocarditis, Chagas' cardiomyopathy, post-myocardial infarction (Dressler's) syndrome, and idiopathic dilated cardiomyopathy. Why the heart is targeted by autoimmunity in these seemingly unrelated conditions has remained enigmatic. Here, we discuss our recent studies indicating that this susceptibility is mediated by impaired negative selection of autoreactive a-myosin heavy-chain-specific CD4(+) T cells in the thymus of both mice and humans. We describe how this process may place the heart at increased risk for autoimmune attack following ischemic or infectious injury, providing a rationale for the development of antigen-specific tolerogenic therapies. (Trends Cardiovasc Med 2012;22:113-117) (c) 2012 Elsevier Inc. All rights reserved. C1 [Lv, HuiJuan; Lipes, Myra A.] Harvard Univ, Joslin Diabet Ctr, Sch Med, Immunobiol Sect, Boston, MA 02215 USA. RP Lipes, MA (reprint author), Harvard Univ, Joslin Diabet Ctr, Sch Med, Immunobiol Sect, 1 Joslin Pl,Rm 373, Boston, MA 02215 USA. EM myra.lipes@joslin.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; Seaver Institute; and the American Diabetes Association; Juvenile Diabetes Research Foundation International FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; the Seaver Institute; and the American Diabetes Association (to M.A.L.). H.L. is the recipient of a Postdoctoral Fellowship Award from the Juvenile Diabetes Research Foundation International. NR 40 TC 7 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD JUL PY 2012 VL 22 IS 5 BP 113 EP 117 AR PII S1050-1738(12)00215-0 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 027XD UT WOS:000310386500001 PM 22902177 ER PT J AU Fan, XP Li, QG Pisarek-Horowitz, A Rasouly, HM Wang, XL Bonegio, RG Wang, H McLaughlin, M Mangos, S Kalluri, R Holzman, LB Drummond, IA Brown, D Salant, DJ Lu, WN AF Fan, Xueping Li, Qinggang Pisarek-Horowitz, Anna Rasouly, Hila Milo Wang, Xiangling Bonegio, Ramon G. Wang, Hang McLaughlin, Margaret Mangos, Steve Kalluri, Raghu Holzman, Lawrence B. Drummond, Iain A. Brown, Dennis Salant, David J. Lu, Weining TI Inhibitory Effects of Robo2 on Nephrin: A Crosstalk between Positive and Negative Signals Regulating Podocyte Structure SO CELL REPORTS LA English DT Article ID ACTIN CYTOSKELETON; ROUNDABOUT RECEPTOR; NEPHROTIC SYNDROME; SLIT-DIAPHRAGM; KIDNEY; MECHANISMS; POLYMERIZATION; EXPRESSION; PROTEINS; GUIDANCE AB Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture. C1 [Fan, Xueping; Li, Qinggang; Pisarek-Horowitz, Anna; Rasouly, Hila Milo; Wang, Xiangling; Bonegio, Ramon G.; Wang, Hang; Salant, David J.; Lu, Weining] Boston Univ, Renal Sect, Dept Med, Med Ctr, Boston, MA 02118 USA. [McLaughlin, Margaret; Mangos, Steve; Drummond, Iain A.; Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [McLaughlin, Margaret; Mangos, Steve; Drummond, Iain A.; Brown, Dennis] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Div Matrix Biol, Boston, MA 02115 USA. [Holzman, Lawrence B.] Univ Penn, Renal Electrolyte & Hypertens Div, Sch Med, Philadelphia, PA 19104 USA. RP Lu, WN (reprint author), Boston Univ, Renal Sect, Dept Med, Med Ctr, Boston, MA 02118 USA. EM wlu@bu.edu RI Kalluri, Raghu/E-2677-2015; OI Bonegio, Ramon/0000-0002-1286-141X; Salant, David/0000-0002-3866-3120; Kalluri, Raghu/0000-0002-2190-547X; Fan, Xueping/0000-0002-3715-6864; Lu, Weining/0000-0002-6570-3044 FU NIH [R01DK078226, R01DK30932]; March of Dimes Foundation [6-FY08-304] FX We thank Ms Juan Liu for technical assistance; Dr. Uta Grieshammer for providing Robo2 riboprobe plasmid; Drs. Herbert Cohen and William Andrews for providing Nphs1 and Robo2 cDNA; Drs. Dezhi Wang and Zhifeng Ren for help with EM facility; and Dr. Peleg Horowitz for critical reading of this manuscript. This work is supported by NIH grants R01DK078226 (to W. L.) and R01DK30932 (to D.J.S.), and is also supported in part by Research Grant #6-FY08-304 from the March of Dimes Foundation (to W.L.). NR 26 TC 19 Z9 20 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REPORTS JI Cell Reports PD JUL PY 2012 VL 2 IS 1 BP 52 EP 61 DI 10.1016/j.celrep.2012.06.002 PG 10 WC Cell Biology SC Cell Biology GA 019CF UT WOS:000309713900007 PM 22840396 ER PT J AU Yeh, DD Velmahos, GC AF Yeh, Daniel Dante Velmahos, George C. TI Prehospital intubation for traumatic brain injury: do it correctly, or not at all SO ANZ JOURNAL OF SURGERY LA English DT Article ID RAPID-SEQUENCE INTUBATION; NEUROMUSCULAR BLOCKING-AGENTS; HEAD-INJURY; CEREBRAL OXYGENATION; HEMORRHAGIC-SHOCK; HYPERVENTILATION; HYPOXIA; IMPACT; VENTILATION; HYPOVENTILATION C1 [Yeh, Daniel Dante; Velmahos, George C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Yeh, DD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. NR 26 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1445-1433 J9 ANZ J SURG JI ANZ J. Surg. PD JUL-AUG PY 2012 VL 82 IS 7-8 BP 484 EP 485 DI 10.1111/j.1445-2197.2012.06130.x PG 2 WC Surgery SC Surgery GA 984BN UT WOS:000307163500003 PM 22863220 ER PT J AU Bleier, BS Preena, D Schlosser, RJ Harvey, RJ AF Bleier, Benjamin S. Preena, Dhulshan Schlosser, Rodney J. Harvey, Richard J. TI Dose quantification of topical drug delivery to the paranasal sinuses by fluorescein luminosity calculation SO INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY LA English DT Article DE topical drug delivery; sinonasal irrigation; fluorescein luminosity; drug distribution ID IRRIGATION; SURGERY; SPRAY AB Background: Our group has previously described a novel method of objectively quantifying the temporospatial distribution of sinonasal irrigation in a nonanesthetized patient. The purpose of this study is to refine this technique to provide an accurate method of determining concentration of dose delivery as well. Methods: An endoscope at a fixed position within 2 dissected cadaveric heads was used to image 4 subsites under blue light. Each site was dosed with 3 mL of successively increasing concentrations of fluorescein-labeled saline. In vitro images of the labeled saline were also captured over a range of depths. Images were exported into a graphics editing program that was used to calculate luminosity at 3 regions per subsite. The relationship between luminosity and fluorescein concentration was calculated using a Pearson product-moment correlation coefficient. Significance was determined using a 2-tailed Student t test. Results: Luminosity of the irrigation delivered to the maxillary sinus, lamina papyracea, ethmoid roof, and frontal sinus positively correlated with fluorescein concentration over a range of 0.1 to 0.01 mg/mL (n = 6; r = 0.95, p < 0.001; r = 0.94, p < 0.001; r = 0.92, p < 0.001; and r= 0.94, p < 0.001; respectively). There was no significant difference between luminosities of a 0.01 mg/mL irrigation layer subtending a range of depths up to 6.6 mm. Conclusion: The described method is capable of determining the concentration of fluorescein delivery to a mucosal surface via objective luminosity quantification. Our data suggest that this method will remain accurate regardless of the potential for heterogeneous pooling of irrigation. This method may be used to optimize delivery strategies of a variety of topical sinonasal therapies. (C) 2012 ARS-AAOA, LLC. C1 [Bleier, Benjamin S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Preena, Dhulshan; Harvey, Richard J.] St Vincents Hosp, Dept Otolaryngol Skull Base Surg, Sydney, NSW 2010, Australia. [Schlosser, Rodney J.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Bleier, BS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM bleierb@gmail.com NR 6 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2042-6976 J9 INT FORUM ALLERGY RH JI Int. Forum Allergy Rhinol. PD JUL-AUG PY 2012 VL 2 IS 4 BP 316 EP 320 DI 10.1002/alr.21034 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 007ZR UT WOS:000308927400009 PM 22411746 ER PT J AU Saverno, KR Rochau, U Stenehjem, DD Morley, K Siebert, U Brixner, DI AF Saverno, Kim R. Rochau, Ursula Stenehjem, David D. Morley, Kimberly Siebert, Uwe Brixner, Diana I. TI Application of Decision-Analytic Models in Personalized Medicine for CML Treatment Decisions Made by Payers, Providers, and Patients SO JOURNAL OF MANAGED CARE PHARMACY LA English DT Editorial Material ID CHRONIC MYELOID-LEUKEMIA; QUALITY-OF-LIFE; TYROSINE KINASE INHIBITORS; INTERFERON-ALPHA; BREAST-CANCER; FOLLOW-UP; CLINICAL-EXCELLENCE; NATIONAL-INSTITUTE; COST-EFFECTIVENESS; IMATINIB C1 [Saverno, Kim R.; Brixner, Diana I.] Univ Utah, Dept Pharmacotherapy, Salt Lake City, UT 84112 USA. [Brixner, Diana I.] Univ Utah, Pharmacotherapy Outcomes Res Ctr, Salt Lake City, UT 84112 USA. [Brixner, Diana I.] Univ Utah, Coll Pharm, Salt Lake City, UT 84112 USA. [Brixner, Diana I.] Univ Utah, Personalized Hlth Care Program, Salt Lake City, UT 84112 USA. [Saverno, Kim R.] UMIT Univ Hlth Sci Med Informat & Technol, Inst Publ Hlth Med Decis Making & Hlth Technol As, Dept Publ Hlth & Hlth Technol Assessment, Hall In Tirol, Austria. [Rochau, Ursula; Siebert, Uwe] UMIT, Inst Publ Hlth Med Decis Making & Hlth Technol As, Dept Publ Hlth & Hlth Technol Assessment, Hall In Tirol, Austria. [Rochau, Ursula; Siebert, Uwe] ONCOTYROL Ctr Personalized Canc Med, Div Publ Hlth Decis Modelling Hlth Technol Assess, Innsbruck, Austria. [Morley, Kimberly] Univ Utah, Huntsman Canc Inst, Dept Internal Med, Sch Med, Salt Lake City, UT 84112 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment,Program Cardiovasc Res, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Brixner, DI (reprint author), Univ Utah, Dept Pharmacotherapy, 30 S 2000 E,Rm 258, Salt Lake City, UT 84112 USA. EM diana.brixner@utah.edu NR 64 TC 3 Z9 3 U1 0 U2 3 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 1083-4087 J9 J MANAGE CARE PHARM JI J. Manag. Care Pharm. PD JUL-AUG PY 2012 VL 18 IS 6 BP 457 EP 463 PG 7 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA 986CO UT WOS:000307318600006 PM 22839687 ER PT J AU Greaney, ML Sprunck-Harrild, K Bennett, GG Puleo, E Haines, J Viswanath, KV Emmons, KM AF Greaney, Mary L. Sprunck-Harrild, Kim Bennett, Gary G. Puleo, Elaine Haines, Jess Viswanath, K. Vish Emmons, Karen M. TI Use of Email and Telephone Prompts to Increase Self-Monitoring in a Web-Based Intervention: Randomized Controlled Trial SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Web-based health promotion intervention; self-monitoring; prompts ID WEIGHT-LOSS MAINTENANCE; PHYSICAL-ACTIVITY PROMOTION; HEALTH INTERVENTIONS; ACHIEVING WEIGHT; OBESE ADULTS; LIFE-STYLE; PROGRAM; CARE; PREVENTION; PARTICIPATION AB Background: Self-monitoring is a key behavior change mechanism associated with sustained health behavior change. Although Web-based interventions can offer user-friendly approaches for self-monitoring, engagement with these tools is suboptimal. Increased use could encourage, promote, and sustain behavior change. Objective: To determine whether email prompts or email plus telephone prompts increase self-monitoring of behaviors on a website created for a multiple cancer risk reduction program. Methods: We recruited and enrolled participants (N = 100) in a Web-based intervention during a primary care well visit at an urban primary care health center. The frequency of daily self-monitoring was tracked on the study website. Participants who tracked at least one behavior 3 or more times during week 1 were classified as meeting the tracking threshold and were assigned to the observation-only group (OO, n = 14). This group was followed but did not receive prompts. Participants who did not meet the threshold during week 1 were randomly assigned to one of 2 prompting conditions: automated assistance (AA, n = 36) or automated assistance + calls (AAC, n = 50). During prompting periods (weeks 2-3), participants in the AA and AAC conditions received daily automated emails that encouraged tracking and two tailored self-monitoring reports (end of week 2, end of week 3) that provided feedback on tracking frequency. Individuals in the AAC condition also received two technical assistance calls from trained study staff. Frequency of self-monitoring was tracked from week 2 through week 17. Results: Self-monitoring rates increased in both intervention conditions during prompting and declined when prompting ceased. Over the 16 weeks of observation, there was a significant between-group difference in the percentage who met the self-monitoring threshold each week, with better maintenance in the AAC than in the AA condition (P < .001). Self-monitoring rates were greater in the OO group than in either the AA or AAC condition (P < .001). Conclusions: Prompting can increase self-monitoring rates. The decrease in self-monitoring after the promoting period suggests that additional reminder prompts would be useful. The use of technical assistance calls appeared to have a greater effect in promoting self-monitoring at a therapeutic threshold than email reminders and the tailored self-monitoring reports alone. C1 [Greaney, Mary L.; Sprunck-Harrild, Kim; Viswanath, K. Vish; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02215 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & & Neurosci, Durham, NC USA. [Bennett, Gary G.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Puleo, Elaine] Univ Massachusetts, Dept Publ Hlth, Amherst, MA 01003 USA. [Haines, Jess] Univ Guelph, Dept Family Relat & Appl Nutr, Guelph, ON N1G 2W1, Canada. [Viswanath, K. Vish; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Greaney, ML (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW664, Boston, MA 02215 USA. EM mary_greaney@dfci.harvard.edu FU NIH [R01 CA123228, 1K05 CA124415] FX We thank Harvard Vanguard Medical Associates for the opportunity to conduct our research in their clinical sites. This work was supported by NIH grants R01 CA123228 and 1K05 CA124415. We also would like to thank the study participants and the Healthy Directions 2 staff: Louisa Bloomstein, Joanne Chin, Lindsay ElShazly, Kristie Usher, and Val Varner. NR 35 TC 16 Z9 16 U1 1 U2 14 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL-AUG PY 2012 VL 14 IS 4 BP 76 EP 86 AR e96 DI 10.2196/jmir.1981 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 003KE UT WOS:000308609600006 PM 22842775 ER PT J AU Nehra, D Oyarvide, VM Mino-Kenudson, M Thayer, SP Ferrone, CR Wargo, JA Muzikansky, A Finkelstein, D Warshaw, AL Fernandez-del Castillo, C AF Nehra, Deepika Oyarvide, Vicente Morales Mino-Kenudson, Mari Thayer, Sarah P. Ferrone, Cristina R. Wargo, Jennifer A. Muzikansky, Alona Finkelstein, Dianne Warshaw, Andrew L. Fernandez-del Castillo, Carlos TI Intraductal papillary mucinous neoplasms: Does a family history of pancreatic cancer matter? SO PANCREATOLOGY LA English DT Article DE Intraductal papillary mucinous neoplasm; Family history; Pancreatic cancer ID ADDITIONAL PRIMARY CANCERS; HIGH-RISK INDIVIDUALS; UPDATED EXPERIENCE; ADENOCARCINOMAS AB Background/Objectives: The purpose of this study is to compare surgically resected intraductal papillary mucinous neoplasms (IPMNs) in patients with and without a family history of pancreatic cancer to gain insight into differences that may suggest the need for differential management. Methods: A retrospective review of patients who underwent resection of an IPMN at the Massachusetts General Hospital (1990-2011) was conducted. Three hundred and twenty-four patients of whom 45 (13.9%) had a family history of pancreatic cancer were identified. Patients with (PFH) and without (NFH) a family history of pancreatic cancer were compared. Results: There were no differences in demographic characteristics between groups. Extra-pancreatic malignancies diagnosed prior to the IPMN were more common in those with a PFH (35.6% vs 20.1%, p = 0.03). There were no differences in IPMN characteristics between groups including no difference in the presence of invasive disease (p = 0.55). Concurrent pancreatic ductal adenocarcinomas were more common in those with a PFH (11.1% vs 2.9%, p = 0.02). The survival in the PFH group was marginally lower than the NFH group, a difference found to be attributable to the higher prevalence of extra-pancreatic malignancies. Conclusion: Characteristics of surgically resected IPMNs are not different between patients with and without a family history of pancreatic cancer. Most importantly, the incidence of invasive disease is not different, suggesting that these lesions may not be more aggressive when they occur in the presence of a family history of pancreatic cancer. Copyright (c) 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. C1 [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Wang Ambulatory Care Ctr, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Muzikansky, Alona; Finkelstein, Dianne] Massachusetts Gen Hosp, Dept Stat, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Massachusetts Gen Hosp, Wang Ambulatory Care Ctr, Dept Surg, 15 Parkman St,WAC 4-460, Boston, MA 02114 USA. EM cfernandez@partners.org FU NCI NIH HHS [P01 CA117969, P50 CA127003] NR 22 TC 13 Z9 13 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PD JUL-AUG PY 2012 VL 12 IS 4 BP 358 EP 363 DI 10.1016/j.pan.2012.05.011 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 003SC UT WOS:000308630600011 PM 22898638 ER PT J AU Olivares, D Deshpande, VK Shi, Y Lahiri, DK Greig, NH Rogers, JT Huang, XD AF Olivares, David Deshpande, Varun K. Shi, Ying Lahiri, Debomoy K. Greig, Nigel H. Rogers, Jack T. Huang, Xudong TI N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer's Disease, Vascular Dementia and Parkinson's Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Article DE Alzheimer's disease; Parkinson's disease; vascular dementia; memantine; NMDAR; amantadine ID FOCAL CEREBRAL-ISCHEMIA; PLACEBO-CONTROLLED TRIAL; MOLECULAR-MECHANISMS; BASAL GANGLIA; OXIDATIVE STRESS; DOUBLE-BLIND; DEPENDENT NEURODEGENERATION; PERIINFARCT DEPOLARIZATIONS; ANTIPARKINSONIAN ACTIONS; ACETYLCHOLINE-RELEASE AB Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer's disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson's disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine-as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine's therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine's tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy. C1 [Olivares, David] Hosp Clin San Carlos, Serv Clin Pharmacol, Madrid 28040, Spain. [Deshpande, Varun K.; Shi, Ying; Huang, Xudong] Harvard Univ, Brigham & Womens Hosp, Div Nucl Med & Mol Imaging, Conjugate & Med Chem Lab,Dept Radiol,Med Sch, Boston, MA 02115 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Inst Psychiat Res, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Rogers, Jack T.; Huang, Xudong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurochem Lab,,Dept Psychiat, Charlestown, MA 02129 USA. RP Huang, XD (reprint author), BWH Radiol, 75 Francis St, Boston, MA 02115 USA. EM xhuang3@partners.org FU Radiology Department of Brigham and Women's Hospital (BWH); National Institute on Aging (NIA); Alzheimer's Association; NIH FX This work was supported in part by Radiology Department of Brigham and Women's Hospital (BWH) and the Intramural Research Program, National Institute on Aging (NIA). Jack T. Rogers is a recipient of Zenith Fellows award of Alzheimer's Association. We want to thank Ms. Kim Lawson at BWH Radiology Department for her editing of our manuscript. This work was also supported by Grants from Alzheimer's Association and NIH to DKL. NR 143 TC 52 Z9 56 U1 8 U2 35 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD JUL PY 2012 VL 9 IS 6 BP 746 EP 758 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 007BT UT WOS:000308864500013 PM 21875407 ER PT J AU Nahab, FB Handforth, A Brown, T Shin, C Quesada, A Dong, CH Haubenberger, D Hallett, M AF Nahab, Fatta B. Handforth, Adrian Brown, Tyler Shin, Christopher Quesada, Arnulfo Dong, Chuanhui Haubenberger, Dietrich Hallett, Mark TI Octanoic Acid Suppresses Harmaline-Induced Tremor in Mouse Model of Essential Tremor SO NEUROTHERAPEUTICS LA English DT Article DE 1-octanol; Octanoic acid; Essential tremor; Harmaline; Therapeutics ID OPEN-LABEL; 1-OCTANOL AB Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET. C1 [Nahab, Fatta B.; Brown, Tyler; Dong, Chuanhui] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Handforth, Adrian] Vet Affairs Greater Los Angeles Healthcare Syst, Neurol Serv, Los Angeles, CA 90073 USA. [Shin, Christopher; Quesada, Arnulfo] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Quesada, Arnulfo] Univ Calif Los Angeles, Dept Neurobiol, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Haubenberger, Dietrich] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Brown, Tyler; Haubenberger, Dietrich; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. RP Nahab, FB (reprint author), Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. EM fnahab@med.miami.edu FU Intramural division of the National Institute of Neurological Disorders and Stroke; Ariston Pharmaceuticals FX This work was supported by the Intramural division of the National Institute of Neurological Disorders and Stroke and a collaborative research and development agreement with Ariston Pharmaceuticals. NR 16 TC 6 Z9 6 U1 4 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2012 VL 9 IS 3 BP 635 EP 638 DI 10.1007/s13311-012-0121-1 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 006NV UT WOS:000308826800014 PM 22454323 ER PT J AU Greka, A Mundel, P AF Greka, Anna Mundel, Peter TI Calcium Regulates Podocyte Actin Dynamics SO SEMINARS IN NEPHROLOGY LA English DT Review DE Cdc42; fibroblasts; synaptopodin; TRPC channels; TRPC5; TRPC6; Rac1; RhoA; tropomyosin ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; OSKAR MESSENGER-RNA; RESISTANT NEPHROTIC SYNDROME; RECEPTOR POTENTIAL CHANNELS; ANGIOTENSIN-II; CARDIAC-HYPERTROPHY; KIDNEY PODOCYTES; CATION CHANNEL; CELL MOTILITY; TRP CHANNELS AB Ca2+-mediated remodeling of the actin cytoskeleton is a dynamic process that regulates cell motility through the modulation of rho guanosine triphosphatase (GTPase) signaling. Kidney podocytes are unique, pericyte-like cells with a complex cellular organization consisting of a cell body, major processes, and foot processes (FPs). The FPs form a characteristic interdigitating pattern with FPs of neighboring podocytes, leaving in between filtration slits that are covered by the slit diaphragm (SD). The actin-based FP and the SD form the final barrier to proteinuria. Mutations affecting several podocyte proteins cause disruption of the filtration barrier and rearrangement of the highly dynamic podocyte actin cytoskeleton. Proteins regulating the plasticity of the podocyte actin cytoskeleton are therefore of critical importance for sustained kidney barrier function. Dynamic regulation of the actin-based contractile apparatus in podocyte FPs is essential for sustained kidney filter function. Thus, the podocyte represents an excellent model system to study calcium signaling and actin dynamics in a physiologic context. Here, we discuss the regulation of podocyte actin dynamics by angiotensin or bradykinin-mediated calcium influx and downstream Rho GTPase signaling pathways and how these pathways are operative in other cells including fibroblasts and cancer cells. Semin Nephrol 32:319-326 (C) 2012 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greka, A (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St, Charlestown, MA 02129 USA. EM greka.anna@mgh.harvard.edu FU American Society of Nephrology; National Institutes of Health [DK083511, DK57683, DK062472] FX Supported in part by an American Society of Nephrology Gottschalk Grant and a National Institutes of Health grant (DK083511 to A.G., and DK57683 and DK062472 to P.M.). NR 101 TC 27 Z9 27 U1 0 U2 18 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2012 VL 32 IS 4 BP 319 EP 326 DI 10.1016/j.semnephrol.2012.06.003 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 011EP UT WOS:000309147900003 PM 22958486 ER PT J AU Caro, MA Sowden, GL Mastromauro, CA Mahnks, S Beach, SR Januzzi, JL Huffman, JC AF Caro, Mario A. Sowden, Gillian L. Mastromauro, Carol A. Mahnks, Stephanie Beach, Scott R. Januzzi, James L. Huffman, Jeff C. TI Risk factors for positive depression screens in hospitalized cardiac patients SO JOURNAL OF CARDIOLOGY LA English DT Article DE Cardiovascular disease; Cardiology practice/management; Quality improvement; Depression; Heart diseases; Screening ID ACUTE CORONARY SYNDROME; ACUTE MYOCARDIAL-INFARCTION; CONGESTIVE-HEART-FAILURE; MAJOR DEPRESSION; OUTCOMES; DISEASE; CARE; INFLAMMATION; ASSOCIATION; PREVALENCE AB Background: Depression is common in patients with cardiac illness and is independently associated with elevated morbidity and mortality. There are screening guidelines for depression in cardiac patients, but the feasibility and cost-effectiveness of screening all cardiac patients is controversial. This process may be improved if a subset of cardiac patients at high risk for depression could be identified using information readily available to clinicians and screened. Objective: To identify risk factors for a positive depression screen at the time of admission in hospitalized cardiac patients. Methods: A total of 561 consecutively screened cardiac inpatients underwent the Patient Health Questionnaire-2 (PHQ-2). A prospective chart review was performed to assess potential risk factors for depression that would be readily available to front-line clinicians. Rates of risk factors were compared between patients with positive and negative PHQ-2 depression screens, and multivariate logistic regression was performed to assess whether specific risk factors were independently associated with positive screens. Results: Of the 561 patients screened, 13.5% (n = 76) had a positive depression screen (PHQ-2 >= 2). In the univariate analyses, several variables were associated with a positive depression screen. On multivariate analysis, an elevated white blood cell (WBC) count (>10 x 10(9) cells per liter) and prescription of an antidepressant on admission were independently associated with a positive depression screen, while current smoking showed a trend toward significance. Conclusion: Information on these three identified risk factors (WBC count, antidepressant use, and smoking) is readily available to clinicians, and patients with these diagnoses may represent a cohort who would benefit from targeted depression screening in certain settings. (C) 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. C1 [Caro, Mario A.; Mastromauro, Carol A.; Mahnks, Stephanie; Beach, Scott R.; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sowden, Gillian L.; Beach, Scott R.; Januzzi, James L.; Huffman, Jeff C.] Harvard Univ, Sch Med, Boston, MA USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Warren 1220C, Boston, MA 02114 USA. EM jhuffman@partners.org FU AHA Scientist Development [0735530T] FX This study was funded in part by AHA Scientist Development Grant No. 0735530T to Jeff Huffman, M.D. The authors of this paper report no financial or other conflict of interests regarding the content of this manuscript. NR 39 TC 9 Z9 9 U1 4 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0914-5087 J9 J CARDIOL JI J. Cardiol. PD JUL-AUG PY 2012 VL 60 IS 1-2 BP 72 EP 77 DI 10.1016/j.jjcc.2012.01.016 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 003OM UT WOS:000308621200013 PM 22436292 ER PT J AU Madan, JC Koestler, DC Stanton, BA Davidson, L Moulton, LA Housman, ML Moore, JH Guill, MF Morrison, HG Sogin, ML Hampton, TH Karagas, MR Palumbo, PE Foster, JA Hibberd, PL O'Toole, GA AF Madan, J. C. Koestler, D. C. Stanton, B. A. Davidson, L. Moulton, L. A. Housman, M. L. Moore, J. H. Guill, M. F. Morrison, H. G. Sogin, M. L. Hampton, T. H. Karagas, M. R. Palumbo, P. E. Foster, J. A. Hibberd, P. L. O'Toole, G. A. TI Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures SO MBIO LA English DT Article ID YOUNG-CHILDREN; PSEUDOMONAS-AERUGINOSA; BACTERIAL COMMUNITIES; INFECTION; GENOTYPE; AGE; DETERIORATION; INFLAMMATION; PREDICTORS; DIVERSITY AB Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. C1 [Stanton, B. A.; Housman, M. L.; Hampton, T. H.; O'Toole, G. A.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA. [Madan, J. C.] Dartmouth Hitchcock Med Ctr, Dept Pediat, Div Neonatol, Lebanon, NH 03766 USA. [Koestler, D. C.; Moore, J. H.] Geisel Sch Med Dartmouth, Translat Genom Res Inst, Hanover, NH USA. [Davidson, L.] Tufts Univ, Sch Med, Div Geog Med & Infect Dis, Ctr Global Hlth Res, Boston, MA 02111 USA. [Moulton, L. A.; Guill, M. F.] Dartmouth Hitchcock Med Ctr, Dept Pediat, Div Pediat Pulmonol, Lebanon, NH 03766 USA. [Morrison, H. G.; Sogin, M. L.] Josephine Bay Paul Ctr, Marine Biol Lab, Woods Hole, MA USA. [Karagas, M. R.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Hanover, NH USA. [Palumbo, P. E.] Geisel Sch Med Dartmouth, Dept Med, Sect Infect Dis & Int Hlth, Lebanon, NH USA. [Foster, J. A.] Univ Idaho, Dept Biol Sci & Initiat Bioinformat & Evolutionar, Moscow, ID 83843 USA. [Hibberd, P. L.] Massachusetts Gen Hosp, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. RP O'Toole, GA (reprint author), Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA. EM georgeo@dartmouth.edu RI Koestler, Devin /D-7902-2015; OI Koestler, Devin /0000-0002-0598-0146; Foster, James/0000-0002-6770-6521; Morrison, Hilary/0000-0003-0281-326X FU Hearst Foundation; Synergy Grant (Dartmouth); Joshua Burnett Career Development Award through the Hitchcock Foundation (Dartmouth); Department of Pediatrics, Dartmouth; NIH/NIEHS [1P20ES018175-02, EPA RD-83459901-0]; Cystic Fibrosis Foundation Research Development Program [STANTO07R0]; Neukom Institute; NIH [R01 AI59694, P20RR16448, P20RR016454, 4UH3DK083993-02, R01 HL074175, 2K24AT003683]; NSF [DBI0939454]; NIEHS [P42 ES7373, P20 ES018175]; GMS/NCRR [P20-RR01878]; National Center for Research Resources [5P20RR018787]; National Institute of General Medical Sciences (NIH) [8 P20 GM103413]; EPA [RD-83459901] FX This work was supported by the Hearst Foundation, the Synergy Grant (Dartmouth), the Joshua Burnett Career Development Award through the Hitchcock Foundation (Dartmouth), and the Department of Pediatrics, Dartmouth, to J.C.M., with additional support from NIH/NIEHS 1P20ES018175-02 and EPA RD-83459901-0. This work was also supported by a pilot grant to G.A.O. from the Cystic Fibrosis Foundation Research Development Program (STANTO07R0). G.A.O. and J.H.M. received joint support from the Neukom Institute. J.H.M. is funded by NIH grant R01 AI59694. J.A.F. was funded in part by NIH grants P20RR16448 and P20RR016454 and by NSF DBI0939454. M. L. S. and H. G. M. are funded by NIH 4UH3DK083993-02. B. A. S. and T. H. H. were funded by the Cystic Fibrosis Foundation Research Development Program (STANTO07R0), NIEHS P42 ES7373, GMS/NCRR P20-RR01878, and NIH R01 HL074175. P. L. H. is funded by NIH grant 2K24AT003683. The translational research core (TRC) for collecting and processing clinical samples is supported by grants from the National Center for Research Resources (5P20RR018787) and the National Institute of General Medical Sciences (8 P20 GM103413) (NIH). M. R. K. is funded by P20 ES018175 from NIEHS and RD-83459901 from the EPA. NR 55 TC 58 Z9 59 U1 5 U2 48 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2012 VL 3 IS 4 AR e00251-12 DI 10.1128/mBio.00251-12 PG 10 WC Microbiology SC Microbiology GA 003DQ UT WOS:000308588800032 ER PT J AU Melville, SA Buros, J Parrado, AR Vardarajan, B Logue, MW Shen, L Risacher, SL Kim, S Jun, G DeCarli, C Lunetta, KL Baldwin, CT Saykin, AJ Farrer, LA AF Melville, Scott A. Buros, Jacqueline Parrado, Antonio R. Vardarajan, Badri Logue, Mark W. Shen, Li Risacher, Shannon L. Kim, Sungeun Jun, Gyungah DeCarli, Charles Lunetta, Kathryn L. Baldwin, Clinton T. Saykin, Andrew J. Farrer, Lindsay A. CA Alzheimers Dis Neuroimaging Initia TI Multiple Loci Influencing Hippocampal Degeneration Identified by Genome Scan SO ANNALS OF NEUROLOGY LA English DT Article ID NEUROIMAGING INITIATIVE ADNI; PROBABLE ALZHEIMERS-DISEASE; WIDE ASSOCIATION; COMMON VARIANTS; QUANTITATIVE TRAIT; GENOTYPE DATA; MRI; ATROPHY; GENES; BRAIN AB Objective: Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH). Methods: Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer's Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer's Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) and strongly associated in both data sets (p < 1.0 x 10(-5)) was evaluated in the African American data set. Results: Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p < 5.0 x 10(-8)) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set. Associations with different SNPs in the same gene (p < 1 x 10(-5) in Caucasians and p < 2.2 x 10(-4) in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH. Interpretation: Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD. ANN NEUROL 2012;72:65-75 C1 [Melville, Scott A.; Buros, Jacqueline; Vardarajan, Badri; Logue, Mark W.; Jun, Gyungah; Baldwin, Clinton T.; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Parrado, Antonio R.] Massachusetts Gen Hosp, Genet & Aging Res Unit, Boston, MA 02114 USA. [Parrado, Antonio R.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Shen, Li; Risacher, Shannon L.; Kim, Sungeun; Saykin, Andrew J.] Indiana Univ, Sch Med, Ctr Neuroimaging, Dept Radiol & Imaging Sci, Indianapolis, IN USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Jun, Gyungah; Lunetta, Kathryn L.; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Baldwin, Clinton T.] Boston Univ, Sch Med, Ctr Human Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. RP Farrer, LA (reprint author), Boston Univ, Sch Med, Dept Med Biomed Genet, Biomed Genet L320,72 E Concord St, Boston, MA 02118 USA. EM farrer@bu.edu RI Saykin, Andrew/A-1318-2007; OI Saykin, Andrew/0000-0002-1376-8532; Logue, Mark/0000-0001-9347-7892; Jun, Gyungah/0000-0002-3230-8697; Lunetta, Kathryn/0000-0002-9268-810X; Farrer, Lindsay/0000-0001-5533-4225; Buros, Jacqueline/0000-0001-9588-4889; Shen, Li/0000-0002-5443-0503 FU National Institute on Aging [R01-AG09029, R01-AG025259, P30-AG13846, P30-AG010129, K01 AG030514]; Dana Foundation; NSF; NIH Clinical and Translational Science Institute [TL1 RR025759]; NIH [U01 AG024904, RC2 AG036535]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; National Cell Repository for Alzheimer's Disease (NIH) [U24 AG021886]; NIH; Indiana University Stark Neuroscience Research Institute Kays Fellowship Award FX This work was supported by National Institute on Aging grants R01-AG09029, R01-AG025259 (L. A. F) P30-AG13846, P30-AG010129, and K01 AG030514, the Dana Foundation, and the NSF (L. S.). S. L. R. received a predoctoral training fellowship (TL1 RR025759) from the NIH Clinical and Translational Science Institute. Collection and sharing of the ADNI data are funded by NIH grants U01 AG024904 and RC2 AG036535 (principal investigator: Michael W. Weiner, MD). ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Merck and Co., Novartis AG, Pfizer, F. Hoffman-La Roche, Schering-Plough, Synarc, and Wyeth, as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California at Los Angeles. The National Cell Repository for Alzheimer's Disease (NIH grant U24 AG021886) provided support for DNA and cell line banking and processing for ADNI.; M.W.L: grant/grants pending, NIH. S.L.R.: grants/grants pending, Indiana University Stark Neuroscience Research Institute Kays Fellowship Award; travel expenses, Alzheimer's Association International Conference on Alzheimer's Disease. C. D.: consultancy, Avid Pharmaceuticals, Takeda Pharmaceuticals; grants/grants pending, NIH. A.J.S.: consultancy, Pfizer, Baxter; employment, Indiana University; grants/grants pending, NIH, Siemens Healthcare, Welch-Allyn, Eli Lilly; Editor in Chief, Brain Imaging and Behavior. L.A.F.: grants/grants pending, NIH. NR 48 TC 23 Z9 23 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2012 VL 72 IS 1 BP 65 EP 75 DI 10.1002/ana.23644 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 994QH UT WOS:000307945700010 PM 22745009 ER PT J AU Dumas, A Dierksen, GA Gurol, ME Halpin, A Martinez-Ramirez, S Schwab, K Rosand, J Viswanathan, A Salat, DH Polimeni, JR Greenberg, SM AF Dumas, Andrew Dierksen, Gregory A. Gurol, M. Edip Halpin, Amy Martinez-Ramirez, Sergi Schwab, Kristin Rosand, Jonathan Viswanathan, Anand Salat, David H. Polimeni, Jonathan R. Greenberg, Steven M. TI Functional Magnetic Resonance Imaging Detection of Vascular Reactivity in Cerebral Amyloid Angiopathy SO ANNALS OF NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; CEREBROVASCULAR DYSFUNCTION; INTRACEREBRAL HEMORRHAGE; BOLD FMRI; BRAIN; DISEASE; BURDEN; MICE AB Objective: In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction. Methods: Functional MRI was performed on 25 nondemented subjects with probable CAA (mean +/- standard deviation age, 70.2 +/- 7.8 years) and 12 healthy elderly controls (age, 75.3 +/- 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling). Results: CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 +/- 0.28 vs 0.89 +/- 0.14; p < 0.01), prolonged time to peak (11.1 +/- 5.1 vs 6.4 +/- 1.8 seconds; p < 0.001), and prolonged time to baseline (16.5 +/- 6.7 vs 11.6 +/- 3.1 seconds; p < 0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 +/- 12.6 vs 45.0 +/- 10.0ml/100g/min, p = 0.8). Interpretation: Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury. ANN NEUROL 2012;72:76-81 C1 [Dumas, Andrew; Dierksen, Gregory A.; Gurol, M. Edip; Halpin, Amy; Martinez-Ramirez, Sergi; Schwab, Kristin; Rosand, Jonathan; Viswanathan, Anand; Greenberg, Steven M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hemorrhag Stroke Res Ctr,Dept Neurol, Boston, MA USA. [Salat, David H.] Boston VA Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Salat, David H.; Polimeni, Jonathan R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Boston, MA USA. RP Greenberg, SM (reprint author), MGH Stroke Res Ctr, 55 Fruit St,CPZ 175,Suite 300, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Polimeni, Jonathan/P-1395-2014; Gurol, Edip/J-2279-2014 OI Polimeni, Jonathan/0000-0002-1348-1179; Gurol, Edip/0000-0002-2169-4457 FU National Institute of Aging; National Institute of Neurological Disorders and Stroke [2R01 AG026484, R01 NS070834]; Center for Functional Neuroimaging Technologies [P41RR14075]; NIH National Center for Research Resources FX This work was supported by grants to SMG from the National Institute of Aging and National Institute of Neurological Disorders and Stroke (2R01 AG026484, R01 NS070834) and was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using a grant provided by the Center for Functional Neuroimaging Technologies (P41RR14075), a P41 Regional Resource supported by the Biomedical Technology Program of the NIH National Center for Research Resources. NR 27 TC 49 Z9 49 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2012 VL 72 IS 1 BP 76 EP 81 DI 10.1002/ana.23566 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 994QH UT WOS:000307945700011 PM 22829269 ER PT J AU Bradley, SM Maynard, C Bryson, CL AF Bradley, Steven M. Maynard, Charles Bryson, Chris L. TI Appropriateness of Percutaneous Coronary Interventions in Washington State SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE appropriateness criteria; percutaneous coronary intervention; utilization; quality improvement; health services research ID CARDIOVASCULAR DATA REGISTRY; INTRAVENOUS THROMBOLYTIC THERAPY; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED-TRIALS; METAANALYSIS; DISEASE; RISK; ANGIOPLASTY; STRATEGIES; OUTCOMES AB Background-In anticipation of applying Appropriate Use Criteria for percutaneous coronary intervention (PCI) quality improvement, we determined the prevalence of appropriate, uncertain, and inappropriate PCIs stratified by indication for all PCIs performed in the state of Washington. Methods and Results-Within the Clinical Outcomes Assessment Program, we assigned appropriateness ratings to all PCIs performed in 2010 in accordance with published Appropriate Use Criteria. Of 13 291 PCIs, we successfully mapped the clinical scenario to the Appropriate Use Criteria in 9924 (75%) cases. Of the 3367 PCIs not classified, common failures to map to the criteria included nonacute PCI without prior noninvasive stress results (n = 1906; 57%) and unstable angina without high-risk features (n = 902; 27%). Of mapped PCIs, 8010 (71%) were for acute indications, with 7887 (98%) rated as appropriate, 39 (<1%) as uncertain, and 84 (1%) as inappropriate. Of 1914 mapped nonacute indications, 847 (44%) were rated as appropriate, 748 (39%) as uncertain, and 319 (17%) as inappropriate. Assuming results for noninvasive stress tests when data were missing, in the best-case scenario, 319 (8%) of nonacute PCIs were classified as inappropriate compared with 1459 (38%) in the worst-case scenario. Variation in inappropriate PCIs by facility was greatest for mapped nonacute indications (median = 14%; 25th to 75th percentiles = 9% to 24%) and nonacute indications with missing data precluding appropriateness classification (median = 54%; 25th to 75th percentiles = 35% to 66%). Conclusions-In a complete cohort of PCIs performed in Washington state, 1% of PCIs for acute indications and 17% of PCIs for nonacute indications were classified as inappropriate. Missing data on noninvasive stress tests present a challenge in the application of the criteria for quality improvement. (Circ Cardiovasc Qual Outcomes. 2012; 5: 445-453.) C1 [Bradley, Steven M.] VA Eastern Colorado Hlth Care Syst, Dept Vet Affairs, Denver, CO 80220 USA. [Bradley, Steven M.] Univ Colorado, Denver, CO 80202 USA. [Maynard, Charles; Bryson, Chris L.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev NW Ctr Excellence, Seattle, WA USA. [Maynard, Charles; Bryson, Chris L.] Univ Washington, Seattle, WA 98195 USA. [Maynard, Charles; Bryson, Chris L.] Fdn Hlth Care Qual, Clin Outcomes Assessment Program, Seattle, WA USA. RP Bradley, SM (reprint author), VA Eastern Colorado Hlth Care Syst, Dept Vet Affairs, 1055 Clermont St 111B, Denver, CO 80220 USA. EM Steven.Bradley@va.gov RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU Health Services Research and Development Service; Health Services Research and Development QuERI Program, Department of Veterans Affairs [RRP 09-040]; VA Health Services Research and Development [1 IK2 HX000779-01] FX This material is based upon work supported by Health Services Research and Development Service and the Health Services Research and Development QuERI Program, Department of Veterans Affairs (Project No.: RRP 09-040). Dr. Steven Bradley is a Career Development Grant Awardee (1 IK2 HX000779-01, funding pending) from VA Health Services Research and Development. NR 24 TC 22 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 445 EP 453 DI 10.1161/CIRCOUTCOMES.111.964320 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500008 PM 22570356 ER PT J AU Keyhani, S Cheng, E Arling, G Li, XL Myers, L Ofner, S Williams, LS Phipps, M Ordin, D Bravata, DM AF Keyhani, Salomeh Cheng, Eric Arling, Greg Li, Xinli Myers, Laura Ofner, Susan Williams, Linda S. Phipps, Michael Ordin, Diana Bravata, Dawn M. TI Does the Inclusion of Stroke Severity in a 30-Day Mortality Model Change Standardized Mortality Rates at Veterans Affairs Hospitals? SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE stroke; outcome assessment (health care); hospital mortality ID ISCHEMIC-STROKE; SCALE; OUTCOMES; SCORE; RISK AB Background-The Centers for Medicare and Medicaid Services is considering developing a 30-day ischemic stroke hospital-level mortality model using administrative data. We examined whether inclusion of the National Institutes of Health Stroke Scale (NIHSS), a measure of stroke severity not included in administrative data, would alter 30-day mortality rates in the Veterans Health Administration. Methods and Results-A total of 2562 veterans admitted with ischemic stroke to 64 Veterans Health Administration Hospitals in the fiscal year 2007 were included. First, we examined the distribution of unadjusted mortality rates across the Veterans Health Administration. Second, we estimated 30-day all-cause, risk standardized mortality rates (RSMRs) for each hospital by adjusting for age, sex, and comorbid conditions using hierarchical models with and without the inclusion of the NIHSS. Finally, we examined whether adjustment for the NIHSS significantly changed RSMRs for each hospital compared with other hospitals. The median unadjusted mortality rate was 3.6%. The RSMR interquartile range without the NIHSS ranged from 5.1% to 5.6%. Adjustment with the NIHSS did not change the RSMR interquartile range (5.1%-5.6%). Among veterans >= 65 years, the RSMR interquartile range without the NIHSS ranged from 9.2% to 10.3%. With adjustment for the NIHSS, the RSMR interquartile range changed from 9.4% to 10.0%. The plot of 30-day RSMRs estimated with and without the inclusion of the NIHSS in the model demonstrated overlapping 95% confidence intervals across all hospitals, with no hospital significantly below or above the mean-unadjusted 30-day mortality rate. The 30-day mortality measure did not discriminate well among hospitals. Conclusion-The impact of the NIHSS on RSMRs was limited. The small number of stroke admissions and the narrow range of 30-day stroke mortality rates at the facility level in the Veterans Health Administration cast doubt on the value of using 30-day RSMRs as a means of identifying outlier hospitals based on their stroke care quality. (Circ Cardiovasc Qual Outcomes. 2012; 5: 508-513.) C1 [Keyhani, Salomeh] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94121 USA. [Keyhani, Salomeh] Univ Calif San Francisco, San Francisco VA Med Ctr HSR& REAP, San Francisco, CA 94121 USA. [Cheng, Eric] VA Greater Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA USA. [Cheng, Eric] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Li, Xinli; Myers, Laura; Williams, Linda S.; Bravata, Dawn M.] Richard L Roudebush VA Med Ctr, VHA HSR & Ctr Excellence Implementing Evidence Ba, Indianapolis, IN USA. [Ofner, Susan] Indiana Univ Sch Med, Div Biostat, Indianapolis, IN USA. [Cheng, Eric; Arling, Greg; Myers, Laura; Ofner, Susan; Williams, Linda S.; Bravata, Dawn M.] VHA HSR & Stroke Qual Enhancement Res Initiat Pro, Indianapolis, IN USA. [Arling, Greg; Williams, Linda S.] Indiana Univ Sch Med, Indiana Univ Ctr Aging Res, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA. [Myers, Laura; Bravata, Dawn M.] Indiana Univ Sch Med, Dept Internal Med, Indianapolis, IN USA. [Arling, Greg; Williams, Linda S.; Bravata, Dawn M.] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Phipps, Michael] Yale Univ, Sch Med, Robert Wood Johnson Fdn Clin Scholars Program, New Haven, CT USA. [Phipps, Michael] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. RP Keyhani, S (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr, Div Gen Internal Med, 4150 Clement 111A1, San Francisco, CA 94121 USA. EM salomeh.keyhani@va.gov OI Phipps, Michael/0000-0001-8398-5404 FU Department of Veterans Affairs; Veterans Health Administration; Office of Quality and Performance and Health Services Research; Development Service Quality Enhancement Research Initiative [RRP 09-184]; VA HSRD FX The Department of Veterans Affairs, Veterans Health Administration, Office of Quality and Performance and Health Services Research, and Development Service Quality Enhancement Research Initiative (RRP 09-184) supported this project. Dr Bravata is the principal investigator of this project at the Richard L. Roudebush VA Medical Center (Indianapolis, IN). Dr Keyhani is currently supported by a VA HSR&D career development award. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 15 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 508 EP 513 DI 10.1161/CIRCOUTCOMES.111.962936 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500016 PM 22787062 ER PT J AU Lin, CB Peterson, ED Smith, EE Saver, JL Liang, L Xian, Y Olson, DM Shah, BR Hernandez, AF Schwamm, LH Fonarow, GC AF Lin, Cheryl B. Peterson, Eric D. Smith, Eric E. Saver, Jeffrey L. Liang, Li Xian, Ying Olson, DaiWai M. Shah, Bimal R. Hernandez, Adrian F. Schwamm, Lee H. Fonarow, Gregg C. TI Emergency Medical Service Hospital Prenotification Is Associated With Improved Evaluation and Treatment of Acute Ischemic Stroke SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE stroke; emergency medicine services; thrombolytics; hospitals; registry ID TISSUE-PLASMINOGEN ACTIVATOR; PREHOSPITAL NOTIFICATION; CARE; TIME; GUIDELINES; MANAGEMENT; STATEMENT; OUTCOMES; COUNCIL; EMS AB Background-The benefits of intravenous tissue-plasminogen activator (tPA) in acute ischemic stroke are time-dependent. Emergency medical services (EMS) hospital prenotification of an incoming patient with potential stroke may provide a means of reducing evaluation and treatment times and improving treatment rates; yet, available data are limited. Methods and Results-We examined 371 988 patients with acute ischemic stroke transported by EMS and enrolled in Get With The Guidelines-Stroke from April 1, 2003, to March 31, 2011. Prenotification occurred in 249 197 (67.0%) of EMS-transported patients. Among eligible patients arriving by 2 hours, patients with EMS prenotification were more likely to be treated with tPA within 3 hours (82.8% versus 79.2%, absolute difference +3.5%, P<0.0001, the National Institutes of Health Stroke Scale-documented cohort; 73.0% versus 64.0%, absolute difference +9.0%, P<0.0001, overall cohort). Patients with EMS prenotification had shorter door-to-imaging times (26 minutes versus 31 minutes, P<0.0001), shorter door-to-needle times (78 minutes versus 80 minutes, P<0.0001), and shorter symptom onset-to-needle times (141 minutes versus 145 minutes, P<0.0001). In multivariable and modified Poisson regression analyses accounting for the clustering of patients within hospitals, use of EMS prenotification was independently associated with greater likelihood of door-to-imaging times <= 25 minutes, door-to-needle times for tPA <= 60 minutes, onset-to-needle times <= 120 minutes, and tPA use within 3 hours. Conclusions-EMS hospital prenotification is associated with improved evaluation, timelier stroke treatment, and more eligible patients treated with tPA. These results support the need for initiatives targeted at increasing EMS prenotification rates as a mechanism from improving quality of care and outcomes in stroke. (Circ Cardiovasc Qual Outcomes. 2012; 5: 514-522.) C1 [Lin, Cheryl B.] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Peterson, Eric D.; Liang, Li; Xian, Ying; Olson, DaiWai M.; Shah, Bimal R.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Smith, Eric E.] Univ Calgary, Calgary Stroke Program, Calgary, AB, Canada. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room 47-123 CHS, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Hernandez, Adrian F./A-7818-2016; OI Saver, Jeffrey/0000-0001-9141-2251; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616; Smith, Eric/0000-0003-3956-1668 FU Boeringher-Ingelheim; Merck; National Institutes of Health (NIH) [NINDS R01 NS062028]; Canadian Stroke Network; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; AHA Pharmaceutical Roundtable grant [0675060N]; Johnson Johnson; Eli Lilly and Company; Bristol-Myers Squibb; Sanofi-aventis; Merck/Schering-Plough; National Institutes of Health FX The GWTG-Stroke program is provided by the American Heart Association/American Stroke Association. The GWTG-Stroke program is currently supported, in part, by a charitable contribution from Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim and Merck.; Dr Smith serves as a member of the GWTG Science Subcommittee and receives research support from the National Institutes of Health (NIH) (NINDS R01 NS062028), the Canadian Stroke Network, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Canada, and has served on an advisory board for Genentech.; Dr Hernandez is a member of the Duke Clinical Research Institute, which serves as the AHA GWTG data coordinating center. Dr Hernandez is a recipient of an AHA Pharmaceutical Roundtable grant (0675060N); has received a research grant from Johnson & Johnson; and has received honorarium from AstraZeneca and Amgen.; Dr Peterson has received research grants from Eli Lilly and Company, Johnson & Johnson, and Bristol-Myers Squibb, Sanofi-aventis, and the Merck/Schering-Plough partnership. Dr Peterson serves as principle investigator of the Data Analytic Center for GTWG.; Dr Fonarow receives research support from the National Institutes of Health (significant) and is an employee of the University of California, which holds a patent on retriever devices for stroke (significant). NR 16 TC 58 Z9 59 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 514 EP 522 DI 10.1161/CIRCOUTCOMES.112.965210 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500017 PM 22787065 ER PT J AU Maddox, TM Ho, PM Tsai, TT Wang, TY Li, S Peng, SA Wiviott, SD Masoudi, FA Rumsfeld, JS AF Maddox, Thomas M. Ho, P. Michael Tsai, Thomas T. Wang, Tracy Y. Li, Shuang Peng, S. Andrew Wiviott, Stephen D. Masoudi, Fredrick A. Rumsfeld, John S. TI Clopidogrel Use and Hospital Quality in Medically Managed Patients With Non-ST-Segment-Elevation Myocardial Infarction SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE myocardial infarction; prevention; coronary artery disease ID ACUTE CORONARY SYNDROMES; CARE; PERFORMANCE; MORTALITY; PRASUGREL; DISCHARGE; OUTCOMES AB Background-Clopidogrel prescription is a class I guideline recommendation for medically managed patients with non-ST-segment-elevation myocardial infarction (NSTEMI). However, clopidogrel has historically been underused in this population. We evaluated contemporary rates of its use and evaluated associated factors, with a particular focus on hospital quality of myocardial infarction (MI) care. Methods and Results-We examined clopidogrel prescription rates among 23 186 patients with NSTEMI discharged from 382 US hospitals between October 2009 and March 2011. Associations between clopidogrel prescription and various patient and hospital factors, including hospital quality of MI care, were determined with regression modeling. Of the sample, 54.9% of eligible patients with NSTEMI received clopidogrel prescription at hospital discharge. Variation in rate by hospital was large, ranging from 22% to 97%. A variety of patient and hospital factors were associated with clopidogrel prescription. Hospital quality of MI care demonstrated modest association with clopidogrel prescription (odds ratio, 0.68; 95% CI, 0.54-0.85) between the lowest and highest hospital quality quartile) and accounted for 5.7% of the variation in prescription rates. Conclusions-Clopidogrel prescription is significantly underused in the medically managed NSTEMI population and demonstrates wide variability by hospital. Although hospital quality of MI care is associated with its use, the findings suggest that it only has a modest effect. Therefore, efforts to improve clopidogrel use likely will require measures beyond improving the overall hospital quality of MI care. (Circ Cardiovasc Qual Outcomes. 2012; 5: 523-531.) C1 [Maddox, Thomas M.; Ho, P. Michael; Tsai, Thomas T.; Rumsfeld, John S.] VA Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. [Maddox, Thomas M.; Ho, P. Michael; Tsai, Thomas T.; Masoudi, Fredrick A.] Univ Colorado Denver, Aurora, CO USA. [Wang, Tracy Y.; Li, Shuang; Peng, S. Andrew] Duke Clin Res Inst, Durham, NC USA. [Wiviott, Stephen D.] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp,Sch Med, Boston, MA 02115 USA. RP Maddox, TM (reprint author), VA Eastern Colorado Hlth Care Syst, 1055 Clermont St, Denver, CO 80220 USA. EM thomas.maddox@va.gov FU Veterans Administration Health Services Research and Development Career Development Award; ACC Foundation's NCDR; Merck; Bristol-Myers Squibb FX Dr Maddox is supported by a Veterans Administration Health Services Research and Development Career Development Award. He had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This research was supported by the ACC Foundation's NCDR. The views expressed in this article represent those of the authors and do not necessarily represent the official views of the NCDR or its associated professional societies identified at www.ncdr.com.; ACTION Registry-GWTG is an initiative of the ACC Foundation and the AHA with partnering support from the Society of Chest Pain Centers, the American College of Emergency Physicians, and the Society of Hospital Medicine. The registry is funded in part by an independent grant from Merck and by Bristol-Myers Squibb (who manufacture clopidogrel). The sponsors had no role in the conception, design, analysis, or writing of this article. NR 14 TC 5 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 523 EP 531 DI 10.1161/CIRCOUTCOMES.112.965285 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500018 PM 22570355 ER PT J AU Subherwal, S Bhatt, DL Li, S Wang, TY Thomas, L Alexander, KP Patel, MR Ohman, EM Gibler, WB Peterson, ED Roe, MT AF Subherwal, Sumeet Bhatt, Deepak L. Li, Shuang Wang, Tracy Y. Thomas, Laine Alexander, Karen P. Patel, Manesh R. Ohman, E. Magnus Gibler, W. Brian Peterson, Eric D. Roe, Matthew T. TI Polyvascular Disease and Long-Term Cardiovascular Outcomes in Older Patients With Non-ST-Segment-Elevation Myocardial Infarction SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE myocardial infarction; peripheral vascular disease; coronary diseasece; rebrovascular disorders; aged ID PERIPHERAL-ARTERIAL-DISEASE; ACUTE CORONARY SYNDROMES; QUALITY-OF-LIFE; VASCULAR-DISEASE; PRACTICE GUIDELINES; GLOBAL REGISTRY; EVENT RATES; TASK-FORCE; RISK; INTERVENTION AB Background-The impact of polyvascular disease (peripheral arterial disease [PAD] and cerebrovascular disease [CVD]) on long-term cardiovascular outcomes among older patients with acute myocardial infarction has not been well studied. Methods and Results-Patients with non-ST-segment-elevation myocardial infarction aged >= 65 years from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines) registry who survived to hospital discharge were linked to longitudinal data from the Centers for Medicare & Medicaid Services (n=34 205). All patients were presumed to have coronary artery disease (CAD) and were classified into the following 4 groups: 10.7% with prior CVD (CAD+CVD group); 11.5% with prior PAD (CAD+PAD); 3.1% with prior PAD and CVD (CAD+PAD+CVD); and 74.7% with no polyvascular disease (CAD alone). Cox proportional hazards modeling was used to examine the hazard of long-term mortality and composite of death or readmission for myocardial infarction or stroke (median follow-up, 35 months; interquartile range, 17-49 months). Compared with the CAD alone group, patients with polyvascular disease had greater comorbidities, were less likely to undergo revascularization, and received less often recommended discharge interventions. Three-year mortality rates increased with number of arterial bed involvement as follows: 33% for CAD alone, 49% for CAD+PAD, 52% for CAD+CVD, and 59% for CAD+PAD+CVD. Relative to the CAD alone group, patients with all 3 arterial beds involved had the highest risk of long-term mortality (adjusted hazard ratio [95% CI], 1.49 [1.38-1.61]; CAD+CVD, 1.38 [1.31-1.44]; CAD+PAD, 1.29 [1.23-1.35]). Similarly, the risk of long-term composite ischemic events was highest among patients in the CAD+PAD+CVD group. Conclusions-Among older patients with non-ST-segment-elevation myocardial infarction, those with polyvascular disease have substantially higher long-term risk for recurrent events or death. Future studies targeting greater adherence to secondary prevention strategies and novel therapies are needed to help to reduce long-term cardiovascular events in this vulnerable population. (Circ Cardiovasc Qual Outcomes. 2012; 5: 541-549.) C1 [Subherwal, Sumeet; Li, Shuang; Wang, Tracy Y.; Thomas, Laine; Alexander, Karen P.; Patel, Manesh R.; Ohman, E. Magnus; Peterson, Eric D.; Roe, Matthew T.] Duke Univ, Med Ctr, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Gibler, W. Brian] Univ Cincinnati, Cincinnati, OH USA. RP Roe, MT (reprint author), Duke Clin Res Inst, DUMC Box 3850,2400 Pratt St, Durham, NC 27705 USA. EM matthew.roe@dm.duke.edu FU Schering-Plough Corporation; Bristol-Myers Squibb/sanofi Pharmaceuticals; Millennium Pharmaceuticals Inc; National Institute on Aging [R01 AG025312-01A1]; Amarin; AstraZeneca; Bristol-Myers Squibb; Eisai; Ethicon; Medtronic; Sanofi-aventis; Medicines Company; Merck; Canyon Pharmaceuticals; Heartscape; Eli Lilly/Daiichi Sankyo; MAQUET Cardiovascular LLC; Johnson Johnson; National Heart, Lung, and Blood Institute; Agency for Healthcare Research and Quality and consults for Genzyme; Daiichi Sankyo; Datascope; Eli Lilly Company; Merck Co; American Heart Association; American College of Cardiology; Society of Thoracic Surgeons and consults for Boehringer Ingelheim; Roche FX CRUSADE was funded by the Schering-Plough Corporation. A Bristol-Myers Squibb/sanofi Pharmaceuticals partnership provided additional funding support. Millennium Pharmaceuticals Inc also funded this work. This work was supported in part by a grant from the National Institute on Aging (R01 AG025312-01A1) to Dr Peterson, principal investigator.; Dr Bhatt has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-aventis, and The Medicines Company. Dr Wang has received research grants to the Duke Clinical Research Institute from a Bristol-Myers Squibb/sanofi Pharmaceuticals partnership, Schering-Plough (now Merck), The Medicines Company, Canyon Pharmaceuticals, Heartscape, and an Eli Lilly/Daiichi Sankyo partnership and has consulted for or received honoraria from Heartscape, Medco, and the American College of Cardiology Foundation. Dr Patel has received research support from MAQUET Cardiovascular LLC (formerly Boston Scientific Cardiac & Vascular); Johnson & Johnson; the National Heart, Lung, and Blood Institute; and the Agency for Healthcare Research and Quality and consults for Genzyme. Dr Ohman has received research support from Daiichi Sankyo, Datascope, and Eli Lilly & Company and consults for AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Gilead Sciences; Liposcience; Merck; Pozen, Inc; sanofi-aventis; The Medicines Company; and WebMD. Dr Peterson has received research support from Bristol-Myers Squibb, Eli Lilly & Company, Johnson & Johnson, Merck & Co, sanofi-aventis, the American Heart Association, the American College of Cardiology, and the Society of Thoracic Surgeons and consults for Boehringer Ingelheim. Dr Roe has received research funding from Eli Lilly, Roche, Bristol-Myers Squibb, the American College of Cardiology, and the American Heart Association and has consulted for or received honoraria from KAI Pharmaceuticals, Bristol-Myers Squibb, sanofi-aventis, Merck, Orexigen, Helsinn Pharmaceuticals, AstraZeneca, and Regeneron. All conflicts of interest for Drs Wang, Patel Ohman, Peterson, and Roe are listed at www.dcri.org. NR 35 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 541 EP 549 DI 10.1161/CIRCOUTCOMES.111.964379 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500020 PM 22715460 ER PT J AU Lambert-Kerzner, A Del Giacco, EJ Fahdi, IE Bryson, CL Melnyk, SD Bosworth, HB Davis, R Mun, H Weaver, J Barnett, C Radcliff, T Hubbard, A Bosket, KD Carey, E Virchow, A Mihalko-Corbitt, R Kaufman, A Marchant-Miros, K Ho, PM AF Lambert-Kerzner, Anne Del Giacco, Eric J. Fahdi, Ibrahim E. Bryson, Chris L. Melnyk, S. Dee Bosworth, Hayden B. Davis, Ryan Mun, Howard Weaver, Jennifer Barnett, Casey Radcliff, Tiffany Hubbard, Amanda Bosket, Kevin D. Carey, Evan Virchow, Allison Mihalko-Corbitt, Renee Kaufman, Amy Marchant-Miros, Kathy Ho, P. Michael CA Multifaceted Intervention Improve TI Patient-Centered Adherence Intervention After Acute Coronary Syndrome Hospitalization SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE acute coronary syndromes; adherence; medication adherence; cost-effectiveness; treatment effectiveness ID ACUTE MYOCARDIAL-INFARCTION; SECONDARY PREVENTION; MEDICATION; CARE; THERAPY; OUTCOMES; DISCONTINUATION; PREVALENCE; PREDICTORS; MORTALITY AB Background-Adherence to cardioprotective medications in the year after acute coronary syndrome hospitalization is generally poor and is associated with increased risk of rehospitalization and mortality. Few interventions have specifically targeted this high-risk patient population to improve medication adherence. We hypothesize that a multifaceted patient-centered intervention could improve adherence to cardioprotective medications. Methods and Results-To evaluate this intervention, we propose enrolling 280 patients with a recent acute coronary syndrome event into a multicenter randomized, controlled trial. The intervention comprises4 main components: (1) pharmacist-led medication reconciliation and tailoring; (2) patient education; (3) collaborative care between pharmacist and primary care provider/cardiologist; and (4) 2 types of voice messaging (educational and medication refill reminder calls). Patients in the intervention arm will visit with the study pharmacist approximate to 1 week post-hospital discharge. The pharmacist will work with the patient and collaborate with providers to reconcile medication issues. Voice messages will augment the educational process and remind patients to refill their cardioprotective medications. The study will compare the intervention versus usual care for 12 months. The primary outcome of interest is adherence using the ReComp method. Secondary and tertiary outcomes include achievement of targets for blood pressure and low-density lipoprotein, and reduction in the combined cardiovascular end points of myocardial infarction hospitalization, coronary revascularization, and all-cause mortality. Finally, we will also evaluate the cost-effectiveness of the intervention compared with usual care. Conclusions-If the intervention is effective in improving medication adherence and demonstrating a lower cost, the intervention has the potential to improve cardiovascular outcomes in this high-risk patient population. (Circ Cardiovasc Qual Outcomes. 2012; 5: 571-576.) C1 [Lambert-Kerzner, Anne; Davis, Ryan; Radcliff, Tiffany; Carey, Evan; Virchow, Allison; Multifaceted Intervention Improve] Denver VA Med Ctr, Denver, CO USA. [Del Giacco, Eric J.; Fahdi, Ibrahim E.; Weaver, Jennifer; Barnett, Casey; Hubbard, Amanda; Mihalko-Corbitt, Renee; Marchant-Miros, Kathy] Little Rock VA Med Ctr, Little Rock, AR USA. [Bryson, Chris L.; Mun, Howard; Bosket, Kevin D.] Puget Sound VA Med Ctr, Seattle, WA USA. [Melnyk, S. Dee; Bosworth, Hayden B.; Kaufman, Amy] Durham VA Med Ctr, Durham, NC USA. RP Lambert-Kerzner, A (reprint author), 1055 Clermont St, Denver, CO 80220 USA. EM anne.lambert-kerzner@va.gov FU Veterans Administration Health Services Research and Development Grant [IIR 08-302]; VA HSR&D Career Development Award; VA HSR&D Career Scientist Award [RCS 08-027] FX The study is being funded by Veterans Administration Health Services Research and Development Grant contract number IIR 08-302.; Dr Ho is supported by a VA HSR&D Career Development Award.5-26 Dr Bosworth was supported by a VA HSR&D Career Scientist Award (RCS 08-027). NR 32 TC 12 Z9 13 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2012 VL 5 IS 4 BP 571 EP 576 DI 10.1161/CIRCOUTCOMES.111.962290 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 002PO UT WOS:000308544500024 PM 22811499 ER PT J AU Farsani, TT Jalian, HR Young, LC AF Farsani, Terry T. Jalian, Hrak Ray Young, Lorraine Clarke TI Chemical Leukoderma Occurring After Use of Hair Dye Containing para-Phenylenediamine SO DERMATITIS LA English DT Editorial Material C1 [Farsani, Terry T.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Jalian, Hrak Ray] Massachusetts Gen Hosp, Dermatol Laser & Cosmet Ctr, Boston, MA 02114 USA. [Young, Lorraine Clarke] Univ Los Angeles, Dept Dermatol, Los Angeles, CA USA. RP Young, LC (reprint author), Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, 200 UCLA Med Plaza,Suite 450, Los Angeles, CA 90095 USA. EM lcyoung@mednet.ucla.edu NR 4 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1710-3568 J9 DERMATITIS JI Dermatitis PD JUL-AUG PY 2012 VL 23 IS 4 BP 181 EP 182 DI 10.1097/DER.0b013e318260d5cd PG 3 WC Dermatology SC Dermatology GA 002MJ UT WOS:000308536000011 PM 22828262 ER PT J AU De La Garza, BH Li, G Shih, YYI Duong, TQ AF De La Garza, Bryan H. Li, Guang Shih, Yen-Yu I. Duong, Timothy Q. TI Layer-Specific Manganese-Enhanced MRI of the Retina in Light and Dark Adaptation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHOROIDAL BLOOD-FLOW; OPTICAL COHERENCE TOMOGRAPHY; RAT RETINA; FUNCTIONAL MRI; OUTER RETINA; IN-VIVO; OXYGEN DISTRIBUTION; GLUCOSE-METABOLISM; CAT RETINA; CONSUMPTION AB PURPOSE. To employ functional manganese-enhanced MRI (MEMRI) to image layer-specific changes in calcium-dependent activities in the rat retina during light versus dark adaptation. METHODS. Functional MEMRI at 203203700 mu m was used to study light and dark adaptation in the same animals (N = 10) in which one eye was covered and the fellow eye was not. The activity encoding of the light and dark adaptation was achieved in awake conditions and imaged under anesthesia. T-1-weighted MRI at 11.7 tesla (T) was performed using two identical radiofrequency transceiver coils to allow interleaved MRI acquisitions of the two eyes. An intravascular contrast agent was also used to verify layer assignments. RESULTS. MEMRI detected contrasts among the inner retina, outer retina, and choroid. Independent confirmation of the vascular layers and boundaries between layers was documented with an intravascular contrast agent. The retinal layer thicknesses agreed with published data. The outer retina had lower MEMRI activity in light compared with dark adaption (P < 0.001), consistent with the increased metabolic demand associated with the "dark current." The inner retina had higher MEMRI activity in light compared with dark adaption (P < 0.05). The choroid MEMRI activity was not statistically different between light and dark adaptation (P > 0.05). CONCLUSIONS. This study demonstrated a high-resolution MEMRI protocol to image functional activities among different layers of the retinas in awake animals during light and dark adaptation. This approach could have potential applications in animal models of retinal dysfunction. (Invest Ophthalmol Vis Sci. 2012;53:4352-4358) DOI:10.1167/iovs.11-8826 C1 [De La Garza, Bryan H.; Li, Guang; Shih, Yen-Yu I.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Li, Guang/C-9539-2011; OI Li, Guang/0000-0002-7648-0464; Shih, Yen-Yu Ian/0000-0001-6529-911X FU NIH/NEI [R01 EY014211, EY018855]; MERIT Award from the Department of Veterans Affairs FX Supported in part by NIH/NEI Grants R01 EY014211 and EY018855 and a MERIT Award from the Department of Veterans Affairs. NR 50 TC 11 Z9 11 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2012 VL 53 IS 8 BP 4352 EP 4358 DI 10.1167/iovs.11-8826 PG 7 WC Ophthalmology SC Ophthalmology GA 983DA UT WOS:000307096400004 PM 22669725 ER PT J AU Staniszewska, M Gu, XL Romano, C Kazlauskas, A AF Staniszewska, Magdalena Gu, Xiaolin Romano, Carmelo Kazlauskas, Andrius TI A Phage Display-Based Approach to Investigate Abnormal Neovessels of the Retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OXYGEN-INDUCED RETINOPATHY; DIABETIC-RETINOPATHY; ANGIOGENESIS; PEPTIDES; RECEPTOR; MOUSE; DEGENERATION; LIBRARIES; THERAPY; TARGET AB PURPOSE. The goal of this project was to identify markers of abnormal neovascularization of the retinal vasculature, which is quintessential of pathologic angiogenesis that occurs in blinding diseases such as proliferative diabetic retinopathy. METHODS. Abnormal retinal neovascularization was induced in rat pups by subjecting them to the 50/10 oxygen-induced retinopathy (OIR) protocol, which involves fluctuating levels of ambient oxygen. A peptide library (that was displayed on phage) was positively and negatively screened over the surface of retinas isolated from experimental and control rats, respectively. Binding of phage to retinal vessels was evaluated by confocal microscopy of retinal flat mounts decorated with fluorescently labeled phage. The topography of the inner limiting membrane was studied by scanning electron microscopy. RESULTS. Screening a library of peptides displayed on phage over the surface of OIR retinas resulted in isolation of a particular phage (SH phage) that distinguished between abnormal neovessels and the normal vasculature. As expected, the recognition of abnormal neovessels relied on the unique peptide insert of SH phage. Abnormal neovessels consisted of at least three cell types that were present in the following order of descending abundance: endothelial > pericytes > macrophage/microglia. SH phage recognized both endothelial cells and macrophage/microglia. Finally, SH phage decorated abnormal neovessels at an early stage of their genesis. CONCLUSIONS. Abnormal development of neovessels is associated with early expression of distinct epitopes on the surface of cells within the pathologic vasculature. Screening phage display libraries is one approach to detecting such changes, and the resulting phage are potential imaging tools and/or drug delivery vehicles. (Invest Ophthalmol Vis Sci. 2012;53:4371-4379) DOI:10.1167/iovs.12-9690 C1 [Staniszewska, Magdalena; Kazlauskas, Andrius] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Gu, Xiaolin; Romano, Carmelo] Alcon Res Ltd, Ft Worth, TX USA. RP Kazlauskas, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM Andrius_kazlauskas@meei.harvard.edu RI Staniszewska, Monika/B-1939-2015 FU Alcon; Knights Templar Eye Foundation; One Sight Foundation FX Supported by grants from Alcon (AK), Knights Templar Eye Foundation, and One Sight Foundation (MS). NR 24 TC 2 Z9 2 U1 1 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2012 VL 53 IS 8 BP 4371 EP 4379 DI 10.1167/iovs.12-9690 PG 9 WC Ophthalmology SC Ophthalmology GA 983DA UT WOS:000307096400007 PM 22661481 ER PT J AU Ulmer, M Li, J Yaspan, BL Ozel, AB Richards, JE Moroi, SE Hawthorne, F Budenz, DL Friedman, DS Gaasterland, D Haines, J Kang, JH Lee, R Lichter, P Liu, YT Pasquale, LR Pericak-Vance, M Realini, A Schuman, JS Singh, K Vollrath, D Weinreb, R Wollstein, G Zack, DJ Zhang, K Young, T Allingham, RR Wiggs, JL Ashley-Koch, A Hauser, MA AF Ulmer, Megan Li, Jun Yaspan, Brian L. Ozel, Ayse Bilge Richards, Julia E. Moroi, Sayoko E. Hawthorne, Felicia Budenz, Donald L. Friedman, David S. Gaasterland, Douglas Haines, Jonathan Kang, Jae H. Lee, Richard Lichter, Paul Liu, Yutao Pasquale, Louis R. Pericak-Vance, Margaret Realini, Anthony Schuman, Joel S. Singh, Kuldev Vollrath, Douglas Weinreb, Robert Wollstein, Gadi Zack, Donald J. Zhang, Kang Young, Terri Allingham, R. Rand Wiggs, Janey L. Ashley-Koch, Allison Hauser, Michael A. TI Genome-Wide Analysis of Central Corneal Thickness in Primary Open-Angle Glaucoma Cases in the NEIGHBOR and GLAUGEN Consortia SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CELL-ADHESION MOLECULES; INTRAOCULAR-PRESSURE; OCULAR HYPERTENSION; ASSOCIATION; VARIANTS; GENE; IDENTIFICATION; POPULATIONS; MUTATIONS; LINKAGE AB PURPOSE. To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia. METHODS. A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n = 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n=6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis. RESULTS. Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P = 0.001; beta = -5.08 mu m/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P = 0.00099; Odds Ratio [OR] = 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; P = 0.018; OR = 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues. CONCLUSIONS. The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases. (Invest Ophthalmol Vis Sci. 2012;53:4468-4474) DOI:10.1167/iovs.12-9784 C1 [Hauser, Michael A.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Li, Jun; Ozel, Ayse Bilge] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Yaspan, Brian L.; Haines, Jonathan] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Richards, Julia E.; Moroi, Sayoko E.; Lichter, Paul] Univ Michigan, Dept Optometry & Visual Sci, Ann Arbor, MI 48109 USA. [Richards, Julia E.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Budenz, Donald L.] Univ N Carolina, Sch Med, Dept Ophthalmol, Chapel Hill, NC USA. [Friedman, David S.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Gaasterland, Douglas] Eye Doctors Washington DC, Washington, DC USA. [Kang, Jae H.; Pasquale, Louis R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Lee, Richard] Univ Miami, Dept Ophthalmol, Miami, FL USA. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Pericak-Vance, Margaret] Univ Miami, Sch Med, Dept Human Genet, Miami, FL USA. [Realini, Anthony] W Virginia Univ, Dept Ophthalmol, Sch Med, Morgantown, WV 26506 USA. [Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Dept Ophthalmol, Pittsburgh, PA 15260 USA. [Singh, Kuldev] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Vollrath, Douglas] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Weinreb, Robert; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, San Diego, CA 92103 USA. [Young, Terri; Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Dept Ophthalmol, Sch Med, Durham, NC 27710 USA. RP Hauser, MA (reprint author), Duke Univ, Med Ctr, Ctr Human Genet, Box 3445, Durham, NC 27710 USA. EM mike.hauser@duke.edu RI Schuman, Joel/K-7304-2012; Haines, Jonathan/C-3374-2012; OI Schuman, Joel/0000-0002-8885-3766; Carnes, Megan/0000-0002-7270-132X; Zack, Don/0000-0002-7966-1973; Ashley-Koch, Allison/0000-0001-5409-9155 FU National Eye Institute Grant [HG005259-01]; GENEVA project Grant [HG004728, U01-HG004424]; National Eye Institute through ARRA [3R01EY015872-05S1, 3R01EY019126-02S1]; NIH [EY015543, EY006827, EY13315, EY019126, CA87969, CA49449, CA55075, EY009149, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, RR015574, EY015872, EY010886, EY009847, EY014685, EY011008, EY144428, EY144448, EY18660, T32EY021453]; Harvard Glaucoma Center for Excellence; Margolis Fund; Glaucoma Research Foundation; American Health Assistance Foundation; Glaucoma Foundation; Research to Prevent Blindness; Duke University's CTSA Grant from NCRR/NIH [1 UL1 RR024128-01] FX Supported by National Eye Institute Grant HG005259-01 (JLW); the GENEVA project Grant HG004728 (LRP) and U01-HG004424 (Broad Institute); the National Eye Institute through ARRA Grants 3R01EY015872-05S1 (JLW) and 3R01EY019126-02S1 (MAH); the NIH Grants EY015543 (RRA), EY006827 (DG), EY13315 and EY019126 (MAH), CA87969, CA49449, and CA55075 (JHK), EY009149 (PL), EY015473 (LRP), EY012118 (MPV), EY015682 (AR), EY011671 and EY09580 (JER), EY013178 (JS), RR015574, EY015872, EY010886, and EY009847 (JLW), EY014685 (TY), EY011008, EY144428, EY144448, and EY18660 (KZ); the Harvard Glaucoma Center for Excellence, and the Margolis Fund (JLW and LRP); in part by the NIH T32EY021453 (BLY); the Glaucoma Research Foundation, American Health Assistance Foundation, and the Glaucoma Foundation (YL); the Research to Prevent Blindness (JLW, LRP, TY, and JER); and in part by Duke University's CTSA Grant 1 UL1 RR024128-01 from NCRR/NIH. NR 32 TC 23 Z9 23 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2012 VL 53 IS 8 BP 4468 EP 4474 DI 10.1167/iovs.12-9784 PG 7 WC Ophthalmology SC Ophthalmology GA 983DA UT WOS:000307096400018 PM 22661486 ER PT J AU Volz, MS Volz, TS Brunoni, AR de Oliveira, JPVTR Fregni, F AF Volz, Magdalena Sarah Volz, Theresa Sophie Brunoni, Andre Russowsky Tostes Ribeiro de Oliveira, Joao Paulo Vaz Fregni, Felipe TI Analgesic Effects of Noninvasive Brain Stimulation in Rodent Animal Models: A Systematic Review of Translational Findings SO NEUROMODULATION LA English DT Review DE Brain stimulation; pain; stroke; systematic review; translational research ID TRANSCRANIAL MAGNETIC STIMULATION; PAIRED ASSOCIATIVE STIMULATION; OPIATE ABSTINENCE SYNDROME; MOTOR CORTEX STIMULATION; RAT STROKE MODEL; ELECTRICAL-STIMULATION; CHRONIC PAIN; ELECTROSTIMULATION; RECOVERY; EXCITABILITY AB Objectives: Noninvasive brain stimulation (NIBS) interventions have demonstrated promising results in the clinical treatment of pain, according to several preliminary trials, although the results have been mixed. The limitations of clinical research on NIBS are the insufficient understanding of its mechanisms of action, a lack of adequate safety data, and several disparities with regard to stimulation parameters, which have hindered the generalizability of such studies. Thus, experimental animal research that allows the use of more invasive interventions and creates additional control of independent variables and confounders is desirable. To this end, we systematically reviewed animal studies investigating the analgesic effects of NIBS. In addition, we also explored the investigation of NIBS in animal models of stroke as to compare these findings with NIBS animal pain research. Methods: Of 1916 articles that were found initially, we identified 15 studies (stroke and pain studies) per our eligibility criteria that used NIBS methods, such as transcranial direct current stimulation, paired associative stimulation, transcranial magnetic stimulation, and transcranial electrostimulation. We extracted the main outcomes on stroke and pain, as well as the methods and electrical parameters of each technique. Results: NIBS techniques are effective in alleviating pain. Similar beneficial clinical effects are observed in stroke. The main insights from these animal studies are the following: 1) combination of NIBS with analgesic drugs has a synergistic effect; 2) effects are dependent on the parameters of stimulation, and in fact, not necessarily the strongest stimulation parameter (i.e., the largest intensity of stimulation) is associated with the largest benefit; 3) pain studies show an overall good quality as indexed by Animals in Research: Reporting In Vivo Experiments guidelines of the reporting of animal experiments, but insufficient with regard to the reporting of safety data for brain stimulation; 4) these studies suggest that NIBS techniques have a primary effect on synaptic plasticity, but they also suggest other mechanisms of action such as via neurovascular modulation. Conclusions: We found a limited number of animal studies for both pain and stroke NIBS experimental research. There is a lack of safety data in animal studies in these two topics and results from these studies have not been yet fully tested and translated to human research. We discuss the challenges and limitations of translating experimental animal research on NIBS into clinical studies. C1 [Volz, Magdalena Sarah; Volz, Theresa Sophie; Tostes Ribeiro de Oliveira, Joao Paulo Vaz; Fregni, Felipe] Spaulding Rehabil Hosp, Lab Neuromodulat, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Volz, Magdalena Sarah; Volz, Theresa Sophie; Tostes Ribeiro de Oliveira, Joao Paulo Vaz; Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Volz, Magdalena Sarah] Charite Univ Med Berlin, Berlin, Germany. [Brunoni, Andre Russowsky; Tostes Ribeiro de Oliveira, Joao Paulo Vaz; Fregni, Felipe] Univ Sao Paulo, Univ Hosp, Sao Paulo, Brazil. RP Fregni, F (reprint author), Spaulding Rehabil Hosp, Lab Neuromodulat, Dept Phys Med & Rehabil, 125 Nashua St,727, Boston, MA 02114 USA. EM fregni.felipe@mgh.harvard.edu RI Brunoni, Andre/H-8394-2012 OI Brunoni, Andre/0000-0002-6310-3571 FU German Academic Exchange Service (Deutscher Akademischer Austausch Dienst [DAAD]); National Institutes of Health grant [5R21DK081773-03]; Christopher and Dana Reeve Foundation; National Institute on Disability and Rehabilitation Research spinal cord injury model systems program FX Magdalena S. Volz was funded by a grant scholarship from the German Academic Exchange Service (Deutscher Akademischer Austausch Dienst [DAAD]). This work was partially supported by a National Institutes of Health grant (5R21DK081773-03), Christopher and Dana Reeve Foundation, and National Institute on Disability and Rehabilitation Research spinal cord injury model systems program. NR 44 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 J9 NEUROMODULATION JI Neuromodulation PD JUL-AUG PY 2012 VL 15 IS 4 BP 283 EP 295 DI 10.1111/j.1525-1403.2012.00478.x PG 13 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA 984VG UT WOS:000307219900004 PM 22759345 ER PT J AU Bikson, M Rahman, A Datta, A Fregni, F Merabet, L AF Bikson, Marom Rahman, Asif Datta, Abhishek Fregni, Felipe Merabet, Lotfi TI High-Resolution Modeling Assisted Design of Customized and Individualized Transcranial Direct Current Stimulation Protocols SO NEUROMODULATION LA English DT Article DE Electrical stimulation; FEM; fMRI; head model; lesion; modeling; neuromodulation; skull defects; stroke; tDCS; TMS; traumatic brain injury ID ELECTRIC-FIELDS; DC STIMULATION; SPINAL-CORD; BRAIN; TDCS; TOLERABILITY; POLARIZATION; EXCITABILITY; APHASIA; FEM AB Objectives: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity currents facilitating or inhibiting spontaneous neuronal activity. tDCS is attractive since dose is readily adjustable by simply changing electrode number, position, size, shape, and current. In the recent past, computational models have been developed with increased precision with the goal to help customize tDCS dose. The aim of this review is to discuss the incorporation of high-resolution patient-specific computer modeling to guide and optimize tDCS. Methods: In this review, we discuss the following topics: 1) The clinical motivation and rationale for models of transcranial stimulation is considered pivotal in order to leverage the flexibility of neuromodulation; 2) the protocols and the workflow for developing high-resolution models; 3) the technical challenges and limitations of interpreting modeling predictions; and 4) real cases merging modeling and clinical data illustrating the impact of computational models on the rational design of rehabilitative electrotherapy. Conclusions: Though modeling for noninvasive brain stimulation is still in its development phase, it is predicted that with increased validation, dissemination, simplification, and democratization of modeling tools, computational forward models of neuromodulation will become useful tools to guide the optimization of clinical electrotherapy. C1 [Bikson, Marom; Rahman, Asif] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Datta, Abhishek; Fregni, Felipe] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Lab Neuromodulat, Boston, MA USA. [Merabet, Lotfi] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Vis Rehabil Ctr,Dept Ophthalmol, Boston, MA USA. RP Bikson, M (reprint author), 160 Convent Ave,Steinman Hall,Rm 403B, New York, NY 10031 USA. EM bikson@ccny.cuny.edu FU National Institutes of Health [S06 GM008168 NS054783, CRCNS 41771]; Andy Grove Foundation; Wallace H Coulter Foundation FX Dr. Datta is cofounder of Soterix Medical. The City University of New York has patent applications in Dr. Datta's name on brain stimulation. Dr. Bikson is funded by the National Institutes of Health (nos. S06 GM008168 NS054783, CRCNS 41771), the Andy Grove Foundation, and the Wallace H Coulter Foundation. The City University of New York has patent applications in Dr. Bikson's name on brain stimulation. Dr. Bikson is cofounder of Soterix Medical. NR 40 TC 40 Z9 40 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 J9 NEUROMODULATION JI Neuromodulation PD JUL-AUG PY 2012 VL 15 IS 4 BP 306 EP 315 DI 10.1111/j.1525-1403.2012.00481.x PG 10 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA 984VG UT WOS:000307219900006 PM 22780230 ER PT J AU Villamar, MF Portilla, AS Fregni, F Zafonte, R AF Villamar, Mauricio Fernando Portilla, Andrea Santos Fregni, Felipe Zafonte, Ross TI Noninvasive Brain Stimulation to Modulate Neuroplasticity in Traumatic Brain Injury SO NEUROMODULATION LA English DT Article DE Diffuse axonal injury; neuroplasticity; transcranial direct current stimulation; transcranial magnetic stimulation; traumatic brain injury ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; LONG-TERM POTENTIATION; THETA-BURST-STIMULATION; LOW-FREQUENCY RTMS; ADULT HUMAN BRAIN; SYNAPTIC PLASTICITY; STROKE PATIENTS; WORKING-MEMORY; CORTICAL EXCITABILITY AB Objective: To review the use of noninvasive brain stimulation (NBS) as a therapeutic tool to enhance neuroplasticity following traumatic brain injury (TBI). Materials and Methods: Based on a literature search, we describe the pathophysiological events following TBI and the rationale for the use of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in this setting. Results: The pathophysiological mechanisms occurring after TBI vary across time and therefore require differential interventions. Theoretically, given the neurophysiological effects of both TMS and tDCS, these tools may: 1) decrease cortical hyperexcitability acutely after TBI; 2) modulate long-term synaptic plasticity as to avoid maladaptive consequences; and 3) combined with physical and behavioral therapy, facilitate cortical reorganization and consolidation of learning in specific neural networks. All of these interventions may help decrease the burden of disabling sequelae after brain injury. Conclusions: Evidence from animal and human studies reveals the potential benefit of NBS in decreasing the extent of injury and enhancing plastic changes to facilitate learning and recovery of function in lesioned neural tissue. However, this evidence is mainly theoretical at this point. Given safety constraints, studies in TBI patients are necessary to address the role of NBS in this condition as well as to further elucidate its therapeutic effects and define optimal stimulation parameters. C1 [Villamar, Mauricio Fernando; Portilla, Andrea Santos; Fregni, Felipe; Zafonte, Ross] Harvard Univ, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Lab Neuromodulat,Med Sch, Boston, MA 02114 USA. [Villamar, Mauricio Fernando; Portilla, Andrea Santos; Fregni, Felipe; Zafonte, Ross] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Zafonte, R (reprint author), Harvard Univ, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Lab Neuromodulat,Med Sch, 125 Nashua St 706, Boston, MA 02114 USA. EM rzafonte@partners.org OI Villamar, Mauricio F./0000-0003-4503-8152 NR 209 TC 27 Z9 27 U1 3 U2 43 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 EI 1525-1403 J9 NEUROMODULATION JI Neuromodulation PD JUL-AUG PY 2012 VL 15 IS 4 BP 326 EP 338 DI 10.1111/j.1525-1403.2012.00474.x PG 13 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA 984VG UT WOS:000307219900008 PM 22882244 ER PT J AU Plow, EB Obretenova, SN Jackson, ML Merabet, LB AF Plow, Ela B. Obretenova, Souzana N. Jackson, Mary Lou Merabet, Lotfi B. TI Temporal Profile of Functional Visual Rehabilitative Outcomes Modulated by Transcranial Direct Current Stimulation SO NEUROMODULATION LA English DT Article DE Brain stimulation; hemianopia; rehabilitation; transcranial direct current stimulation (tDCS); vision restoration therapy (VRT); visual field ID NONINVASIVE BRAIN-STIMULATION; VISION RESTORATION THERAPY; CORTICAL STIMULATION; CEREBRAL BLINDNESS; STROKE PATIENTS; FIELD DEFECTS; RECOVERY; HEMIANOPIA; PERCEPTION; PLASTICITY AB Objectives: We have previously reported that transcranial direct current stimulation (tDCS) delivered to the occipital cortex enhances visual functional recovery when combined with three months of computer-based rehabilitative training in patients with hemianopia. The principal objective of this study was to evaluate the temporal sequence of effects of tDCS on visual recovery as they appear over the course of training and across different indicators of visual function. Methods: Primary objective outcome measures were 1) shifts in visual field border and 2) stimulus detection accuracy within the affected hemifield. These were compared between patients randomized to either vision restoration therapy (VRT) combined with active tDCS or VRT paired with sham tDCS. Training comprised two half-hour sessions, three times a week for three months. Primary outcome measures were collected at baseline (pretest), monthly interim intervals, and at posttest (three months). As secondary outcome measures, contrast sensitivity and reading performance were collected at pretest and posttest time points only. Results: Active tDCS combined with VRT accelerated the recovery of stimulus detection as between-group differences appeared within the first month of training. In contrast, a shift in the visual field border was only evident at posttest (after three months of training). tDCS did not affect contrast sensitivity or reading performance. Conclusions: These results suggest that tDCS may differentially affect the magnitude and sequence of visual recovery in a manner that is task specific to the type of visual rehabilitative training strategy employed. C1 [Jackson, Mary Lou; Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Vis Rehabil Ctr,Dept Ophthalmol, Boston, MA 02114 USA. [Plow, Ela B.; Obretenova, Souzana N.; Merabet, Lotfi B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Med Sch, Boston, MA 02114 USA. [Plow, Ela B.] Cleveland Clin Fdn, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. RP Merabet, LB (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Vis Rehabil Ctr,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM lotfi_merabet@meei.harvard.edu FU Novavision VRT Inc.; National Institutes of Health [K23-EY016131] FX This work was supported by an investigator-initiated pilot grant from Novavision VRT Inc. and by the National Institutes of Health (K23-EY016131 to LBM). NR 47 TC 16 Z9 17 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 J9 NEUROMODULATION JI Neuromodulation PD JUL-AUG PY 2012 VL 15 IS 4 BP 367 EP 373 DI 10.1111/j.1525-1403.2012.00440.x PG 7 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA 984VG UT WOS:000307219900012 PM 22376226 ER PT J AU Okereke, OI Pantoja-Galicia, N Copeland, M Hyman, BT Wanggaard, T Albert, MS Betensky, RA Blacker, D AF Okereke, Olivia I. Pantoja-Galicia, Norberto Copeland, Maura Hyman, Bradley T. Wanggaard, Taylor Albert, Marilyn S. Betensky, Rebecca A. Blacker, Deborah TI The SIST-M Predictive Validity of a Brief Structured Clinical Dementia Rating Interview SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; mild cognitive impairment; dementia; CDR; instrument; questionnaire; validity; prediction; psychometric ID MILD COGNITIVE IMPAIRMENT; DIAGNOSTIC-CRITERIA; ALZHEIMERS-DISEASE; RELIABILITY AB Background: We have previously established the reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI). Objective: To test the predictive validity of the SIST-M. Methods: Participants were 342 community-dwelling, nondemented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either (1) clinician interviews or (2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age + sex + education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either a clinician interview or an algorithm; models were run for the full sample (n = 342) and among those jointly classified as vMCI using clinician-based and algorithm-based CDR ratings (n = 156). We directly compared predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. Results: AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, the respective HRs [95% confidence interval (CI)] were 3.1 (2.5, 3.9) and 2.8 (2.2, 3.5); among those with vMCI, the respective HRs (95% CI) were 2.2 (1.6, 3.2) and 2.1 (1.5, 3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 versus 0.76 using clinician-based versus algorithm-based CDR-SB. Conclusion: CDR scores based on items from this shortened interview had high predictive ability for AD-comparable to that using a lengthy clinical interview. C1 [Okereke, Olivia I.; Copeland, Maura; Wanggaard, Taylor; Blacker, Deborah] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02138 USA. [Hyman, Bradley T.; Blacker, Deborah] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Cambridge, MA 02138 USA. [Pantoja-Galicia, Norberto; Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Albert, Marilyn S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Okereke, OI (reprint author), MGH Gerontol Res Unit, 149 13th St,Suite 2691, Charlestown, MA 02129 USA. EM ookereke@partners.org RI Okereke, Olivia/R-9934-2016 FU Harvard Neuro Discovery Center; National Institute on Aging of the National Institutes of Health [P01-AG004953, P50-AG005134]; NIH; Alzheimer's Association; GE Healthcare; Fidelity Foundation FX Supported by the Harvard Neuro Discovery Center and the National Institute on Aging of the National Institutes of Health (P01-AG004953, P50-AG005134). This study is not industry sponsored. The copyrights in the 2 instruments referred to in this article, the SIST-M and the SIST-M-IR, belong to The General Hospital Corporation d/b/a Massachusetts General Hospital. Additional information and downloadable. pdfs are freely available at http://madrc.mgh.harvard.edu/structured-interview-scoring-tool-massachu setts-adrc-sist-m.; Drs Okereke, Pantoja-Galicia, and Betensky completed all statistical analyses. Dr Okereke receives funding from the NIH and the Alzheimer's Association. She serves on the Board of Directors of the Alzheimer's Association, Massachusetts/New Hampshire Chapter. Dr Pantoja-Galicia reports current employment by the U.S. Food and Drug Administration. He reports no financial disclosures or conflicts. Dr Copeland reports no disclosures. Dr Hyman receives funding from the NIH, the Alzheimer's Association, and Fidelity Biosciences. He reports consulting with pharmaceutical and biotechnology companies: EMD Serrano, Janssen, Takeda, BMS, Neurophage, Pfizer, Quanterix, foldrx, Elan, and Link. He holds no stock options. He reports no conflicts pertaining to this article. Ms Wanggaard reports no disclosures. Dr Albert reports serving as a consultant for Genentech and Eli Lilly, and receiving grants to her institution from GE Healthcare. Dr Betensky reports no disclosures. Dr Blacker receives funding from the NIH, the Alzheimer's Association, and Fidelity Foundation. She serves on the Board of Directors of the Alzheimer's Association, Massachusetts/New Hampshire Chapter. NR 21 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2012 VL 26 IS 3 BP 225 EP 231 DI 10.1097/WAD.0b013e318231cd30 PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 997SR UT WOS:000308186900005 PM 21986342 ER PT J AU Quintana, A Hoth, M AF Quintana, Ariel Hoth, Markus TI Mitochondrial dynamics and their impact on T cell function SO CELL CALCIUM LA English DT Article DE Mitochondria; Calcium; Transport; Fusion; Fission; Tethering; Endoplasmic reticulum; CRAC; ORAI; PMCA; Calcium microdomain; T cells; T lymphocytes; Immune synapse ID IMMUNOLOGICAL SYNAPSE; PLASMA-MEMBRANE; CALCIUM SIGNALS; IMMUNE SYNAPSE; CRAC CHANNELS; CA2+ INFLUX; ESSENTIAL COMPONENT; REDOX REGULATION; BUDDING YEAST; ION CHANNELS AB Energy supply is the most prominent function of mitochondria, but in addition, mitochondria are indispensable for a multitude of other important cellular functions including calcium (Ca2+) signaling and buffering, the supply of metabolites and the sequestration of apoptotic factors. The efficiency of those functions highly depends on the proper positioning of mitochondria within the cytosol. In lymphocytes, mitochondria preferentially localize into the vicinity (similar to 200 nm) of the immune synapse (IS). This localization is regulated by motor-based cytoskeleton-mediated transport, the fusion/fission dynamics of mitochondria, and probably also through tethering with the ER. IS formation also induces the accumulation of CRAC/ORAI1 Ca2+ channels, the CRAC/ORAI channel activator STIM1, K+ channels and plasma membrane Ca2+ ATPase (PMCA) within the IS. Such a large agglomeration of Ca2+ binding organelles and proteins highlights the IS as a critical cellular compartment for Ca2+ dependent lymphocyte activation. At the IS, Ca2+ microdomains generated beneath open CRAC/ORAI channels provide a rapid, robust and reliable mechanism for driving cellular responses in mast cells and T cells. Here, we discuss the relevance of motor-based mitochondrial transport, fusion, fission and tethering for mitochondrial localization in T cells and the importance of subplasmalemmal mitochondria to control local CRAC/ORAI1-dependent Ca2+ microdomains at the IS for efficient T lymphocyte activation. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Hoth, Markus] Univ Saarland, Dept Biophys, D-66421 Homburg, Germany. [Quintana, Ariel] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Quintana, Ariel] Harvard Univ, Immune Dis Inst, Dept Pathol, Boston, MA 02115 USA. RP Hoth, M (reprint author), Univ Saarland, Dept Biophys, Gebaude 58, D-66421 Homburg, Germany. EM markus.hoth@uks.eu OI Hoth, Markus/0000-0001-7080-4643 FU Deutsche Forschungsgemeinschaft (DFG); DFG [QU-298/1-1] FX We would like to acknowledge funding by the Deutsche Forschungsgemeinschaft (DFG). In particular we acknowledge collaborative research center SFB 894 and two research training groups (GRK 845 and GRK 1326) all to M.H. A.Q. was funded by a DFG fellowship (QU-298/1-1) NR 79 TC 33 Z9 33 U1 1 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD JUL PY 2012 VL 52 IS 1 SI SI BP 57 EP 63 DI 10.1016/j.ceca.2012.02.005 PG 7 WC Cell Biology SC Cell Biology GA 980DU UT WOS:000306874600009 PM 22425631 ER PT J AU Wilson, R Anzueto, A Miravitlles, M Arvis, P Alder, J Haverstock, D Trajanovic, M Sethi, S AF Wilson, Robert Anzueto, Antonio Miravitlles, Marc Arvis, Pierre Alder, Jeff Haverstock, Daniel Trajanovic, Mila Sethi, Sanjay TI Moxifloxacin versus amoxicillin/clavulanic acid in outpatient acute exacerbations of COPD: MAESTRAL results SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE Acute exacerbations of chronic obstructive pulmonary disease; amoxicillin/clavulanic acid; antibiotic; clinical trial design; exacerbation; moxifloxacin ID OBSTRUCTIVE PULMONARY-DISEASE; GEORGES RESPIRATORY QUESTIONNAIRE; ACUTE BACTERIAL EXACERBATIONS; LONG-TERM OUTCOMES; CHRONIC-BRONCHITIS; ANTIBIOTIC-TREATMENT; TRACT INFECTION; LUNG-FUNCTION; HEALTH-STATUS; FREE INTERVAL AB Bacterial infections causing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) frequently require antibacterial treatment. More evidence is needed to guide antibiotic choice. The Moxifloxacin in Acute Exacerbations of Chronic Bronchitis TriaL (MAESTRAL) was a multiregional, randomised, double-blind non-inferiority outpatient study. Patients were aged >= 60 yrs, with an Anthonisen type I exacerbation, a forced expiratory volume in 1 s <60% predicted and two or more exacerbations in the last year. Following stratification by steroid use patients received moxifloxacin 400 mg p.o.q.d. (5 days) or amoxicillin/clavulanic acid 875/125 mg p.o. b.i.d. (7 days). The primary end-point was clinical failure 8 weeks post-therapy in the per protocol population. Moxifloxacin was noninferior to amoxicillin/clavulanic acid at the primary end-point (111 (20.6%) out of 538, versus 114 (22.0%) out of 518, respectively; 95% CI -5.89-3.83%). In patients with confirmed bacterial AECOPD, moxifloxacin led to significantly lower clinical failure rates than amoxicillin/clavulanic acid (in the intent-to-treat with pathogens, 62 (19.0%) out of 327 versus 85 (25.4%) out of 335, respectively; p=0.016). Confirmed bacterial eradication at end of therapy was associated with higher clinical cure rates at 8 weeks post-therapy overall (p=0.0014) and for moxifloxacin (p=0.003). Patients treated with oral corticosteroids had more severe disease and higher failure rates. The MAESTRAL study showed that moxifloxacin was as effective as amoxicillin/clavulanic acid in the treatment of outpatients with AECOPD. Both therapies were well tolerated. C1 [Wilson, Robert] Royal Brompton Hosp, Host Def Unit, London SW3 6NP, England. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Alder, Jeff; Haverstock, Daniel] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Sethi, Sanjay] SUNY Buffalo, Div Pulm Crit Care & Sleep Med, Buffalo, NY 14260 USA. [Miravitlles, Marc] Hosp Clin Barcelona, Ciber Enfermedades Resp CIBERES, IDIBAPS, Barcelona, Spain. [Arvis, Pierre] Bayer HealthCare, Loos, France. [Trajanovic, Mila] Bayer Inc, Toronto, ON, Canada. RP Wilson, R (reprint author), Royal Brompton Hosp, Host Def Unit, Sydney St, London SW3 6NP, England. EM r.wilson@rbht.nhs.uk OI Miravitlles, Marc/0000-0002-9850-9520 FU Bayer HealthCare Pharmaceuticals AG, Berlin, Germany; NIHR Respiratory Disease Biomedical Research Unit; Bayer HealthCare FX This study was sponsored by Bayer HealthCare Pharmaceuticals AG, Berlin, Germany. R. Wilson was supported by the NIHR Respiratory Disease Biomedical Research Unit.; Highfield Communication Consultancy, Oxford, UK, funded by Bayer HealthCare, provided editorial support in the development of this paper. All analyses were carried out by the study sponsor and the Data Review Committee was responsible for validating all clinical failure data. The authors thank G. Farago (Bayer Inc., Toronto, ON, Canada), study manager, for excellent and dedicated support throughout the trial and R. Kay (RK Statistics Ltd, Bakewell, UK) for independent statistical assessment. They are also grateful to all physicians who enrolled patients in the study; a full list is given in the online supplementary material. NR 52 TC 33 Z9 36 U1 1 U2 3 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUL PY 2012 VL 40 IS 1 BP 17 EP 27 DI 10.1183/09031936.00090311 PG 11 WC Respiratory System SC Respiratory System GA 985RS UT WOS:000307287500007 PM 22135277 ER PT J AU Lipinski, B Pretorius, E AF Lipinski, B. Pretorius, E. TI Hydroxyl radical-modified fibrinogen as a marker of thrombosis: the role of iron SO HEMATOLOGY LA English DT Article DE Fibrinogen; Fibrinolysis; Hydroxyl radicals; Iron; Thrombosis ID OXIDATIVE STRESS; LABILE IRON; INTRAVASCULAR HEMOLYSIS; ARTERIAL THROMBOSIS; HUMAN-DISEASE; HEMOGLOBIN; CHELATION; ATHEROSCLEROSIS; MECHANISMS; TOXICITY AB Excessive free iron in blood and in organ tissues (so called iron overload) has been observed in degenerative diseases such as atherosclerosis, cancer, neurological, and certain autoimmune diseases, in which fibrin-like deposits are also found. Although most of the body iron is bound to hemoglobin and myoglobin in a divalent ferrous form, a certain amount of iron exists in blood as a trivalent (ferric) ion. This particular chemical state of iron has been shown to be toxic to the human body when not controlled by endogenous and/or dietary chelating agents. Experiments described in this paper show for the first time that ferric ions (Fe3+) can generate hydroxyl radicals without participation of any redox agent, thus making it a special case of the Fenton reaction. Ferric chloride was also demonstrated to induce aggregation of purified fibrinogen at the same molar concentrations that were used for the generation of hydroxyl radicals. Iron-aggregated fibrinogen, by contrast to native molecule, could not be dissociated into polypeptide subunit chains as shown in a polyacrylamide gel electrophoresis. The mechanism of this phenomenon is very likely based on hydroxyl radical-induced modification of fibrinogen tertiary structure with the formation of insoluble aggregates resistant to enzymatic and chemical degradations. Soluble modified fibrinogen species can be determined in blood of thrombotic patients by the reaction with protamine sulfate and/or by scanning electron microscopy. In view of these findings, it is postulated that iron-induced alterations in fibrinogen structure is involved in pathogenesis of certain degenerative diseases associated with iron overload and persistent thrombosis. It is concluded that the detection of hydroxyl radical-modified fibrinogen may be utilized as a marker of a thrombotic condition in human subjects. C1 [Pretorius, E.] Univ Pretoria, Dept Physiol, Fac Hlth Sci, ZA-0007 Arcadia, South Africa. [Lipinski, B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Pretorius, E (reprint author), Univ Pretoria, Dept Physiol, Fac Hlth Sci, Private Bag X323, ZA-0007 Arcadia, South Africa. EM resia.pretorius@up.ac.za OI Pretorius, Etheresia/0000-0002-9108-2384 NR 64 TC 18 Z9 18 U1 2 U2 14 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1024-5332 J9 HEMATOLOGY JI Hematology PD JUL PY 2012 VL 17 IS 4 BP 241 EP 247 DI 10.1179/1607845412Y.0000000004 PG 7 WC Hematology SC Hematology GA 999XV UT WOS:000308349900010 PM 22889519 ER PT J AU Viktorsdottir, O Barth, WH Hartnick, C Pian-Smith, MCM AF Viktorsdottir, O. Barth, W. H., Jr. Hartnick, C. Pian-Smith, M. C. M. TI Severe glottic stenosis in a parturient with ectodermal dysplasia SO INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA LA English DT Article DE Tracheal stenosis; Pregnancy; Airway management; Ectodermal dysplasia; Tracheostomy ID ELEVATED LIVER-ENZYMES; LOW PLATELET COUNT; HELLP-SYNDROME; PREGNANCY; PREECLAMPSIA; HEMOLYSIS; HEMATOMA AB Airway stenosis in pregnancy is challenging and the literature does not offer consensus regarding its evaluation and anesthetic management. A 21-year-old nulliparous woman with ectodermal dysplasia and severe glottic stenosis was referred to the obstetric anesthesia team for evaluation and peripartum management recommendations. She had a history of a congenital complete glottic web that required a tracheostomy at birth. After decannulation at age four, she was lost to follow-up. On examination in early pregnancy, she was found to have a dangerously narrow airway with fixed vocal cords and a glottic aperture of 2-3 mm. At nine weeks of gestation an elective tracheostomy was performed under local anesthesia. She later underwent an uneventful cesarean delivery under spinal anesthesia. Ultimately, early interdisciplinary planning for an elective tracheostomy helped assure patient safety during advancing pregnancy and delivery. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Viktorsdottir, O.; Pian-Smith, M. C. M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Barth, W. H., Jr.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Hartnick, C.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Viktorsdottir, O (reprint author), Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. EM olofvik@gmail.com NR 10 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-289X J9 INT J OBSTET ANESTH JI Int. J. Obstet. Anesth. PD JUL PY 2012 VL 21 IS 3 BP 273 EP 279 DI 10.1016/j.ijoa.2012.04.007 PG 7 WC Anesthesiology; Obstetrics & Gynecology SC Anesthesiology; Obstetrics & Gynecology GA 991ET UT WOS:000307685000011 PM 22658712 ER PT J AU Unglert, CI Namati, E Warger, WC Liu, LB Yoo, HK Kang, DK Bouma, BE Tearney, GJ AF Unglert, Carolin I. Namati, Eman Warger, William C., II Liu, Linbo Yoo, Hongki Kang, DongKyun Bouma, Brett E. Tearney, Guillermo J. TI Evaluation of optical reflectance techniques for imaging of alveolar structure SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE backscattering; biomedical optics; coherent optics; confocal optics; medical imaging; optical coherence tomography; alveolar imaging ID ENCODED CONFOCAL MICROSCOPY; RAY-COMPUTED-TOMOGRAPHY; COHERENCE TOMOGRAPHY; IN-VIVO; ANIMAL-MODELS; BIOPSY; TISSUE; PROBE; LUNG AB Three-dimensional (3-D) visualization of the fine structures within the lung parenchyma could advance our understanding of alveolar physiology and pathophysiology. Current knowledge has been primarily based on histology, but it is a destructive two-dimensional (2-D) technique that is limited by tissue processing artifacts. Micro-CT provides high-resolution three-dimensional (3-D) imaging within a limited sample size, but is not applicable to intact lungs from larger animals or humans. Optical reflectance techniques offer the promise to visualize alveolar regions of the large animal or human lung with sub-cellular resolution in three dimensions. Here, we present the capabilities of three optical reflectance techniques, namely optical frequency domain imaging, spectrally encoded confocal microscopy, and full field optical coherence microscopy, to visualize both gross architecture as well as cellular detail in fixed, phosphate buffered saline-immersed rat lung tissue. Images from all techniques were correlated to each other and then to corresponding histology. Spatial and temporal resolution, imaging depth, and suitability for in vivo probe development were compared to highlight the merits and limitations of each technology for studying respiratory physiology at the alveolar level. (C) 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.JBO.17.7.071303] C1 [Unglert, Carolin I.; Namati, Eman; Warger, William C., II; Liu, Linbo; Yoo, Hongki; Kang, DongKyun; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Unglert, Carolin I.] Air Liquide Ctr Rech Claude Delorme, Med Gases Grp, Les Loges En Josas, France. [Bouma, Brett E.; Tearney, Guillermo J.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Unglert, CI (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, 40 Parkman St,RSL 160, Boston, MA 02114 USA. EM cunglert@mgh.harvard.edu RI Yoo, Hongki/B-6421-2013; Kang, Dongkyun/C-1085-2013 OI Yoo, Hongki/0000-0001-9819-3135; Kang, Dongkyun/0000-0001-5063-5387 FU Air Liquide, Medical Gases, Les-Loges-en-Josas, France FX The authors thank Jenny Zhao and the Wellman Center Photo-pathology Laboratory staff for expert histology processing, and Joseph Gardecki and Yukako Yagi for their help digitizing the histology. This work was supported by Air Liquide, Medical Gases, Les-Loges-en-Josas, France. NR 39 TC 5 Z9 5 U1 0 U2 10 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL PY 2012 VL 17 IS 7 AR 071303 DI 10.1117/1.JBO.17.7.071303 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 995EA UT WOS:000307989500008 PM 22894464 ER PT J AU van Soest, G Villiger, M Regar, E Tearney, GJ Bouma, BE van der Steen, AFW AF van Soest, Gijs Villiger, Martin Regar, Evelyn Tearney, Guillermo J. Bouma, Brett E. van der Steen, Antonius F. W. TI Frequency domain multiplexing for speckle reduction in optical coherence tomography SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE optical coherence tomography; speckle; filtering; image processing; quantitative analysis; intravascular imaging ID ATTENUATION COEFFICIENTS; BIOLOGICAL TISSUES; IMAGES; MICROSCOPY AB Quantitative analysis of optical coherence tomography data can be strongly hampered by speckle. Here, we introduce a new method to reduce speckle, which leverages from Fourier-domain configurations and operates on individual axial scans. By subdividing the digitized spectrum into a number of distinct narrower windows, each with a different center frequency, several independent speckle patterns result. These can be averaged to yield a lower-resolution image with strongly reduced speckle. The full resolution image remains available for human interpretation; the low resolution version can be used for parametric imaging or quantitative analysis. We demonstrate this technique using intravascular optical frequency domain imaging data acquired in vivo. (C) 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.JBO.17.7.076018] C1 [van Soest, Gijs; Regar, Evelyn; van der Steen, Antonius F. W.] Erasmus MC, Ctr Thorax, NL-3000 CA Rotterdam, Netherlands. [Villiger, Martin; Tearney, Guillermo J.; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [van der Steen, Antonius F. W.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. RP van Soest, G (reprint author), Erasmus MC, Ctr Thorax, Ee23-02,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM g.vansoest@erasmusmc.nl RI van Soest, Gijs/B-4881-2008 NR 28 TC 12 Z9 12 U1 0 U2 5 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL PY 2012 VL 17 IS 7 AR 076018 DI 10.1117/1.JBO.17.7.076018 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 995EA UT WOS:000307989500045 PM 22894501 ER PT J AU Hess, MJ Hough, S AF Hess, Marika J. Hough, Sigmund TI Impact of spinal cord injury on sexuality: Broad-based clinical practice intervention and practical application SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Review DE Sexuality; Spinal cord injuries; Intervention; Best practice; Erectile dysfunction; Rehabilitation; Physical; Patient education; Tetraplegia; Paraplegia; Autonomic dysreflexia; Assistive devices ID QUALITY-OF-LIFE; AUTONOMIC DYSREFLEXIA; VIBRATORY STIMULATION; SELF-STIMULATION; MEN; WOMEN; SATISFACTION; ADJUSTMENT; TESTOSTERONE; HEALTH AB This study focuses on the impact a spinal cord injury may have on achieving physical and emotional intimacy, and potential to maximize sexual ability and quality of life. Spinal cord injury is a traumatic, life-altering event that is usually associated with loss of motor and sensory function, as well as sexual impairment. At the time of injury, the individual is faced with devastating loss and an abundance of new information in a setting of extreme stress and challenge. In the acute rehabilitation setting, there is often a considerable void in providing education and resources regarding sexual concerns and needs. There is a positive relationship between sexual education and sexual activity. The impact of inadequate sexual counseling and education as a part of rehabilitation can be deleterious. C1 [Hess, Marika J.] Tufts Sch Med, Boston, MA USA. [Hess, Marika J.; Hough, Sigmund] Harvard Univ, Sch Med, Boston, MA USA. [Hough, Sigmund] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hess, Marika J.; Hough, Sigmund] VA Boston Healthcare Syst, Spinal Cord Injury Serv, W Roxbury, MA 02132 USA. RP Hess, MJ (reprint author), VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM marika.hess@va.go NR 79 TC 11 Z9 11 U1 5 U2 28 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD JUL PY 2012 VL 35 IS 4 BP 211 EP 218 DI 10.1179/2045772312Y.0000000025 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 999XQ UT WOS:000308349400007 PM 22925747 ER PT J AU Rickles, RJ Tam, WF Giordano, TP Pierce, LT Farwell, M McMillin, DW Necheva, A Crowe, D Chen, M Avery, W Kansra, V Nawrocki, ST Carew, JS Giles, FJ Mitsiades, CS Borisy, AA Anderson, KC Lee, MS AF Rickles, Richard J. Tam, Winnie F. Giordano, Thomas P., III Pierce, Laura T. Farwell, Melissa McMillin, Douglas W. Necheva, Antoaneta Crowe, David Chen, Mei Avery, William Kansra, Vikram Nawrocki, Steffan T. Carew, Jennifer S. Giles, Francis J. Mitsiades, Constantine S. Borisy, Alexis A. Anderson, Kenneth C. Lee, Margaret S. TI Adenosine A2A and Beta-2 Adrenergic Receptor Agonists: Novel Selective and Synergistic Multiple Myeloma Targets Discovered through Systematic Combination Screening SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MULTICOMPONENT THERAPEUTICS; DRUG-RESISTANCE; SOLID TUMORS; CELLS; THERAPY; PROLIFERATION; CORTICOSTEROIDS; OVEREXPRESSION; CHEMOTHERAPY; MONOTHERAPY AB The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and beta-2 adrenergic receptor (beta 2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and beta 2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and beta 2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes. Mol Cancer Ther; 11(7); 1432-42. (c) 2012 AACR. C1 [Rickles, Richard J.; Tam, Winnie F.; Giordano, Thomas P., III; Pierce, Laura T.; Farwell, Melissa; Necheva, Antoaneta; Crowe, David; Chen, Mei; Avery, William; Kansra, Vikram; Borisy, Alexis A.; Lee, Margaret S.] Zalicus Inc, Cambridge, MA 02142 USA. [Nawrocki, Steffan T.; Carew, Jennifer S.; Giles, Francis J.] Univ Texas Hlth Sci Ctr, CTRC, Inst Drug Dev, San Antonio, TX USA. [McMillin, Douglas W.; Mitsiades, Constantine S.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Rickles, RJ (reprint author), Zalicus Inc, 245 1st St,3rd Floor, Cambridge, MA 02142 USA. EM rrickles@zalicus.com FU Amgen; AVEO Pharma; OSI; EMD Serono; Sunesis; Gloucester Pharmaceuticals; Genzyme; Johnson Johnson; licensing royalties from PharmaMar FX R.J. Rickles and M.S. Lee have ownership interest in Zalicus. D.W. McMillin has ownership interest in and is employed by Axios Biosciences as the founder. C.S. Mitsiades has received commercial research grants from Amgen, AVEO Pharma, OSI, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme, Johnson & Johnson, licensing royalties from PharmaMar, and is a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Merck & Co., Kosan Pharmaceuticals, Pharmion, Centocor, and Amnis Therapeutics. A.A. Borisy is employed by Zalicus and CombinatoRx (as the CEO); has an ownership interest in Zalicus, CombinatoRx, Forma Therapuetics, and Blueprint Medicines; and is a consultant/advisory board member for Gene Network Sciences. K.C. Anderson is a consultant/advisory board member for Celgene, Novartis, Millenium, BMS, Onyx, and Merck and is a founder of Acetylon. No potential conflicts of interest were disclosed by the other authors. NR 41 TC 8 Z9 8 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2012 VL 11 IS 7 BP 1432 EP 1442 DI 10.1158/1535-7163.MCT-11-0925 PG 11 WC Oncology SC Oncology GA 995OY UT WOS:000308021100006 PM 22474168 ER PT J AU Kim, K Schuetz, C Elias, N Veillette, GR Wamala, I Varma, M Smith, RN Robson, SC Cosimi, AB Sachs, DH Hertl, M AF Kim, Karen Schuetz, Christian Elias, Nahel Veillette, Gregory R. Wamala, Isaac Varma, Manish Smith, R. Neal Robson, Simon C. Cosimi, A. Benedict Sachs, David H. Hertl, Martin TI Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons SO XENOTRANSPLANTATION LA English DT Article DE baboon; liver; swine; xenotransplantation ID CLINICAL XENOTRANSPLANTATION; CARDIAC XENOGRAFTS; HEPATIC-FUNCTION; TRANSGENIC PIGS; POTENTIAL USE; HUMAN BLOOD; TRANSPLANTATION; REJECTION; PRIMATE; LINE AB Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9-day survival and control of thrombocytopenia following GalT-KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256264.. (c) 2012 John Wiley & Sons A/S. Abstract: Background: With standard miniature swine donors, survivals of only 3 days have been achieved in primate liver-transplant recipients. The recent production of alpha1,3-galactosyl transferase knockout (GalT-KO) miniature swine has made it possible to evaluate xenotransplantation of pig organs in clinically relevant pig-to-non-human primate models in the absence of the effects of natural anti-Gal antibodies. We are reporting our results using GalT-KO liver grafts. Methods: We performed GalT-KO liver transplants in baboons using an immunosuppressive regimen previously used by our group in xeno heart and kidney transplantation. Post-operative liver function was assessed by laboratory function tests, coagulation parameters and histology. Results: In two hepatectomized recipients of GalT-KO grafts, post-transplant liver function returned rapidly to normal. Over the first few days, the synthetic products of the donor swine graft appeared to replace those of the baboon. The first recipient survived for 6 days and showed no histopathological evidence of rejection at the time of death from uncontrolled bleeding, probably caused by transfusion-refractory thrombocytopenia. Amicar treatment of the second and third recipients led to maintenance of platelet counts of over 40 000 per mu l throughout their 9- and 8-day survivals, which represents the longest reported survival of pig-to-primate liver transplants to date. Both of the last two animals nevertheless succumbed to bleeding and enterococcal infection, without evidence of rejection. Conclusions: These observations suggest that thrombocytopenia after liver xenotransplantation may be overcome by Amicar therapy. The coagulopathy and sepsis that nevertheless occurred suggest that additional causes of coagulation disturbance must be addressed, along with better prevention of infection, to achieve long-term survival. C1 [Kim, Karen; Schuetz, Christian; Elias, Nahel; Veillette, Gregory R.; Wamala, Isaac; Varma, Manish; Cosimi, A. Benedict; Sachs, David H.; Hertl, Martin] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kim, Karen; Schuetz, Christian; Wamala, Isaac; Sachs, David H.] Massachusetts Gen Hosp, Transplant Biol Res Ctr, Boston, MA 02114 USA. [Smith, R. Neal] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Robson, Simon C.] Beth Israel Deaconess Med Ctr, Dept Hepatol, Boston, MA 02215 USA. RP Hertl, M (reprint author), 55 Fruit St,White 546, Boston, MA 02114 USA. EM mhertl@partners.org RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 FU NIAID NIH HHS [P01 AI045897] NR 25 TC 18 Z9 19 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD JUL-AUG PY 2012 VL 19 IS 4 BP 256 EP 264 DI 10.1111/j.1399-3089.2012.00717.x PG 9 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 994OG UT WOS:000307939600006 PM 22909139 ER PT J AU Ellard, KK Deckersbach, T Sylvia, LG Nierenberg, AA Barlow, DH AF Ellard, Kristen K. Deckersbach, Thilo Sylvia, Louisa G. Nierenberg, Andrew A. Barlow, David H. TI Transdiagnostic Treatment of Bipolar Disorder and Comorbid Anxiety With the Unified Protocol: A Clinical Replication Series SO BEHAVIOR MODIFICATION LA English DT Article DE Bipolar Disorder; Anxiety Disorders; Transdiagnostic; CBT ID TREATMENT ENHANCEMENT PROGRAM; RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; EMOTIONAL DISORDERS; STEP-BD; RELAPSE PREVENTION; RATING-SCALE; DSM-IV; PREVALENCE; ILLNESS AB Bipolar disorder (BD) is a chronic, debilitating disorder with recurrent manic and depressive episodes. More than 75% of bipolar patients have a current or lifetime diagnosis of a comorbid anxiety disorder. Comorbid anxiety in BD is associated with greater illness severity, greater functional impairment, and poorer illness-related outcomes. Effectively treating comorbid anxiety in individuals with BD has been recognized as one of the biggest unmet needs in the field of BD. Recently, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) was developed to be applicable to the full range of anxiety and mood disorders, based on converging evidence from genetics, cognitive and affective neuroscience, and behavioral research suggesting common, core emotion-related pathology. Here, the authors present a preliminary evaluation of the efficacy of the UP for the treatment of BD with comorbid anxiety, in a clinical replication series consisting of three cases. C1 [Ellard, Kristen K.; Deckersbach, Thilo; Sylvia, Louisa G.; Nierenberg, Andrew A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Barlow, David H.] Boston Univ, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. RP Ellard, KK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 15 Parkman St,ACC 815, Boston, MA 02114 USA. EM kellard@partners.org FU AHRQ HHS [1R01HS01937101]; NIMH NIH HHS [1F31MH084422, 1K23MH074895-01A2, 1K23MH091182-01A1, 1R01MH090053., F32 MH098490, R01MH079157-01A2] NR 45 TC 14 Z9 14 U1 2 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD JUL PY 2012 VL 36 IS 4 SI SI BP 482 EP 508 DI 10.1177/0145445512451272 PG 27 WC Psychology, Clinical SC Psychology GA 986IO UT WOS:000307335500006 PM 22822175 ER PT J AU Thase, ME AF Thase, Michael E. TI Social Skills Training for Depression and Comparative Efficacy Research: A 30-Year Retrospective SO BEHAVIOR MODIFICATION LA English DT Article DE social skills training; depression; major depressive disorder; comparative efficacy ID COGNITIVE-BEHAVIOR THERAPY; UNIPOLAR DEPRESSION; MAJOR DEPRESSION; PHARMACOTHERAPY; PSYCHOTHERAPY AB By the late 1970s it was clear that cognitive and behavioral therapies were promising alternatives to antidepressant medications for treatment of depressed outpatients. One such model of therapy, Social Skills Training, was developed by Michel Hersen and his colleagues specifically for treatment of depressed women. Professor Hersen and his colleagues obtained funding from the National Institute of Mental Health to conduct the first well-controlled randomized trial of this intervention, contrasting Social Skills Training, in combination with either placebo or active amitriptyline, against two active standards: amitriptyline alone and time-limited, psychodynamic psychotherapy in combination with placebo. The results of this study suggested that Social Skills Training (plus placebo) was at least as effective as amitriptyline alone or psychodynamic psychotherapy (plus placebo), with superior mode-specific effects on measures of social skill. The current narrative, which provides an autobiographical perspective of four critical years (1980-1984) in the early career of the author that were intertwined with the conduct and completion of this clinical trial, is an homage to Professor Hersen's talents as a supervisor, researcher, and mentor. C1 [Thase, Michael E.] Univ Penn, Perelman Sch Med, Mood & Anxiety Sect, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Thase, Michael E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. RP Thase, ME (reprint author), Univ Penn, Perelman Sch Med, Mood & Anxiety Sect, 3535 Market St,Suite 670, Philadelphia, PA 19104 USA. EM thase@mail.med.upenn.edu NR 20 TC 1 Z9 2 U1 2 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD JUL PY 2012 VL 36 IS 4 SI SI BP 545 EP 557 DI 10.1177/0145445512445610 PG 13 WC Psychology, Clinical SC Psychology GA 986IO UT WOS:000307335500009 PM 22718283 ER PT J AU Gros, DF Price, M Strachan, M Yuen, EK Milanak, ME Acierno, R AF Gros, Daniel F. Price, Matthew Strachan, Martha Yuen, Erica K. Milanak, Melissa E. Acierno, Ron TI Behavioral Activation and Therapeutic Exposure: An Investigation of Relative Symptom Changes in PTSD and Depression During the Course of Integrated Behavioral Activation, Situational Exposure, and Imaginal Exposure Techniques SO BEHAVIOR MODIFICATION LA English DT Article DE behavioral activation and therapeutic exposure; BA-TE; depression; PTSD; comorbidity; transdiagnostic ID POSTTRAUMATIC-STRESS-DISORDER; PROLONGED EXPOSURE; MAJOR DEPRESSION; RANDOMIZED-TRIAL; PRIMARY-CARE; COMORBIDITY; PREVALENCE; COMMUNITY; VETERANS; VICTIMS AB Effectiveness of exposure therapy for posttraumatic stress disorder (PTSD) may be adversely influenced by comorbid disorders. The present study investigated behavioral activation and therapeutic exposure (BA-TE), a new integrated treatment designed specifically for comorbid symptoms of PTSD and depression. Combat veterans with PTSD (N = 117) completed eight sessions of BA-TE that included two phases of treatment: (a) behavioral activation (BA) in which some activities involved situational exposures and (b) BA and situational exposures with imaginal exposures. Findings supported improvements in symptoms of PTSD, and overlapping symptoms of PTSD and depression, but not in nonoverlapping symptoms of depression. The findings also demonstrated a relatively consistent rate of change in PTSD and depression symptoms during BA-TE, despite the addition of imaginal exposures midway through the treatment. Together, these findings provide preliminary support for BA-TE as a treatment for PTSD and depression, and highlight the utility of transdiagnostic treatments in addressing comorbidity and symptom overlap. C1 [Gros, Daniel F.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv 116, Charleston, SC 29401 USA. [Milanak, Melissa E.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Ctr, Charleston, SC USA. [Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, Posttraumat Stress Disorder Clin Team, Charleston, SC 29401 USA. RP Gros, DF (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu FU NIDA NIH HHS [R01 DA030143] NR 54 TC 27 Z9 28 U1 7 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD JUL PY 2012 VL 36 IS 4 SI SI BP 580 EP 599 DI 10.1177/0145445512448097 PG 20 WC Psychology, Clinical SC Psychology GA 986IO UT WOS:000307335500011 PM 22679240 ER PT J AU Polyak, K AF Polyak, Kornelia TI On Using Functional Genetics to Understand Breast Cancer Biology SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Polyak, K (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM kornelia_polyak@dfci.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JUL PY 2012 VL 4 IS 7 AR a013516 DI 10.1101/cshperspect.a013516 PG 2 WC Cell Biology SC Cell Biology GA 995RH UT WOS:000308029300014 PM 22751154 ER PT J AU Wisco, OJ Sober, AJ AF Wisco, Oliver J. Sober, Arthur J. TI Prognostic Factors for Melanoma SO DERMATOLOGIC CLINICS LA English DT Article DE Melanoma; Prognosis; Histology; Biomarkers; Survival ID PRIMARY CUTANEOUS MELANOMA; SOLID-ORGAN TRANSPLANT; STAGE-IV-MELANOMA; MALIGNANT-MELANOMA; METASTATIC MELANOMA; UNITED-STATES; UNKNOWN PRIMARY; SENTINEL NODES; PREGNANCY; SURVIVAL AB The current melanoma staging system, as defined by the American Joint Committee on Cancer (AJCC), is the standard by which melanoma prognosis is determined. This article focuses on the components of the AJCC melanoma staging system regarding patient prognosis. In addition, this article summarizes the other commonly researched clinical and histologic melanoma prognostic factors and reviews the recent advancements in genetic biomarkers associated with prognosis. C1 [Wisco, Oliver J.] 81st Med Grp, Dermatol Clin, Keesler AFB, MS 39534 USA. [Wisco, Oliver J.] Massachusetts Gen Hosp, Wellman Ctr Photobiol Res, Boston, MA 02114 USA. [Sober, Arthur J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Wisco, OJ (reprint author), 81 MDOS SGOMD,301 Fisher St,Suite 1F-136, Keesler AFB, MS 39534 USA. EM wiscooj@gmail.com NR 65 TC 9 Z9 11 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8635 J9 DERMATOL CLIN JI Dermatol. Clin. PD JUL PY 2012 VL 30 IS 3 BP 469 EP + DI 10.1016/j.det.2012.04.008 PG 18 WC Dermatology SC Dermatology GA 982EA UT WOS:000307023600011 PM 22800552 ER PT J AU Neal, EG Zupec-Kania, B Pfeifer, HH AF Neal, E. G. Zupec-Kania, B. Pfeifer, H. H. TI Carnitine, nutritional supplementation and discontinuation of ketogenic diet therapies SO EPILEPSY RESEARCH LA English DT Article DE Ketogenic therapies; Carnitine; Supplementation; Discontinuation ID EPILEPTIC CHILDREN; CHILDHOOD EPILEPSY; ANTIEPILEPTIC DRUGS; SODIUM VALPROATE; VITAMIN-D; SERUM; EFFICACY; ACID; HYPERAMMONEMIA; CARBAMAZEPINE AB Nutritional adequacy of a prescribed diet is integral to clinical implementation of the ketogenic diet therapies in intractable epilepsy. This review discusses the evidence for using additional carnitine and the importance of full micronutrient supplementation. The optimal duration of a diet therapy is also discussed, drawing on results of an internationally applied questionnaire. (C) 2012 Elsevier B.V. All rights reserved. C1 [Neal, E. G.] Matthews Friends Char & Clin, London, England. [Neal, E. G.] UCL Inst Child Hlth, London, England. [Pfeifer, H. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Neal, EG (reprint author), Matthews Friends Char & Clin, London, England. EM e.neal@ucl.ac.uk; bkania@chw.org; hpfeifer@partners.org NR 30 TC 8 Z9 9 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD JUL PY 2012 VL 100 IS 3 SI SI BP 267 EP 271 DI 10.1016/j.eplepsyres.2012.04.021 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 988ZQ UT WOS:000307530400012 PM 22704584 ER PT J AU Ogino, S Fuchs, CS Giovannucci, E AF Ogino, Shuji Fuchs, Charles S. Giovannucci, Edward TI How many molecular subtypes? Implications of the unique tumor principle in personalized medicine SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE genomics; holistic; intratumor heterogeneity; molecular classification; molecular pathological epidemiology; MPE; neoplasia; phenome; systems biology; tumor-host interaction; unique tumor paradigm ID ISLAND METHYLATOR PHENOTYPE; METASTATIC COLORECTAL-CANCER; POPULATION-BASED SAMPLE; CELL LUNG-CANCER; COLON-CANCER; MICROSATELLITE INSTABILITY; LINE-1 HYPOMETHYLATION; PATHOLOGICAL EPIDEMIOLOGY; FREQUENT MUTATION; GENOMIC ANALYSES AB Cancers are complex multifactorial diseases. For centuries, conventional organ-based classification system (i.e., breast cancer, lung cancer, colon cancer, colorectal cancer, prostate cancer, lymphoma, leukemia, and so on) has been utilized. Recently, molecular diagnostics has become an essential component in clinical decision-making. However, tumor evolution and behavior cannot accurately be predicted, despite numerous research studies reporting promising tumor biomarkers. To advance molecular diagnostics, a better understanding of intratumor and intertumor heterogeneity is essential. Tumor cells interact with the extracellular matrix and host non-neoplastic cells in the tumor microenvironment, which is influenced by genomic variation, hormones, and dietary, lifestyle and environmental exposures, implicated by molecular pathological epidemiology. Essentially, each tumor possesses its own unique characteristics in terms of molecular make-up, tumor microenvironment and interactomes within and between neoplastic and host cells. Starting from the unique tumor concept and paradigm, we can better classify tumors by molecular methods, and move closer toward personalized cancer medicine and prevention. C1 [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA USA. [Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU US NIH [R01 CA151993, P50 CA127003, R01 CA118553, R01 CA124908, P01 CA87969, P01 CA55075] FX This work was supported by US NIH grants (S Ogino received support from R01 CA151993, CS Fuchs received support from P50 CA127003, R01 CA118553 and R01 CA124908, SE Hankinson received support from P01 CA87969 and WC Willett received support from P01 CA55075). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or NIH. Funding agencies did not have any role in the decision to submit the manuscript for publication, or the writing of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 108 TC 64 Z9 66 U1 1 U2 17 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2012 VL 12 IS 6 BP 621 EP 628 DI 10.1586/ERM.12.46 PG 8 WC Pathology SC Pathology GA 994MW UT WOS:000307935900013 PM 22845482 ER PT J AU Chieffo, A Meliga, E Latib, A Park, SJ Onuma, Y Capranzano, P Valgimigli, M Jegere, S Makkar, RR Palacios, IF Kim, YH Buszman, PE Chakravarty, T Sheiban, I Mehran, R Naber, C Margey, R Agnihotri, A Marra, S Capodanno, D Leon, MB Moses, JW Fajadet, J Lefevre, T Morice, MC Erglis, A Tamburino, C Alfieri, O Serruys, PW Colombo, A AF Chieffo, Alaide Meliga, Emanuele Latib, Azeem Park, Seung-Jung Onuma, Yoshinobu Capranzano, Piera Valgimigli, Marco Jegere, Sanda Makkar, Raj R. Palacios, Igor F. Kim, Young-Hak Buszman, Pawel E. Chakravarty, Tarun Sheiban, Imad Mehran, Roxana Naber, Christoph Margey, Ronan Agnihotri, Arvind Marra, Sebastiano Capodanno, Davide Leon, Martin B. Moses, Jeffrey W. Fajadet, Jean Lefevre, Thierry Morice, Marie-Claude Erglis, Andrejs Tamburino, Corrado Alfieri, Ottavio Serruys, Patrick W. Colombo, Antonio TI Drug-Eluting Stent for Left Main Coronary Artery Disease The DELTA Registry: A Multicenter Registry Evaluating Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Treatment SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE coronary artery bypass graft; drug-eluting stent; left main coronary artery disease; percutaneous coronary intervention ID UNPROTECTED LEFT MAIN; BARE-METAL STENTS; SURGICAL REVASCULARIZATION; STENOSIS; IMPLANTATION; OUTCOMES; SURGERY; EXPERIENCE; CARDIOLOGY AB Objectives The aim of this study was to compare, in a large all-comers registry, major adverse cardiac and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in unprotected left main coronary artery (ULMCA) stenosis. Background Percutaneous coronary intervention with DES implantation in ULMCA has been shown to be a feasible and safe approach at midterm clinical follow-up. Methods All consecutive patients with ULMCA stenosis treated by PCI with DES versus CABG were analyzed in this multinational registry. A propensity score analysis was performed to adjust for baseline differences in the overall cohort. Results In total 2,775 patients were included: 1,874 were treated with PCI versus 901 with CABG. At 1,295 (interquartile range: 928 to 1,713) days, there were no differences, at the adjusted analysis, in the primary composite endpoint of death, cerebrovascular accidents, and myocardial infarction (MI) (adjusted hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.85 to 1.42; p = 0.47), mortality (adjusted HR: 1.16; 95% CI: 0.87 to 1.55; p = 0.32), or composite endpoint of death and MI (adjusted HR: 1.25; 95% CI: 0.95 to 1.64; p = 0.11). An advantage of CABG over PCI was observed in the composite secondary endpoint of MACCE (adjusted HR: 1.64; 95% CI: 1.33 to 2.03; p < 0.0001), driven exclusively by the higher incidence of target vessel revascularization with PCI. Conclusions In our multinational all-comers registry, no difference was observed in the occurrence of death, cerebrovascular accidents, and MI between PCI and CABG. An advantage of CABG over PCI was observed in the incidence of MACCE, driven by the higher incidence of target vessel revascularization with PCI. (J Am Coll Cardiol Intv 2012;5:718-27) (C) 2012 by the American College of Cardiology Foundation C1 [Chieffo, Alaide; Latib, Azeem; Alfieri, Ottavio; Colombo, Antonio] Ist Sci San Raffaele, Dept Cardiothorac & Vasc Dis, I-0132 Milan, Italy. [Meliga, Emanuele] AO Ordine Mauriziano Umberto I, Intervent Cardiol Unit, Turin, Italy. [Park, Seung-Jung; Kim, Young-Hak] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Cardiol,Ctr Med Res & Informat, Seoul, South Korea. [Onuma, Yoshinobu; Serruys, Patrick W.] Erasmus MC, Thoraxctr, Rotterdam, Netherlands. [Capranzano, Piera; Capodanno, Davide; Tamburino, Corrado] Univ Catania, Ferrarotto Hosp, Catania, Italy. [Valgimigli, Marco] Univ Ferrara, S Anna Hosp, Cardiovasc Inst, I-44100 Ferrara, Italy. [Jegere, Sanda; Erglis, Andrejs] Pauls Stradins Clin Univ Hosp, Latvian Ctr Cardiol, Riga, Latvia. [Jegere, Sanda; Erglis, Andrejs] Univ Latvia, Inst Cardiol, Riga, Latvia. [Makkar, Raj R.; Chakravarty, Tarun] Cedars Sinai Med Ctr, Cedars Sinai Heart Inst, Los Angeles, CA 90048 USA. [Palacios, Igor F.; Margey, Ronan; Agnihotri, Arvind] Massachusetts Gen Hosp, Cardiac Catheterizat Lab, Boston, MA 02114 USA. [Palacios, Igor F.; Margey, Ronan; Agnihotri, Arvind] Harvard Univ, Sch Med, Boston, MA USA. [Buszman, Pawel E.] Amer Heart Poland Inc, Katowice, Poland. [Sheiban, Imad; Marra, Sebastiano] Univ Turin, Div Cardiol, S Giovanni Battista Molinette Hosp, Turin, Italy. [Mehran, Roxana] Mt Sinai Med Ctr, New York, NY 10029 USA. [Leon, Martin B.; Moses, Jeffrey W.] Columbia Univ, Med Ctr, New York, NY USA. [Leon, Martin B.; Moses, Jeffrey W.] Cardiovasc Res Fdn, New York, NY USA. [Naber, Christoph; Fajadet, Jean] Clin Pasteur, Toulouse, France. [Lefevre, Thierry; Morice, Marie-Claude] Inst Hosp Jacques Cartier, Massy, France. RP Colombo, A (reprint author), Ist Sci San Raffaele, Dept Cardiothorac & Vasc Dis, Via Olgettina 60, I-0132 Milan, Italy. EM colombo.antonio@hsr.it RI Latib, Azeem/B-4165-2008; OI TAMBURINO, Corrado/0000-0002-4940-9742; Capodanno, Davide/0000-0002-5156-7723 FU Lilly; Medtronic; BMS/Sanofi; Medicines Co.; Lily/Daiichi Sankyo; Abbott; Biotronik; Sadra Medical; Stentys; Icon FX Dr. Makkar is a consultant to Medtronic and Abiomed; has received speaker's fees from Lilly and Medtronic; and has received equity from Entourage Medical Technologies. Dr. Mehran is a consultant to Abbott, The Medicines Co., Janssen, and Regado; and has received research grant support from BMS/Sanofi, The Medicines Co., and Lily/Daiichi Sankyo. Dr. Naber is a speaker for Abbott, Cordis, Biotronik, Biosensors, Cirdus, Medtronic, Stentys, Daiichi Sankyo, and The Medicines Company; has received research support from Abbott, Biotronik, Sadra Medical, Stentys, and Icon; and is on the advisory board of Biotronik and Abbott. Dr. Capodanno has received speaker's honoraria from Eli-Lilly and AstraZeneca. Dr. Moses is a consultant for Cordis and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Chieffo and Meliga contributed equally to this paper. NR 27 TC 50 Z9 53 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD JUL PY 2012 VL 5 IS 7 BP 718 EP 727 DI 10.1016/j.jcin.2012.03.022 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 979QZ UT WOS:000306836200004 PM 22814776 ER PT J AU Yung, RL Hassett, MJ Chen, K Gesten, FC Roohan, PJ Boscoe, FP Sinclair, AH Schymura, MJ Schrag, D AF Yung, Rachel L. Hassett, Michael J. Chen, Kun Gesten, Foster C. Roohan, Patrick J. Boscoe, Francis P. Sinclair, Amber H. Schymura, Maria J. Schrag, Deborah TI Initiation of Adjuvant Hormone Therapy by Medicaid Insured Women With Nonmetastatic Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HEALTH-INSURANCE COVERAGE; ENDOCRINE THERAPY; SURVIVAL; DISPARITIES; STAGE; DIAGNOSIS; RACE; CHEMOTHERAPY; DISABILITIES; POPULATION AB Hormone therapy is the mainstay of adjuvant treatment for hormone receptor positive (HR-positive) nonmetastatic breast cancer. We evaluated adjuvant hormone therapy (AHT) initiation among Medicaid-insured women aged 2164years with stage IIII HR-positive breast cancer. We used multivariable logistic regression to identify independent predictors of AHT initiation. Within 1year of diagnosis, 68% (1049/1538) initiated AHT; by 18months, 80% (1168/1461) initiated AHT. In multivariable analysis, women less likely to initiate AHT had more comorbidity (epsilon 2 vs none: adjusted odds ratio (AOR)=0.55; 95% CI=0.32 to 0.97), more advanced disease (stage III vs I: AOR=0.27; 95% CI=0.18 to 0.39), and no radiation after breast conserving surgery (AOR=0.15; 95% CI=0.10 to 0.22). Race, age, and history of mental health disorders were not independently associated with initiation of AHT. Among initiators of AHT, 58% (604/1049) were adherent to treatment for the year after initiation. Despite comprehensive prescription coverage, only 39% (604/1538) received optimal AHT including prompt initiation and adherence for the year after treatment. Partnerships between Medicaid programs and cancer registries may help identify at-risk women and facilitate the implementation of quality improvement strategies. C1 [Yung, Rachel L.; Hassett, Michael J.; Chen, Kun; Schrag, Deborah] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Gesten, Foster C.; Roohan, Patrick J.] New York State Dept Hlth, Off Hlth Insurance Programs, Albany, NY USA. [Boscoe, Francis P.; Sinclair, Amber H.; Schymura, Maria J.] New York State Dept Hlth, New York State Canc Registry, Albany, NY USA. RP Yung, RL (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Policy Res, 450 Brookline Ave, Boston, MA 02215 USA. EM ryung1@partners.org FU Association of Schools of Public Health/Centers for Disease Control and Prevention [S3888]; Susan G. Komen for the Cure Career Catalyst in Disparities Award; National Cancer Institute [R01-CA131847] FX This work was supported by Cooperative Agreement S3888 from the Association of Schools of Public Health/Centers for Disease Control and Prevention (to MJS), Susan G. Komen for the Cure Career Catalyst in Disparities Award (to MJH), and National Cancer Institute (grant no. R01-CA131847 to DS). NR 29 TC 7 Z9 7 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2012 VL 104 IS 14 BP 1102 EP 1105 DI 10.1093/jnci/djs273 PG 4 WC Oncology SC Oncology GA 981LG UT WOS:000306969100012 PM 22773822 ER PT J AU Volpe, EM Hardie, TL Cerulli, C AF Volpe, Ellen M. Hardie, Thomas L. Cerulli, Catherine TI Associations among Depressive Symptoms, Dating Violence, and Relationship Power in Urban, Adolescent Girls SO JOGNN-JOURNAL OF OBSTETRIC GYNECOLOGIC AND NEONATAL NURSING LA English DT Article DE dating violence; depression; relationship power; adolescent; aggression ID INTIMATE PARTNER VIOLENCE; PHYSICAL HEALTH CONSEQUENCES; SEXUAL RELATIONSHIP POWER; ROMANTIC RELATIONSHIPS; GENDER SYMMETRY; UNITED-STATES; MENTAL-HEALTH; CES-D; RISK; AGGRESSION AB Objective To explore the associations among dating violence (DV), aggression, relationship power, and depressive symptoms. Design A cross-sectional survey secondary analysis. Setting An urban, school based health center, October, 2009 through May, 2009. Participants Low income, adolescent girls (n = 155), ages 1418. Methods Descriptive and bivariate analyses were conducted to illustrate patterns and associations among variables. Key variables included depressive symptoms, DV victimization and aggression, and relationship power. We used mediation analyses to determine the direct and indirect effects among variables. Results Both DV victimization and aggression were reported frequently. Furthermore, DV victimization had a significant direct effect on depression and an indirect effect through relationship power. Depressive symptoms and relationship power were associated with DV aggression. Although relationship power did have a significant inverse effect on depressive symptoms, it was not through DV aggression. Conclusions Complex associations remain between mental health and DV; however, relationship power partially accounts for DV victimization's effect on depressive symptoms. Depressive symptoms are associated with DV victimization and aggression; therefore, nurses should address relationship power in clinical and community interventions. C1 [Volpe, Ellen M.] Univ Penn, Ctr Hlth Equ Res, Sch Nursing, Philadelphia, PA 19104 USA. [Volpe, Ellen M.] Univ Penn, Ctr Global Womans Hlth, Sch Nursing, Philadelphia, PA 19104 USA. Univ Penn, Ctr Hlth Equ Res, Sch Nursing, Philadelphia, PA 19104 USA. [Hardie, Thomas L.] Drexel Univ, Coll Nursing & Hlth Profess, Philadelphia, PA 19104 USA. [Cerulli, Catherine] Univ Rochester, Med Ctr, Dept Psychiat, Lab Interpersonal Violence & Victimizat, Rochester, NY 14642 USA. RP Volpe, EM (reprint author), Univ Penn, Ctr Hlth Equ Res, Sch Nursing, 418 Curie Blvd,233L, Philadelphia, PA 19104 USA. EM evolpe@nursing.upenn.edu RI Hardie, Thomas/J-7776-2012; OI Hardie, Thomas/0000-0002-4547-7991 FU National Institutes of Health [F31MH082646-01A2]; National Institute of Nursing Research [T32NR 007100]; Sigma Theta Tau; Epsilon Xi Chapter; Susan B. Anthony Institute FX Supported in part by grants from the National Institutes of Health, the National Institutes of Mental Health (F31MH082646-01A2), the National Institute of Nursing Research (T32NR 007100), Sigma Theta Tau, Epsilon Xi Chapter, and Susan B. Anthony Institute. The authors thank Drs. Morrison-Beedy, Tuttle, Fals-Stewart, and Sommers. NR 73 TC 7 Z9 7 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-2175 J9 JOGNN-J OBST GYN NEO JI JOGNN PD JUL-AUG PY 2012 VL 41 IS 4 BP 506 EP 518 DI 10.1111/j.1552-6909.2012.01384.x PG 13 WC Nursing; Obstetrics & Gynecology SC Nursing; Obstetrics & Gynecology GA 974ZN UT WOS:000306476300007 PM 22697267 ER PT J AU Walling, SM Meehan, JC Marshall, AD Holtzworth-Munroe, A Taft, CT AF Walling, Sherry M. Meehan, Jeffrey C. Marshall, Amy D. Holtzworth-Munroe, Amy Taft, Casey T. TI The Relationship of Intimate Partner Aggression to Head Injury, Executive Functioning, and Intelligence SO JOURNAL OF MARITAL AND FAMILY THERAPY LA English DT Article ID FRONTAL-LOBE; DOMESTIC VIOLENCE; MARITALLY VIOLENT; MEN; DEFICITS; ABUSE; TYPOLOGY; NEUROBIOLOGY; PSYCHOPATHY; RELIABILITY AB Measures of head injury, executive functioning, and intelligence were given to a community sample composed of 102 male perpetrators of intimate partner aggression (IPA) and 62 nonaggressive men. A history of head injury and lower mean score on a measure of verbal intelligence were associated with the frequency of male-perpetrated physical IPA as reported by male perpetrators and their female partners. Lower mean scores on a measure of verbal intelligence also predicted frequency of psychological IPA perpetration. Using the perpetrator subtypes outlined by Holtzworth-Munroe et al. (2000), analyses revealed that compared with other groups, the most severely aggressive subtypes (i.e., borderline-dysphoric and generally violent-antisocial) were the most likely to report a history of head injury and to have significantly lower mean scores on a neuropsychological test of verbal intelligence. The possible role of neuropsychological factors in IPA perpetration and implications for prevention and intervention programs are discussed. C1 [Walling, Sherry M.] Fresno Pacific Univ, Dept Psychol, Fresno, CA 93702 USA. [Holtzworth-Munroe, Amy] Indiana Univ, Coll Arts & Sci, Bloomington, IN 47405 USA. [Marshall, Amy D.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Taft, Casey T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Taft, Casey T.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Walling, SM (reprint author), Fresno Pacific Univ, Dept Psychol, 1717 S Chestnut Ave, Fresno, CA 93702 USA. EM sherry.walling@fresno.edu FU NIMH NIH HHS [R01-MH51935] NR 46 TC 11 Z9 11 U1 9 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0194-472X J9 J MARITAL FAM THER JI J. Marital Fam. Ther. PD JUL PY 2012 VL 38 IS 3 BP 471 EP 485 DI 10.1111/j.1752-0606.2011.00226.x PG 15 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 973ZO UT WOS:000306399600004 PM 22804466 ER PT J AU Lee, SM Brandt, LK Coakley, EE Rideout, ML Blakeney, BA Dahlin, C AF Lee, Susan M. Brandt, Lynda K. Coakley, Edward E. Rideout, Marion L. Blakeney, Barbara A. Dahlin, Constance TI The National AgeWISE Pilot SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article ID GEROPALLIATIVE CARE AB AgeWISE is a 6-month nurse residency program designed to prepare hospital nurses to meet the needs of older adults, a population that comprises nearly 50% of all US hospital admissions. The goal of AgeWISE, now being piloted in 12 hospitals in the United States, is to produce a tested and refined national model for building geropalliative care capacity among hospital nurses. C1 [Lee, Susan M.] Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, Boston, MA 02114 USA. [Coakley, Edward E.; Blakeney, Barbara A.] Massachusetts Gen Hosp, Ctr Innovat Care Delivery, Boston, MA 02114 USA. [Brandt, Lynda K.; Rideout, Marion L.] Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. [Dahlin, Constance] N Shore Med Ctr, Palliat Care Serv, Salem, MA USA. RP Lee, SM (reprint author), Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, 275 Cambridge St,4th Floor, Boston, MA 02114 USA. EM slee40@partners.org NR 16 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD JUL-AUG PY 2012 VL 42 IS 7-8 BP 356 EP 360 DI 10.1097/NNA.0b013e318261939f PG 5 WC Nursing SC Nursing GA 979VW UT WOS:000306851000005 PM 22832410 ER PT J AU McHugh, RK Weitzman, M Safren, SA Murray, HW Pollack, MH Otto, MW AF McHugh, R. Kathryn Weitzman, Meara Safren, Steven A. Murray, Heather W. Pollack, Mark H. Otto, Michael W. TI Sexual HIV Risk Behaviors in a Treatment-Refractory Opioid-Dependent Sample SO JOURNAL OF PSYCHOACTIVE DRUGS LA English DT Article DE age; HIV; methadone; opioids; risk behaviors; substance dependence ID ADDICTION SEVERITY INDEX; INJECTION-DRUG USERS; SENSATION-SEEKING; TRANSMITTED-DISEASE; SUBSTANCE-ABUSE; DEPRESSIVE SYMPTOMS; ANXIETY SENSITIVITY; GENDER-DIFFERENCES; HEROIN-ADDICTS; UNITED-STATES AB The propensity to engage in risk behaviors confers an elevated risk of HIV and other infectious disease transmission in opioid-dependent populations. Although drug abuse treatment may decrease drug-related risk behaviors such as needle-sharing, additional intervention may be needed to reduce HIV risk behavior. In this investigation, we assessed sexual HIV risk behaviors in opioid-dependent patients who were engaging in regular drug use despite ongoing counseling and methadone maintenance therapy. Potential risk and protective factors for engaging in sexual HIV risk behavior were examined. Taking into account demographic, psychiatric, substance use, and psychological variables, the only significant predictor of risk behavior was age. Specifically, younger patients were more likely to engage in sexual HIV risk behavior. The implications of these results for reducing sexual HIV risk behavior and for HIV prevention in methadone-maintained, treatment-refractory opioid-dependent patients are discussed. C1 [McHugh, R. Kathryn; Weitzman, Meara; Murray, Heather W.; Otto, Michael W.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Safren, Steven A.; Pollack, Mark H.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP McHugh, RK (reprint author), Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat,Div Alcohol & Drug Abuse, Proctor House 3,MS 222, Belmont, MA 02478 USA. EM kmchugh@mclean.harvard.edu OI McHugh, R. Kathryn/0000-0002-3011-8697 FU NIDA NIH HHS [R01 DA017904] NR 42 TC 4 Z9 4 U1 3 U2 4 PU HAIGHT-ASHBURY PUBL PI SAN FRANCISCO PA 409 CLAYTON ST, SAN FRANCISCO, CA 94117 USA SN 0279-1072 J9 J PSYCHOACTIVE DRUGS JI J. Psychoact. Drugs PD JUL-AUG PY 2012 VL 44 IS 3 BP 237 EP 242 DI 10.1080/02791072.2012.703507 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 992QH UT WOS:000307794300006 PM 23061323 ER PT J AU Kantoff, PW Higano, CS Small, EJ Whitmore, JB Frohlich, MW Schellhammer, PF AF Kantoff, Philip W. Higano, Celestia S. Small, Eric J. Whitmore, James B. Frohlich, Mark W. Schellhammer, Paul F. CA IMPACT TI Re: Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in Castration-Resistant Prostate Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID CELLULAR IMMUNOTHERAPY; DOUBLE-BLIND; DOCETAXEL; SURVIVAL; TRIALS; PAIN; MEN C1 [Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Genitourinary Oncol Program, Boston, MA 02215 USA. [Higano, Celestia S.] Univ Washington, Sch Med, Seattle, WA USA. [Small, Eric J.] Univ Calif San Francisco, Urol Oncol Program, San Francisco, CA 94143 USA. [Frohlich, Mark W.] Dendreon Corp, Seattle, WA USA. [Schellhammer, Paul F.] Eastern Virginia Med Sch, Dept Urol, Norfolk, VA 23501 USA. RP Kantoff, PW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Genitourinary Oncol Program, 450 Brookline Ave, Boston, MA 02215 USA. EM Philip_Kantoff@dfci.harvard.edu NR 15 TC 15 Z9 15 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2012 VL 104 IS 14 BP 1107 EP 1109 DI 10.1093/jnci/djs279 PG 3 WC Oncology SC Oncology GA 981LG UT WOS:000306969100014 PM 22825556 ER PT J AU Jones, DA DeMaio, D Dee, V Roy, C Watson, J Clark, P Wright, B AF Jones, Dorothy A. DeMaio, Dorothy Dee, Vivien Roy, Callista, Sr. Watson, Jean Clark, Pamela Wright, Barbara TI Expert panel on nursing theory guided practice position paper: Nursing knowledge and the impact on Nursing's Preferred Future a plan for enhancing Raise the Voice Phase II SO NURSING OUTLOOK LA English DT Editorial Material C1 [Jones, Dorothy A.; Roy, Callista, Sr.] Boston Coll, Sch Nursing, Chestnut Hill, MA 02467 USA. [Jones, Dorothy A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [DeMaio, Dorothy] Rutgers State Univ, Coll Nursing, Newark, NJ 07102 USA. [Dee, Vivien] Azusa Pacific Univ, Azusa, CA USA. [Watson, Jean] Univ Colorado, Coll Nursing, Denver, CO 80202 USA. [Watson, Jean] Watson Caring Sci Inst, Boulder, CO USA. [Clark, Pamela] Univ Wyoming, Laramie, WY 82071 USA. [Wright, Barbara] Ctr Champ Nursing Amer, Washington, DC USA. RP Jones, DA (reprint author), Boston Coll, Sch Nursing, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. EM Dorothy.jones@bc.edu NR 1 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 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD JUL-AUG PY 2012 VL 60 IS 4 BP 228 EP 228 DI 10.1016/j.outlook.2012.05.001 PG 1 WC Nursing SC Nursing GA 980DZ UT WOS:000306875100010 PM 22977893 ER PT J AU Faust, K Sathirapongsasuti, JF Izard, J Segata, N Gevers, D Raes, J Huttenhower, C AF Faust, Karoline Sathirapongsasuti, J. Fah Izard, Jacques Segata, Nicola Gevers, Dirk Raes, Jeroen Huttenhower, Curtis TI Microbial Co-occurrence Relationships in the Human Microbiome SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HUMAN GUT MICROBIOME; HUMAN ORAL-CAVITY; FUSOBACTERIUM-NUCLEATUM; BACTERIAL INTERACTIONS; BIOFILM DEVELOPMENT; COMPOSITIONAL DATA; DIGESTIVE-TRACT; GENOME SEQUENCE; DENTAL BIOFILM; COMMUNITIES AB The healthy microbiota show remarkable variability within and among individuals. In addition to external exposures, ecological relationships (both oppositional and symbiotic) between microbial inhabitants are important contributors to this variation. It is thus of interest to assess what relationships might exist among microbes and determine their underlying reasons. The initial Human Microbiome Project (HMP) cohort, comprising 239 individuals and 18 different microbial habitats, provides an unprecedented resource to detect, catalog, and analyze such relationships. Here, we applied an ensemble method based on multiple similarity measures in combination with generalized boosted linear models (GBLMs) to taxonomic marker (16S rRNA gene) profiles of this cohort, resulting in a global network of 3,005 significant co-occurrence and co-exclusion relationships between 197 clades occurring throughout the human microbiome. This network revealed strong niche specialization, with most microbial associations occurring within body sites and a number of accompanying inter-body site relationships. Microbial communities within the oropharynx grouped into three distinct habitats, which themselves showed no direct influence on the composition of the gut microbiota. Conversely, niches such as the vagina demonstrated little to no decomposition into region-specific interactions. Diverse mechanisms underlay individual interactions, with some such as the co-exclusion of Porphyromonaceae family members and Streptococcus in the subgingival plaque supported by known biochemical dependencies. These differences varied among broad phylogenetic groups as well, with the Bacilli and Fusobacteria, for example, both enriched for exclusion of taxa from other clades. Comparing phylogenetic versus functional similarities among bacteria, we show that dominant commensal taxa (such as Prevotellaceae and Bacteroides in the gut) often compete, while potential pathogens (e. g. Treponema and Prevotella in the dental plaque) are more likely to co-occur in complementary niches. This approach thus serves to open new opportunities for future targeted mechanistic studies of the microbial ecology of the human microbiome. C1 [Faust, Karoline; Raes, Jeroen] VIB, Dept Biol Struct, Brussels, Belgium. [Faust, Karoline; Raes, Jeroen] Vrije Univ Brussel, Dept Appl Biol Sci DBIT, Brussels, Belgium. [Sathirapongsasuti, J. Fah; Segata, Nicola; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Izard, Jacques] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Izard, Jacques] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Gevers, Dirk; Huttenhower, Curtis] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Faust, K (reprint author), VIB, Dept Biol Struct, Brussels, Belgium. EM jeroen.raes@vib-vub.be; chuttenh@hsph.harvard.edu OI Izard, Jacques/0000-0002-5904-5436; Huttenhower, Curtis/0000-0002-1110-0096; Segata, Nicola/0000-0002-1583-5794 FU NIH [CA139193, U54HG004969, 1R01HG005969]; Crohn's and Colitis Foundation of America; Juvenile Diabetes Research Foundation; NSF [DBI-1053486]; ARO [W911NF-11-1-0473]; Research Foundation Flanders (FWO) FX This work was supported in part by NIH CA139193 (JI), NIH U54HG004969 (DG), the Crohn's and Colitis Foundation of America (DG), and the Juvenile Diabetes Research Foundation (DG and CH), NSF DBI-1053486 (CH), ARO W911NF-11-1-0473 (CH), NIH 1R01HG005969 (CH) and the Research Foundation Flanders (FWO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 252 Z9 258 U1 23 U2 167 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 JUL PY 2012 VL 8 IS 7 AR e1002606 DI 10.1371/journal.pcbi.1002606 PG 17 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 979TH UT WOS:000306842200029 PM 22807668 ER PT J AU Flannick, J Korn, JM Fontanillas, P Grant, GB Banks, E Depristo, MA Altshuler, D AF Flannick, Jason Korn, Joshua M. Fontanillas, Pierre Grant, George B. Banks, Eric Depristo, Mark A. Altshuler, David TI Efficiency and Power as a Function of Sequence Coverage, SNP Array Density, and Imputation SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; POPULATION-SCALE; COMMON DISEASES; RARE VARIANTS; DISCOVERY; GENOTYPE; HISTORY; LOCI; SUSCEPTIBILITY; INFERENCE AB High coverage whole genome sequencing provides near complete information about genetic variation. However, other technologies can be more efficient in some settings by (a) reducing redundant coverage within samples and (b) exploiting patterns of genetic variation across samples. To characterize as many samples as possible, many genetic studies therefore employ lower coverage sequencing or SNP array genotyping coupled to statistical imputation. To compare these approaches individually and in conjunction, we developed a statistical framework to estimate genotypes jointly from sequence reads, array intensities, and imputation. In European samples, we find similar sensitivity (89%) and specificity (99.6%) from imputation with either 1 x sequencing or 1 M SNP arrays. Sensitivity is increased, particularly for low-frequency polymorphisms (MAF <5%), when low coverage sequence reads are added to dense genome-wide SNP arrays - the converse, however, is not true. At sites where sequence reads and array intensities produce different sample genotypes, joint analysis reduces genotype errors and identifies novel error modes. Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling. C1 [Flannick, Jason; Korn, Joshua M.; Fontanillas, Pierre; Grant, George B.; Banks, Eric; Depristo, Mark A.; Altshuler, David] Broad Inst Harvard & MIT, Cambridge, MA USA. [Flannick, Jason; Korn, Joshua M.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Flannick, Jason; Korn, Joshua M.; Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Korn, Joshua M.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Korn, Joshua M.] Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA USA. RP Flannick, J (reprint author), Broad Inst Harvard & MIT, Cambridge, MA USA. EM altshuler@molbio.mgh.harvard.edu RI Altshuler, David/A-4476-2009 OI Altshuler, David/0000-0002-7250-4107 FU National Human Genome Research Institute [U01HG005208]; NIH [5-T32-GM007748-33] FX This work was supported in part by Award Number U01HG005208 from the National Human Genome Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Human Genome Research Institute or the National Institutes of Health. JF was supported in part by NIH Training Grant 5-T32-GM007748-33. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 15 Z9 15 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2012 VL 8 IS 7 AR e1002604 DI 10.1371/journal.pcbi.1002604 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 979TH UT WOS:000306842200027 PM 22807667 ER PT J AU Li, CY Zeliadt, SB Hall, IJ Smith, JL Ekwueme, DU Moinpour, CM Penson, DF Thompson, IM Keane, TE Ramsey, SD AF Li, Chunyu Zeliadt, Steven B. Hall, Ingrid J. Smith, Judith Lee Ekwueme, Donatus U. Moinpour, Carol M. Penson, David F. Thompson, Ian M. Keane, Thomas E. Ramsey, Scott D. TI Willingness to Pay for Prostate Cancer Treatment among Patients and Their Family Members at 1 Year After Diagnosis SO VALUE IN HEALTH LA English DT Article DE family member; patient; prostate cancer; side effect; willingness to pay ID QUALITY-OF-LIFE; TREATMENT DECISION-MAKING; SEER-MEDICARE DATA; CARE; COSTS; TIME; MEN; SURGERY; COUPLES AB Objectives: To explore an alternative approach to quantifying the burden of side effects at 1 year after treatment for prostate cancer among both patients and their partners. Methods: We analyzed data from 75 couples in the Family and Cancer Therapy Selection study. Paired patients and family members were independently asked about their willingness to pay (WTP) for a hypothetical new treatment that cures prostate cancer without side effects if they could reconsider their treatment decision by indicating the maximum amount they would be willing to pay given 11 separate "bids" ranging from $0 to $1500 per month. Descriptive and regression analyses were conducted for patients and family members controlling for sociodemographic characteristics and health status; Spearman correlations were also examined. Results: Among 75 couples analyzed, the income-adjusted mean WTP estimates per month were $400.8 (standard error [SE] $54.3) for patients and $650.2 (SE 72.2) for family members. The WTP between patients and family members was correlated (Pearson rho 0.30; P = 0.01). After adjusting for covariates, the adjusted mean WTP per month was $588.1 (SE 65.77) for patients and $819.4 (SE 74.33) for family members. Wanting to avoid side effects at baseline predicted higher WTP for patients (P = 0.010). Experiencing sexual side effects was predictive of higher WTP for family members (P = 0.047). Conclusions: Fairly high WTP amounts for a hypothetical treatment without side effects suggests that patients and their partners are experiencing important burdens 1 year after treatment. The higher amounts partners are willing to pay and the correlation with sexual side effects suggest that they are perceptive of significant treatment burdens. C1 [Li, Chunyu; Hall, Ingrid J.; Smith, Judith Lee; Ekwueme, Donatus U.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Zeliadt, Steven B.; Moinpour, Carol M.; Ramsey, Scott D.] Fred Hutchinson Canc Res Ctr, Publ Hlth Serv Div, Seattle, WA 98104 USA. [Zeliadt, Steven B.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. [Penson, David F.] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Med & Publ Hlth, Nashville, TN USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Keane, Thomas E.] Med Univ S Carolina, Urol Serv, Charleston, SC 29425 USA. RP Li, CY (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway NE,MS K-55, Atlanta, GA 30341 USA. EM Cli11@cdc.gov FU Centers for Disease Control and Prevention, Prevention Research Centers Program, through the University of Washington Health Promotion Research Center [SIP 25-04 1-U48-DP-000050] FX This study was supported by Cooperative Agreement Number SIP 25-04 1-U48-DP-000050 from the Centers for Disease Control and Prevention, Prevention Research Centers Program, through the University of Washington Health Promotion Research Center. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 35 TC 4 Z9 4 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD JUL-AUG PY 2012 VL 15 IS 5 BP 716 EP 723 DI 10.1016/j.jval.2012.03.003 PG 8 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 986AH UT WOS:000307311100015 PM 22867781 ER PT J AU Long, AA Fanta, CH AF Long, Aidan A. Fanta, Christopher H. TI Difficult asthma: Assessment and management, Part 1 SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; POORLY CONTROLLED ASTHMA; IMPERMEABLE BED COVERS; CHURG-STRAUSS-SYNDROME; QUALITY-OF-LIFE; MITE ALLERGEN; CONTROLLER MEDICATION; LATEX ALLERGY; RISK-FACTORS; DISEASE AB A minority of asthma patients have disease that proves difficult to control with usual medications and experience ongoing symptoms, poor quality of life, and limitations in activity and/or frequent asthma exacerbations. This group of patients accounts for much of the expense associated with asthma care and is the focus of national and international collaborative study groups. Distinguishing between "difficult-to-manage asthma" and truly "therapy-resistant asthma" is helpful and promotes a systematic consideration of contributory factors. Critical evaluation of factors contributing to difficult-to-manage asthma including adverse environment, comorbidities, nonadherence, and incorrect diagnosis is recommended in a systematic fashion in Part 1 of this contribution. C1 [Long, Aidan A.] Massachusetts Gen Hosp, Partners Asthma Ctr, Boston, MA 02114 USA. [Fanta, Christopher H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Pulm & Crit Care Div, Boston, MA 02115 USA. [Long, Aidan A.] Massachusetts Gen Hosp, Allergy & Clin Immunol Div, Boston, MA 02114 USA. RP Long, AA (reprint author), Massachusetts Gen Hosp, Partners Asthma Ctr, COX Room 201,55 Fruit St, Boston, MA 02114 USA. EM aalong@partners.org NR 65 TC 2 Z9 3 U1 0 U2 2 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2012 VL 33 IS 4 BP 305 EP 312 DI 10.2500/aap.2012.33.3583 PG 8 WC Allergy SC Allergy GA 984QC UT WOS:000307205100002 PM 22856631 ER PT J AU Fanta, CH Long, AA AF Fanta, Christopher H. Long, Aidan A. TI Difficult asthma: Assessment and management, Part 2 SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; OMALIZUMAB-ASSOCIATED ANAPHYLAXIS; CORTICOSTEROID-DEPENDENT ASTHMA; OBSTRUCTIVE PULMONARY-DISEASE; BASE-LINE CHARACTERISTICS; LIFE-THREATENING ASTHMA; LUNG-FUNCTION DECLINE; DOUBLE-BLIND; VITAMIN-D; BRONCHIAL THERMOPLASTY AB Patients with severe asthma have considerable morbidity related to their asthma and are at risk for serious, life-threatening exacerbations. Their management requires an intensive and comprehensive approach, including attention to reducing exposure to environmental inciters of airway inflammation and triggers of symptoms, patient education (including an asthma action plan), and opportunity for close patient-provider communication. Approved medical options include the lipoxygenase inhibitor, zileuton; the anti-immunoglobulin E monoclonal antibody, omalizumab; and bronchial thermoplasty. Nonapproved interventions of potential benefit are ultrahigh-dose inhaled corticosteroids, anticholinergic bronchodilators (tiotropium), macrolide antibiotics, and vitamin D supplementation for the vitamin D-deficient patient. Potentially toxic, "steroid-sparing" therapies such as methotrexate, cyclosporine, and etanercept are best reserved for patients participating in clinical trials. Recognition of specific subtypes of patients with therapy-resistant asthma permits more targeted treatment approaches, such as for aspirin-sensitive asthma, persistent eosinophilic asthma, asthma complicated by allergic bronchopulmonary aspergillosis, asthma with persistent airflow obstruction, and asthma with life-threatening (near fatal) asthmatic attacks. Novel therapies based on an improved understanding of the pathobiology of therapy-resistant asthma are greatly needed. C1 [Fanta, Christopher H.] Brigham & Womens Hosp, Partners Asthma Ctr, Boston, MA 02115 USA. [Fanta, Christopher H.] Brigham & Womens Hosp, Pulm & Crit Care Div, Boston, MA 02115 USA. [Long, Aidan A.] Harvard Univ, Sch Med, Allergy & Clin Immunol Div, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fanta, CH (reprint author), 75 Francis St, Boston, MA 02115 USA. EM cfanta@partners.org NR 70 TC 2 Z9 2 U1 0 U2 7 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 EI 1539-6304 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2012 VL 33 IS 4 BP 313 EP 323 DI 10.2500/aap.2012.33.3577 PG 11 WC Allergy SC Allergy GA 984QC UT WOS:000307205100003 PM 22856632 ER PT J AU Turke, AB Song, Y Costa, C Cook, R Arteaga, CL Asara, JM Engelman, JA AF Turke, Alexa B. Song, Youngchul Costa, Carlotta Cook, Rebecca Arteaga, Carlos L. Asara, John M. Engelman, Jeffrey A. TI MEK Inhibition Leads to PI3K/AKT Activation by Relieving a Negative Feedback on ERBB Receptors SO CANCER RESEARCH LA English DT Article ID CANCER CELL-LINES; BREAST-CANCER; LUNG-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; KINASE; EGFR; THERAPY; PHOSPHORYLATION; GAB1; AKT AB The phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-agent targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found thatMEKinhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer. Cancer Res; 72(13); 3228-37. (C) 2012 AACR. C1 [Turke, Alexa B.; Song, Youngchul; Costa, Carlotta; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Turke, Alexa B.; Asara, John M.; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. [Cook, Rebecca; Arteaga, Carlos L.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Boston, MA 02129 USA. EM jengelman@partners.org FU AstraZeneca; GalaxoSmithKline; NIH Gastrointestinal Cancer SPORE [P50 CA127003, CA120060-01, R01CA137008-01, R01CA140594, 1U01CA141457-01]; Lung SPORE [P50CA090578]; V Foundation; American Cancer Society [RSG-06-102-01-CCE]; Ellison Foundation Scholar Award; American Lung Cancer Association Lung Cancer Discovery Award; NIH [5P01CA120964-04]; NIH DF/HCC Cancer Center [5P30CA006516-46, R01CA80195]; Vanderbilt Breast Cancer SPORE [P50 CA98131] FX J.A. Engelman receives research support from AstraZeneca and GalaxoSmithKline and consults for AstraZeneca, GalaxoSmithKline, Novartis, and Genentech. No potential conflicts of interest were disclosed by the other authors.; This study is supported by the NIH Gastrointestinal Cancer SPORE P50 CA127003, K08 grant CA120060-01, R01CA137008-01, R01CA140594, 1U01CA141457-01, Lung SPORE P50CA090578, the V Foundation, American Cancer Society RSG-06-102-01-CCE, the Ellison Foundation Scholar Award, and the American Lung Cancer Association Lung Cancer Discovery Award (all to J.A. Engelman); NIH 5P01CA120964-04 and NIH DF/HCC Cancer Center Support Grant 5P30CA006516-46 (J.M. Asara); and R01CA80195 and Vanderbilt Breast Cancer SPORE P50 CA98131 (C. L. Arteaga). NR 37 TC 94 Z9 96 U1 0 U2 13 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 JUL 1 PY 2012 VL 72 IS 13 BP 3228 EP 3237 DI 10.1158/0008-5472.CAN-11-3747 PG 10 WC Oncology SC Oncology GA 986OB UT WOS:000307350700013 PM 22552284 ER PT J AU Duvvuri, U Shiwarski, DJ Xiao, D Bertrand, C Huang, X Edinger, RS Rock, JR Harfe, BD Henson, BJ Kunzelmann, K Schreiber, R Seethala, RS Egloff, AM Chen, X Lui, VW Grandis, JR Gollin, SM AF Duvvuri, Umamaheswar Shiwarski, Daniel J. Xiao, Dong Bertrand, Carol Huang, Xin Edinger, Robert S. Rock, Jason R. Harfe, Brian D. Henson, Brian J. Kunzelmann, Karl Schreiber, Rainer Seethala, Raja S. Egloff, Ann Marie Chen, Xing Lui, Vivian W. Grandis, Jennifer R. Gollin, Susanne M. TI TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ACTIVATED CHLORIDE CHANNEL; CA2+-ACTIVATED CL-CHANNELS; TRANSMEMBRANE CONDUCTANCE REGULATOR; GASTROINTESTINAL STROMAL TUMORS; ORAL-CANCER; TRANSCRIPTOME ANALYSIS; INTERSTITIAL-CELLS; EPITHELIAL-CELLS; 11Q13 AMPLICON AB Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK) 1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN. Cancer Res; 72(13); 3270-81. (C) 2012 AACR. C1 [Duvvuri, Umamaheswar; Shiwarski, Daniel J.; Xiao, Dong; Egloff, Ann Marie; Chen, Xing; Lui, Vivian W.; Grandis, Jennifer R.; Gollin, Susanne M.] Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Bertrand, Carol] Univ Pittsburgh, Med Ctr, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Seethala, Raja S.; Gollin, Susanne M.] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15213 USA. [Grandis, Jennifer R.] Univ Pittsburgh, Med Ctr, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Edinger, Robert S.] Univ Pittsburgh, Med Ctr, Renal & Electrolyte Div, Pittsburgh, PA 15213 USA. [Huang, Xin] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Huang, Xin] Univ Pittsburgh, Med Ctr, Magee Womens Res Inst, Pittsburgh, PA 15213 USA. [Duvvuri, Umamaheswar] Vet Affairs Pittsburgh Hlth Syst, Pittsburgh, PA USA. [Henson, Brian J.; Gollin, Susanne M.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Henson, Brian J.; Gollin, Susanne M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Rock, Jason R.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Harfe, Brian D.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Harfe, Brian D.] Univ Florida, Genet Inst, Gainesville, FL USA. [Kunzelmann, Karl; Schreiber, Rainer] Univ Regensburg, Dept Physiol, Regensburg, Germany. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol, 200 Lothrop St,W948 Biomed Sci Tower, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu RI Lui, Vivian/I-5458-2016; OI Kunzelmann, Karl/0000-0002-4583-7037; Shiwarski, Daniel/0000-0001-6978-303X FU Head and Neck Cancer SPORE grant [NIH P50CA097190]; Department of Otolaryngology; Deutsche Krebshilfe Projekt [109438]; CPPF; [P30CA047904] FX This work was supported by the Head and Neck Cancer SPORE grant (NIH P50CA097190 J.R. Grandis), through a Veterans Administration CDA; CPPF (U. Duvvuri) and start-up funds from the Department of Otolaryngology (U. Duvvuri). The molecular cytogenetic studies were carried out in the University of Pittsburgh Cancer Institute Cytogenetics Facility, supported in part by P30CA047904 to N.E. Davidson/R.B. Herberman/S.M. Gollin. KK was supported by Deutsche Krebshilfe Projekt 109438. NR 48 TC 95 Z9 101 U1 1 U2 11 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 JUL 1 PY 2012 VL 72 IS 13 BP 3270 EP 3281 DI 10.1158/0008-5472.CAN-12-0475-T PG 12 WC Oncology SC Oncology GA 986OB UT WOS:000307350700017 PM 22564524 ER PT J AU Xu, L Kikuchi, E Xu, CX Ebi, H Ercan, D Cheng, KA Padera, R Engelman, JA Janne, PA Shapiro, GI Shimamura, T Wong, KK AF Xu, Lu Kikuchi, Eiki Xu, Chunxiao Ebi, Hiromichi Ercan, Dalia Cheng, Katherine A. Padera, Robert Engelman, Jeffrey A. Jaenne, Pasi A. Shapiro, Geoffrey I. Shimamura, Takeshi Wong, Kwok-Kin TI Combined EGFR/MET or EGFR/HSP90 Inhibition Is Effective in the Treatment of Lung Cancers Codriven by Mutant EGFR Containing T790M and MET SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; KINASE DOMAIN MUTATIONS; GEFITINIB RESISTANCE; ACTIVATING MUTATIONS; DRUG-RESISTANCE; AMPLIFICATION; TUMORIGENESIS; SENSITIVITY; CARCINOMAS; ERLOTINIB AB Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non-small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR kinase domain mutations. Unfortunately, acquired resistance eventually emerges in these chronically treated cancers. Two of the most common mechanisms of acquired resistance to TKIs seen clinically are the acquisition of a secondary "gatekeeper" T790M EGFR mutation that increases the affinity of mutant EGFR for ATP and activation of MET to offset the loss of EGFR signaling. Although up to one-third of patient tumors resistant to reversible EGFR TKIs harbor concurrent T790M mutation and MET amplification, potential therapies for these tumors have not been modeled in vivo. In this study, we developed a preclinical platform to evaluate potential therapies by generating transgenic mouse lung cancer models expressing EGFR-mutant Del19-T790M or L858R-T790M, each with concurrent MET overexpression. We found that monotherapy targeting EGFR or MET alone did not produce significant tumor regression. In contrast, combination therapies targeting EGFR and MET simultaneously were highly efficacious against EGFR TKI-resistant tumors codriven by Del19-T790M or L858R-T790M and MET. Our findings therefore provide an in vivo model of intrinsic resistance to reversible TKIs and offer preclinical proof-of-principle that combination targeting of EGFR and MET may benefit patients with NSCLC. Cancer Res; 72(13); 3302-11. (C) 2012 AACR. C1 [Xu, Lu; Kikuchi, Eiki; Xu, Chunxiao; Ercan, Dalia; Cheng, Katherine A.; Jaenne, Pasi A.; Shapiro, Geoffrey I.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Xu, Lu; Kikuchi, Eiki; Xu, Chunxiao; Jaenne, Pasi A.; Shapiro, Geoffrey I.; Wong, Kwok-Kin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Kikuchi, Eiki; Xu, Chunxiao; Ercan, Dalia; Cheng, Katherine A.; Jaenne, Pasi A.; Wong, Kwok-Kin] Belfer Inst Appl Canc Sci, Boston, MA USA. [Kikuchi, Eiki; Xu, Chunxiao; Cheng, Katherine A.; Jaenne, Pasi A.; Wong, Kwok-Kin] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. [Ebi, Hiromichi; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Ebi, Hiromichi; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Padera, Robert] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Xu, Lu] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Shimamura, Takeshi] Loyola Univ Chicago, Stritch Sch Med, Inst Oncol, Dept Mol Pharmacol & Therapeut, Maywood, IL USA. RP Wong, KK (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,HIM243, Boston, MA 02215 USA. EM kwong1@partners.org RI Kikuchi, Eiki/M-9688-2014; OI Ebi, Hiromichi/0000-0003-3155-7576; wong, kwok kin/0000-0001-6323-235X FU NIH [CA122794, CA140594, CA163896, CA141576, P50 CA090578]; United Against Lung Cancer; American Lung Association; Susan Spooner Research Fund; DF/HCC Lung SPORE Career Development Award FX This work is supported by NIH grants CA122794, CA140594, CA163896, and CA141576, as well as grants from United Against Lung Cancer, American Lung Association, and the Susan Spooner Research Fund, all to K.-K. Wong. K.-K. Wong, G. I. Shapiro, J.A. Engelman, and P. A. Janne were supported by NIH grant P50 CA090578 [Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Lung Cancer]. T. Shimamura was supported by a DF/HCC Lung SPORE Career Development Award. NR 41 TC 50 Z9 51 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2012 VL 72 IS 13 BP 3302 EP 3311 DI 10.1158/0008-5472.CAN-11-3720 PG 10 WC Oncology SC Oncology GA 986OB UT WOS:000307350700020 PM 22552292 ER PT J AU Cohen, MJ Shaykevich, S Cawthon, C Kripalani, S Paasche-Orlow, MK Schnipper, JL AF Cohen, Marya J. Shaykevich, Shimon Cawthon, Courtney Kripalani, Sunil Paasche-Orlow, Michael K. Schnipper, Jeffrey L. TI Predictors of medication adherence postdischarge: The impact of patient age, insurance status, and prior adherence SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID ADVERSE DRUG EVENTS; LOW HEALTH LITERACY; HOSPITAL DISCHARGE; CHINESE PATIENTS; COHORT; CARE; QUESTIONNAIRES; DISCREPANCIES; INTERVENTION; NONADHERENCE AB BACKGROUND: Optimizing postdischarge medication adherence is a target for avoiding adverse events. Nevertheless, few studies have focused on predictors of postdischarge medication adherence. METHODS: The Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) study used counseling and follow-up to improve postdischarge medication safety. In this secondary data analysis, we analyzed predictors of self-reported medication adherence after discharge. Based on an interview at 30-days postdischarge, an adherence score was calculated as the mean adherence in the previous week of all regularly scheduled medications. Multivariable linear regression was used to determine the independent predictors of postdischarge adherence. RESULTS: The mean age of the 646 included patients was 61.2 years, and they were prescribed an average of 8 daily medications. The mean postdischarge adherence score was 95% (standard deviation [SD] = 10.2%). For every 10-year increase in age, there was a 1% absolute increase in postdischarge adherence (95% confidence interval [CI] 0.4% to 2.0%). Compared to patients with private insurance, patients with Medicaid were 4.5% less adherent (95% CI -7.6% to -1.4%). For every 1-point increase in baseline medication adherence score, as measured by the 4-item Morisky score, there was a 1.6% absolute increase in postdischarge medication adherence (95% CI 0.8% to 2.4%). Surprisingly, health literacy was not an independent predictor of postdischarge adherence. CONCLUSIONS: In patients hospitalized for cardiovascular disease, predictors of lower medication adherence postdischarge included younger age, Medicaid insurance, and baseline nonadherence. These factors can help predict patients who may benefit from further interventions. Journal of Hospital Medicine 2012;. (C) 2012 Society of Hospital Medicine C1 [Cohen, Marya J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gen Med,Gen Med Unit, Boston, MA 02114 USA. [Schnipper, Jeffrey L.] Harvard Univ, Brigham & Womens Hosp, Div Gen Med, Sch Med, Boston, MA 02114 USA. [Cawthon, Courtney; Kripalani, Sunil] Vanderbilt Ctr Hlth Serv Res, Inst Med & Publ Hlth, Nashville, TN USA. [Kripalani, Sunil] Vanderbilt Univ, Dept Med, Div Gen Internal Med & Publ Hlth, Sect Hosp Med, Nashville, TN USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Boston Med Ctr, Sect Gen Internal Med, Boston, MA 02118 USA. [Schnipper, Jeffrey L.] Harvard Univ, Brigham & Womens Hosp, BWH Hospitalist Serv, Sch Med, Boston, MA 02114 USA. RP Cohen, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gen Med,Gen Med Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM mjcohen@partners.org OI Paasche-Orlow, Michael/0000-0002-9276-7190 FU NHLBI [R01 HL089755, K23 HL077597, K08 HL072806]; Division of General Medicine, Massachusetts General Hospital; Harvard Medical School; [T32HP10251-02] FX Disclosures: Financial support was provided by R01 HL089755 (NHLBI, Kripalani), K23 HL077597 (NHLBI, Kripalani), K08 HL072806 (NHLBI, Schnipper), T32HP10251-02 (Cohen), and by the Division of General Medicine, Massachusetts General Hospital and the Harvard Medical School Fellowship in General Medicine and Primary Care (Cohen). Dr Kripalani is a consultant to and holds equity in PictureRx, LLC, which makes patient education tools to improve medication management. PictureRx did not provide materials or funding for this study. All other authors disclose no relevant or financial conflicts of interest. NR 40 TC 18 Z9 19 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD JUL-AUG PY 2012 VL 7 IS 6 BP 470 EP 475 DI 10.1002/jhm.1940 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 982NW UT WOS:000307053200003 PM 22473754 ER PT J AU Krassner, A Dhaliwal, G Baudendistel, TE AF Krassner, Alexander Dhaliwal, Gurpreet Baudendistel, Thomas E. TI Overcome by weakness SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID NOCARDIOSIS C1 [Krassner, Alexander; Baudendistel, Thomas E.] Kaiser Oakland Med Ctr, Dept Med, Oakland, CA 94611 USA. [Dhaliwal, Gurpreet] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. RP Krassner, A (reprint author), Kaiser Oakland Med Ctr, Dept Med, 280 W MacArthur Blvd, Oakland, CA 94611 USA. EM alexander.d.krassner@kp.org NR 7 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD JUL-AUG PY 2012 VL 7 IS 6 BP 513 EP 516 DI 10.1002/jhm.1930 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 982NW UT WOS:000307053200010 PM 22407607 ER PT J AU Mahindra, A Anderson, KC AF Mahindra, Anuj Anderson, Kenneth C. TI Role of Interleukin 16 in Multiple Myeloma Pathogenesis: A Potential Novel Therapeutic Target? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CD4 LIGAND; IL-16; ASSOCIATION; CANCER; ACTIVATION; EXPRESSION; CYTOKINES; DEATH; RISK C1 [Anderson, Kenneth C.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02215 USA. [Mahindra, Anuj] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA USA. [Mahindra, Anuj; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Div Hematol Oncol, 450 Brookline Ave,Mayer 557, Boston, MA 02215 USA. EM kenneth_anderson@dfci.harvard.edu FU NCI NIH HHS [R01 CA050947, P50 CA100707, P01 CA155258, P01 CA078378] NR 22 TC 4 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL PY 2012 VL 104 IS 13 BP 964 EP 965 DI 10.1093/jnci/djs274 PG 3 WC Oncology SC Oncology GA 973OO UT WOS:000306369800003 PM 22745468 ER PT J AU Verfaelllie, M LaRocque, KF Keane, MM AF Verfaelllie, Mieke LaRocque, Karen F. Keane, Margaret M. TI Intact implicit verbal relational memory in medial temporal lobe amnesia SO NEUROPSYCHOLOGIA LA English DT Article DE Amnesia; Relational memory; Implicit memory; Associative priming; Medial temporal lobes; Hippocampus ID DEPENDENT EYE-MOVEMENTS; NEUROPSYCHOLOGICAL EVIDENCE; ASSOCIATIONS; HIPPOCAMPUS; ATTENTION; AWARENESS; SYSTEMS; CONSCIOUSNESS; INFORMATION; RETENTION AB To elucidate the role of the hippocampus in unaware relational memory, the present study examined the performance of amnesic patients with medial temporal lobe (MTL) lesions on a cued category-exemplar generation task. In contrast to a prior study in which amnesic patients showed impaired performance.(Verfaellie et al., Cognitive, Affective, and Behavioral Neuroscience, 2006, 6, 91-101), the current study employed a task that required active processing of the context word at test. In this version of the task, amnesic patients, like control participants, showed enhanced category exemplar priming when the context word associated with the target at study was reinstated at test. The finding of intact implicit memory for novel associations following hippocampal lesions in a task that requires flexible use of retrieval cues is inconsistent with a relational memory view that suggests that the hippocampus is critical for all forms of relational memory, regardless of awareness. Instead, it suggests that unaware memory for within-domain associations does not require MTL mediation. Published by Elsevier Ltd. C1 [Verfaelllie, Mieke; LaRocque, Karen F.; Keane, Margaret M.] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA USA. [Verfaelllie, Mieke; LaRocque, Karen F.; Keane, Margaret M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Keane, Margaret M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02181 USA. RP Verfaelllie, M (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA USA. EM verf@bu.edu OI LaRocque, Karen/0000-0002-6058-2706 FU NIMH [57681]; Medical Research Service of the Department of Veterans Affairs FX This research was supported by NIMH grant 57681 and by the Medical Research Service of the Department of Veterans Affairs. The authors thank Amanda Utevsky and Matt Cruz for research assistance. NR 41 TC 6 Z9 6 U1 2 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUL PY 2012 VL 50 IS 8 BP 2100 EP 2106 DI 10.1016/j.neuropsychologia.2012.05.011 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 982ES UT WOS:000307025600041 PM 22609574 ER PT J AU Brennan, DJ O'Connor, DP Laursen, H McGee, SF McCarthy, S Zagozdzon, R Rexhepaj, E Culhane, AC Martin, FM Duffy, MJ Landberg, G Ryden, L Hewitt, SM Kuhar, MJ Bernards, R Millikan, RC Crown, JP Jirstrom, K Gallagher, WM AF Brennan, D. J. O'Connor, D. P. Laursen, H. McGee, S. F. McCarthy, S. Zagozdzon, R. Rexhepaj, E. Culhane, A. C. Martin, F. M. Duffy, M. J. Landberg, G. Ryden, L. Hewitt, S. M. Kuhar, M. J. Bernards, R. Millikan, R. C. Crown, J. P. Jirstrom, K. Gallagher, W. M. TI The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER alpha, and is an independent prognostic factor in node-negative breast cancer SO ONCOGENE LA English DT Article DE cocaine- and amphetamine-regulated transcript; breast cancer; prognosis; estrogen receptor ID NERVE GROWTH-FACTOR; ESTROGEN-RECEPTOR; RANDOMIZED-TRIALS; GENE-EXPRESSION; PROTEIN-KINASE; CART PEPTIDES; TAMOXIFEN; CELLS; PHOSPHORYLATION; THERAPY AB Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ER alpha in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. Oncogene (2012) 31, 3483-3494; doi:10.1038/onc.2011.519; published online 5 December 2011 C1 [Brennan, D. J.; O'Connor, D. P.; Laursen, H.; McGee, S. F.; McCarthy, S.; Zagozdzon, R.; Rexhepaj, E.; Martin, F. M.; Gallagher, W. M.] Univ Coll Dublin, UCD Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin 4, Ireland. [Culhane, A. C.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biost & Computat Biol, Boston, MA 02115 USA. [Duffy, M. J.] Univ Coll Dublin, UCD Sch Med & Med Sci, UCD Conway Inst, Dublin 2, Ireland. [Duffy, M. J.] St Vincents Univ Hosp, Dept Pathol & Lab Med, Dublin 4, Ireland. [Landberg, G.] Lund Univ, Skane Univ Hosp, Ctr Mol Pathol, Dept Lab Med, Malmo, Sweden. [Hewitt, S. M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kuhar, M. J.] Emory Univ, Yerkes Natl Primate Res Ctr, Div Neurosci, Atlanta, GA 30322 USA. [Bernards, R.] Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands. [Millikan, R. C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Crown, J. P.] St Vincents Univ Hosp, Dublin 4, Ireland. [Ryden, L.] Lund Univ, Div Surg, Skane Univ Hosp, Dept Clin Sci, Lund, Sweden. [Jirstrom, K.] Lund Univ, Skane Univ Hosp, Div Pathol, Dept Clin Sci, Lund, Sweden. RP Gallagher, WM (reprint author), Univ Coll Dublin, UCD Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin 4, Ireland. EM william.gallagher@ucd.ie RI Zagozdzon, Radoslaw/K-2141-2012; OI Hewitt, Stephen/0000-0001-8283-1788; Bernards, Rene/0000-0001-8677-3423 FU Program for Third Level Institutions; Health Research Board of Ireland; Enterprise Ireland; Science Foundation Ireland [08/SRC/B1410]; European Community [224865]; [RR00165] FX The UCD Conway Institute is funded by the Program for Third Level Institutions, as administered by the Higher Education Authority of Ireland. Funding is acknowledged from the Health Research Board of Ireland, Enterprise Ireland and the Science Foundation Ireland Strategic Research Cluster award to Molecular Therapeutics for Cancer Ireland (08/SRC/B1410). The work of Dr R Zagozdzon has been supported by a Marie Curie International Reintegration Grant no. 224865 within the 7th European Community Framework Program. Dr MJ Kuhar is funded by RR00165. NR 43 TC 4 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL PY 2012 VL 31 IS 30 BP 3483 EP 3494 DI 10.1038/onc.2011.519 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 979UA UT WOS:000306844100001 PM 22139072 ER PT J AU Camacho-Soto, A Sowa, GA Perera, S Weiner, DK AF Camacho-Soto, Alejandra Sowa, Gwendolyn A. Perera, Subashan Weiner, Debra K. TI Fear Avoidance Beliefs Predict Disability in Older Adults With Chronic Low Back Pain SO PM&R LA English DT Article ID GAIT SPEED; PHYSICAL FUNCTION; RISK-FACTORS; QUESTIONNAIRE; PEOPLE; PREVALENCE; DEPRESSION; SURVIVAL; DECLINE; SCALE AB Objectives: To determine whether fear avoidance beliefs (FABs) in older adults with chronic low back pain (CLBP) are significantly associated with gait speed decline and/or self-report of greater disability. Design: Cross-sectional analysis. Setting: An academic medical center (single site). Participants: Two hundred English-speaking participants aged 65 years and older with CLBP every day or almost every day of moderate or greater intensity for >= 3 months. Main Outcome Measurements: The physical activity portion of the FAB questionnaire assessed FABs. Disability was measured with gait speed and the Roland Morris Questionnaire. Covariates measured included age, gender, body mass index, chronic disease (Cumulative Illness Rating Scale), depression (Geriatric Depression Scale), and pain (McGill Pain Questionnaire Short Form). Results: FABs were significantly associated with the Roland Morris Questionnaire (P < .0001) and gait speed (P = .002) after controlling for all covariates. Conclusion: FABs related to physical activity in older adults with CLBP were significantly associated with both self-reported and performance-based disability after controlling for known confounders. Previous studies have reported similar associations between self-reported measures of disabling back pain and FABs. Ours is the first study to examine the relationship between FAB and gait speed, a powerful predictor of morbidity and mortality. Future work should examine whether targeting fear avoidance in addition to other psychosocial measures in older adults with CLBP improves gait speed and functional independence. PM R 2012;4:493-497 C1 [Camacho-Soto, Alejandra; Sowa, Gwendolyn A.] Univ Pittsburgh, Sch Med, Dept Med & Phys Med & Rehabil, Pittsburgh, PA USA. [Perera, Subashan] Univ Pittsburgh, Sch Med, Dept Biostat & Med, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Camacho-Soto, A (reprint author), 333 E Ontario 18048, Chicago, IL 60611 USA. EM acamachosoto@gmail.com RI Perera, Subashan/D-7603-2014 FU Pittsburgh Claude D. Pepper Older Americans Independence Center [AG024827]; National Center for Complementary and Alternative Medicine [R01 AT000985]; National Institute on Aging, National Institutes of Health, Pitt Clinical Research Training Geriatrics/Gerontology [AG21885] FX Research support: Pittsburgh Claude D. Pepper Older Americans Independence Center, AG024827, grant R01 AT000985 from the National Center for Complementary and Alternative Medicine and the National Institute on Aging, National Institutes of Health, Pitt Clinical Research Training Geriatrics/Gerontology, AG21885 NR 31 TC 13 Z9 13 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD JUL PY 2012 VL 4 IS 7 BP 493 EP 497 DI 10.1016/j.pmrj.2012.01.017 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 981RR UT WOS:000306987800005 PM 22516436 ER PT J AU Brunoni, AR Nitsche, MA Bolognini, N Bikson, M Wagner, T Merabet, L Edwards, DJ Valero-Cabre, A Rotenberg, A Pascual-Leone, A Ferrucci, R Priori, A Boggio, PS Fregni, F AF Brunoni, Andre Russowsky Nitsche, Michael A. Bolognini, Nadia Bikson, Marom Wagner, Tim Merabet, Lotfi Edwards, Dylan J. Valero-Cabre, Antoni Rotenberg, Alexander Pascual-Leone, Alvaro Ferrucci, Roberta Priori, Alberto Boggio, Paulo Sergio Fregni, Felipe TI Clinical research with transcranial direct current stimulation (tDCS): Challenges and future directions SO BRAIN STIMULATION LA English DT Review DE transcranial direct current stimulation; brain stimulation; clinical research; physical medicine; neuropsychiatry; medical devices ID HUMAN MOTOR CORTEX; NONINVASIVE BRAIN-STIMULATION; SOMATOSENSORY-EVOKED POTENTIALS; MAGNETIC STIMULATION; DC-STIMULATION; PREFRONTAL CORTEX; MAJOR DEPRESSION; WORKING-MEMORY; ELECTRICAL-STIMULATION; CORTICAL EXCITABILITY AB Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase H, and phase HI studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS. (C) 2012 Elsevier Inc. All rights reserved. C1 [Fregni, Felipe] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Lab Neuromodulat, Boston, MA 02114 USA. [Brunoni, Andre Russowsky] Univ Sao Paulo, Inst Psychol, Dept Neurosci & Behav, Sao Paulo, Brazil. [Nitsche, Michael A.] Univ Gottingen, Dept Clin Neurophysiol, D-3400 Gottingen, Germany. [Bolognini, Nadia] Univ Milanobicocca, Dept Psychol, Milan, Italy. [Bolognini, Nadia] IRCCS Inst Auxol Italiano, Neuropsychol Lab, Milan, Italy. [Bikson, Marom] CUNY City Coll, New York, NY 10031 USA. [Wagner, Tim] MIT, Boston, MA USA. [Merabet, Lotfi] Harvard Univ, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Edwards, Dylan J.] Cornell Univ, Coll Med, Burke Med Res Inst, White Plains, NY 10605 USA. [Valero-Cabre, Antoni] Boston Univ, Sch Med, Boston, MA 02118 USA. [Rotenberg, Alexander] Harvard Univ, Childrens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Ferrucci, Roberta; Priori, Alberto] Univ Milan, Dipartimento Sci Neurol, Osped Maggiore Policlin, Fdn IRCCS Ca Granda,Ctr Clin Neurostimolaz Neurot, Milan, Italy. [Boggio, Paulo Sergio] Mackenzie Prebyterian Univ, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, Sao Paulo, Brazil. [Boggio, Paulo Sergio] Mackenzie Prebyterian Univ, Ctr Hlth & Biol Sci, Dev Disorders Program, Sao Paulo, Brazil. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Fregni, F (reprint author), Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Lab Neuromodulat, 125 Nashua St 727, Boston, MA 02114 USA. EM fregni.felipe@mgh.harvard.edu RI Brunoni, Andre/H-8394-2012; Boggio, Paulo/K-6272-2012; BOLOGNINI, NADIA/J-5746-2016; Ferrucci, Roberta/K-6081-2016; OI Brunoni, Andre/0000-0002-6310-3571; Boggio, Paulo/0000-0002-6109-0447; BOLOGNINI, NADIA/0000-0002-2921-8658; Ferrucci, Roberta/0000-0001-5109-9483; Valero-Cabre, Antoni/0000-0002-5033-2279 FU NIH [R21HD060999, 5R21DK081773-03] FX We are thankful to Erin Connors for copyediting this manuscript. We are also grateful to Scala Institute and Mackenzie University (Sao Paulo, Brazil) for the additional support to organize this working group meeting in the II International Symposium in Neuromodulation. This working group meeting was the 2nd International tDCS club workshop, which took place in Sao Paulo, Brazil, in March 2010, at the Social and Cognitive Neuroscience Laboratory of Mackenzie Presbiterian University. The first meeting was held in Milan, Italy in 2008. D.E. was supported by NIH grant R21HD060999 and F.F. was supported by NIH grant (5R21DK081773-03). NR 150 TC 299 Z9 308 U1 15 U2 118 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD JUL PY 2012 VL 5 IS 3 BP 175 EP 195 DI 10.1016/j.brs.2011.03.002 PG 21 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 984NW UT WOS:000307198700002 PM 22037126 ER PT J AU Solin, LJ Gray, R Goldstein, LJ Recht, A Baehner, FL Shak, S Badve, S Perez, EA Shulman, LN Martino, S Davidson, NE Sledge, GW Sparano, JA AF Solin, Lawrence J. Gray, Robert Goldstein, Lori J. Recht, Abram Baehner, Frederick L. Shak, Steven Badve, Sunil Perez, Edith A. Shulman, Lawrence N. Martino, Silvana Davidson, Nancy E. Sledge, George W., Jr. Sparano, Joseph A. TI Prognostic value of biologic subtype and the 21-gene recurrence score relative to local recurrence after breast conservation treatment with radiation for early stage breast carcinoma: results from the Eastern Cooperative Oncology Group E2197 study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Early stage breast carcinoma; Breast conservation treatment; Radiation treatment; 21-Gene recurrence score; Local recurrence; Local-regional recurrence ID CONSERVING THERAPY; LOCOREGIONAL RECURRENCE; PROGESTERONE-RECEPTOR; SINGLE-INSTITUTION; ESTROGEN-RECEPTOR; CANCER SUBTYPES; PATTERNS; WOMEN; FEATURES; RELAPSE AB The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local-regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1-3 positive lymph nodes or negative lymph nodes with tumor size > 1.0 cm. The study population was a subset of 388 patients with known 21-gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7-11.6 years). The 10-year rates of local recurrence and local-regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local-regional recurrence on univariate or multivariate analyses (all P a parts per thousand yen 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2-negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors (P = 0.76), and the 10-year rates of local-regional recurrence were 6.3, 6.9, and 7.2 %, respectively (P = 0.79). For hormone receptor-positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively (P = 0.17), and the 10-year rates of local-regional recurrence were 3.8, 5.1, and 12.0 %, respectively (P = 0.12). For hormone receptor-positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local-regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local-regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation. C1 [Solin, Lawrence J.] Albert Einstein Med Ctr, Dept Radiat Oncol, Philadelphia, PA 19141 USA. [Gray, Robert; Shulman, Lawrence N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gray, Robert] Coordinating Ctr, Eastern Cooperat Oncol Grp, Boston, MA USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Baehner, Frederick L.; Shak, Steven] Genom Hlth Inc, Redwood City, CA USA. [Badve, Sunil] Indiana Univ, Dept Pathol, Indianapolis, IN 46204 USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Sledge, George W., Jr.] Indiana Univ, Dept Med Oncol, Indianapolis, IN 46204 USA. [Sparano, Joseph A.] Albert Einstein Coll Med, Dept Med Oncol, Montefiore Med Ctr, New York, NY USA. RP Solin, LJ (reprint author), Albert Einstein Med Ctr, Dept Radiat Oncol, 5501 Old York Rd, Philadelphia, PA 19141 USA. EM solin@einstein.edu FU Public Health Service [CA23318, CA66636, CA21115, CA14958, CA80775, CA49883, CA39229, CA27525, CA25224, CA32102, CA45389]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Sanofi-Aventis; Breast Cancer Research Foundation; Genomic Health, Inc. FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair), and supported in part by the Public Health Service Grants CA23318, CA66636, CA21115, CA14958, CA80775, CA49883, CA39229, CA27525, CA25224, CA32102, CA45389, the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Other supporting grants include Sanofi-Aventis and The Breast Cancer Research Foundation. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Biospecimens were provided by the ECOG Pathology Coordinating Office and Reference Laboratory.; Compensated Robert Gray: Research Funding, Genomic Health, Inc.; Lori J. Goldstein: Member, Advisory Board, Genomic Health, Inc.; Frederick L. Baehner: Employee, Genomic Health, Inc., also with stock ownership; Steven Shak: Employee, Genomic Health, Inc., also with stock ownership; Sunil Badve: Other remuneration, Genomic Health, Inc. NR 29 TC 17 Z9 19 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2012 VL 134 IS 2 BP 683 EP 692 DI 10.1007/s10549-012-2072-y PG 10 WC Oncology SC Oncology GA 978HD UT WOS:000306730500020 PM 22547108 ER PT J AU Sparano, JA Goldstein, LJ Davidson, NE Sledge, GW Gray, R AF Sparano, Joseph A. Goldstein, Lori J. Davidson, Nancy E. Sledge, George W., Jr. Gray, Robert TI TOP2A RNA expression and recurrence in estrogen receptor-positive breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; TOP2A RNA expression; Recurrence ID TOPOISOMERASE-II-ALPHA; GENE-EXPRESSION; ASSAY; CHEMOTHERAPY; MULTICENTER; CARCINOMAS; TAMOXIFEN; PROGNOSIS; SIGNATURE AB The purpose of this study is to evaluate the relationship between TOP2A RNA expression and recurrence in patients with operable estrogen receptor (ER)-positive breast cancer. We evaluated TOP2A expression in a pooled analysis of four independent datasets with gene expression data including 752 patients with early stage, ER-positive, HER2-negative breast cancer, most of whom received either no adjuvant therapy or only endocrine therapy without chemotherapy. We also used an algorithm to simulate the Oncotype DX Recurrence Score (simRS) and the proliferation component of the Recurrence Score (simPS). Results are expressed as the hazard ratio (HR) for estimates of the effect of a 1SD increase in the value of the log gene expression (x + 1SD vs. x) as a continuous function. TOP2A expression was significantly associated with recurrence (HR 1.56, p < 0.0001), and after adjustment for simRS (HR 1.26, p = 0.003). TOP2A correlated somewhat with simRS (0.45), but more strongly with simPS (0.69). For those with an intermediate simRS, high TOP2A expression (above the median) was associated with significantly higher relapse rates at 5 years (HR 1.82, p = 0.007). TOP2A expression provides prognostic information in patients with ER-positive, HER2-negative breast cancer, a population known to have low incidence of TOP2A gene alterations. These findings confirm prior reports indicating that TOP2A expression provides prognostic information in ER-positive breast cancer. TOP2A expression may also be useful for identifying those with an intermediate RS who are more likely to relapse, although additional validation in datasets including measured rather than simulated RS will be required. C1 [Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Weiler Div, Montefiore Einstein Canc Ctr, Bronx, NY 10461 USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Sledge, George W., Jr.] Indiana Univ Sch Med, Indianapolis, IN USA. [Gray, Robert] Harvard Univ, Eastern Cooperat Oncol Grp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Weiler Div, Montefiore Einstein Canc Ctr, 1825 Eastchester Rd, Bronx, NY 10461 USA. EM sparano@jimmy.harvard.edu FU Department of Health and Human Services; National Institutes of Health [CA23318] FX This study was supported in part by Grants from the Department of Health and Human Services and the National Institutes of Health (CA23318 to the ECOG statistical center). NR 19 TC 4 Z9 6 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2012 VL 134 IS 2 BP 751 EP 757 DI 10.1007/s10549-012-2112-7 PG 7 WC Oncology SC Oncology GA 978HD UT WOS:000306730500028 PM 22706628 ER PT J AU Li, DH Duell, EJ Yu, K Risch, HA Olson, SH Kooperberg, C Wolpin, BM Jiao, L Dong, XQ Wheeler, B Arslan, AA Bueno-de-Mesquita, HB Fuchs, CS Gallinger, S Gross, M Hartge, P Hoover, RN Holly, EA Jacobs, EJ Klein, AP LaCroix, A Mandelson, MT Petersen, G Zheng, W Agalliu, I Albanes, D Boutron-Ruault, MC Bracci, PM Buring, JE Canzian, F Chang, K Chanock, SJ Cotterchio, M Gaziano, JM Giovannucci, EL Goggins, M Hallmans, G Hankinson, SE Bolton, JAH Hunter, DJ Hutchinson, A Jacobs, KB Jenab, M Khaw, KT Kraft, P Krogh, V Kurtz, RC McWilliams, RR Mendelsohn, JB Patel, AV Rabe, KG Riboli, E Shu, XO Tjonneland, A Tobias, GS Trichopoulos, D Virtamo, J Visvanathan, K Watters, J Yu, H Zeleniuch-Jacquotte, A Amundadottir, L Stolzenberg-Solomon, RZ AF Li, Donghui Duell, Eric J. Yu, Kai Risch, Harvey A. Olson, Sara H. Kooperberg, Charles Wolpin, Brian M. Jiao, Li Dong, Xiaoqun Wheeler, Bill Arslan, Alan A. Bueno-de-Mesquita, H. Bas Fuchs, Charles S. Gallinger, Steven Gross, Myron Hartge, Patricia Hoover, Robert N. Holly, Elizabeth A. Jacobs, Eric J. Klein, Alison P. LaCroix, Andrea Mandelson, Margaret T. Petersen, Gloria Zheng, Wei Agalliu, Ilir Albanes, Demetrius Boutron-Ruault, Marie-Christine Bracci, Paige M. Buring, Julie E. Canzian, Federico Chang, Kenneth Chanock, Stephen J. Cotterchio, Michelle Gaziano, J. Michael Giovannucci, Edward L. Goggins, Michael Hallmans, Goran Hankinson, Susan E. Bolton, Judith A. Hoffman Hunter, David J. Hutchinson, Amy Jacobs, Kevin B. Jenab, Mazda Khaw, Kay-Tee Kraft, Peter Krogh, Vittorio Kurtz, Robert C. McWilliams, Robert R. Mendelsohn, Julie B. Patel, Alpa V. Rabe, Kari G. Riboli, Elio Shu, Xiao-Ou Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Virtamo, Jarmo Visvanathan, Kala Watters, Joanne Yu, Herbert Zeleniuch-Jacquotte, Anne Amundadottir, Laufey Stolzenberg-Solomon, Rachael Z. TI Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer SO CARCINOGENESIS LA English DT Article ID NUCLEAR FACTOR 1-ALPHA; C-REACTIVE PROTEIN; SIGNALING PATHWAYS; LOGIC REGRESSION; MICE LEADS; RISK; METABOLISM; MUTATIONS; GLUCOSE; LIVER AB Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 x 10(-6), 1.6 x 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 x 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer. C1 [Yu, Kai; Hartge, Patricia; Hoover, Robert N.; Albanes, Demetrius; Chanock, Stephen J.; Hutchinson, Amy; Jacobs, Kevin B.; Mendelsohn, Julie B.; Tobias, Geoffrey S.; Amundadottir, Laufey; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Li, Donghui; Dong, Xiaoqun] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Barcelona, Spain. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Kooperberg, Charles; LaCroix, Andrea; Mandelson, Margaret T.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Wolpin, Brian M.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian M.; Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Wolpin, Brian M.; Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Jiao, Li] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Wheeler, Bill] Informat Management Serv Inc, Silver Spring, MD USA. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gallinger, Steven] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Gross, Myron] Univ Minnesota, Sch Med, Dept Lab Med Pathol, Minneapolis, MN 55455 USA. [Holly, Elizabeth A.; Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Johns Hopkins Med Inst, Dept Epidemiol, Bloomberg Sch Publ Hlth, Sol Goldman Pancreat Res Ctr, Baltimore, MD 21205 USA. [Mandelson, Margaret T.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Petersen, Gloria; Rabe, Kari G.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Dept Med, Div Epidemiol, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Agalliu, Ilir] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Boutron-Ruault, Marie-Christine] Univ Paris 11, INSERM, Inst Gustave Roussy, Villejuif, France. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Buring, Julie E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02115 USA. [Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang, Kenneth] Univ Calif Irvine, Irvine Med Ctr, Comprehens Digest Dis Ctr, Orange, CA 92668 USA. [Chanock, Stephen J.; Amundadottir, Laufey] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chanock, Stephen J.; Hutchinson, Amy; Jacobs, Kevin B.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Gaziano, J. Michael] Brigham & Womens Hosp, Phy Hlth Study, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Kraft, Peter; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael; Visvanathan, Kala] Johns Hopkins Univ, Sch Med, Dept Pathol & Med, Baltimore, MD USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Bolton, Judith A. Hoffman] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Jenab, Mazda] WHO, IARC, Lyon, France. [Khaw, Kay-Tee] Univ Cambridge, Addenbrookes Hosp, Dept Publ Hlth & Primary Care, Cambridge CB2 2QQ, England. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Nutr Epidemiol Unit, Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [McWilliams, Robert R.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Div Epidemiol & Biostat, London, England. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Watters, Joanne] NCI, Div Canc Prevent & Populat Control, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Stolzenberg-Solomon, RZ (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3022, Rockville, MD 20852 USA. EM amundadottirl@mail.nih.gov; rs221z@nih.gov RI Boutron Ruault, Marie-Christine/G-3705-2013; Gallinger, Steven/E-4575-2013; Boutron, Marie-Christine/K-8168-2013; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Krogh, Vittorio/K-2628-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Krogh, Vittorio/0000-0003-0122-8624; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Duell, Eric J/0000-0001-5256-0163 FU National Institutes of Health (NIH), Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services; Insituto de Salud Carlos III (RETICC) [RD06/0020]; NCI [R01CA098661, P30CA016087, P50CA62924, R01CA97075, R01 CA82729, R37 CA70867, CA59706, CA108370, CA109767, CA89726, CA98889, NO1-CN-25514, CA105069, CA73790]; National Institute of Environmental Health Sciences [ES000260]; National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]; NCI, NIH [5R01CA098870, P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467, HHSN261200800001E]; Lustgarten Foundation for Pancreatic Cancer Research; The Society of MSKCC; Geoffrey Beene Cancer Research Fund; NIH [RO1 CA98380]; Rombauer Pancreatic Cancer Research Fund; NIH (as part of the PACGENE consortium) [R01 CA97075]; The Lustgarten Foundation for Pancreatic Cancer Research; Ontario Cancer Research Network; Georgetown University [NO1-CN25522]; Pacific Health Research Institute [NO1-CN-25515]; Henry Ford Health System [NO1-CN-25512]; University of Minnesota [NO1-CN25513]; Washington University [NO1-CN-25516]; University of Pittsburgh [NO1-CN-25511]; University of Utah [NO1-CN-25524]; Marshfield Clinic Research Foundation [NO1-CN-25518]; University of Alabama at Birmingham [NO1-CN-75022]; Westat, Inc. [NO1-CN-25476]; University of California, Los Angeles [NO1-CN-25404]; NCI, NIH; US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; European Commission: Public Health and Consumer Protection Directorate; Ligue contre le Cancer; Societe 3M; Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); ISCIII RETIC of the Spanish Ministry of Health [RD06/0020]; National Institute of Aging [5U01AG018033]; State of Maryland; Maryland Cigarette Restitution Fund; National Program of Cancer Registries of the Centers for Disease Control and Prevention; American Cancer Society FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services.; E.J.D. supported by Insituto de Salud Carlos III (RETICC, RD06/0020).; The NYU Women's Health Study is supported by research grant (R01CA098661) and center grant (P30CA016087) from the NCI and the center grant (ES000260) from the National Institute of Environmental Health Sciences.; The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32 and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.; The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The authors would like to acknowledge William Bamlet, Traci Hammer, Jodie Cogswell, Hugues Sicotte, Janet Olson, Martha Matsumoto, and Dennis Robinson.; The Yale University study was supported by grant number (5R01CA098870) from the NCI, NIH. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.; The PHS, NHS, HPFS and WHS at Harvard were supported by the NCI, NIH (grants no. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, RO1 CA97193, RO1 CA34944, RO1 CA40360, RO1 HL26490, RO1 HL34595, RO1 CA047988, RO1 HL043851, RO1 HL080467).; The work at Johns Hopkins University was supported by the NCI (grants P50CA62924 and R01CA97075) and the Lustgarten Foundation for Pancreatic Cancer Research.; The Shanghai Men's Health Study was supported by the NCI extramural research grant (R01 CA82729). The Shanghai Women's Health Study was supported by the NCI extramural research grant (R37 CA70867) and, partially for biological sample collection, by the Intramural Research Program of NCI (Division of Cancer Epidemiology and Genetics). We are in debt to the contributions of Drs Yu-Tang Gao and Yong-Bing Xiang in these two cohort studies. The studies would not be possible without the continuing support and devotion from the study participants and staff of the SMHS and SWHS. Pancreatic cancer research at Memorial Sloan-Kettering Cancer Center was supported by The Society of MSKCC and by the Geoffrey Beene Cancer Research Fund. The work at M. D. Anderson was supported by NIH grant (RO1 CA98380). The UCSF study was supported in part by NCI grants [CA59706, CA108370, CA109767, CA89726 (E. A. H., PI) and CA98889 (E. J. D., PI] and by the Rombauer Pancreatic Cancer Research Fund. The University of Toronto study was supported by grants from the NIH (R01 CA97075, as part of the PACGENE consortium), The Lustgarten Foundation for Pancreatic Cancer Research and the Ontario Cancer Research Network. We acknowledge the Pancreatic Cancer Canada Foundation (www.pancreaticcancercanada.ca) for their continued support of research into the early detection of pancreatic cancer and the Pancreas Cancer Screening Study at Mount Sinai Hospital and Princess Margaret Hospital. The authors acknowledge Ayelet Borgida and Heidi Rothenmund for their dedicated contributions toward data collection and study co-ordination. PLCO was supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota (NO1-CN25513), Washington University (NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). The ATBC Study was supported by funding provided by the Intramural Research Program of the NCI, NIH and through US Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI. For the EPIC cohorts, all coauthors coordinated the initial recruitment and management of the studies. All authors contributed to the final paper. The authors thank all the participants who took part in this research and the funders and support and technical staff who made this study possible. The work described in this paper was carried out with the support of the European Commission: Public Health and Consumer Protection Directorate 1993-2004; Research Directorate-General 2005-2008.; ; Ligue contre le Cancer, Societe 3M, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); ISCIII RETIC (RD06/0020) of the Spanish Ministry of Health, The participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (UK); Greek Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for Research on Cancer (AIRC) (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Vasterbotten (Sweden). CLUE II was supported by National Institute of Aging grant (5U01AG018033) and NCI grants (CA105069, CA73790). Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, USA, www.fha.state.md.us/cancer/registry/, 410-7674055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The authors thank all the men and women in the Cancer Prevention Study II Nutrition Cohort for their many years of dedicated participation in the study. This project has been funded in whole or in part with federal funds from the NCI, NIH, under Contract No. HHSN261200800001E. NR 50 TC 40 Z9 42 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2012 VL 33 IS 7 BP 1384 EP 1390 DI 10.1093/carcin/bgs151 PG 7 WC Oncology SC Oncology GA 980WT UT WOS:000306925600018 PM 22523087 ER PT J AU Earnshaw, SR McDade, C Chapman, AM Jackson, D Schwamm, L AF Earnshaw, Stephanie R. McDade, Cheryl Chapman, Ann-Marie Jackson, Daniel Schwamm, Lee TI Economic Impact of Using Additional Diagnostic Tests to Better Select Patients With Stroke for Intravenous Thrombolysis in the United Kingdom SO CLINICAL THERAPEUTICS LA English DT Article DE computed tomography perfusion imaging; cost-effectiveness; diagnostics; magnetic resonance imaging; stroke ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; COST-EFFECTIVENESS; POOLED ANALYSIS; CONTRAST-MEDIA; PERFUSION; MRI; DIFFUSION; ATLANTIS; TRIALS AB Background: Eligibility for thrombolysis as an acute stroke treatment is determined through the use of unenhanced noncontrast computed tomography (CT), time since stroke onset, and patient history. Assessing penumbral patterns, which can be examined only through the use of diagnostic technologies such as magnetic resonance imaging (MRI) and perfusion CT (CTP), may be able to better select patients for thrombolysis. However, trade-offs in terms of administration time and cost may affect the value of using these diagnostic studies. Objective: We examined the trade-offs among patient selection via usual care with CT, usual care plus MRI using diffusion-weighted and perfusion imaging, and usual care plus CTP for their effect on costs and outcomes when diagnosing stroke and selecting candidates for thrombolysis in the United Kingdom. Methods: A decision-analytic model was developed. Efficacy and utilities were obtained from published studies. Costs were obtained from standard UK costing sources and were supplemented with data from the published literature. Outcomes included a favorable outcome (modified Rankin Scale score <2), costs, life-years, quality-adjusted life-years, and incremental cost-effectiveness ratios. Results: Compared with usual care selection, adding CTP or MRI to better select patients for thrombolysis reduced the number of patients receiving thrombolysis by 9 and 14.6 per 1000 patients treated, respectively, while improving favorable outcome (19.2 and 17.6 per 1000 patients treated, respectively). In both scenarios, costs were decreased slightly. Both CTP and MRI selection were cost saving (more efficacious and less costly) compared with unenhanced CT selection; CTP selection was found to dominate MRI selection. Conclusions: Adding diagnostic tests such as CTP and MRI to select UK patients for thrombolysis may be a good value for the money and may improve patient outcomes. If a preferred diagnostic test had to be chosen based on economic value, CTP might be the best compromise between unenhanced CT selection and MRI selection. (Clin Ther. 2012;34:1544-1558) (C) 2012 Published by Elsevier HS Journals, Inc. C1 [Earnshaw, Stephanie R.; McDade, Cheryl] RTI Hlth Solut, Res Triangle Pk, NC 27709 USA. [Jackson, Daniel] Univ Surrey, Dept Econ, Guildford GU2 5XH, Surrey, England. [Schwamm, Lee] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Earnshaw, SR (reprint author), RTI Hlth Solut, 200 Pk Off Dr, Res Triangle Pk, NC 27709 USA. EM searnshaw@rti.org OI Schwamm, Lee/0000-0003-0592-9145 FU GE Healthcare FX GE Healthcare was the funding source for this study. Dr. Earnshaw and Ms. McDade are employees of RTI Health Solutions, an independent contract research organization that has received research funding for this and other studies from GE Healthcare and from pharmaceutical companies that market medical devices, diagnostics, and drugs for use in the treatment of patients with stroke and other medical conditions. Dr. Chapman is an employee of GE Healthcare, a medical device and diagnostics manufacturer. Mr. Jackson is a Research Fellow at the University of Surrey. Dr. Schwamm is vice chairman of the Department of Neurology at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School. He is a paid consultant to RTI Health Solutions. He serves on the advisory board of CoAxia, Inc, a maker of medical devices for acute stroke treatment, and serves on the international steering committee for the DIAS3/4 trial, a trial of extended-window thrombolysis using desmoteplase. He occasionally provides expert legal testimony in court cases involving acute stroke management. The authors have indicated that they have no other conflicts of interest regarding the content of this article. NR 39 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD JUL PY 2012 VL 34 IS 7 BP 1544 EP 1558 DI 10.1016/j.clinthera.2012.05.004 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 980ZY UT WOS:000306936200009 PM 22695225 ER PT J AU Park, SJ Freise, CE Hirose, R Kerlan, RK Yao, FY Roberts, JP Vagefi, PA AF Park, Sang-Jae Freise, Chris E. Hirose, Ryutaro Kerlan, Robert K. Yao, Francis Y. Roberts, John P. Vagefi, Parsia A. TI Risk factors for liver transplant waitlist dropout in patients with hepatocellular carcinoma SO CLINICAL TRANSPLANTATION LA English DT Article DE hepatocellular carcinoma; liver transplantation; waitlist dropout; loco-regional therapy; MELD; MELD exception points ID INTENTION-TO-TREAT; ORGAN ALLOCATION POLICY; WAITING-LIST; TRANSARTERIAL CHEMOEMBOLIZATION; MODEL; SURVIVAL; DISEASE; ABLATION; CRITERIA; BRIDGE AB Loco-regional therapy has been developed to reduce waitlist dropout in patients with hepatocellular carcinoma (HCC) awaiting liver transplantation. We evaluated the probability of transplantation and waitlist dropout, and analyzed risk factors for waitlist dropout, in 76 patients with HCC from September 2004 to August 2006. Seventy-three (96.1%) patients received one or more preoperative loco-regional treatments and 55 (72.3%) received an orthotopic liver transplantation with a median wait time of seven months (range, 226 months). There were 11 dropouts (14.5%) associated with tumor progression or hepatic decompensation (median waiting time; 5.4 months and range, 0.413 months). Cumulative probabilities of transplantation at three, six, nine, 12, 15, and 18 months were 5.4%, 35.4%, 67.5%, 78.8%, 80.7%, and 80.7%, respectively and those of waitlist dropout at three, six, nine, 12, 15, and 18 months were 3.9%, 8.7%, 12.8%, 22.9%, 29.3%, and 29.3%, respectively. A laboratory model for end-stage liver disease (MELD) score >15 or multiple tumors at the time of UNOS listing were significant risk factors for waitlist dropout (p = 0.006 and 0.026, respectively). Patients with HCC being managed with loco-regional therapy who have a laboratory MELD score >15 or multiple tumors should be considered for earlier access to liver transplantation to prevent waitlist dropout. C1 [Vagefi, Parsia A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Transplant Surg, Boston, MA 02114 USA. [Park, Sang-Jae] Natl Canc Ctr, Ctr Liver Canc, Goyang, South Korea. [Freise, Chris E.; Hirose, Ryutaro; Roberts, John P.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Kerlan, Robert K.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Yao, Francis Y.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Vagefi, PA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Transplant Surg, 55 Fruit St,White 544B, Boston, MA 02114 USA. EM pvagefi@partners.org NR 24 TC 17 Z9 17 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD JUL-AUG PY 2012 VL 26 IS 4 BP E359 EP E364 DI 10.1111/j.1399-0012.2012.01668.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 986LZ UT WOS:000307344400005 PM 22693962 ER PT J AU Wei, NJ Grant, RW Nathan, DM Wexler, DJ AF Wei, Nancy J. Grant, Richard W. Nathan, David M. Wexler, Deborah J. TI EFFECT OF HOSPITAL ADMISSION ON GLYCEMIC CONTROL 1 YEAR AFTER DISCHARGE SO ENDOCRINE PRACTICE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; HEMOGLOBIN A1C; FOLLOW-UP; CARE; INPATIENT; OUTPATIENT; INSULIN; ASSOCIATION; PREVALENCE; MANAGEMENT AB Objective: To assess the effect of hospital admission on glycemic control in patients with diabetes up to 1 year after discharge. Methods: We retrospectively studied 826 adults with diabetes admitted to a tertiary care medical center and with available hemoglobin A(1c) (A1C) values for 6 months before admission and 1 year after discharge. We compared them with 826 nonhospitalized adults with diabetes matched for age, sex, race, comorbidity, and baseline A1C level. We determined the change in A1C value relative to hospitalization and baseline A1C level by using multivariate random effects models for repeated measures. Logistic regression analysis was performed to determine predictors of achieving recommended A1C levels at 1 year. Results: Patients with baseline A1C levels >= 9% had an adjusted rate of change in A1C value of -0.10% per month (95% confidence interval [CI], -0.18 to -0.022; P = .012) during the course of I year, without significant differences between hospitalized and nonhospitalized patients in the mean rate of change. Hospitalized patients, however, were less likely to achieve an A1C goal of <= 7% at 1 year (odds ratio, 0.68; 95% CI, 0.55 to 0.86; P<.001) or an A1C of <8% at 1 year (odds ratio, 0.62; 95% CI, 0.48 to 0.81; P<.001) in comparison with the nonhospitalized patients. Conclusion: Despite an overall trend toward improved glycemia over time, hospitalized patients with uncontrolled diabetes were less likely to achieve glycemic targets at 1 year in comparison with matched nonhospitalized patients. These results suggest a missed opportunity to improve long-term glycemic control in hospitalized patients with diabetes. (Endoer Pract. 2012;18:456-463) C1 [Wei, Nancy J.; Nathan, David M.; Wexler, Deborah J.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Grant, Richard W.] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wei, NJ (reprint author), Massachusetts Gen Hosp, Ctr Diabet, 55 Fruit St,Bulfinch 402, Boston, MA 02114 USA. EM ncwei@partners.org OI Grant, Richard/0000-0002-6164-8025 FU National Institute of Diabetes and Digestive and Kidney Diseases [T32 DK007028-36]; National Institute of Diabetes and Digestive and Kidney Diseases Patient-Oriented Research Career Development Award [K23-DK 080-228]; Charlton Fund for Innovative Research in Diabetes FX Dr. Nancy J. Wei is supported by a National Institute of Diabetes and Digestive and Kidney Diseases training grant (T32 DK007028-36). Dr. Deborah J. Wexler is supported by a National Institute of Diabetes and Digestive and Kidney Diseases Patient-Oriented Research Career Development Award (K23-DK 080-228). Dr. David M. Nathan is supported in part by the Charlton Fund for Innovative Research in Diabetes. NR 26 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD JUL-AUG PY 2012 VL 18 IS 4 BP 456 EP 463 DI 10.4158/EP11309.OR PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 981BU UT WOS:000306941300003 PM 22805110 ER PT J AU Leblanc, PR Yuan, JP Brauns, T Gelfand, JA Poznansky, MC AF Leblanc, Pierre R. Yuan, Jianping Brauns, Tim Gelfand, Jeffrey A. Poznansky, Mark C. TI Accelerated vaccine development against emerging infectious diseases SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Editorial Material DE emerging infectious diseases; human artificial lymph node; immunoinformatics; immunomics; immunopeptides; immunostimulatory; immunotoxicity; metagenomics; proteomics; self-assembling vaccine ID INFLUENZA C1 [Leblanc, Pierre R.; Yuan, Jianping; Brauns, Tim; Gelfand, Jeffrey A.; Poznansky, Mark C.] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Charlestown, MA USA. RP Poznansky, MC (reprint author), Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Charlestown, MA USA. EM mpoznansky@partners.org NR 11 TC 0 Z9 0 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUL PY 2012 VL 8 IS 7 DI 10.4161/hv.20805 PG 3 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 983GL UT WOS:000307107600033 ER PT J AU Schmidt, MG Attaway, HH Sharpe, PA John, J Sepkowitz, KA Morgan, A Fairey, SE Singh, S Steed, LL Cantey, JR Freeman, KD Michels, HT Salgado, CD AF Schmidt, Michael G. Attaway, Hubert H. Sharpe, Peter A. John, Joseph, Jr. Sepkowitz, Kent A. Morgan, Andrew Fairey, Sarah E. Singh, Susan Steed, Lisa L. Cantey, J. Robert Freeman, Katherine D. Michels, Harold T. Salgado, Cassandra D. TI Sustained Reduction of Microbial Burden on Common Hospital Surfaces through Introduction of Copper SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; ACUTE-CARE HOSPITALS; ENVIRONMENTAL CONTAMINATION; CLOSTRIDIUM-DIFFICILE; INFECTION; SURVIVAL; RISK; ACQUISITION; HYGIENE; UNIT AB The contribution of environmental surface contamination with pathogenic organisms to the development of health care-associated infections (HAI) has not been well defined. The microbial burden (MB) associated with commonly touched surfaces in intensive care units (ICUs) was determined by sampling six objects in 16 rooms in ICUs in three hospitals over 43 months. At month 23, copper-alloy surfaces, with inherent antimicrobial properties, were installed onto six monitored objects in 8 of 16 rooms, and the effect that this application had on the intrinsic MB present on the six objects was assessed. Census continued in rooms with and without copper for an additional 21 months. In concert with routine infection control practices, the average MB found for the six objects assessed in the clinical environment during the preintervention phase was 28 times higher (6,985 CFU/100 cm(2); n = 3,977 objects sampled) than levels proposed as benign immediately after terminal cleaning (< 250 CFU/100 cm(2)). During the intervention phase, the MB was found to be significantly lower for both the control and copper-surfaced objects. Copper was found to cause a significant (83%) reduction in the average MB found on the objects (465 CFU/100 cm(2); n = 2714 objects) compared to the controls (2,674 CFU/100 cm(2); n = 2,831 objects [P < 0.0001]). The introduction of copper surfaces to objects formerly covered with plastic, wood, stainless steel, and other materials found in the patient care environment significantly reduced the overall MB on a continuous basis, thereby providing a potentially safer environment for hospital patients, health care workers (HCWs), and visitors. C1 [Schmidt, Michael G.; Attaway, Hubert H.; Morgan, Andrew; Fairey, Sarah E.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Sharpe, Peter A.] Irwin P Sharpe & Associates, W Orange, NJ USA. [John, Joseph, Jr.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Sepkowitz, Kent A.; Singh, Susan] Mem Sloan Kettering Canc Ctr, Dept Med, Div Infect Dis, New York, NY 10021 USA. [Steed, Lisa L.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Cantey, J. Robert; Salgado, Cassandra D.] Med Univ S Carolina, Dept Med, Div Infect Dis, Charleston, SC 29425 USA. [Freeman, Katherine D.] Yeshiva Univ, Albert Einstein Coll Med, Montefiore Med Ctr, Dept Epidemiol & & Populat Hlth, Bronx, NY USA. [Michels, Harold T.] Copper Dev Assoc, New York, NY USA. RP Schmidt, MG (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. EM schmidtm@musc.edu OI Schmidt, Michael G/0000-0002-7794-7265 FU U.S. Army Material Command [W81XWH-07-C-0053] FX This work was supported by the U.S. Army Material Command (contract W81XWH-07-C-0053). NR 40 TC 56 Z9 56 U1 2 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2012 VL 50 IS 7 BP 2217 EP 2223 DI 10.1128/JCM.01032-12 PG 7 WC Microbiology SC Microbiology GA 986RB UT WOS:000307360800008 PM 22553242 ER PT J AU Rhodes, ML Meyers, CC Underhill, ML AF Rhodes, Mattie L. Meyers, Claire C. Underhill, Meghan L. TI EVALUATION OUTCOMES OF A DEDICATED EDUCATION UNIT IN A BACCALAUREATE NURSING PROGRAM SO JOURNAL OF PROFESSIONAL NURSING LA English DT Article DE Evaluation outcomes; Dedicated education unit model; Clinical learning environment; Innovative clinical teaching strategy ID CLINICAL LEARNING-ENVIRONMENT; STUDENTS PERCEPTIONS; PROFESSIONAL-DEVELOPMENT; NURSES PERCEPTIONS; MODEL; JUDGMENT AB Quality clinical learning environments (CLE) are crucial to student education and clinical learning and are influenced by both academic and nursing service factors. The University at Buffalo School of Nursing implemented an innovative academic service partnership model for clinical education of students called a Dedicated Education Unit (DEU). The aims of this study were to (a) investigate students perceived outcomes of the DEU model on the CLE and (b) explore staff nurses' and faculty's perceived outcomes of the DEU. Qualitative and quantitative methodologies were used. Descriptive statistics and thematic analysis of focus groups are reported. Students and DEU nurses reported high scores for satisfaction. Focus group themes for students, faculty, and DEU nurse revealed appreciation for the benefits of the DEU model. The DEU is a worthwhile approach to clinical education that can enhance student's ability to receive diverse clinical experiences and access to clinical experts. Such programs can strengthen academic/service relationships. C1 [Rhodes, Mattie L.; Meyers, Claire C.] SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. [Underhill, Meghan L.] Univ Massachusetts, Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02125 USA. RP Rhodes, ML (reprint author), SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. EM mlrhodes@buffalo.edu FU University at Buffalo School of Nursing Garmen Funds FX This research was supported by the University at Buffalo School of Nursing Garmen Funds. NR 28 TC 17 Z9 17 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 8755-7223 J9 J PROF NURS JI J. Prof. Nurs. PD JUL-AUG PY 2012 VL 28 IS 4 BP 223 EP 230 DI 10.1016/j.profnurs.2011.11.019 PG 8 WC Nursing SC Nursing GA 980FU UT WOS:000306879800005 PM 22818192 ER PT J AU O'Horo, JC Jones, A Stemke, M Harper, C Safdar, N AF O'Horo, John C. Jones, Amy Stemke, Matthew Harper, Christopher Safdar, Nasia TI Molecular Techniques for Diagnosis of Clostridium difficile Infection: Systematic Review and Meta-analysis SO MAYO CLINIC PROCEEDINGS LA English DT Review ID REAL-TIME PCR; POLYMERASE-CHAIN-REACTION; MEDIATED ISOTHERMAL AMPLIFICATION; TOXIN-B GENE; STOOL SAMPLES; ENZYME-IMMUNOASSAY; RAPID DETECTION; PROSPECTIVE MULTICENTER; LABORATORY DIAGNOSIS; TESTING ALGORITHMS AB Objective: To assess the usefulness of 2 rapid molecular diagnostic techniques, polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP), in Clostridium difficile infection (CDI). Methods: We conducted a systematic review and meta-analysis to evaluate the accuracy of PCR and LAMP in diagnosis of CDI, including studies that used toxigenic culture or cytotoxicity assay as reference standard. Results: A search of PubMed and CinAHL medical databases yielded 25 PCR studies, including 11,801 samples that met inclusion criteria and 6 heterogeneous studies that evaluated LAMP. With toxigenic culture as a standard, pooled sensitivity was 0.92 (95% confidence interval [Cl], 0.91-0.94); specificity, 0.94 (95% Cl, 0.94-0.95); and diagnostic odds ratio, 378 (95% Cl, 260-547). With cytotoxicity as a standard, pooled sensitivity was 0.87 (95% Cl, 0.84-0.90); specificity, 0.97 (95% Cl, 0.97-0.98); and diagnostic odds ratio, 370 (95% Cl, 226-606). Conclusion: Polymerase chain reaction is a highly accurate test for identifying CDI. Heterogeneity in LAMP studies did not allow meta-analysis; however, further research into this promising method is warranted. (C) 2012 Mayo Foundation for Medical Education and Research Mayo Clin Proc. 2012:87(7):643-651 C1 [Safdar, Nasia] Univ Wisconsin Hosp & Clin, Sect Infect Dis, Dept Med, Madison, WI 53705 USA. [O'Horo, John C.] Aurora UW Med Grp, Dept Grad Med Educ, Milwaukee, WI USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, William S Middleton Mem Vet Hosp, Madison, WI USA. RP Safdar, N (reprint author), Univ Wisconsin Hosp & Clin, Sect Infect Dis, Dept Med, MFCB 5221, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu RI O'Horo, John/A-8787-2013; O'Horo, John/N-8681-2013 OI O'Horo, John/0000-0002-0880-4498; O'Horo, John/0000-0002-0880-4498 NR 64 TC 29 Z9 31 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2012 VL 87 IS 7 BP 643 EP 651 DI 10.1016/j.mayocp.2012.02.024 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 980DC UT WOS:000306872800007 PM 22766084 ER PT J AU Villar, J Kacmarek, RM AF Villar, J. Kacmarek, R. M. TI Positive end-expiratory pressure after uncomplicated coronary artery bypass grafting: a two-edge sword SO MINERVA ANESTESIOLOGICA LA English DT Editorial Material ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; ADAPTIVE SUPPORT VENTILATION; RANDOMIZED CONTROLLED-TRIAL; CARDIOTHORACIC SURGERY; STRATEGY C1 [Villar, J.] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Las Palmas Gran Canaria 35010, Spain. [Villar, J.] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Kacmarek, R. M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, R. M.] Harvard Univ, Dept Anesthesia, Boston, MA 02115 USA. RP Villar, J (reprint author), Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Barranco Ballena S-N,4th Floor S Wing, Las Palmas Gran Canaria 35010, Spain. EM jesus.villar54@gmail.com NR 13 TC 0 Z9 0 U1 0 U2 1 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0375-9393 J9 MINERVA ANESTESIOL JI Minerva Anestesiol. PD JUL PY 2012 VL 78 IS 7 BP 743 EP 745 PG 3 WC Anesthesiology; Critical Care Medicine SC Anesthesiology; General & Internal Medicine GA 982KH UT WOS:000307041500002 PM 22732911 ER PT J AU Ruff, RL Rutecki, P AF Ruff, Robert L. Rutecki, Paul TI Faster, slower, but never better Mutations of the skeletal muscle acetylcholine receptor SO NEUROLOGY LA English DT Editorial Material ID NICOTINIC RECEPTOR; AGONIST BINDING; SUBUNIT C1 [Ruff, Robert L.] Case Western Reserve Univ, Dept Neurol, Neurol Serv, Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Cleveland, OH 44106 USA. [Rutecki, Paul] Univ Wisconsin, Dept Neurol, William S Middleton Mem Vet Hosp, Neurol Serv, Madison, WI 53706 USA. RP Ruff, RL (reprint author), Case Western Reserve Univ, Dept Neurol, Neurol Serv, Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Cleveland, OH 44106 USA. EM robert.ruff1@va.gov NR 10 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 2012 VL 79 IS 5 BP 404 EP 405 DI 10.1212/WNL.0b013e31825b5bee PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 984AY UT WOS:000307161100009 PM 22592368 ER PT J AU Mohr, DC Lovera, J Brown, T Cohen, B Neylan, T Henry, R Siddique, J Jin, L Daikh, D Pelletier, D AF Mohr, David C. Lovera, Jesus Brown, Ted Cohen, Bruce Neylan, Thomas Henry, Roland Siddique, Juned Jin, Ling Daikh, David Pelletier, Daniel TI A randomized trial of stress management for the prevention of new brain lesions in MS SO NEUROLOGY LA English DT Article ID TELEPHONE-ADMINISTERED PSYCHOTHERAPY; COGNITIVE-BEHAVIORAL THERAPY; REMITTING MULTIPLE-SCLEROSIS; PSYCHOLOGICAL STRESS; DOUBLE-BLIND; LIFE EVENTS; DEPRESSION; METAANALYSIS; DISABILITY; SYMPTOMS AB Objectives: This trial examined the efficacy of a stress management program in reducing neuroimaging markers of multiple sclerosis (MS) disease activity. Methods: A total of 121 patients with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress. Results: SMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period. Conclusions: This trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment. Classification of evidence: This study provides Class I evidence that SMT-MS, a manualized stress management therapy program, reduced the number of Gd+ lesions in patients with MS during a 24-week treatment period. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits. C1 [Mohr, David C.; Cohen, Bruce; Siddique, Juned; Jin, Ling] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Lovera, Jesus] Louisiana State Univ, Hlth Sci Ctr, Sch Med, New Orleans, LA USA. [Brown, Ted] Evergreen Hosp Med Ctr, Seattle, WA USA. [Neylan, Thomas; Henry, Roland; Daikh, David; Pelletier, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Neylan, Thomas; Daikh, David] San Francisco VA Med Ctr, San Francisco, CA USA. RP Mohr, DC (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM d-mohr@northwestern.edu FU NIH; Lilly Inc.; Acorda; Teva Neuroscience; Northwestern University from Biogen-Idec; EMD Serono; Novartis; Roche; CME program (through Northwestern University) from Teva Neuroscience; Actelion; Glaxo Smith Kline; National Institutes of Health, NINDS [R01NS062885]; NICHD [R01-HD043323] FX D. Mohr receives research funding from the NIH. J. Lovera has honoraria for consulting and speaking from Biogen Idec, Serono, and Teva. T. Brown has served as a consultant for Acorda, Biogen, EMD Serono, and Teva Neuroscience and has received honoraria from Acorda, Pfizer, and Teva and has been funded by research grants from Lilly Inc., Acorda, and Teva Neuroscience. B. Cohen has received payments for consulting or speaking honoraria from Accorda, Astellis, Bayer, Biogen-Idec, EMD Serono, Genentech, Novartis, Pfizer, and Teva Neuroscience. He has received research support through Northwestern University from Biogen-Idec, EMD Serono, Novartis, Roche, and an Unrestricted Educational Grant in support of a CME program (through Northwestern University) from Teva Neuroscience. T. Neylan has received research support (supply of investigative medication) from Actelion and Glaxo Smith Kline. R. Henry, J. Siddique, L. Jin, and D. Daikh report no disclosures. D. Pelletier receives research support from the National Institutes of Health, NINDS (R01NS062885). Go to Neurology.org for full disclosures.; This study was funded by NICHD grant R01-HD043323. NR 33 TC 31 Z9 32 U1 3 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 2012 VL 79 IS 5 BP 412 EP 419 DI 10.1212/WNL.0b013e3182616ff9 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 984AY UT WOS:000307161100011 PM 22786596 ER PT J AU Endoh, M Endo, TA Endoh, T Isono, K Sharif, J Ohara, O Toyoda, T Ito, T Eskeland, R Bickmore, WA Vidal, M Bernstein, BE Koseki, H AF Endoh, Mitsuhiro Endo, Takaho A. Endoh, Tamie Isono, Kyo-ichi Sharif, Jafar Ohara, Osamu Toyoda, Tetsuro Ito, Takashi Eskeland, Ragnhild Bickmore, Wendy A. Vidal, Miguel Bernstein, Bradley E. Koseki, Haruhiko TI Histone H2A Mono-Ubiquitination Is a Crucial Step to Mediate PRC1-Dependent Repression of Developmental Genes to Maintain ES Cell Identity SO PLOS GENETICS LA English DT Article ID POLYCOMB-GROUP PROTEINS; TRANSCRIPTIONAL REGULATORY CIRCUITRY; METHYLTRANSFERASE ACTIVITY; CHROMATIN-STRUCTURE; X-INACTIVATION; COMPLEX; RING1B; H3; EXPRESSION; RNA AB Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3), respectively. Compared to H3K27me3, localization and the role of H2AK119u1 are not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation. C1 [Endoh, Mitsuhiro; Endoh, Tamie; Isono, Kyo-ichi; Sharif, Jafar; Koseki, Haruhiko] RIKEN Res Ctr Allergy & Immunol, Lab Dev Genet, Yokohama, Kanagawa, Japan. [Endoh, Mitsuhiro; Koseki, Haruhiko] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Yokohama, Kanagawa, Japan. [Endo, Takaho A.; Toyoda, Tetsuro] RIKEN Bioinformat & Syst Engn Div, Yokohama, Kanagawa, Japan. [Ohara, Osamu] RIKEN Res Ctr Allergy & Immunol, Labs Immunogen, Yokohama, Kanagawa, Japan. [Ito, Takashi] Nagasaki Univ, Sch Med, Dept Biochem, Nagasaki 852, Japan. [Eskeland, Ragnhild; Bickmore, Wendy A.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Vidal, Miguel] CSIC, Ctr Invest Biol, Madrid, Spain. [Vidal, Miguel] RIKEN Res Ctr Allergy & Immunol, Res Unit Immunoepigenet, Yokohama, Kanagawa, Japan. [Bernstein, Bradley E.] Mol Pathol Unit, Charlestown, MA USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bernstein, Bradley E.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Endoh, M (reprint author), RIKEN Res Ctr Allergy & Immunol, Lab Dev Genet, Yokohama, Kanagawa, Japan. EM mendoh@rcai.riken.jp; koseki@rcai.riken.jp RI Bickmore, Wendy/C-7314-2013; Koseki, Haruhiko/I-3825-2014; Eskeland, Ragnhild/K-7018-2014; Ohara, Osamu/G-5448-2015; Endo, Takaho/B-5763-2017; OI Bickmore, Wendy/0000-0001-6660-7735; Koseki, Haruhiko/0000-0001-8424-5854; Eskeland, Ragnhild/0000-0003-2789-3171; Ohara, Osamu/0000-0002-3328-9571; Endo, Takaho/0000-0002-2801-2463; Vidal, Miguel/0000-0003-4374-6761 FU Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan; Japan Science and Technology Agency (JST) CREST; Japan Society for the Promotion of Science (JSPS) [21602006]; MEXT, Japan [17045038] FX This work was supported in part by a grant of the Genome Network Project (to HK) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan; by the Japan Science and Technology Agency (JST) CREST (to ME and HK); by a grant-in-aid for Scientific Research (C) (21602006; to ME) from the Japan Society for the Promotion of Science (JSPS); and by a grant-in-aid for Scientific Research on Priority Areas (17045038; to ME) from the MEXT, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 87 Z9 90 U1 1 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 JUL PY 2012 VL 8 IS 7 AR e1002774 DI 10.1371/journal.pgen.1002774 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 979SP UT WOS:000306840400010 PM 22844243 ER PT J AU Lovejoy, CA Li, WD Reisenweber, S Thongthip, S Bruno, J de Lange, T De, S Petrini, JHJ Sung, PA Jasin, M Rosenbluh, J Zwang, Y Weir, BA Hatton, C Ivanova, E Macconaill, L Hanna, M Hahn, WC Lue, NF Reddel, RR Jiao, YC Kinzler, K Vogelstein, B Papadopoulos, N Meeker, AK AF Lovejoy, Courtney A. Li, Wendi Reisenweber, Steven Thongthip, Supawat Bruno, Joanne de Lange, Titia De, Saurav Petrini, John H. J. Sung, Patricia A. Jasin, Maria Rosenbluh, Joseph Zwang, Yaara Weir, Barbara A. Hatton, Charlie Ivanova, Elena Macconaill, Laura Hanna, Megan Hahn, William C. Lue, Neal F. Reddel, Roger R. Jiao, Yuchen Kinzler, Kenneth Vogelstein, Bert Papadopoulos, Nickolas Meeker, Alan K. CA ALT Starr Canc Consortium TI Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway SO PLOS GENETICS LA English DT Article ID COPY-NUMBER ALTERATION; HUMAN-CELLS; HOMOLOGOUS RECOMBINATION; DYSFUNCTIONAL TELOMERES; HISTONE CHAPERONE; CHROMOSOME ENDS; HUMAN CANCERS; PROTEIN; TUMORS; DAXX AB The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers. C1 [Lovejoy, Courtney A.; Li, Wendi; Reisenweber, Steven; Thongthip, Supawat; Bruno, Joanne; de Lange, Titia] Rockefeller Univ, Lab Cell Biol & Genet, New York, NY 10021 USA. [De, Saurav; Petrini, John H. J.] Mem Sloan Kettering Canc Ctr, Program Mol Biol, Sloan Kettering Inst, New York, NY 10021 USA. [Sung, Patricia A.; Jasin, Maria] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dev Biol Program, New York, NY 10021 USA. [Rosenbluh, Joseph; Zwang, Yaara; Weir, Barbara A.; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Zwang, Yaara; Hatton, Charlie; Ivanova, Elena; Macconaill, Laura; Hanna, Megan; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lue, Neal F.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, WR Hearst Microbiol Res Ctr, New York, NY 10021 USA. [Reddel, Roger R.] Childrens Med Res Inst, Westmead, NSW, Australia. [Reddel, Roger R.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Jiao, Yuchen; Kinzler, Kenneth; Vogelstein, Bert; Papadopoulos, Nickolas] Johns Hopkins Sidney Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD USA. [Vogelstein, Bert] Johns Hopkins Sidney Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA. [Meeker, Alan K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Lovejoy, CA (reprint author), Rockefeller Univ, Lab Cell Biol & Genet, 1230 York Ave, New York, NY 10021 USA. EM delange@mail.rockefeller.edu RI Papadopoulos, Nickolas/K-7272-2012; Reddel, Roger/A-6635-2014 OI Reddel, Roger/0000-0002-6302-6107 FU Starr Cancer Consortium; NIH [GM049046, CA076027]; Virginia and D. K. Ludwig Fund for Cancer Research; Cancer Council NSW Program Grant; DOD; NIH/NIA [F32GM090437] FX This work was made possible by a grant from the Starr Cancer Consortium and grants from the NIH to TdL (GM049046 and CA076027), WCH, NFL, MJ, and JHJP. TdL is an American Cancer Society Research Professor. NP, BV, KK, and YJ are supported by The Virginia and D. K. Ludwig Fund for Cancer Research. RRR is supported by a Cancer Council NSW Program Grant. CAL and YZ are supported by DOD Breast Cancer Research Program Postdoctoral Fellowships. JR was supported by a NIH/NIA fellowship (F32GM090437). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 144 Z9 145 U1 1 U2 17 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 JUL PY 2012 VL 8 IS 7 AR e1002772 DI 10.1371/journal.pgen.1002772 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 979SP UT WOS:000306840400009 PM 22829774 ER PT J AU Shore, DE Carr, CE Ruvkun, G AF Shore, David E. Carr, Christopher E. Ruvkun, Gary TI Induction of Cytoprotective Pathways Is Central to the Extension of Lifespan Conferred by Multiple Longevity Pathways SO PLOS GENETICS LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; UNFOLDED PROTEIN RESPONSE; HEAT-SHOCK RESPONSE; C-ELEGANS; OXIDATIVE STRESS; GENE-EXPRESSION; SMALL RNAS; TRANSLATIONAL INHIBITION; SUPEROXIDE-DISMUTASE; SIGNALING MUTANTS AB Many genetic and physiological treatments that extend lifespan also confer resistance to a variety of stressors, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of cytoprotective pathways is essential for lifespan extension or merely correlated. Using a panel of GFP-fused stress response genes, we identified the suites of cytoprotective pathways upregulated by 160 gene inactivations known to increase Caenorhabditis elegans longevity, including the mitochondrial UPR (hsp-6, hsp-60), the ER UPR (hsp-4), ROS response (sod-3, gst-4), and xenobiotic detoxification (gst-4). We then screened for other gene inactivations that disrupt the induction of these responses by xenobiotic or genetic triggers, identifying 29 gene inactivations required for cytoprotective gene expression. If cytoprotective responses contribute directly to lifespan extension, inactivation of these genes would be expected to compromise the extension of lifespan conferred by decreased insulin/IGF-1 signaling, caloric restriction, or the inhibition of mitochondrial function. We find that inactivation of 25 of 29 cytoprotection-regulatory genes shortens the extension of longevity normally induced by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, without disrupting normal longevity nearly as dramatically. These data demonstrate that induction of cytoprotective pathways is central to longevity extension and identify a large set of new genetic components of the pathways that detect cellular damage and couple that detection to downstream cytoprotective effectors. C1 [Shore, David E.; Carr, Christopher E.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Shore, David E.; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Carr, Christopher E.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA USA. RP Shore, DE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu OI Carr, Christopher/0000-0002-7946-5622 FU National Institute on Aging [AG16636] FX This work was funded by the National Institute on Aging (http://www.nia.nih.gov/) (AG16636). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 95 TC 45 Z9 52 U1 2 U2 18 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 JUL PY 2012 VL 8 IS 7 AR e1002792 DI 10.1371/journal.pgen.1002792 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 979SP UT WOS:000306840400015 PM 22829775 ER PT J AU Woods, DC Telfer, EE Tilly, JL AF Woods, Dori C. Telfer, Evelyn E. Tilly, Jonathan L. TI Oocyte Family Trees: Old Branches or New Stems? SO PLOS GENETICS LA English DT Editorial Material ID PRIMORDIAL GERM-CELLS; UNILATERAL OVARIECTOMY; FOLLICULAR DEVELOPMENT; CYCLING RATS; MOUSE OVARY; MICE; LINEAGE; DIFFERENTIATION; OOGENESIS; OVULATION C1 [Woods, Dori C.; Tilly, Jonathan L.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, MGH Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Woods, Dori C.; Tilly, Jonathan L.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Telfer, Evelyn E.] Univ Edinburgh, Inst Cell Biol, Edinburgh, Midlothian, Scotland. [Telfer, Evelyn E.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland. RP Woods, DC (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, MGH Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. EM jtilly@partners.org FU Medical Research Council [G0901839]; NIA NIH HHS [R37 AG012279, R37-AG012279] NR 32 TC 12 Z9 12 U1 0 U2 16 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 JUL PY 2012 VL 8 IS 7 AR e1002848 DI 10.1371/journal.pgen.1002848 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 979SP UT WOS:000306840400052 PM 22844256 ER PT J AU Van Cleave, J Kuhlthau, KA Bloom, S Newacheck, PW Nozzolillo, AA Homer, CJ Perrin, JM AF Van Cleave, Jeanne Kuhlthau, Karen A. Bloom, Sheila Newacheck, Paul W. Nozzolillo, Alixandra A. Homer, Charles J. Perrin, James M. TI Interventions to Improve Screening and Follow-Up in Primary Care: A Systematic Review of the Evidence SO ACADEMIC PEDIATRICS LA English DT Review DE mass screening; physician's practice patterns; preventive health services; quality of health care ID YOUNG-CHILDREN PROGRAM; PREVENTIVE SERVICES; DEVELOPMENTAL SERVICES; QUALITY IMPROVEMENT; ADOLESCENT GIRLS; RANDOMIZED-TRIAL; HEALTHY STEPS; DELIVERY; IMPLEMENTATION; STRATEGIES AB BACKGROUND: The American Academy of Pediatrics and other organizations recommend several screening tests as part of preventive care. The proportion of children who are appropriately screened and who receive follow-up care is low. OBJECTIVE: To conduct a systematic review of the evidence for practice-based interventions to increase the proportion of patients receiving recommended screening and follow-up services in pediatric primary care. DATA SOURCE: Medline database of journal citations. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We developed a strategy to search MEDLINE to identify relevant articles. We selected search terms to capture categories of conditions (eg, developmental disabilities, obesity), screening tests, specific interventions (eg, quality improvement initiatives, electronic records enhancements), and primary earn. We searched references of selected articles and reviewed articles suggested by experts. We included all studies with a distinct, primary care-based intervention and post-intervention screening data, and studies that focused on children and young adults (<= 21 years of age). We excluded studies of newborn screening. STUDY APPRAISAL AND SYNTHESIS METHODS: Abstracts were screened by 2 reviewers and articles with relevant abstracts received full text review and were evaluated for inclusion criteria. A structured tool was used to abstract data from selected articles. Because of heterogeneous interventions and outcomes, we did not attempt a meta-analysis. RESULTS: From 2547 returned titles and abstracts, 23 articles were reviewed. Nine were pre-post comparisons, 5 were randomized trials, 3 were postintervention comparisons with a control group, 3 were postintervention cross-sectional analyses only, and 3 reported time series data. Of 14 articles with preintervention or control group data and significance testing, 12 reported increases in the proportion of patients appropriately screened. Interventions were heterogeneous and often multifaceted, and several types of interventions, such as provider/staff training, electronic medical record templates/prompts, and learning collaboratives, appeared effective in improving screening quality. Few articles described interventions to track screening results or referral completion for those with abnormal tests. Data were often limited by single-site, nonrandomized design. CONCLUSIONS: Several feasible, practice- and provider-level interventions appear to increase the quality of screening in pediatric primary care. Evidence for interventions to improve follow-up of screening tests is scant. Future research should focus on which specific interventions are most effective, whether effects are sustained over time, and what interventions improve follow-up of abnormal screening tests. C1 [Van Cleave, Jeanne; Kuhlthau, Karen A.; Bloom, Sheila; Nozzolillo, Alixandra A.; Perrin, James M.] MassGen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Van Cleave, Jeanne; Kuhlthau, Karen A.; Homer, Charles J.; Perrin, James M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Homer, Charles J.] Harvard Univ, Natl Initiat Childrens Healthcare Qual, Boston, MA 02115 USA. [Newacheck, Paul W.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA 94143 USA. RP Van Cleave, J (reprint author), MassGen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, 15th Floor C100,100 Cambridge St, Boston, MA 02114 USA. EM jvancleave@partners.org FU Maternal and Child Health Bureau [5 U53MC04473-03-00] FX We are grateful to the Maternal and Child Health Bureau, who provided funding for this study (Cooperative agreement #5 U53MC04473-03-00). NR 49 TC 20 Z9 20 U1 2 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD JUL-AUG PY 2012 VL 12 IS 4 BP 269 EP 282 PG 14 WC Pediatrics SC Pediatrics GA 976XH UT WOS:000306620200006 PM 22575809 ER PT J AU Bleier, BS Feldman, R Sadow, PM Wu, A Ting, J Metson, R AF Bleier, Benjamin S. Feldman, Rachel Sadow, Peter M. Wu, Arthur Ting, Jonathan Metson, Ralph TI The accessory posterolateral nerve: An immunohistological analysis SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article; Proceedings Paper CT Meeting of the American-Rhinologic-Society CY APR 20, 2012 CL San Diego, CA SP Amer Rhinol Soc ID PTERYGOPALATINE GANGLION EFFERENTS; MUCOSA AB Background: Recent endoscopic dissection studies have redefined the postganglionic pterygopalatine autonomic pathways suggesting that neurovascular rami, termed "accessory posterolateral nerves," project directly through the palatine bone to innervate the posterolateral nasal mucosa rather than traveling with trigeminal arborizations. The goal of this study was to characterize these accessory posterolateral nerves by immunohistochemistry to determine their morphology and composition. Methods: This is an Institutional Review Board approved study in seven patients in whom the presence of accessory posterolateral nerves were surgically identified exiting the perpendicular plate of the palatine bone and sampled. The presence of neural tissue was confirmed by hematoxylin and eosin and S-100 protein staining. Nerves were then stained with anti-human choline acetyl-transferase (ChAT; 1:100) and anti-human dopamine beta-hydroxylase (DBH; 1:100) followed by a fluorescein isothiocyanate-labeled secondary antibody to test for the presence of peripheral parasympathetic and sympathetic fibers, respectively. Human cadaveric sensory nerves were used as a negative control. Results: All seven samples contained neural elements. Two specimens were also associated with arteries. All nerves were comprised of a single fascicle containing an approximately equal distribution of ChAT(+) and DBH+ fibers. Conclusion: This histological study supports prior descriptions defining a newly recognized neural pathway for innervation of the nasal mucosa. Our data confirm that these accessory posterolateral nerves project directly through the perpendicular plate of the palatine bone and are composed of autonomic fibers. Recognition of this pathway may be exploited in the treatment of sinonasal disease resulting from autonomic dysregulation. (Am J Rhinol Allergy 26, 271-273, 2012; doi: 10.2500/ajra.2012.26.3804) C1 [Bleier, Benjamin S.; Feldman, Rachel; Wu, Arthur; Ting, Jonathan; Metson, Ralph] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Sadow, Peter M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Bleier, BS (reprint author), 243 Charles St, Boston, MA USA. EM benjamin_bleier@meei.harvard.edu NR 12 TC 3 Z9 3 U1 0 U2 3 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD JUL-AUG PY 2012 VL 26 IS 4 BP 271 EP 273 DI 10.2500/ajra.2012.26.3804 PG 3 WC Otorhinolaryngology SC Otorhinolaryngology GA 979HW UT WOS:000306809100006 PM 22801012 ER PT J AU Brierley, KL Blouch, E Cogswell, W Homer, JP Pencarinha, D Stanislaw, CL Matloff, ET AF Brierley, Karina L. Blouch, Erica Cogswell, Whitney Homer, Jeanne P. Pencarinha, Debbie Stanislaw, Christine L. Matloff, Ellen T. TI Adverse Events in Cancer Genetic Testing Medical, Ethical, Legal, and Financial Implications SO CANCER JOURNAL LA English DT Review DE genetic counseling; genetic testing; BRCA1; BRCA2; Lynch syndrome; cancer genetics ID PRIMARY-CARE PHYSICIANS; NONPOLYPOSIS COLORECTAL-CANCER; KNOWLEDGE; HEALTH; US; RECOMMENDATIONS; ADOLESCENTS; STATEMENT; AWARENESS; BARRIERS AB Cancer genetic counseling and testing are now integral services in progressive cancer care. There has been much debate over whether these services should be delivered by providers with specialized training in genetics or by all clinicians. Adverse outcomes resulting from cancer genetic counseling and testing performed by clinicians without specialization in genetics have been reported, but formal documentation is sparse. In this review, we present a series of national cases illustrating major patterns of errors in cancer genetic counseling and testing and the resulting impact on medical liability, health care costs, and the patients and their families. C1 [Brierley, Karina L.; Matloff, Ellen T.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA. [Blouch, Erica] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Cogswell, Whitney] Med Ctr Cent Georgia, Macon, GA USA. [Homer, Jeanne P.] Hoag Hosp, Newport Beach, CA USA. [Pencarinha, Debbie] Wellmont Canc Inst, Kingsport, TN USA. [Stanislaw, Christine L.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. RP Brierley, KL (reprint author), Yale Univ, Sch Med, Yale Canc Ctr, 55 Church St,Suite 402, New Haven, CT 06510 USA. EM karina.brierley@yale.edu NR 40 TC 30 Z9 31 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2012 VL 18 IS 4 SI SI BP 303 EP 309 DI 10.1097/PPO.0b013e3182609490 PG 7 WC Oncology SC Oncology GA 981YR UT WOS:000307009300004 PM 22846730 ER PT J AU Shannon, KM Chittenden, A AF Shannon, Kristen Mahoney Chittenden, Anu TI Genetic Testing by Cancer Site SO CANCER JOURNAL LA English DT Review DE BRCA1; BRCA2; TP53; PTEN; CDH1; STK11; Cowden syndrome: hereditary breast and ovarian cancer (HBOC) syndrome; Li-Fraumeni syndrome (LFS); Peutz-Jeghers syndrome (PJS) ID LI-FRAUMENI-SYNDROME; DIFFUSE GASTRIC-CANCER; BRCA2 MUTATION CARRIERS; HEREDITARY BREAST/OVARIAN CANCER; P53 GERMLINE MUTATIONS; PEUTZ-JEGHERS-SYNDROME; BILATERAL PROPHYLACTIC MASTECTOMY; CONTRALATERAL BREAST-CANCER; MYH-ASSOCIATED POLYPOSIS; OVARIAN-CANCER AB Women in the United States have a 12% lifetime risk of developing breast cancer. Although only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene, individuals who carry a mutation in one of these genes have a significantly higher risk of developing breast cancer, as well as other cancers, over their lifetime compared with the general population. The ability to distinguish those individuals at high risk allows health care providers to intervene with appropriate counseling and education, surveillance, and prevention-with the overall goal of improved survival for these individuals. This article focuses on the identification of patients at high risk for breast cancer and provides an overview of the clinical features, cancer risks, causative genes, and medical management for the most clearly described hereditary breast cancer syndromes. Newer genes that have also been implicated in familial breast cancer are also briefly reviewed. C1 [Shannon, Kristen Mahoney] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Chittenden, Anu] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. RP Shannon, KM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Risk Assessment, 55 Fruit St,YAW 10B, Boston, MA 02114 USA. EM keshannon@partners.org NR 137 TC 12 Z9 12 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2012 VL 18 IS 4 SI SI BP 310 EP 319 DI 10.1097/PPO.0b013e318260946f PG 10 WC Oncology SC Oncology GA 981YR UT WOS:000307009300005 PM 22846731 ER PT J AU Chan-Smutko, G AF Chan-Smutko, Gayun TI Genetic Testing by Cancer Site Urinary Tract SO CANCER JOURNAL LA English DT Review DE Carcinoma; renal cell; genetic predisposition to disease; genetic testing; genetic counseling; hereditary cancer syndrome ID HOGG-DUBE-SYNDROME; RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; MET PROTOONCOGENE; MUTATION CARRIERS; LYNCH SYNDROME; HEREDITARY LEIOMYOMATOSIS; SPONTANEOUS PNEUMOTHORAX; SOMATIC MUTATIONS; LINDAU-DISEASE AB The roles of renal cell carcinoma (RCC) and urothelial cancers of the upper urinary tract are often overlooked as indicators for genetic risk assessment. The key features of 5 hereditary cancer susceptibility conditions involving an increased risk for RCC are discussed. von Hippel-Lindau disease, hereditary papillary RCC, and hereditary leiomyomatosis and RCC each predispose to a specific histological type of RCC, whereas Birt-Hogg-Dube and hereditary paraganglioma/pheochromocytoma entail a variety of histologic findings. Familiarity with the rare or uncommon clinical features associated with these conditions, such as cutaneous neoplasms, paraganglioma/pheochromocytoma, and recurrent spontaneous pneumothoraces, aids in identifying patients with an underlying RCC susceptibility. A path to identifying syndromic cases lies in thorough investigation of the patient's medical history, their family history, and the histological type of RCC reported in the family. A guide to genetic predisposition testing for RCC is proposed. Upper urinary tract cancers in Lynch syndrome are also discussed. C1 [Chan-Smutko, Gayun] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Chan-Smutko, G (reprint author), 55 Fruit St,YAW9A, Boston, MA 02114 USA. EM gchansmutko@partners.org NR 34 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD JUL-AUG PY 2012 VL 18 IS 4 SI SI BP 343 EP 349 DI 10.1097/PPO.0b013e31826246ac PG 7 WC Oncology SC Oncology GA 981YR UT WOS:000307009300010 PM 22846736 ER PT J AU Gabree, M Seidel, M AF Gabree, Michele Seidel, Meredith TI Genetic Testing by Cancer Site Skin SO CANCER JOURNAL LA English DT Review DE Hereditary melanoma; basal cell nevus syndrome; neurofibromatosis type 1; neurofibromatosis type 2; melanoma; neurofibroma; schwannomas; cafe-au-lait macules ID BASAL-CELL CARCINOMA; OF-THE-LITERATURE; GORLIN SYNDROME; NEUROFIBROMATOSIS TYPE-1; GERMLINE MUTATIONS; FAMILIAL MELANOMA; PANCREATIC-CANCER; CDKN2A MUTATIONS; TUMOR SYNDROME; RISK AB Many hereditary cancer predisposition syndromes are associated with cutaneous findings, both benign and malignant. Dermatological examination and histopathology, when combined with a thorough personal and family medical history, play an important role in the diagnosis of cancer predisposition syndromes. Skin findings are an important diagnostic tool for a variety of cancer syndromes, including Cowden syndrome, Birt-Hogg-Dube , hereditary leiomyomatosis renal cell carcinoma, and others. This article focuses on the phenotype, medical management, and genetic testing for 4 hereditary cancer syndromes that include cutaneous findings: hereditary melanoma, basal cell nevus syndrome, neurofibromatosis type 1, and neurofibromatosis type 2. C1 [Gabree, Michele; Seidel, Meredith] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. RP Gabree, M (reprint author), Massachusetts Gen Hosp, Ctr Canc Risk Assessment, 55 Fruit St,Yawkey 10B, Boston, MA 02114 USA. EM mcgabree@partners.org NR 69 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD JUL-AUG PY 2012 VL 18 IS 4 SI SI BP 372 EP 380 DI 10.1097/PPO.0b013e3182624664 PG 9 WC Oncology SC Oncology GA 981YR UT WOS:000307009300014 PM 22846740 ER PT J AU Even, C Weintraub, D AF Even, Christian Weintraub, Daniel TI Is depression in Parkinson's Disease (PD) a specific entity? SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Review DE Depression; Parkinson's Disease; Mood disorders ID SEROTONIN TRANSPORTER GENE; PLACEBO-CONTROLLED TRIAL; MAJOR DEPRESSION; FUNCTIONAL POLYMORPHISM; STRIATAL DOPAMINE; ALLELIC VARIATION; INCREASED RISK; DOUBLE-BLIND; LATE-LIFE; SYMPTOMS AB Background: Clinical lore and research have suggested for a long time that depression and PD are closely related. We examined the validity of depression associated with PD (dPD) as a specific subtype of depression according to face validity, descriptive validity, construct validity and predictive validity. Methods: The English literature was reviewed after searching the MEDLINE database up to June 2010. Results: There appears to be three possible subtypes of comorbid depression: 1) patients who would have been depressed even if they had no PD (nonspecific-casual comorbid dPD), 2) patients who would have been depressed if they had had another disabling medical illness (nonspecific-reactive comorbid dPD) 3) those for which depression is directly related to the underlying pathophysiology of PD (specific comorbid dPD). These latter patients may more often present with particular clinical characteristics (descriptive validity): absence of history of depression or only within 5 years prior to onset of PD, absence of guilty thoughts and self-blame, absence of suicidal behavior, right-sided onset. However, dPD is only partly responsive to dopamine replacement and cannot be solely explained by dopamine deficiency. Other neurotransmitter systems are affected in PD and are involved in the pathophysiology of dPD. Their relative involvement however may differ from that in idiopathic depression (i.e.: lesser involvement of serotonergic systems). Limitations: Therapeutic data are limited to few controlled trials. Conclusions: Further research may allow differential diagnosis between dPD subtypes (i.e.: those who do and do not result from the underlying pathophysiological process of PD) and help inform treatment choice. (C) 2011 Elsevier B.V. All rights reserved. C1 [Even, Christian] Ctr Hosp St Anne, Clin Malad Mentales & Encephale, F-75674 Paris 14, France. [Even, Christian] Univ Paris 05, INSERM, U894, Ctr Psychiat & Neurosci, Paris, France. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Philadelphia, PA USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Even, C (reprint author), Ctr Hosp St Anne, Clin Malad Mentales & Encephale, 100 Rue Sante, F-75674 Paris 14, France. EM c.even@ch-sainte-anne.fr FU Sanofi-Synthelabo; Novartis; Boehringer-Ingelheim FX Dr Weintraub has received grants and honoraria from Sanofi-Synthelabo, Novartis and Boehringer-Ingelheim. NR 119 TC 7 Z9 7 U1 5 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL PY 2012 VL 139 IS 2 BP 103 EP 112 DI 10.1016/j.jad.2011.07.002 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 975TV UT WOS:000306535300001 PM 21794923 ER PT J AU Elias, PZ Spector, M AF Elias, Paul Z. Spector, Myron TI Characterization of a Bilateral Penetrating Brain Injury in Rats and Evaluation of a Collagen Biomaterial for Potential Treatment SO JOURNAL OF NEUROTRAUMA LA English DT Article DE collagen; penetrating brain injury; rat brain; scaffold; traumatic brain injury ID CENTRAL-NERVOUS-SYSTEM; CRANIOCEREBRAL GUNSHOT WOUNDS; MESENCHYMAL STEM-CELLS; SPINAL-CORD; HEAD-INJURY; INTRACRANIAL-PRESSURE; TISSUE REGENERATION; GAG SCAFFOLDS; ADULT MICE; IN-VITRO AB Penetrating brain injury (PBI) encountered in both the military and civilian sectors results in high morbidity and mortality due to the absence of effective treatment options for survivors of the initial trauma. Developing therapies for such injuries requires a better understanding of the complex pathology involved when projectiles enter the skull and disrupt the brain parenchyma. This study presents a histological characterization of bilateral PBI using a relatively new injury model in the rat, and also investigates the implantation of a collagen scaffold into the PBI lesion as a potential treatment option. At 1 week post-PBI, the lesion was characterized by dense macrophage infiltration, evolving astrogliosis, hypervascularity, and an absence of viable neurons, oligodendrocytes, and myelinated axons. Histomorphometric analysis revealed that the PBI lesion volume expanded by 29% between 1 week and 5 weeks post-injury, resulting in formation of a large acellular cavity. Immunohistochemistry showed a decrease in the presence of CD68-positive macrophages from 1 to 5 weeks post-PBI as the necrotic tissue in the lesion was cleared, while persistent glial scarring remained in the form of upregulated GFAP expression surrounding the PBI cavity. Implanted type I collagen scaffolds remained intact with open pores after time periods of 1 week and 4 weeks in vivo, and were found to be sparsely infiltrated with macrophages, astrocytes, and endothelial cells. Collagen scaffolds appear to be an appropriate delivery vehicle for cellular and pharmacological therapeutic agents in future studies of PBI. C1 [Elias, Paul Z.; Spector, Myron] VA Boston Healthcare Syst, Tissue Engn Labs, Boston, MA 02130 USA. [Elias, Paul Z.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Spector, Myron] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. RP Elias, PZ (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, Mail Stop 151,Room D1-151,150 S Huntington Ave, Boston, MA 02130 USA. EM pzelias@alum.mit.edu FU U.S. Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service FX The research reported here was supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service. M. S. is a VA Research Career Scientist. NR 77 TC 5 Z9 5 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 11 BP 2086 EP 2102 DI 10.1089/neu.2011.2181 PG 17 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 983CX UT WOS:000307095800009 PM 22519932 ER PT J AU Lee, HR Park, JH Kim, CH Min, CH AF Lee, Han Rim Park, Jong Hoon Kim, Chan Hyeong Min, Chul Hee TI Design optimization of a 2D prompt-gamma measurement system for proton dose verification SO JOURNAL OF THE KOREAN PHYSICAL SOCIETY LA English DT Article; Proceedings Paper CT 15th International Conference on Accelerators and Beam Utilizations CY SEP 29-30, 2011 CL Gyeongju, SOUTH KOREA DE Proton therapy; Prompt-gamma; Range verification; Monte Carlo; MCNPX ID MONTE-CARLO; RANGE VERIFICATION; THERAPY AB To verify in-vivo proton dose distribution, a 2-dimensional (2D) prompt-gamma measurement system, comprised of a multi-hole collimation system, a 2D array of CsI(Tl) scintillators, and a position-sensitive photomultiplier tube (PS-PMT), is under development. In the present study, to determine the optimal dimension of the measurement system, we employed a series of Monte Carlo simulations with the MCNPX code. To effectively measure the high-energy prompt gammas while minimizing background gammas, we determined the collimator hole size, collimator thickness, and scintillator length to be 0.4 x 0.4 cm(2), 15 cm, and 5 cm, respectively. Thereafter, the performance of the optimized measurement system was estimated for monoenergetic proton pencil beams. The peak locations of the prompt-gamma distributions for 80- and 150-MeV proton beams were clearly distinguished, and the correlation between the beam range and the peak location was confirmed by using the measurement system. For a 200-MeV proton beam, however, the peak location could not be determined due to the dominance of background gammas and the lateral dispersion of the proton beam at the end of the beam range. Based on these simulation results, a prototype 2D prompt-gamma measurement system currently is under construction and, upon completion, will be tested with therapeutic proton beams. C1 [Lee, Han Rim; Park, Jong Hoon; Kim, Chan Hyeong] Hanyang Univ, Dept Nucl Engn, Seoul 133791, South Korea. [Min, Chul Hee] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Min, Chul Hee] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lee, HR (reprint author), Hanyang Univ, Dept Nucl Engn, Seoul 133791, South Korea. EM chkim@hanyang.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2010-0028913, 2010-0023825, 2012-K001146] FX This research was supported by the National Nuclear R&D Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Nos. 2010-0028913, 2010-0023825, and 2012-K001146). NR 16 TC 5 Z9 5 U1 0 U2 2 PU KOREAN PHYSICAL SOC PI SEOUL PA 635-4, YUKSAM-DONG, KANGNAM-KU, SEOUL 135-703, SOUTH KOREA SN 0374-4884 EI 1976-8524 J9 J KOREAN PHYS SOC JI J. Korean Phys. Soc. PD JUL PY 2012 VL 61 IS 2 SI SI BP 239 EP 242 DI 10.3938/jkps.61.239 PG 4 WC Physics, Multidisciplinary SC Physics GA 985PR UT WOS:000307280400014 ER PT J AU Li, XH Zhang, D Liu, B AF Li, Xinhua Zhang, Da Liu, Bob TI Transmission of broad W/Rh and W/Al (target/filter) x-ray beams operated at 25-49 kVp through common shielding materials SO MEDICAL PHYSICS LA English DT Article DE radiation protection; x rays; shielding; transmission; breast tomosynthesis ID TUNGSTEN-ANODE; REQUIREMENTS; ATTENUATION; FACILITIES AB Purpose: To provide transmission data for broad 25-39 kVp (kilovolt peak) W/Rh and 25-49 kVp W/Al (target/filter, W-tungsten, Rh-rhodium, and Al-aluminum) x-ray beams through common shielding materials, such as lead, concrete, gypsum wallboard, wood, steel, and plate glass. Methods: The unfiltered W-target x-ray spectra measured on a Selenia Dimensions system (Hologic Inc., Bedford, MA) set at 20-49 kVp were, respectively, filtered using 50-mu m Rh and 700-mu m Al, and were subsequently used for Monte Carlo calculations. The transmission of broad x-ray beams through shielding materials was simulated using Geant4 low energy electromagnetic physics package with photon- and electron-processes above 250 eV, including photoelectric effect, Compton scattering, and Rayleigh scattering. The calculated transmission data were fitted using Archer equation with a robust fitting algorithm. Results: The transmission of broad x-ray beams through the above-mentioned shielding materials was calculated down to about 10(-5) for 25-39 kVp W/Rh and 25-49 kVp W/Al. The fitted results of alpha, beta and gamma in Archer equation were provided. The a values of kVp >= 40 were approximately consistent with those of NCRP Report No. 147. Conclusions: These data provide inputs for the shielding designs of x-ray imaging facilities with W-anode x-ray beams, such as from Selenia Dimensions. (C) 2012 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4725755] C1 [Li, Xinhua; Zhang, Da; Liu, Bob] Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, Boston, MA 02114 USA. RP Liu, B (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, Boston, MA 02114 USA. EM bliu7@bics.bwh.harvard.edu NR 14 TC 5 Z9 5 U1 0 U2 6 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2012 VL 39 IS 7 BP 4132 EP 4138 DI 10.1118/1.4725755 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 980KV UT WOS:000306893000010 PM 22830746 ER PT J AU Bebien, M Hensler, ME Davanture, S Hsu, LC Karin, M Park, JM Alexopoulou, L Liu, GY Nizet, V Lawrence, T AF Bebien, Magali Hensler, Mary E. Davanture, Suzel Hsu, Li-Chung Karin, Michael Park, Jin Mo Alexopoulou, Lena Liu, George Y. Nizet, Victor Lawrence, Toby TI The Pore-Forming Toxin beta hemolysin/cytolysin Triggers p38 MAPK-Dependent IL-10 Production in Macrophages and Inhibits Innate Immunity SO PLOS PATHOGENS LA English DT Article ID ACTIVATED PROTEIN-KINASE; GROUP-B STREPTOCOCCUS; INFLAMMATORY FUNCTIONS; STAPHYLOCOCCUS-AUREUS; SIGNALING PATHWAYS; INTERFERON-GAMMA; EPITHELIAL-CELLS; CONTRIBUTES; RECOGNITION; INFECTION AB Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns and immune-compromised adults. The pore-forming toxin (PFT) beta hemolysin/cytolysin (beta h/c) is a major virulence factor for GBS, which is generally attributed to its cytolytic functions. Here we show beta h/c has immunomodulatory properties on macrophages at sub-lytic concentrations. beta h/c-mediated activation of p38 MAPK drives expression of the anti-inflammatory and immunosuppressive cytokine IL-10, and inhibits both IL-12 and NOS2 expression in GBS-infected macrophages, which are critical factors in host defense. Isogenic mutant bacteria lacking beta h/c fail to activate p38-mediated IL-10 production in macrophages and promote increased IL-12 and NOS2 expression. Furthermore, targeted deletion of p38 in macrophages increases resistance to invasive GBS infection in mice, associated with impaired IL-10 induction and increased IL-12 production in vivo. These data suggest p38 MAPK activation by beta h/c contributes to evasion of host defense through induction of IL-10 expression and inhibition of macrophage activation, a new mechanism of action for a PFT and a novel anti-inflammatory role for p38 in the pathogenesis of invasive bacterial infection. Our studies suggest p38 MAPK may represent a new therapeutic target to blunt virulence and improve clinical outcome of invasive GBS infection. C1 [Bebien, Magali; Davanture, Suzel; Alexopoulou, Lena; Lawrence, Toby] Aix Marseille Univ, Ctr Immunol Marseille Luminy CIML, UM2, Marseille, France. [Bebien, Magali; Davanture, Suzel; Alexopoulou, Lena; Lawrence, Toby] INSERM, U1104, F-13258 Marseille, France. [Bebien, Magali; Davanture, Suzel; Alexopoulou, Lena; Lawrence, Toby] CNRS, UMR7280, Marseille, France. [Hensler, Mary E.; Nizet, Victor] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Hensler, Mary E.; Nizet, Victor] Univ Calif San Diego, Sch Med, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Hsu, Li-Chung; Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Liu, George Y.] Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Inst Immunobiol, Los Angeles, CA USA. RP Bebien, M (reprint author), Aix Marseille Univ, Ctr Immunol Marseille Luminy CIML, UM2, Marseille, France. EM lawrence@ciml.univ-mrs.fr RI Lawrence, Toby/F-4461-2015; Alexopoulou, Lena/A-5041-2017; OI Alexopoulou, Lena/0000-0003-4619-697X; Hsu, Li-Chung/0000-0001-7206-5231 FU Agence Nationale Recherche of France [ANR-09-MIEN-029-01]; CNRS; INSERM FX This work was supported by grants from the Agence Nationale Recherche of France (project; ANR-09-MIEN-029-01) to TL and institutional grants from CNRS and INSERM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 28 Z9 29 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2012 VL 8 IS 7 AR e1002812 DI 10.1371/journal.ppat.1002812 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 979RO UT WOS:000306837700033 PM 22829768 ER PT J AU Luhachack, LG Visvikis, O Wollenberg, AC Lacy-Hulbert, A Stuart, LM Irazoqui, JE AF Luhachack, Lyly G. Visvikis, Orane Wollenberg, Amanda C. Lacy-Hulbert, Adam Stuart, Lynda M. Irazoqui, Javier E. TI EGL-9 Controls C. elegans Host Defense Specificity through Prolyl Hydroxylation-Dependent and -Independent HIF-1 Pathways SO PLOS PATHOGENS LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; CAENORHABDITIS-ELEGANS; INNATE IMMUNITY; ULCERATIVE-COLITIS; GENE-EXPRESSION; TRANSCRIPTIONAL REPRESSION; HIF-1-DEPENDENT REPRESSION; PSEUDOMONAS-AERUGINOSA; BACTERICIDAL CAPACITY; SIGNALING PATHWAY AB Understanding host defense against microbes is key to developing new and more effective therapies for infection and inflammatory disease. However, how animals integrate multiple environmental signals and discriminate between different pathogens to mount specific and tailored responses remains poorly understood. Using the genetically tractable model host Caenorhabditis elegans and pathogenic bacterium Staphylococcus aureus, we describe an important role for hypoxia-inducible factor (HIF) in defining the specificity of the host response in the intestine. We demonstrate that loss of egl-9, a negative regulator of HIF, confers HIF-dependent enhanced susceptibility to S. aureus while increasing resistance to Pseudomonas aeruginosa. In our attempt to understand how HIF could have these apparently dichotomous roles in host defense, we find that distinct pathways separately regulate two opposing functions of HIF: the canonical pathway is important for blocking expression of a set of HIF-induced defense genes, whereas a less well understood noncanonical pathway appears to be important for allowing the expression of another distinct set of HIF-repressed defense genes. Thus, HIF can function either as a gene-specific inducer or repressor of host defense, providing a molecular mechanism by which HIF can have apparently opposing roles in defense and inflammation. Together, our observations show that HIF can set the balance between alternative pathogen-specific host responses, potentially acting as an evolutionarily conserved specificity switch in the host innate immune response. C1 [Luhachack, Lyly G.] Harvard Univ, Sch Med, Dept Pediat, Program Dev Immunol,Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Luhachack, LG (reprint author), Harvard Univ, Sch Med, Dept Pediat, Program Dev Immunol,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM javier@molbio.mgh.harvard.edu RI Irazoqui, Javier/A-8028-2013; VISVIKIS, ORANE/N-1818-2016; OI VISVIKIS, ORANE/0000-0001-7719-5836; Irazoqui, Javier/0000-0001-6553-1329; Lacy-Hulbert, Adam/0000-0003-2162-0156 FU NIH [5P30GM092431-02]; Department of Pediatrics (MGH); Center for the Study of Inflammatory Bowel Diseases (MGH-NIDDK) [DK043351]; NIH National Center for Research Resources (NCRR) FX Funding was provided by NIH grant 5P30GM092431-02, startup funds from the Department of Pediatrics (MGH), and Pilot and Feasibility Study Grant DK043351 from the Center for the Study of Inflammatory Bowel Diseases (MGH-NIDDK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank Dr. Raffi Aroian, Dr. Jo Anne Powell-Coffman, Dr. Cori Bargmann, Dr. Creg Darby, and the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR), for nematode strains. NR 61 TC 7 Z9 12 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2012 VL 8 IS 7 AR e1002798 DI 10.1371/journal.ppat.1002798 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 979RO UT WOS:000306837700023 PM 22792069 ER PT J AU Cunningham, MA Naga, OS Eudaly, JG Scott, JL Gilkeson, GS AF Cunningham, Melissa A. Naga, Osama S. Eudaly, Jackie G. Scott, Jennifer L. Gilkeson, Gary S. TI Estrogen receptor alpha modulates toll-like receptor signaling in murine lupus SO CLINICAL IMMUNOLOGY LA English DT Article DE Estrogen receptor alpha; Systemic lupus erythematosus; Dendritic cells; Toll-like receptors ID DENDRITIC CELL-DIFFERENTIATION; ANTIGEN-PRESENTING CELLS; BONE-MARROW; AUTOANTIBODY PRODUCTION; NEUROPSYCHIATRIC LUPUS; CEREBROSPINAL-FLUID; ERYTHEMATOSUS; EXPRESSION; PROMOTES; DISEASE AB Systemic lupus erythematosus (SLE) is a disease that disproportionately affects females. Despite significant research effort, the mechanisms underlying the female predominance in this disease are largely unknown. Previously, we showed that estrogen receptor alpha knockout (ER alpha KO) lupus prone female mice had significantly less pathologic renal disease and proteinuria, and significantly prolonged survival. Since autoantibody levels and number and percentage of BIT cells were not significantly impacted by ER alpha genotype, we hypothesized that the primary benefit of ERa deficiency in lupus nephritis was via modulation of the innate immune response. Using BMDCs and spleen cells/B cells from female wild-type or ER alpha KO mice, we found that ER alpha KO-derived cells have a significantly reduced inflammatory response after stimulation with TLR agonists. Our results indicate that the inflammatory response to TLR ligands is significantly impacted by the presence of ER alpha despite the absence of estradiot, and may partially explain the protective effect of ER alpha deficiency in lupus-prone animals. (C) 2012 Published by Elsevier Inc. C1 Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Hosp, Charleston, SC 29425 USA. RP Gilkeson, GS (reprint author), 96 Jonathan Lucas St,Suite 912,MSC637, Charleston, SC 29425 USA. EM gilkeson@musc.edu OI Cunningham, Melissa/0000-0002-9207-1986 FU NIAMS NIH HHS [T32 AR050958] NR 44 TC 12 Z9 12 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2012 VL 144 IS 1 BP 1 EP 12 DI 10.1016/j.clim.2012.04.001 PG 12 WC Immunology SC Immunology GA 977PX UT WOS:000306678000001 PM 22659029 ER PT J AU Ganda, OP Jumes, CG Abrahamson, MJ Molla, M AF Ganda, O. P. Jumes, C. G. Abrahamson, M. J. Molla, M. TI Quantification of concordance and discordance between apolipoprotein-B and the currently recommended non-HDL-cholesterol goals for cardiovascular risk assessment in patients with diabetes and hypertriglyceridemia SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Lipid goals; Apo-B; Non-HDL-C; Diabetic dyslipidemia ID DENSITY-LIPOPROTEIN CHOLESTEROL; MYOCARDIAL-INFARCTION; EXPERT PANEL; US ADULTS; A-I; DISEASE; THERAPY; MARKERS; ROSUVASTATIN; ASSOCIATION AB Aims: In patients with diabetes and hypertriglyceridemia, LDL-cholesterol (LDL-C) provides an inaccurate reflection of LDL particle burden. The relative value of non-HDL-cholesterol (non-HDL-C) and apolipoprotein-B (Apo-B) in estimating cardiovascular risk is controversial. We assessed the discordance between non-HDL-C and Apo-B targets in patients with diabetes with TG 200-499 mg/dl. Methods: Data from 1430 determinations of LDL-C, non-HDL-C, and Apo-B in ambulatory patients with diabetes were analyzed. Rates of discordance were calculated, based on the currently recommended LDL-C, non-HDL-C, and Apo-B goals. Results: In patients with non-HDL-C goal of < 130 mg/dl, there was a discordance with Apo-B level goal of < 90 mg/dl, in 31% of samples. In patients with non-HDL-C goal of < 100 mg/dl, 6% of samples had Apo-B >= 80 and 18% had Apo-B < 80 mg/dl. Using the Apo-B goal of < 70 mg/dl, these numbers were 37% and 3.5% respectively. There was also a significant gender difference, i.e. under-estimation of risk by suggested non-HDL-C cut-offs, in females, compared to males. Conclusions: In patients with diabetes and hypertriglyceridemia, a considerable discordance exists between non-HDL-C and Apo-B. Our data suggest a need for prospective studies to compare the relative merits of non-HDL-C and Apo-B targets in the assessment of cardiovascular risk. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Ganda, O. P.] Joslin Diabet Ctr, Sect Adult Med, Boston, MA 02215 USA. Joslin Diabet Ctr, Sect Clin Res, Boston, MA 02215 USA. Joslin Diabet Ctr, Sect Bioinformat, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Ganda, OP (reprint author), Joslin Diabet Ctr, Sect Adult Med, 1 Joslin Pl,Rm 242, Boston, MA 02215 USA. EM om.ganda@joslin.harvard.edu FU DRC - Enrichment core and the Bioinformatics core [P30DK36836]; Joslin Clinical Research Center FX The studies were supported, in part, by DRC - Enrichment core and the Bioinformatics core P30DK36836, and the Joslin Clinical Research Center. Richard DiVincezo assisted with the data extraction from the electronic health records. NR 30 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JUL PY 2012 VL 97 IS 1 BP 51 EP 56 DI 10.1016/j.diabres.2012.02.013 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 977JS UT WOS:000306655500013 PM 22459987 ER PT J AU Ho, JE Gona, P Pencina, MJ Tu, JV Austin, PC Vasan, RS Kannel, WB D'Agostino, RB Lee, DS Levy, D AF Ho, Jennifer E. Gona, Philimon Pencina, Michael J. Tu, Jack V. Austin, Peter C. Vasan, Ramachandran S. Kannel, William B. D'Agostino, Ralph B. Lee, Douglas S. Levy, Daniel TI Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community SO EUROPEAN HEART JOURNAL LA English DT Article DE Heart failure; Epidemiology; Risk factors; Ejection fraction ID VENTRICULAR SYSTOLIC FUNCTION; OF-CARDIOLOGY; FRAMINGHAM; DISEASE; DIAGNOSIS; SPECTRUM; OUTCOMES; VALIDATION; MANAGEMENT; PHENOTYPES AB Heart failure (HF) is a major public health burden worldwide. Of patients presenting with HF, 3055 have a preserved ejection fraction (HFPEF) rather than a reduced ejection fraction (HFREF). Our objective was to examine discriminating clinical features in new-onset HFPEF vs. HFREF. Of 712 participants in the Framingham Heart Study (FHS) hospitalized for new-onset HF between 1981 and 2008 (median age 81 years, 53 female), 46 had HFPEF (EF 45) and 54 had HFREF (EF 45). In multivariable logistic regression, coronary heart disease (CHD), higher heart rate, higher potassium, left bundle branch block, and ischaemic electrocardiographic changes increased the odds of HFREF; female sex and atrial fibrillation increased the odds of HFPEF. In aggregate, these clinical features predicted HF subtype with good discrimination (c-statistic 0.78). Predictors were examined in the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study. Of 4436 HF patients (median age 75 years, 47 female), 32 had HFPEF and 68 had HFREF. Distinguishing clinical features were consistent between FHS and EFFECT, with comparable discrimination in EFFECT (c-statistic 0.75). In exploratory analyses examining the traits of the intermediate EF group (EF 3555), CHD predisposed to a decrease in EF, whereas other clinical traits showed an overlapping spectrum between HFPEF and HFREF. Multiple clinical characteristics at the time of initial HF presentation differed in participants with HFPEF vs. HFREF. While CHD was clearly associated with a lower EF, overlapping characteristics were observed in the middle of the left ventricular EF range spectrum. C1 [Ho, Jennifer E.; Gona, Philimon; Vasan, Ramachandran S.; Kannel, William B.; D'Agostino, Ralph B.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Div Biostat & Hlth Serv Res, Dept Quantitat Hlth Sci, Amherst, MA 01003 USA. [Pencina, Michael J.; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Tu, Jack V.; Lee, Douglas S.] Schulich Hlth Sci Ctr, Div Cardiol, Toronto, ON, Canada. [Austin, Peter C.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Toronto, ON M5S 1A1, Canada. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA USA. EM levyd@nhlbi.nih.gov RI Lee, Douglas/J-4315-2014; OI Ho, Jennifer/0000-0002-7987-4768; Tu, Jack/0000-0003-0111-722X; Ramachandran, Vasan/0000-0001-7357-5970; Austin, Peter/0000-0003-3337-233X FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Canadian Institutes of Health Research [MOP 114937]; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; Tier 1 Canada Research Chair in Health Services Research; Heart and Stroke Foundation of Ontario FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 to J.E.H. and D. L.), and an operating grant from the Canadian Institutes of Health Research (Grant No. MOP 114937). The EFFECT study was supported by a Canadian Institutes of Health Research team grant in cardiovascular outcomes research and a grant from the Heart and Stroke Foundation of Canada. J.V.T. is supported by a Tier 1 Canada Research Chair in Health Services Research and a career investigator award from the Heart and Stroke Foundation of Ontario. P.C.A. is supported by a Career Investigator award from the Heart and Stroke Foundation of Ontario. D.S.L. is supported by a clinician-scientist award from the Canadian Institutes of Health Research. The sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the article for publication, and researchers were independent from funders. NR 32 TC 34 Z9 35 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2012 VL 33 IS 14 BP 1734 EP 1741 DI 10.1093/eurheartj/ehs070 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 977RW UT WOS:000306683100013 PM 22507977 ER PT J AU Jacobs, RL Harper, N He, WJ Andrews, CP Rather, CG Ramirez, DA Ahuja, SK AF Jacobs, Robert L. Harper, Nathan He, Weijing Andrews, Charles P. Rather, Cynthia G. Ramirez, Daniel A. Ahuja, Sunil K. TI Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergic diseases; environmental chamber; ragweed; endotypes ID VALIDATION; NASAL; RHINITIS; ASTHMA; ONSET; UNIT AB Background: The level of concordance between allergic symptoms induced on exposure to pollen in a pollen challenge chamber (PCC) versus the natural season is unknown. Objective: We sought to test the hypothesis that the symptom levels of allergic rhinoconjunctivitis elicited after out-of-season exposure to short ragweed in a PCC and during the natural season for giant ragweed pollen are highly correlated. Methods: Thirty-one ragweed-sensitive participants recorded symptoms for 15 days during the natural giant ragweed season in San Antonio, Texas. Twenty-six of these participants were challenged to short ragweed pollen in a PCC for 3 hours per day for up to 4 days. Results: In the PCC participants were dichotomized into those in whom low versus high levels of symptoms developed slowly or rapidly (ie, slow/low vs rapid/high). Each successive exposure visit associated with a progressive increase in symptom levels that approximated those experienced during the natural season. Hierarchic clustering identified 3 endotypes: endotypes I and II reflected concordantly low (n = 7) versus high (n = 14) total symptom scores (TSSs) in both the natural season and the PCC, respectively. Accordingly, the correlation between the TSSs recorded in the natural season and in the PCC for these 21 participants was very high. Although participants with endotype III (n = 5) had greater TSSs in the natural season than in the PCC, the degree of correlation between the TSSs remained high. Conclusions: Our findings affirm our hypothesis, underscore the high cross-reactivity between distinct pollens, and highlight the utility of the PCC to identify novel allergy endotypes that might have contrasting mechanistic underpinnings and potentially therapeutic responses. (J Allergy Clin Immunol 2012;130:122-7.) C1 [Jacobs, Robert L.; Andrews, Charles P.; Rather, Cynthia G.; Ramirez, Daniel A.] Biogen Res Chamber LLC, San Antonio, TX 78229 USA. [Harper, Nathan; He, Weijing; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Ctr Personalized Med, San Antonio, TX USA. [Harper, Nathan; He, Weijing; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Jacobs, RL (reprint author), Biogen Res Chamber LLC, 8299 Fredericksburg Rd, San Antonio, TX 78229 USA. EM robert.jacobs7025@sbcglobal.net OI Andrews, Charles/0000-0002-8944-8404; Jacobs, Robert/0000-0002-2831-9086 FU Doris Duke Distinguished Clinical Scientist Award; Burroughs Wellcome Clinical Scientist in Translational Research Award; Max and Minnie Tomerlin Voelcker Scholar Award; Center for Personalized Medicine at the South Texas Veterans Health Care System; National Institutes of Health FX S.K.A. received support from the following grants: the Doris Duke Distinguished Clinical Scientist Award, the Burroughs Wellcome Clinical Scientist in Translational Research Award, the Max and Minnie Tomerlin Voelcker Scholar Award, and the Center for Personalized Medicine at the South Texas Veterans Health Care System.; Disclosure of potential conflict of interest: R. L. Jacobs is the owner of the Biogenics Research Chamber and Biogenics Research Institute. C. P. Andrews is a partner in the Biogenics Research Chamber and Director of Clinical Research at the Diagnostics Research Group. C. G. Rather is Executive Director of the Biogenics Research Chamber. D. A. Ramirez is a partner in the Biogenics Research Chamber. S. K. Ahuja has received research support from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. NR 20 TC 23 Z9 23 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 JUL PY 2012 VL 130 IS 1 BP 122 EP + DI 10.1016/j.jaci.2012.03.031 PG 14 WC Allergy; Immunology SC Allergy; Immunology GA 977GN UT WOS:000306644800017 PM 22554707 ER PT J AU Butts, SC Setlur, J AF Butts, Sydney C. Setlur, Jennifer TI Excision of Forehead and Malar Lesions Using Endoscopic Techniques SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the Triological-Society/112th Combined Otolaryngology Spring Meeting CY MAY 28-31, 2009 CL Phoenix, AZ SP Triol Soc DE Endoscope; dermoid; midface; brow; minimally invasive ID LIFT AB The use of endoscopes via limited incisions to access areas of the forehead and cheek has allowed facial rejuvenation procedures to be performed in a way that minimizes some of the morbidities associated with more traditional approaches. The possibility of expanding the indications for these approaches arises when endoscopic, minimally invasive techniques can be applied to the excision of lesions of the upper part of the face and the midface. Such methods offer several advantages without compromising therapeutic outcome. The specific techniques used will be illustrated as they were applied in several cases. C1 [Butts, Sydney C.] Suny Downstate Med Ctr, Dept Otolaryngol, New York, NY USA. [Setlur, Jennifer] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Butts, SC (reprint author), Suny Downstate Med Ctr, Div Facial & Reconstruct Surg, Dept Otolaryngol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. EM Sydney.Butts@Downstate.edu NR 15 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD JUL PY 2012 VL 23 IS 4 BP 1146 EP 1148 DI 10.1097/SCS.0b013e31824e2645 PG 3 WC Surgery SC Surgery GA 978AJ UT WOS:000306710200091 PM 22777436 ER PT J AU Wittels, KA Takayesu, JK Nadel, ES AF Wittels, Kathleen A. Takayesu, James K. Nadel, Eric S. TI A TWO-YEAR EXPERIENCE OF AN INTEGRATED SIMULATION RESIDENCY CURRICULUM SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE patient simulation; curricula; Graduate Medical Education; teaching methods; educational techniques ID HUMAN PATIENT SIMULATOR; TRAUMA MANAGEMENT-SKILLS; EMERGENCY-MEDICINE; ANESTHESIA SIMULATOR; CLINICAL CORRELATION; PERFORMANCE; EDUCATION; ANESTHETISTS; VALIDITY; STUDENTS AB Background: Human Patient Simulation (HPS) is increasingly used in medical education, but its role in Emergency Medicine (EM) residency education is uncertain. Study Objectives: The objective of this study was to evaluate the perceived effectiveness of HPS when fully integrated into an EM residency didactic curriculum. Methods: The study design was a cross-sectional survey performed in 2006, 2 years after the implementation of an integrated simulation curriculum. Fifty-four residents (postgraduate year [PGY] 1-4) of a 4-year EM residency were surveyed with demographic and curricular questions on the perceived value of simulation relative to other teaching formats. Survey items were rated on a bipolar linear numeric scale of 1 (strongly disagree) to 9 (strongly agree), with 5 being neutral. Data were analyzed using Student t-tests. Results: Forty residents responded to the survey (74% response rate). The perceived effectiveness of HPS was higher for junior residents than senior residents (8.0 vs. 6.2, respectively, p < 0.001). There were no differences in perceived effectiveness of lectures (7.8 vs. 7.9, respectively, p = 0.1), morbidity and mortality conference (8.5 vs. 8.7, respectively, p = 0.3), and trauma conference (8.4 vs. 8.8, respectively, p = 0.2) between junior and senior residents. Scores for perceptions of improvement in residency training (knowledge acquisition and clinical decision-making) after the integration of HPS into the curriculum were positive for all residents. Conclusion: Residents' perceptions of HPS integration into an EM residency curriculum are positive for both improving knowledge acquisition and learning clinical decision-making. HPS was rated as more effective during junior years than senior years, while the perceived efficacy of more traditional educational modalities remained constant throughout residency training. (C) 2012 Published by Elsevier Inc. C1 [Wittels, Kathleen A.; Nadel, Eric S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. [Takayesu, James K.; Nadel, Eric S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. RP Wittels, KA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 41 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2012 VL 43 IS 1 BP 134 EP 138 DI 10.1016/j.jemermed.2011.05.086 PG 5 WC Emergency Medicine SC Emergency Medicine GA 978GP UT WOS:000306729100029 PM 22221985 ER PT J AU Lenehan, G AF Lenehan, Gail TI CONTAINING COSTS: EMERGENCY NURSES CRUCIAL TO THE CHALLENGES AHEAD SO JOURNAL OF EMERGENCY NURSING LA English DT Editorial Material C1 [Lenehan, Gail] Emergency Nurses Assoc, Boston, MA USA. [Lenehan, Gail] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lenehan, G (reprint author), Emergency Nurses Assoc, Boston, MA USA. EM gail.lenehan@gmail.com 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 0099-1767 J9 J EMERG NURS JI J. Emerg. Nurs. PD JUL PY 2012 VL 38 IS 4 BP 317 EP 317 DI 10.1016/j.jen.2012.06.003 PG 1 WC Emergency Medicine; Nursing SC Emergency Medicine; Nursing GA 979JY UT WOS:000306814500001 PM 22770393 ER PT J AU Smith, T Capitulo, KL Griffin, MTQ Fitzpatrick, JJ AF Smith, Thomas Capitulo, Kathleen Leask Griffin, Mary T. Quinn Fitzpatrick, Joyce J. TI Structural empowerment and anticipated turnover among behavioural health nurses SO JOURNAL OF NURSING MANAGEMENT LA English DT Article DE anticipated turnover; behavioural health nurse; registered nurse; structural empowerment; workforce retention ID WORK ENVIRONMENTS; SATISFACTION; STAFF; SETTINGS; MODEL; PERCEPTIONS; WORKPLACE; INTENT; IMPACT; LEAVE AB smith t., capitulo k.l., quinn griffin m.t. & fitzpatrick j.j. (2012) Journal of Nursing Management similar to 20, 679684 Structural empowerment and anticipated turnover among behavioural health nurses Aim The aim of this pilot study was to examine the relationship between structural empowerment and anticipated turnover among behavioural health nurses. Background There have been several studies relating structural empowerment to a range of organizational characteristics and personal attributes of nurses themselves. There are also previous studies linking the key variables in the present study, but no previous research of behavioural health nurses was available. Methods A quantitative design was used for this cross-sectional pilot study. All registered nurses (RN) working on inpatient units in the study facility were invited to participate (n = 97). An anonymous survey was sent to all potential participants. Results The response rate was 53% (n = 50). The majority of participants perceived themselves as moderately empowered. There was a significant negative correlation between empowerment and anticipated turnover. Conclusion The results of this pilot study among behavioural health nurses are similar to the results among nurses working in other clinical areas. Implications for nursing management Nurse managers should be cognizant of the factors that enhance nurses perceptions of empowerment, particularly related to issues of retention and anticipated turnover among behavioural health nurses. C1 [Griffin, Mary T. Quinn; Fitzpatrick, Joyce J.] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. [Smith, Thomas] Maimonides Hosp, Brooklyn, NY 11219 USA. [Capitulo, Kathleen Leask] James J Peters VA Med Ctr, Bronx, NY USA. RP Fitzpatrick, JJ (reprint author), Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. EM joyce.fitzpatrick@case.edu NR 25 TC 5 Z9 5 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0966-0429 J9 J NURS MANAGE JI J. Nurs. Manag. PD JUL PY 2012 VL 20 IS 5 SI SI BP 679 EP 684 DI 10.1111/j.1365-2834.2012.01384.x PG 6 WC Management; Nursing SC Business & Economics; Nursing GA 977IE UT WOS:000306649300013 PM 22823224 ER PT J AU Robinson, TN Wu, DS Pointer, LF Dunn, CL Moss, M AF Robinson, Thomas N. Wu, Daniel S. Pointer, Lauren F. Dunn, Christina L. Moss, Marc TI Preoperative Cognitive Dysfunction Is Related to Adverse Postoperative Outcomes in the Elderly SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article; Proceedings Paper CT 119th Scientific Session of the Western-Surgical-Association CY NOV, 2011 CL Tucson, AZ SP Western Surg Assoc ID INTENSIVE-CARE-UNIT; MECHANICALLY VENTILATED PATIENTS; CONFUSION ASSESSMENT METHOD; MINI-COG; DISCHARGE INSTITUTIONALIZATION; GERIATRIC-PATIENT; DELIRIUM; DEMENTIA; POPULATION; FRAILTY AB BACKGROUND: Preoperative risk stratification is commonly performed by assessing end-organ function (such as cardiac and pulmonary) to define postoperative risk. Little is known about impaired preoperative cognition and outcomes. The purpose of this study was to evaluate the impact of baseline impaired cognition on postoperative outcomes in geriatric surgery patients. STUDY DESIGN: Subjects 65 years and older undergoing a planned elective operation requiring postoperative ICU admission were recruited prospectively. Preoperative baseline cognition was assessed using the validated Mini-Cog test. Impaired cognition was defined as a Mini-Cog score of <= 3. Delirium was assessed using the Confusion Assessment Method-ICU by a trained research team. Adverse outcomes were defined using the Veterans Affairs Surgical Quality Improvement Program definitions. RESULTS: One hundred and eighty-six subjects were included, with a mean age of 73 +/- 6 years. Eighty-two subjects (44%) had baseline impaired cognition. The impaired cognition group had the following unadjusted outcomes: increased incidence of 1 or more postoperative complications (41% vs 24%; p = 0.011), higher incidence of delirium (78% vs 37%; p < 0.001), longer hospital stays (15 +/- 14 vs 9 +/- 9 days; p = 0.001), higher rate of discharge institutionalization (42% vs 18%; p = 0.001), and higher 6-month mortality (13% vs 5%; p = 0.040). Adjusting for potential confounders determined by univariate analysis, logistic regression found impaired cognition was still associated with the occurrence of 1 or more postoperative complications (odds ratio = 2.401; 95% CI, 1.185 +/- 4.865; p = 0.015). Kaplan-Meier survival analysis revealed higher mortality in the impaired cognition group (log-rank p = 0.008). CONCLUSIONS: Baseline cognitive impairment in older adults undergoing major elective operations is related to adverse postoperative outcomes including increased complications, length of stay, and long-term mortality. Improved understanding of baseline cognition and surgical outcomes can aid surgical decision making in older adults. (J Am Coll Surg 2012; 215: 12-18. (C) 2012 by the American College of Surgeons) C1 [Robinson, Thomas N.; Wu, Daniel S.; Dunn, Christina L.] Univ Colorado, Denver Sch Med, Dept Surg, Aurora, CO 80045 USA. [Moss, Marc] Univ Colorado, Denver Sch Med, Dept Med, Aurora, CO USA. [Robinson, Thomas N.; Wu, Daniel S.] Denver Vet Affairs Med Ctr, Dept Surg, Denver, CO USA. [Pointer, Lauren F.] Denver Vet Affairs Med Ctr, Dept Biostat, Denver, CO USA. RP Robinson, TN (reprint author), Univ Colorado, Denver Sch Med, Dept Surg, 12631 E 17th Ave,MS C313, Aurora, CO 80045 USA. EM thomas.robinson@ucdenver.edu FU NHLBI NIH HHS [K24 HL089223, K24-HL-089223]; NIA NIH HHS [K23 AG034632, K23AG034632] NR 28 TC 43 Z9 44 U1 3 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD JUL PY 2012 VL 215 IS 1 BP 12 EP 17 DI 10.1016/j.jamcollsurg.2012.02.007 PG 6 WC Surgery SC Surgery GA 977GE UT WOS:000306643900002 PM 22626912 ER PT J AU McCarter, MD Antonescu, CR Ballman, KV Maki, RG Pisters, PWT Demetri, GD Blanke, CD von Mehren, M Brennan, MF McCall, L Ota, DM DeMatteo, RP AF McCarter, Martin D. Antonescu, Cristina R. Ballman, Karla V. Maki, Robert G. Pisters, Peter W. T. Demetri, George D. Blanke, Charles D. von Mehren, Margaret Brennan, Murray F. McCall, Linda Ota, David M. DeMatteo, Ronald P. CA Amer Coll Surg Oncology Grp ACOSO TI Microscopically Positive Margins for Primary Gastrointestinal Stromal Tumors: Analysis of Risk Factors and Tumor Recurrence SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article; Proceedings Paper CT 119th Scientific Session of the Western-Surgical-Association CY NOV, 2011 CL Tucson, AZ SP Western Surg Assoc ID SOFT-TISSUE SARCOMAS; PROGNOSTIC-FACTORS; SURGICAL-MANAGEMENT; RESECTION; SURGERY; AUDIT; GIST AB BACKGROUND: Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. STUDY DESIGN: We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. RESULTS: Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (>= 10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio [HR] 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. CONCLUSIONS: Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size >= 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years. (J Am Coll Surg 2012; 215: 53-60. (C) 2012 by the American College of Surgeons) C1 [McCarter, Martin D.] Univ Colorado Denver, Dept Surg, Div GI Tumor & Endocrine Surg, Sch Med, Aurora, CO 80045 USA. [Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY USA. [McCarter, Martin D.; Brennan, Murray F.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY USA. [Maki, Robert G.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Ballman, Karla V.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Pisters, Peter W. T.] Univ Texas MD Anderson Canc Ctr, Dept Surg, Houston, TX 77030 USA. [Demetri, George D.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Blanke, Charles D.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Blanke, Charles D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [von Mehren, Margaret] Fox Chase Canc Ctr, Dept Med, Philadelphia, PA 19111 USA. [Ota, David M.] Duke Univ, Duke Clin Res Inst, Durham, NC 27706 USA. ACOSOG, Durham, NC USA. RP McCarter, MD (reprint author), Univ Colorado Denver, Dept Surg, Div GI Tumor & Endocrine Surg, Sch Med, Acad Off 1,MS C-313,12631 E 17th Ave, Aurora, CO 80045 USA. EM martin.mccarter@ucdenver.edu OI Ballman, Karla/0000-0002-4492-0357; Brennan, Murray/0000-0003-2358-4371 FU NCI NIH HHS [R01 CA102613, R21 CA094503, U10 CA076001] NR 22 TC 30 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD JUL PY 2012 VL 215 IS 1 BP 53 EP 59 DI 10.1016/j.jamcollsurg.2012.05.008 PG 7 WC Surgery SC Surgery GA 977GE UT WOS:000306643900010 PM 22726733 ER PT J AU Hussar, DA Hallinan, SE AF Hussar, Daniel A. Hallinan, Sarah E. TI Clobazam, ezogabine, and tafluprost SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT News Item C1 [Hussar, Daniel A.] Univ Sci, Philadelphia Coll Pharm, Philadelphia, PA 19104 USA. [Hallinan, Sarah E.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Hussar, DA (reprint author), Univ Sci, Philadelphia Coll Pharm, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD JUL-AUG PY 2012 VL 52 IS 4 BP 546 EP 550 DI 10.1331/JAPhA.2012.12529 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 977GG UT WOS:000306644100019 PM 22825237 ER PT J AU Vassy, JL O'Brien, KE Waxler, JL Park, ER Delahanty, LM Florez, JC Meigs, JB Grant, RW AF Vassy, Jason L. O'Brien, Kelsey E. Waxler, Jessica L. Park, Elyse R. Delahanty, Linda M. Florez, Jose C. Meigs, James B. Grant, Richard W. TI Impact of Literacy and Numeracy on Motivation for Behavior Change After Diabetes Genetic Risk Testing SO MEDICAL DECISION MAKING LA English DT Article DE genetics; diabetes; internal medicine; risk communication or perception; decision aids and tools; numeracy; individual differences; health literacy; judgment and decision psychology ID LIFE-STYLE INTERVENTION; CARDIOVASCULAR-DISEASE; DEMAND CHARACTERISTICS; PREVENTION PROGRAM; HEALTH LITERACY; INFORMATION; ADULTS; SKILLS; CARE; POLYMORPHISMS AB Background. Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. Objective. The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. Design and Measurements. Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high'' and "low'' genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. Results. Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy 38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. Conclusions. While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect. C1 [Vassy, Jason L.; O'Brien, Kelsey E.; Meigs, James B.; Grant, Richard W.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Vassy, Jason L.; Park, Elyse R.; Delahanty, Linda M.; Florez, Jose C.; Meigs, James B.; Grant, Richard W.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Vassy, Jason L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Waxler, Jessica L.] Partners Ctr Human Genet, Boston, MA USA. [Park, Elyse R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Delahanty, Linda M.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broand Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Vassy, JL (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jvassy@partners.org OI Grant, Richard/0000-0002-6164-8025 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney [R21 DK84527, K24 DK080140]; National Institutes of Health, National Research Service from Health Resources and Services Administration [HP12706-02-00]; National Institutes of Health's Loan Repayment Program FX We thank Katherine Stember for her assistance with data entry and figure design. Dr. Florez has received consulting honoraria from Daiichi- Sankyo and AstraZeneca. Dr. Meigs has a consulting agreement with Interleukin Genetics, Inc. This work was funded by the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney (R21 DK84527). Dr. Vassy is supported by an National Institutes of Health T32 National Research Service Award (HP12706-02-00) from the Health Resources and Services Administration and the National Institutes of Health's Loan Repayment Program (per the National Institute of Diabetes and Digestive and Kidney). Dr. Meigs is supported by the National Institute of Diabetes and Digestive and Kidney (K24 DK080140). The funding agreements ensured our independence in designing the study, interpreting the data, writing, and publishing the report. NR 43 TC 15 Z9 15 U1 1 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL-AUG PY 2012 VL 32 IS 4 BP 606 EP 615 DI 10.1177/0272989X11431608 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 976TU UT WOS:000306609000010 PM 22247420 ER PT J AU Gurol, ME Dierksen, G Betensky, R Gidicsin, C Halpin, A Becker, A Carmasin, J Ayres, A Schwab, K Viswanathan, A Salat, D Rosand, J Johnson, KA Greenberg, SM AF Gurol, M. Edip Dierksen, Gregory Betensky, Rebecca Gidicsin, Christopher Halpin, Amy Becker, Alex Carmasin, Jeremy Ayres, Alison Schwab, Kristin Viswanathan, Anand Salat, David Rosand, Jonathan Johnson, Keith A. Greenberg, Steven M. TI Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID PITTSBURGH COMPOUND-B; LOBAR INTRACEREBRAL HEMORRHAGE; WHITE-MATTER LESIONS; SMALL VESSEL DISEASE; MICROBLEEDS; BURDEN; BRAIN; MRI AB Objective: We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). Methods: We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at "simulated" hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained. Results: Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, inter-quartile range [IQR] 1-9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23-1.46) than simulated lesions (1.14, 95% CI 1.07-1.22, p < 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p < 0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003). Conclusions: Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. Neurology (R) 2012;79:320-326 C1 [Gurol, M. Edip; Dierksen, Gregory; Halpin, Amy; Becker, Alex; Schwab, Kristin; Viswanathan, Anand; Rosand, Jonathan; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Gidicsin, Christopher; Becker, Alex; Carmasin, Jeremy; Salat, David; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gurol, M. Edip; Betensky, Rebecca] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Gurol, ME (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM egurol@yahoo.com RI Gurol, Edip/J-2279-2014; OI Gurol, Edip/0000-0002-2169-4457; Ayres, Alison/0000-0002-5492-1695 FU NIH [T32NS048005, 5R01NS070834-01/02, R01AG026484, R01 NS070834-02]; Bristol Myers Squibb; Novartis; Medtronics; Pfizer Global Research and Development; Harvard NeuroDiscovery Center; Harvard Catalyst (CTSA); Maine Medical Center; Arex; Sekisui; Gerson Lehrman Group; Leerink Swann; Guidepoint Global; HLM Venture Partners; Clinical Trials Solutions; Cowen Inc. FX Supported by NIH (T32NS048005, 5R01NS070834-01/02, R01AG026484).; M.E. Gurol receives research support from the NIH (T32NS048005, R01 NS070834-02). G. Dierksen reports no disclosures. R. Betensky has received funding from NIH for the development of statistical methodology and for collaborations in brain tumors, stroke, CAA, Alzheimer disease, cancer, and multiple sclerosis. She has received funding from the Harvard NeuroDiscovery Center and the Harvard Catalyst (CTSA) for statistical support of collaborative projects. She has received funding from Bristol Myers Squibb and NIH for DSMB service, from Novartis for statistical methodology development with applications to MS, and from Maine Medical Center, Arex, Sekisui, Gerson Lehrman Group, Leerink Swann, Guidepoint Global, HLM Venture Partners, Clinical Trials Solutions, and Cowen Inc. for general statistical consultation. C. Gidicsin, A. Halpin, A. Becker, J. Carmasin, A. Ayres, K. Schwab, A. Viswanathan, D. Salat, J. Rosand, and K. A. Johnson report no disclosures. S. M. Greenberg served on Scientific Advisory Boards (1-NINDS Data Safety Monitoring Board for clinical trials in intracerebral hemorrhage, 2-Hoffman-Laroche, MRI Review Committee) and has received funding for travel or speaker honoraria (Medtronics, research lecture, 2010 Pfizer Global Research and Development, research lecture, 2010). Dr. Greenberg is also on the editorial boards of several journals (Stroke, Editorial Board, 2010-present; Cerebrovascular Disease, Editorial Board, 2008-present; Neurology (R), Editorial Board, 2005-present; Journal of Alzheimer's Disease and Other Dementias, Editorial Board, 2005-present). Dr. Greenberg worked as a consultant for Hoffman-LaRoche, Janssen Alzheimer Immunotherapy, and Bristol-Myers Squibb Company. He received research support from the NIH. Go to Neurology.org for full disclosures. NR 25 TC 51 Z9 53 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 2012 VL 79 IS 4 BP 320 EP 326 DI 10.1212/WNL.0b013e31826043a9 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 977UK UT WOS:000306690100011 PM 22786597 ER PT J AU Lagler, CNP Freitag, SK AF Lagler, Christine N. Pham Freitag, Suzanne K. TI Management of Periocular Actinic Keratosis: A Review of Practice Patterns Among Ophthalmic Plastic Surgeons SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; IMIQUIMOD; EFFICACY; FACE; SKIN AB Purpose: To determine the practice patterns of ophthalmic plastic surgeons regarding the management of actinic keratosis (AK) of the eyelid and periocular area. Methods: A brief electronic survey was distributed to members of the American Society of Ophthalmic Plastic and Reconstructive Surgery requesting their demographic information and treatment approaches to AK. Results: One hundred and seven of 523 (20.5%) American Society of Ophthalmic Plastic and Reconstructive Surgery members completed the survey. Most respondents treat AK < 2 mm from the eyelid margin by excision with permanent pathology (62.6%), followed by referral for Mohs excision (10.3%) and excision with frozen section control (9.3%). Similar responses were recorded for the treatment of AK > 2 mm from the eyelid margin, with most respondents treating by excision with permanent pathology (56.1%), followed by referral to dermatology for Mohs or non-Mohs treatment and topical chemotherapy (8.4% each). Conclusion: Although most American Society of Ophthalmic Plastic and Reconstructive Surgery members use excisional biopsy with permanent section pathology control of margins for the treatment of AK of the eyelid and periocular region, multiple alternative treatment approaches are also used. (Ophthal Plast Reconstr Surg 2012;28:277-281) C1 [Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Freitag, Suzanne K.] Harvard Univ, Sch Med, Boston, MA USA. [Lagler, Christine N. Pham] Boston Univ, Sch Med, Dept Ophthalmol, Boston Med Ctr, Boston, MA 02118 USA. RP Freitag, SK (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM Suzanne_Freitag@meei.harvard.edu NR 23 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD JUL-AUG PY 2012 VL 28 IS 4 BP 277 EP 281 DI 10.1097/IOP.0b013e318257f5f2 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 977KE UT WOS:000306657200024 PM 22785585 ER PT J AU Yoon, MK McCulley, TJ AF Yoon, Michael K. McCulley, Timothy J. TI Non-Traumatic Subperiosteal Orbital Hematoma as a Presenting Sign of Chronic Myelogenous Leukemia SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID HEMORRHAGE AB We present a case with a nontraumatic subperiosteal orbital hematoma as a presenting sign of chronic myelogenous leukemia. A previously healthy 34 year-old man presented with a 2-day history of right upper eyelid swelling. CT scan revealed a subperiosteal mass, and routine blood tests revealed a white blood cell count of 290,000/mu l with normal platelet count. Chronic myelogenous leukemia was diagnosed based on a subsequent bone marrow biopsy. After orbitotomy and evacuation of the hematoma, the patient's visual acuity and motility returned to normal. In conclusion, chronic myelogenous leukemia should be considered in the differential diagnosis of nontraumatic subperiosteal orbital hematoma. C1 [McCulley, Timothy J.] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [McCulley, Timothy J.] King Khalid Eye Specialist Hosp, Riyadh, Saudi Arabia. [Yoon, Michael K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP McCulley, TJ (reprint author), Johns Hopkins Sch Med, Wilmer Eye Inst, 600 N Wolfe St,Wilmer 110, Baltimore, MD 21287 USA. EM tmccull5@jhmi.edu FU Research to Prevent Blindness Inc., New York, New York, U.S.A. FX Supported in part by an unrestricted grant to the Wilmer Ophthalmological Institute from Research to Prevent Blindness Inc., New York, New York, U.S.A. NR 7 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD JUL-AUG PY 2012 VL 28 IS 4 BP E79 EP E80 DI 10.1097/IOP.0b013e31822ddf85 PG 2 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 977KE UT WOS:000306657200001 PM 22082590 ER PT J AU Hirn, C Zweifel, SA Toteberg-Harms, M Funk, J AF Hirn, C. Zweifel, S. A. Toeteberg-Harms, M. Funk, J. TI Effectiveness of selective laser trabeculoplasty in patients with insufficient control of intraocular pressure despite maximum tolerated medical therapy SO OPHTHALMOLOGE LA German DT Article DE Selective laser trabeculoplasty; Prostaglandin; Pseudophakia; Intraocular pressure; Glaucoma ID OPEN-ANGLE GLAUCOMA; RANDOMIZED CLINICAL-TRIAL; OUTFLOW FACILITY; PROSTAGLANDIN; PHACOEMULSIFICATION; IMPLANTATION; REDUCTION; MECHANISM; EFFICACY; EYES AB Reduction of intraocular pressure (IOP) is still the primary goal of glaucoma treatment. The aim of this prospective study was to examine the IOP lowering effect of selective laser trabeculoplasty (SLT) in patients on maximum tolerated medical therapy (MTMT), especially with regard to a potential influence of pseudophakia and topical prostaglandin analogues (PGA) on IOP reduction. A total of 30 patients with a diagnosis of primary open angle glaucoma, normal tension glaucoma and pseudoexfoliative glaucoma with uncontrolled IOP despite MTMT underwent SLT treatment circumferentially over 360A degrees. Follow-up visits were conducted 1 day after SLT and then 1, 3, 6, 9, and 12 months post-treatment. The initial medication was continued unchanged for 3 months. Median follow-up was 11.97 +/- 3.1 months, mean IOP at baseline was 19.60 +/- 4.69 mmHg, mean IOP reduction was -19.95 +/- 17.14% 1 month after and -14.07 +/- 23.57% 12 months after SLT (p < 0.001 and p = 0.003, respectively). Patients with higher baseline IOP had greater reduction of IOP after SLT (R-2 = 0.482, p < 0.001). Phakic patients had a significantly greater IOP reduction compared to pseudophakic patients (-aEuro parts per thousand 4.55 +/- 4.45 mmHg and + 2.75 +/- 6.75 mmHg, respectively, p = 0.010). Patients without PGA had a statistically insignificant greater IOP reduction compared to patients with PGA (-aEuro parts per thousand 7.40 +/- 4.72 mmHg and -2.48 +/- 5.22 mmHg, respectively, p = 0.066) and four patients needed additional surgery to lower IOP. Even in patients already on maximum IOP lowering medication, SLT has the potential to significantly reduce IOP up to 1 year after treatment. The IOP reduction is most pronounced in phakic eyes with high preoperative IOP. C1 [Hirn, C.; Zweifel, S. A.; Toeteberg-Harms, M.; Funk, J.] Univ Spital Zurich, Augenklin, CH-8091 Zurich, Switzerland. [Hirn, C.] Moorfields Eye Hosp NHS Fdn Trust, NIHR BRC Ophthalmol, London, England. [Toeteberg-Harms, M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Hirn, C (reprint author), Univ Spital Zurich, Augenklin, Frauenklin Str 24, CH-8091 Zurich, Switzerland. EM corneliahirn@aol.de RI Toteberg-Harms, Marc/J-4954-2013 OI Toteberg-Harms, Marc/0000-0002-2134-1336 NR 37 TC 9 Z9 10 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-293X J9 OPHTHALMOLOGE JI Ophthalmologe PD JUL PY 2012 VL 109 IS 7 BP 683 EP 690 DI 10.1007/s00347-012-2593-0 PG 8 WC Ophthalmology SC Ophthalmology GA 976LV UT WOS:000306587100009 PM 22555462 ER PT J AU Benyamin, RM Manchikanti, L Parr, AT Diwan, S Singh, V Falco, FJE Datta, S Abdi, S Hirsch, JA AF Benyamin, Ramsin M. Manchikanti, Laxmaiah Parr, Allan T. Diwan, Sudhir Singh, Vijay Falco, Frank J. E. Datta, Sukdeb Abdi, Salahadin Hirsch, Joshua A. TI The Effectiveness of Lumbar Interlaminar Epidural Injections in Managing Chronic Low Back and Lower Extremity Pain SO PAIN PHYSICIAN LA English DT Review DE Chronic low back pain; lower extremity pain; disc herniation; radiculitis; spinal stenosis; discogenic pain; lumbar interlaminar epidural injections; fluoroscopy ID RANDOMIZED CONTROLLED-TRIALS; ACTIVE-CONTROLLED-TRIAL; MEDIAL BRANCH BLOCKS; EVIDENCE-BASED MEDICINE; OF-THE-LITERATURE; 2-YEAR FOLLOW-UP; CENTRAL SEROUS CHORIORETINOPATHY; EQUIVALENCE CONTROLLED-TRIAL; CLINICAL-PRACTICE GUIDELINES; UPDATED METHOD GUIDELINES AB Background: Intervertebral disc herniation, spinal stenosis, intervertebral disc degeneration without disc herniation, and post lumbar surgery syndrome are the most common diagnoses of chronic persistent low back and lower extremity symptoms, resulting in significant economic, societal, and health care impact. Epidural injections are one of the most commonly performed interventions in the United States in managing chronic low back pain. However the evidence is highly variable among different techniques utilized - namely interlaminar, caudal, and transforaminal - and for various conditions, namely - intervertebral disc herniation, spinal stenosis, and discogenic pain without disc herniation or radiculitis. Multiple systematic reviews conducted in the evaluation of the effectiveness of interlaminar epidural injections have been marred with controversy. Consequently, the debate continues with regards to the effectiveness, indications, and medical necessity of interlaminar epidural injections. Study Design: A systematic review of lumbar interlaminar epidural injections with or without steroids. Objective: To evaluate the effect of lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back and lower extremity pain emanating as a result of disc herniation or radiculitis, spinal stenosis, and chronic discogenic pain. Methods: The available literature on lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back pain with or without lower extremity pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or limited based on the quality of evidence developed by the U. S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. Outcome Measures: The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. Results: Overall, 82 lumbar interlaminar trials were identified. All non-randomized studies without fluoroscopy and randomized trials not meeting the inclusion criteria were excluded. Overall, 15 randomized trials and 11 non-randomized studies were included in the analysis. Analysis was derived mainly from fluoroscopically-guided randomized trials and non-randomized studies. The evidence is good for radiculitis secondary to disc herniation with local anesthetics and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids, with fluoroscopically-guided epidural injections. Limitations: The limitations of this study include that we were unable to perform meta-analysis for disc herniation, and the paucity of evidence for discogenic pain and spinal stenosis. Further, methodological criteria have been highly variable along with sample sizes. The studies were heterogenous. Conclusion: The evidence based on this systematic review is good for lumbar epidural injections under fluoroscopy for radiculitis secondary to disc herniation with local anesthetic and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids. C1 [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL 61701 USA. [Benyamin, Ramsin M.] Univ Illinois, Urbana, IL 61801 USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Parr, Allan T.] Premier Pain Ctr, Covington, LA USA. [Diwan, Sudhir] Spine & Pain Inst New York, New York, NY USA. [Singh, Vijay] Spine Pain Diagnost Associates, Niagara, WI USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys Newark, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Datta, Sukdeb] Laser Spine & Pain Inst, New York, NY USA. [Abdi, Salahadin] Beth Israel Deaconess Med Ctr, Brookline, MA USA. [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Benyamin, RM (reprint author), Millennium Pain Ctr, 1015 S Mercer, Bloomington, IL 61701 USA. EM ramsinbenyamin@yahoo.com FU Cephalon/Teva; BioDelivery Sciences International, Inc.; Mundipharma Research GmbH Co.; AstraZeneca; Theravance; Sucampo Pharmaceuticals; Purdue Pharma, LP FX Dr. Benyamin is a clinical investigator with Epimed and receives research support from Cephalon/Teva, BioDelivery Sciences International, Inc., Mundipharma Research GmbH & Co., AstraZeneca, Purdue Pharma, LP, and Theravance. Dr. Datta receives research support from Sucampo Pharmaceuticals and an honorarium from Smith and Nephew. Dr. Hirsch is a consultant for CareFusion and receives royalties for products related to vertebral augmentation. He also participated in an Aetrium focus group and received compensation NR 300 TC 72 Z9 73 U1 3 U2 12 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2012 VL 15 IS 4 BP E363 EP E404 PG 42 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 979PJ UT WOS:000306831900003 PM 22828691 ER PT J AU Saad, F Eastham, JA Smith, MR AF Saad, Fred Eastham, James A. Smith, Matthew R. TI Biochemical markers of bone turnover and clinical outcomes in men with prostate cancer SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Review DE Bisphosphonate; Bone loss; Bone metastases; Bone mineral density; Bone turnover markers; Prostate cancer ID ANDROGEN-DEPRIVATION THERAPY; RESISTANT ACID-PHOSPHATASE; ZOLEDRONIC ACID; MINERAL DENSITY; BREAST-CANCER; SKELETAL COMPLICATIONS; PLASMA OSTEOPONTIN; METASTATIC SPREAD; NATURAL-HISTORY; SOLID TUMORS AB Objectives: Disrupted skeletal homeostasis is common in patients with prostate cancer. Low bone density is common at diagnosis, and fracture risk is further elevated by the effects of androgen-deprivation therapy. Later in the disease course, bone metastases can result in skeletal morbidity. Although prostate-specific antigen (PSA) levels can provide important insights into overall disease progression, convenient, noninvasive tools for monitoring skeletal health are lacking. Biochemical markers released into serum and urine as a result of bone turnover might fulfill this unmet need. The objectives of this article are to assess current evidence examining the potential utility of bone turnover markers for monitoring skeletal health, bone disease progression, and response to antiresorptive therapies in the prostate cancer setting. Methods: Published articles and abstracts from major oncology or urology congresses pertaining to the use of bone turnover markers to monitor skeletal health and disease progression were identified and assessed for relevance and methodologic stringency. Results: Several randomized trials and correlative studies support the utility of bone marker level changes to assess disease progression in the metastatic setting, bone health during hormonal therapy, and response to bisphosphonate therapy. The available data support potential associations between levels of the collagen type I telopeptides (NTX and CTX) and the severity of metastatic bone disease as well as outcomes during antiresorptive therapy. Evidence linking bone marker level changes with early diagnosis of skeletal metastases is emerging. Although several markers have shown promising results in correlative studies, results from ongoing prospective trials are needed to establish the role of bone markers in this setting. Conclusions: Bone marker levels reflect ongoing skeletal metabolism and can provide important insights into bone health and response to bisphosphonate therapy in patients with prostate cancer. The data supporting a role for bone markers to monitor skeletal disease progression and response to zoledronic acid therapy are especially strong. Bone marker assessments may complement established diagnostic and monitoring paradigms in prostate cancer. (C) 2012 Elsevier Inc. All rights reserved. C1 [Saad, Fred] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Eastham, James A.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saad, F (reprint author), Ctr Hosp Univ Montreal, Montreal, PQ, Canada. EM fred.saad@umontreal.ca FU Novartis Pharmaceuticals Corporation; Novartis Oncology; Amgen; Novartis; GTx Inc FX Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.; Received research funding, attended advisory board meetings, and received honoraria for speaking on behalf of Novartis Oncology.; Received research funding and/or served as a consultant to Amgen, Novartis, and GTx Inc. NR 81 TC 12 Z9 12 U1 0 U2 12 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 JUL-AUG PY 2012 VL 30 IS 4 BP 369 EP 378 DI 10.1016/j.urolonc.2010.08.007 PG 10 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 977EH UT WOS:000306638700005 PM 21163673 ER PT J AU Penson, DF Lange, PH AF Penson, David F. Lange, Paul H. TI Systemic therapy and the urologic oncologist: A unique opportunity for the specialty to provide comprehensive care that ultimately benefits the patient SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Systemic therapy; Urologic cancers; Practice models ID CANCER AB The changing healthcare environment will demand greater integration and coordination of care for patients. By incorporating systemic therapies into the practice of urologic oncology, our specialty has the opportunity to take the lead in this initiative. By learning how to deliver these therapies to patients in need, urologic oncologists likely will improve communication and trust, as patients often will already have a long and positive relationship with their urologist. In turn, this will likely lead to increased satisfaction with care and possibly improved outcomes. The development of comprehensive urologic oncology practices that include the administration of systemic therapy will maintain the relevance of the specialty and ultimately benefit our patients. (C) 2012 Elsevier Inc. All rights reserved. C1 [Penson, David F.] Vanderbilt Univ, Dept Urol Surg, Nashville, TN 37203 USA. [Penson, David F.] VA Tennessee Valley Geriatr Res Educ & Clin Ctr G, Nashville, TN 37203 USA. [Lange, Paul H.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Lange, Paul H.] VA Puget Sound Healthcare Syst, Seattle, WA 98195 USA. RP Penson, DF (reprint author), Vanderbilt Univ, Dept Urol Surg, Nashville, TN 37203 USA. EM david.penson@vanderbilt.edu NR 4 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 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL-AUG PY 2012 VL 30 IS 4 SU S BP S2 EP S4 DI 10.1016/j.urolonc.2011.04.008 PG 3 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 977EI UT WOS:000306638800002 PM 22795076 ER PT J AU Larsen, MS Bjerre, K Giobbie-Hurder, A Laenkholm, AV Henriksen, KL Ejlertsen, B Lykkesfeldt, AE Rasmussen, BB AF Larsen, Mathilde S. Bjerre, Karsten Giobbie-Hurder, Anita Laenkholm, Anne-Vibeke Henriksen, Katrine L. Ejlertsen, Bent Lykkesfeldt, Anne E. Rasmussen, Birgitte B. TI Prognostic value of Bcl-2 in two independent populations of estrogen receptor positive breast cancer patients treated with adjuvant endocrine therapy SO ACTA ONCOLOGICA LA English DT Article ID EXPRESSION; TAMOXIFEN; EFFICACY; SUBTYPES; MARKER; WOMEN; P53 AB Introduction. Estrogen receptor (ER) status is not an optimal marker for response to adjuvant endocrine therapy since approximately 30% of patients with ER-positive tumors eventually relapse. Bcl-2 is regulated by ER and may thus be considered as an indicator of ER activity and a candidate supplementary marker to ER status. Patients and methods. Tumor tissue from 257 patients with ER-positive breast cancer treated with tamoxifen was used for determination of the best threshold for immunohistochemical Bcl-2 assessment as prognostic marker. Subsequently, samples from the Danish patients of the randomized clinical trial BIG 1-98 comprising 1191 ER-positive patients treated with tamoxifen, letrozole or a sequence of the two were immunohistochemically stained for Bcl-2 to further explore the prognostic value of Bcl-2. Results. Two Bcl-2 levels were found to divide the population of the primary study into significantly different groups according to disease-free survival (DFS). Multivariate analysis confirmed the significance of the lowest level, and showed Bcl-2 to be an independent prognostic marker. Analysis of the Danish cohort of the BIG 1-98 confirmed that Bcl-2 was a significant predictor of DFS, independent of known prognostic markers. However, in an additional analysis of a subset of the Danish cohort of BIG 1-98 including only HER-2 normal patients, the effect of Bcl-2 was not statistically significant. Discussion. Low Bcl-2 can predict poor outcome of patients with ER-positive tumors treated with adjuvant endocrine therapy, whereas the use of Bcl-2 for determination of addition of chemotherapy was not supported by this study. C1 [Larsen, Mathilde S.; Rasmussen, Birgitte B.] Herlev Hosp, Dept Pathol, DK-2730 Herlev, Denmark. [Bjerre, Karsten; Ejlertsen, Bent] Rigshosp, Danish Breast Canc Cooperat Grp, DK-2100 Copenhagen, Denmark. [Giobbie-Hurder, Anita] Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. [Laenkholm, Anne-Vibeke] Slagelse Hosp, Dept Pathol, Slagelse, Denmark. [Larsen, Mathilde S.; Henriksen, Katrine L.; Lykkesfeldt, Anne E.] Danish Canc Soc, Dept Breast Canc Res, Copenhagen O, Denmark. RP Larsen, MS (reprint author), Herlev Hosp, Dept Pathol, DK-2730 Herlev, Denmark. EM maskla01@heh.regionh.dk FU Breast Friends; Dansk Kraeftforsknings Fond; Danish Agency for Science Technology and Innovation; A Race Against Breast Cancer; U.S. National Institutes of Health [CA-75362] FX The authors thank the steering committee of IBCSG for access to the BIG 1-98 data. We wish to thank "Breast Friends ", "Dansk Kraeftforsknings Fond", "Danish Agency for Science Technology and Innovation" and "A Race Against Breast Cancer" for financial support. Partial funding for BIG1-98 was provided by the U.S. National Institutes of Health, grant number CA-75362. NR 16 TC 10 Z9 11 U1 1 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PD JUL PY 2012 VL 51 IS 6 BP 781 EP 789 DI 10.3109/0284186X.2011.653009 PG 9 WC Oncology SC Oncology GA 975BB UT WOS:000306480600013 PM 22462654 ER PT J AU Baicu, CF Zhang, YH Van Laer, AO Renaud, L Zile, MR Bradshaw, AD AF Baicu, Catalin F. Zhang, Yuhua Van Laer, An O. Renaud, Ludivine Zile, Michael R. Bradshaw, Amy D. TI Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE procollagen; procollagen C-proteinase enhancer-2; fibrosis; hypertrophy ID BONE MORPHOGENETIC PROTEIN-1; FRIZZLED-RELATED PROTEIN-2; DIASTOLIC HEART-FAILURE; FIBRILLAR COLLAGEN; LEFT-VENTRICLE; RAT-HEART; EXPRESSION; GENE; INFARCTION; FIBROSIS AB Baicu CF, Zhang Y, Van Laer AO, Renaud L, Zile MR, Bradshaw AD. Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload. Am J Physiol Heart Circ Physiol 303: H234-H240, 2012. First published May 18, 2012; doi:10.1152/ajpheart.00227.2012.-Cardiac interstitial fibrillar collagen accumulation, such as that associated with chronic pressure overload (PO), has been shown to impair left ventricular diastolic function. Therefore, insight into cellular mechanisms that mediate excessive collagen deposition in the myocardium is pivotal to this important area of research. Collagen is secreted as a soluble procollagen molecule with NH2- and COOH (C)-terminal propeptides. Cleavage of these propeptides is required for collagen incorporation to insoluble collagen fibrils. The C-procollagen proteinase, bone morphogenic protein 1, cleaves the C-propeptide of procollagen. Procollagen C-endopeptidase enhancer (PCOLCE) 2, an enhancer of bone morphogenic protein-1 activity in vitro, is expressed at high levels in the myocardium. However, whether the absence of PCOLCE2 affects collagen content at baseline or after PO induced by transverse aortic constriction (TAC) has never been examined. Accordingly, in vivo procollagen processing and deposition were examined in wild-type (WT) and PCOLCE2-null mice. No significant differences in collagen content or myocardial stiffness were detected in non-TAC (control) PCOLCE2-null versus WT mice. After TAC-induced PO, PCOLCE2-null hearts demonstrated a lesser collagen content (PCOLCE2-null TAC collagen volume fraction, 0.41% +/- 0.07 vs. WT TAC, 1.2% +/- 0.3) and lower muscle stiffness compared with WT PO hearts [PCOLCE2-null myocardial stiffness (beta), 0.041 +/- 0.002 vs. WT myocardial stiffness, 0.065 +/- 0.001]. In addition, in vitro, PCOLCE2-null cardiac fibroblasts exhibited reductions in efficiency of C-propeptide cleavage, as demonstrated by increases in procollagen alpha 1(I) and decreased levels of processed collagen alpha 1(I) versus WT cardiac fibroblasts. Hence, PCOLCE2 is required for efficient procollagen processing and deposition of fibrillar collagen in the PO myocardium. These results support a critical role for procollagen processing in the regulation of collagen deposition in the heart. C1 [Bradshaw, Amy D.] Med Univ S Carolina, Dept Med, Div Cardiol, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. Vet Affairs Med Ctr, Ralph H Johnson Dept, Charleston, SC 29403 USA. RP Bradshaw, AD (reprint author), Med Univ S Carolina, Dept Med, Div Cardiol, Gazes Cardiac Res Inst, 114 Doughty St,Rm 223 Gazes Strom Thurmond Res Bl, Charleston, SC 29425 USA. EM bradshad@musc.edu FU Research Service of the Department of Veterans Affairs; National Institutes of Health [PO1-HL-48788, HL-094517, P20-RR-017696] FX This study was supported by the Research Service of the Department of Veterans Affairs (to M. R. Zile and A. D. Bradshaw) and National Institutes of Health Grants PO1-HL-48788 (to M. R. Zile), HL-094517 (to A. D. Bradshaw), and P20-RR-017696 (to A. D. Bradshaw). NR 27 TC 16 Z9 16 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2012 VL 303 IS 2 BP H234 EP H240 DI 10.1152/ajpheart.00227.2012 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 974JD UT WOS:000306429900011 PM 22610170 ER PT J AU Kentsis, A Ahmed, S Kurek, K Brennan, E Bradwin, G Steen, H Bachur, R AF Kentsis, Alex Ahmed, Saima Kurek, Kyle Brennan, Eileen Bradwin, Gary Steen, Hanno Bachur, Richard TI Detection and Diagnostic Value of Urine Leucine-Rich alpha-2-Glycoprotein in Children With Suspected Acute Appendicitis SO ANNALS OF EMERGENCY MEDICINE LA English DT Article AB Study objective: Previously, we used a proteomics approach for the discovery of new diagnostic markers of acute appendicitis and identified leucine-rich alpha-2-glycoprotein (LRG) that was elevated in the urine of children with acute appendicitis and enriched in diseased appendices. Here, we sought to evaluate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) of urine LRG in a blinded, prospective, cohort study of children being evaluated for acute abdominal pain. Methods: Urine LRG concentration was measured with a commercially available LRG ELISA and selected ion monitoring mass spectrometry. Urine LRG test performance was evaluated blindly against the pathologic diagnosis and histologic grade of appendicitis. Results: Urine LRG was measured in 49 patients. Mean urine LRG concentration measured with commercial LRG ELISA was significantly elevated in patients with acute appendicitis but exhibited an interference effect. Direct measurements using selected ion monitoring mass spectrometry demonstrated that LRG was elevated more than 100-fold in patients with acute appendicitis compared with those without, with the receiver operating characteristic area under the curve of 0.98 (95% confidence interval 0.96 to 1.0). Among patients with acute appendicitis, elevations of urine LRG measured with ELISA and selected ion monitoring mass spectrometry correlated with the histologic severity of appendicitis. Conclusion: Urine LRG ELISA allows for discrimination between patients with and without acute appendicitis but exhibits limited accuracy because of immunoassay interference. Direct measurements of urine LRG with selected ion monitoring mass spectrometry demonstrate superior diagnostic performance. Development of a clinical-grade urine LRG assay is needed to advance the diagnostic accuracy of clinical evaluations of appendicitis. [Ann Emerg Med. 2012;60:78-83.] C1 [Bachur, Richard] Harvard Univ, Sch Med, Dept Med, Div Emergency Med,Childrens Hosp Boston, Boston, MA 02115 USA. [Kentsis, Alex] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Childrens Hosp Boston, Boston, MA 02115 USA. [Kentsis, Alex] Harvard Univ, Sch Med, Dept Med, Div Hematol Oncol,Childrens Hosp Boston, Boston, MA USA. [Kentsis, Alex; Ahmed, Saima; Steen, Hanno] Harvard Univ, Sch Med, Childrens Hosp Boston, Prote Ctr, Boston, MA USA. [Kurek, Kyle; Steen, Hanno] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Pathol, Boston, MA USA. [Brennan, Eileen; Bradwin, Gary] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Lab Med, Boston, MA USA. RP Bachur, R (reprint author), Harvard Univ, Sch Med, Dept Med, Div Emergency Med,Childrens Hosp Boston, Boston, MA 02115 USA. EM hanno.steen@childrens.harvard.edu; richard.bachur@childrens.harvard.edu OI Kentsis, Alex/0000-0002-8063-9191 FU Children's Hospital Boston Technology and Innovation Development Office; Children's Hospital Boston Clinical Research Program; Harvard Catalyst/The Harvard Clinical and Translational Science Center [UL1 RR 025758] FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. This research was funded by the Children's Hospital Boston Technology and Innovation Development Office and supported by the Children's Hospital Boston Clinical Research Program and Harvard Catalyst/The Harvard Clinical and Translational Science Center (UL1 RR 025758). NR 10 TC 18 Z9 18 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD JUL PY 2012 VL 60 IS 1 BP 78 EP 83 DI 10.1016/j.annemergmed.2011.12.015 PG 6 WC Emergency Medicine SC Emergency Medicine GA 975HQ UT WOS:000306501700015 PM 22305331 ER PT J AU Kimball, AB AF Kimball, Alexa Boer TI Sex, Academics, and Dermatology Leadership Progress Made, but No More Excuses SO ARCHIVES OF DERMATOLOGY LA English DT Editorial Material ID WORKFORCE; MENTORSHIP; RESIDENTS; SURGERY C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Kimball, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, 50 Staniford St,Ste 240, Boston, MA 02114 USA. NR 19 TC 2 Z9 2 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2012 VL 148 IS 7 BP 844 EP 846 PG 3 WC Dermatology SC Dermatology GA 974FT UT WOS:000306417100016 PM 22801620 ER PT J AU Berry, D AF Berry, D. TI DECISION SUPPORT FOR PROSTATE CANCER TREATMENT SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Berry, D.] Dana Farber Canc Inst, Boston, MA 02115 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 1743-7555 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD JUL PY 2012 VL 8 SU 1 SI SI BP 23 EP 23 DI 10.1111/j.1743-7563.2012.01573_7.x PG 1 WC Oncology SC Oncology GA 975JJ UT WOS:000306507300007 ER PT J AU Berry, D AF Berry, D. TI QOL FOR INTERMITTENT ANDROGEN DEPRIVATION THERAPY SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Berry, D.] Dana Farber Canc Inst, Boston, MA 02115 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 1743-7555 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD JUL PY 2012 VL 8 SU 1 SI SI BP 25 EP 25 PG 1 WC Oncology SC Oncology GA 975JJ UT WOS:000306507300020 ER PT J AU Li, TH Guo, MY Gradishar, WJ Sparano, JA Perez, EA Wang, ML Sledge, GW AF Li, Tianhong Guo, Mengye Gradishar, William J. Sparano, Joseph A. Perez, Edith A. Wang, Molin Sledge, George W. TI A phase II trial of capecitabine in combination with the farnesyltransferase inhibitor tipifarnib in patients with anthracycline-treated and taxane-resistant metastatic breast cancer: an Eastern Cooperative Oncology Group Study (E1103) SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Farnesyltransferase inhibitor; Tipifarnib; Capecitabine; Metastatic breast cancer ID IXABEPILONE PLUS CAPECITABINE; TRANSFERASE INHIBITOR; SOLID TUMORS; EFFICACY; MULTICENTER; SURVIVAL; LEUKEMIA; THERAPY; R115777 AB Capecitabine produces an objective response rate of up to 25 % in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib-capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m(2) twice daily plus oral tipifarnib 300 mg twice daily on days 1-14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40 %. Among 63 eligible, partial response occurred in six patients (9.5 %; 90 % CI 4.2-17.9 %), median progression-free survival was 2.6 months (95 % CI 2.1-4.4), and median overall survival was 11.4 months (95 % CI 7.7-14.0). Dose modifications were required for 43 patients (68 %) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44 %; 90 % CI 44.4-67.0 %) and 11 patients (16 %; 90 % CI 10.8-29.0 %), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib-capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy. C1 [Li, Tianhong; Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Guo, Mengye; Wang, Molin] Dana Farber Canc, Boston, MA USA. [Gradishar, William J.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Sledge, George W.] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. RP Li, TH (reprint author), Univ Calif Davis, Ctr Canc, Div Hematol & Oncol, 4501 X St,Suite 3016, Sacramento, CA 95817 USA. EM tianhong.li@ucdmc.ucdavis.edu FU Public Health Service [CA23318, CA66636, CA21115, CA14958, CA17145, CA49883, CA25224]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; National Center for Research Resources [UL1 RR024146] FX This study was conducted by the ECOG (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318 (to the EGOG statistical center), CA66636 (to the ECOG data management center), CA21115 (to the ECOG coordinating center), CA14958 (to Albert Einstein College of Medicine), CA17145 (to Northwestern University Medical Center), CA49883 (to Indiana University Medical Center), CA25224 (to NCCTG) and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. TL is also supported by UL1 RR024146 from the National Center for Research Resources. NR 27 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2012 VL 134 IS 1 BP 345 EP 352 DI 10.1007/s10549-012-2071-z PG 8 WC Oncology SC Oncology GA 974LS UT WOS:000306437500035 PM 22547107 ER PT J AU Cortesi, L De Nicolo, A Medici, V Marino, M Turchetti, D Pradella, LM Rossi, G Parisini, E Federico, M AF Cortesi, Laura De Nicolo, Arcangela Medici, Veronica Marino, Marco Turchetti, Daniela Pradella, Laura Maria Rossi, Giulio Parisini, Emilio Federico, Massimo TI Collective evidence supports neutrality of BRCA1 V1687I, a novel sequence variant in the conserved THV motif of the first BRCT repeat SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE BRCA1; BRCT domain; Variants of uncertain significance; Triple negative breast cancer ID UNKNOWN CLINICAL-SIGNIFICANCE; INTERACT IN-VIVO; BREAST-CANCER; UNCERTAIN SIGNIFICANCE; PROTEIN; MUTATION; CLASSIFICATION; DOMAIN; CTIP AB Unambiguous classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) is a challenging task that vexes health care providers and has profound implications for patients and their family members. Numerous VUS have been described to date, which await assessment of their functional, hence clinical, impact. As a result of a routine BRCA1/BRCA2 mutational screening, we identified a previously unreported BRCA1 sequence alteration [c.5178G > A (V1687I)] in a patient diagnosed with early onset triple negative breast cancer. The sequence alteration falls in the invariant THV motif of the BRCT domain. To investigate its significance, we applied an integrated approach that, in addition to genetic and histopathological data, included in silico analyses, comparative structural modeling and verification of BRCT-mediated interactions. In line with web-based algorithms that predicted the benign nature of BRCA1 V1687I, the three-dimensional model of the BRCA1 V1687I BRCT domain did not reveal any major structural changes relative to its wild-type counterpart, thus suggesting that BRCA1 V1687I has a negligible impact on both the local architecture and the overall stability of the protein. Consistently, the BRCA1 V1687I protein was properly expressed and localized to the nucleus, and it was still capable of binding three BRCT-interacting, DNA damage response, and repair partner proteins, namely BRIP1/FANCJ, CtIP, and Abraxas. Our collected evidence suggests that, although occurring in a highly conserved region, the BRCA1 V1687I variant is likely a benign sequence alteration. C1 [Cortesi, Laura; Medici, Veronica; Federico, Massimo] Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, I-41100 Modena, Italy. [De Nicolo, Arcangela] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [De Nicolo, Arcangela] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Marino, Marco] Univ Modena & Reggio Emilia, Dept Biomed Sci, I-41100 Modena, Italy. [Turchetti, Daniela; Pradella, Laura Maria] Univ Bologna, Med Genet Serv, I-40126 Bologna, Italy. [Rossi, Giulio] Univ Modena & Reggio Emilia, Dept Lab Diagnost, I-41100 Modena, Italy. [Parisini, Emilio] Ist Italiano Tecnol, Ctr Nano Sci & Technol PoliMi, I-20133 Milan, Italy. RP Cortesi, L (reprint author), Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, Via Pozzo 71, I-41100 Modena, Italy. EM hbc@unimo.it; Arcangela_Denicolo@dfci.harvard.edu RI Turchetti, Daniela/A-2794-2013; Federico, Massimo/J-5984-2014; Federico, Massimo/A-6801-2012; Rossi, Giulio/K-6217-2016; OI Federico, Massimo/0000-0002-5074-3262; Federico, Massimo/0000-0002-9889-3796; Rossi, Giulio/0000-0001-8855-1218; Marino, Marco/0000-0002-7470-7493; Turchetti, Daniela/0000-0002-6792-3921; Rossi, Antonio/0000-0003-3295-0345 FU Dana-Farber Cancer Institute, Boston, MA, USA; Ministero dell'Istruzione, dell'Universita' e della Ricerca (MIUR) [2008RFCMH]; Associazione Angela Serra per la Ricerca sul Cancro FX We are grateful to the patients and their families for their collaboration. A.D.N. wishes to thank Dr. D. M. Livingston (Dana-Farber Cancer Institute, Boston, MA, USA) for financial support, Dr. V. Joukov (Dana-Farber Cancer Institute, Boston, MA, USA) for helpful discussions, and Dr. C. Colin (Dana-Farber Cancer Institute, Boston, MA, USA) for assistance with cell irradiation experiments. This work was, in part, supported by a PRIN 2008 grant (2008RFCMH) from the Ministero dell'Istruzione, dell'Universita' e della Ricerca (MIUR) and by funds from the Associazione Angela Serra per la Ricerca sul Cancro. NR 25 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2012 VL 134 IS 1 BP 435 EP 441 DI 10.1007/s10549-012-2052-2 PG 7 WC Oncology SC Oncology GA 974LS UT WOS:000306437500045 PM 22527099 ER PT J AU Freeman, MP AF Freeman, Marlene P. TI Complementary and Alternative Medicine for Psychiatrists SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Editorial Material ID DIETARY PATTERN; ASSOCIATION; DEPRESSION C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Womens Mental Hlth, Perinatal & Reprod Psychiat Clin Res Program, Boston, MA 02114 USA. RP Freeman, MP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Womens Mental Hlth, Perinatal & Reprod Psychiat Clin Res Program, 185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM mfreeman@partners.org NR 9 TC 1 Z9 1 U1 0 U2 3 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD JUL PY 2012 VL 57 IS 7 BP 395 EP 396 PG 2 WC Psychiatry SC Psychiatry GA 976XX UT WOS:000306621800001 PM 22762293 ER PT J AU Wu, JM Yeung, AS Schnyer, R Wang, YF Mischoulon, D AF Wu, Junmei Yeung, Albert S. Schnyer, Rosa Wang, Yunfei Mischoulon, David TI Acupuncture for Depression: A Review of Clinical Applications SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE acupuncture; depression; augmentation; antidepressants; nonresponse; effectiveness; side effect; adverse events ID RANDOMIZED-CONTROLLED-TRIAL; STAR-ASTERISK-D; NATIONAL-COMORBIDITY-SURVEY; MAJOR DEPRESSION; ERECTILE DYSFUNCTION; DISORDER; ELECTROACUPUNCTURE; SYMPTOMS; THERAPY; PRACTITIONERS AB While increasing numbers of patients are seeking acupuncture treatment for depression in recent years, there is limited evidence of the antidepressant (AD) effectiveness of acupuncture. Given the unsatisfactory response rates of many Food and Drug Administration-approved ADs, research on acupuncture remains of potential value. Therefore, we sought to review the efficacy and safety of acupuncture treatment for depression in clinical applications. We conducted a PubMed search for publications through 2011. We assessed the adequacy of each report and abstracted information on reported effectiveness or efficacy of acupuncture as monotherapy for major depressive disorder (MDD) and as augmentation of ADs. We also examined adverse events associated with acupuncture, and evidence for acupuncture as a means of reducing side effects of ADs. Published data suggest that acupuncture, including manual-, electrical-, and laser-based, is a generally beneficial, well-tolerated, and safe monotherapy for depression. However, acupuncture augmentation in AD partial responders and nonresponders is not as well studied as monotherapy; and available studies have only investigated MDD, but not other depressive spectrum disorders. Manual acupuncture reduced side effects of ADs in MDD. We found no data on depressive recurrence rates after recovery with acupuncture treatment. Acupuncture is a potential effective monotherapy for depression, and a safe, well-tolerated augmentation in AD partial responders and nonresponders. However, the body of evidence based on well-designed studies is limited, and further investigation is called for. C1 [Yeung, Albert S.; Mischoulon, David] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Wu, Junmei] Massachusetts Gen Hosp, Neural Syst Grp, Boston, MA 02114 USA. [Wu, Junmei] Chengdu Univ Tradit Chinese Med, Sichuan, Peoples R China. [Yeung, Albert S.; Mischoulon, David] Harvard Univ, Sch Med, Boston, MA USA. [Schnyer, Rosa] Univ Texas Austin, Austin, TX 78712 USA. [Wang, Yunfei] Taizhou Hosp Tradit Chinese Med, Taizhou, Jiangsu, Peoples R China. RP Mischoulon, D (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM dmischoulon@partners.org FU revenues of the Massachusetts General Hospital Depression Clinical and Research Program FX The work related to this paper was funded by the revenues of the Massachusetts General Hospital Depression Clinical and Research Program. No external funds were used. NR 97 TC 27 Z9 27 U1 1 U2 11 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD JUL PY 2012 VL 57 IS 7 BP 397 EP 405 PG 9 WC Psychiatry SC Psychiatry GA 976XX UT WOS:000306621800002 PM 22762294 ER PT J AU Papakostas, GI Cassiello, CF Iovieno, N AF Papakostas, George I. Cassiello, Clair F. Iovieno, Nadia TI Folates and S-Adenosylmethionine for Major Depressive Disorder SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE major depressive disorder; S-adenosylmethionine; folate; L-methylfolate; antidepressant therapy; augmentation therapy ID ADENOSYL-L-METHIONINE; SEROTONIN REUPTAKE INHIBITORS; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND MULTICENTER; ONE-CARBON METABOLISM; FOLIC-ACID; PSYCHIATRIC-DISORDERS; RESISTANT-DEPRESSION; MONOAMINE METABOLISM AB Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased significantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efficacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium. C1 [Papakostas, George I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Treatment Resistant Depress,Dept Psychiat, Boston, MA 02114 USA. [Cassiello, Clair F.; Iovieno, Nadia] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Treatment Resistant Depress,Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 FU AstraZeneca PLC; Bristol-Myers Squibb Company; Forest Pharmaceuticals; National Institute of Mental Health; PAMLAB LLC; Pfizer Inc; Ridge Diagnostics FX Dr Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc, Dey Pharma, LP, Eli Lilly Co, GlaxoSmithKline, Evotec AG, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Theracos, Inc, and Wyeth, Inc. He has received honoraria from Abbott Laboratories, Astra Zeneca PLC, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc, Dey Pharma, LP, Eli Lilly Co, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Theracos, Inc, Titan Pharmaceuticals, and Wyeth Inc, and he has received research support from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc, and Ridge Diagnostics (formerly known as Precision Human Biolaboratories). Finally, Dr Papakostas has served (in the past, but not currently) on the speaker's bureau for BristolMyersSquibb Co and Pfizer, Inc. NR 90 TC 38 Z9 38 U1 0 U2 18 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD JUL PY 2012 VL 57 IS 7 BP 406 EP 413 PG 8 WC Psychiatry SC Psychiatry GA 976XX UT WOS:000306621800003 PM 22762295 ER PT J AU Franceschi, AM Matthews, R Mankes, S Safaie, E Franceschi, D AF Franceschi, Ana M. Matthews, Robert Mankes, Seth Safaie, Elham Franceschi, Dinko TI Four Chamber FDG Uptake in the Heart An Indirect Sign of Pulmonary Embolism SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE FDG; PET/CT; pulmonary embolism ID POSITRON-EMISSION-TOMOGRAPHY; PET; HYPERTENSION; DISEASE AB A 57-year-old-male presented for whole-body PET with CT for restaging of lung cancer. Besides revealing postradiation changes, we noticed an unusual pattern of FDG uptake in the myocardium, with prominent metabolic uptake involving 4 chambers of the heart. Later that day, the patient was referred to the emergency department for increased heart rate, but otherwise asymptomatic. CT angiography was performed, which showed scattered filling defects in bilateral pulmonary arteries consistent with pulmonary embolism. The finding of prominent FDG uptake involving all cardiac chambers in this patient is likely related to heart strain caused by acute pulmonary embolism. C1 [Franceschi, Dinko] SUNY Stony Brook, Med Ctr, Hlth Sci Ctr, Dept Radiol, Stony Brook, NY 11794 USA. [Franceschi, Ana M.] Harvard Univ, Sch Med, Boston, MA USA. [Franceschi, Ana M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Franceschi, D (reprint author), SUNY Stony Brook, Med Ctr, Hlth Sci Ctr, Dept Radiol, Level 4,Rm 120, Stony Brook, NY 11794 USA. EM dinko.franceschi@stonybrook.edu OI Franceschi, Ana/0000-0003-2577-9738 NR 11 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2012 VL 37 IS 7 BP 687 EP 691 DI 10.1097/RLU.0b013e31824c5e64 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 959DE UT WOS:000305290900019 PM 22691515 ER PT J AU Gagnon, C Aime, A Belanger, C Markowitz, JT AF Gagnon, Cynthia Aime, Annie Belanger, Claude Markowitz, Jessica Tuttman TI Comorbid Diabetes and Eating Disorders in Adult Patients Assessment and Considerations for Treatment SO DIABETES EDUCATOR LA English DT Article ID BULIMIA-NERVOSA; YOUNG-WOMEN; INSULIN OMISSION; ADOLESCENT FEMALES; MELLITUS; BEHAVIOR; PSYCHOEDUCATION; POPULATION; THERAPY; GIRLS AB Purpose The lack of research concerning treatment for individuals with diabetes mellitus (DM) and comorbid eating disorders (ED) contributes to the gulf between the psychosocial needs of individuals with the two conditions and the treatment they receive. Empirical evidence has established that the prognosis of patients with this comorbid diagnosis (ED-DM) is poor in the absence of a specialized DM treatment specifically adapted to ED. In individuals with DM, comorbid ED is associated with numerous complications. Despite these interactions, current knowledge about the comorbid diagnosis is limited, and eating disorders in patients with diabetes often remain undiagnosed. This article presents standard procedures for assessment and optimal therapeutic interventions for patients with ED and DM. Conclusion In patients with diabetes, problematic eating behaviors and symptoms should be assessed routinely. When an eating disorder is detected, diabetes management needs to be adapted, binge eating or medication misuse needs to be addressed, and eating disorder specialists should be included in the multidisciplinary team. C1 [Aime, Annie] Univ Quebec Outaouais, Dept Psychoeduc & Psychol, St Jerome, PQ J7Z 0B7, Canada. [Gagnon, Cynthia] Univ Quebec, Dept Psychol, Montreal, PQ H3C 3P8, Canada. [Belanger, Claude] Douglas Mental Hlth Inst, Montreal, PQ, Canada. [Belanger, Claude] McGill Univ, Dept Psychol, Montreal, PQ, Canada. [Markowitz, Jessica Tuttman] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. RP Aime, A (reprint author), Univ Quebec Outaouais, Dept Psychoeduc & Psychol, Campus St Jerome,5 Rue St Joseph, St Jerome, PQ J7Z 0B7, Canada. EM annie.aime@uqo.ca NR 54 TC 10 Z9 10 U1 3 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL-AUG PY 2012 VL 38 IS 4 BP 537 EP 542 DI 10.1177/0145721712446203 PG 6 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 976AX UT WOS:000306554000007 PM 22585871 ER PT J AU Moita, CF Chora, A Hacohen, N Moita, LF AF Moita, Catarina F. Chora, Angelo Hacohen, Nir Moita, Luis F. TI RNAi screen for kinases and phosphatases that play a role in antigen presentation by dendritic cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Antigen cross-presentation; Dendritic cells; Kinases; Phosphatases; RNA interference ID CROSS-PRESENTATION; RECEPTOR ALK7; EXPRESSION; VECTOR AB Effective CD8+ T-cell responses against tumor or microbial antigens that are not directly expressed in antigen-presenting cells (APCs) depend on the cross-presentation of these antigens on MHC class I in APCs. To identify signaling molecules that regulate cross-presentation, we used lentiviral-based RNA interference to test the roles of hundreds of kinases and phosphatases in this process. Our study uncovered eight previously unknown genes, consisting of one positive and seven negative regulators of antigen cross-presentation. Depletion of Acvr1c, a type I receptor for TGF-beta family of signaling molecules, led to an increase in CD80 and CD86 co-stimulator surface expression and secreted IL-12 in mouse bone marrow-derived DCs, as well as antigen-specific T-cell proliferation. C1 [Moita, Luis F.] Univ Lisbon, Fac Med, Cell Biol Immune Syst Unit, Inst Mol Med, P-1649028 Lisbon, Portugal. [Hacohen, Nir] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Hacohen, Nir] Harvard Univ, Sch Med, Boston, MA USA. [Hacohen, Nir] Broad Inst & Harvard, Cambridge, MA USA. RP Moita, LF (reprint author), Univ Lisbon, Fac Med, Cell Biol Immune Syst Unit, Inst Mol Med, Edificio Egas Moniz,Av Prof Egas Moniz, P-1649028 Lisbon, Portugal. EM lmoita@fm.ul.pt RI Moita, Luis/L-1296-2013; OI Moita, Luis/0000-0003-0707-315X; Ferreira Chora, Angelo/0000-0002-7941-7196; Ferreira Moita, Catarina/0000-0002-9910-2343 FU Fundacao para a Ciencia e Tecnologia [PIC/IC/82991/2007, PTDC/SAU-MII/100780/2008, PTDC/SAU-IMU/110303/2009]; Fundacao Luso-Americana para o Desenvolvimento; Human Frontier Science Program FX This work was supported by Fundacao para a Ciencia e Tecnologia (PIC/IC/82991/2007, PTDC/SAU-MII/100780/2008, and PTDC/SAU-IMU/110303/2009), Fundacao Luso-Americana para o Desenvolvimento, and the Human Frontier Science Program. NR 21 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2012 VL 42 IS 7 BP 1843 EP 1849 DI 10.1002/eji.201142167 PG 7 WC Immunology SC Immunology GA 975FN UT WOS:000306493100022 PM 22585713 ER PT J AU Chang, H Biswas, S Tallarico, AS Sarkis, PTN Geng, S Panditrao, MM Zhu, Q Marasco, WA AF Chang, H. Biswas, S. Tallarico, A. S. Sarkis, P. T. N. Geng, S. Panditrao, M. M. Zhu, Q. Marasco, W. A. TI Human B-cell ontogeny in humanized NOD/SCID gamma c(null) mice generates a diverse yet auto/poly- and HIV-1-reactive antibody repertoire SO GENES AND IMMUNITY LA English DT Article DE humanized mouse; single B cell; antibody repertoire; autoreactive; checkpoint control ID HUMAN MONOCLONAL-ANTIBODIES; GENE REPLACEMENT; AUTOANTIBODY PRODUCTION; IMMUNE-RESPONSES; CORD BLOOD; HIV-1; EXPRESSION; AUTOREACTIVITY; SELECTION; POLYSPECIFICITY AB Characterization of the human antibody (Ab) repertoire in mouse models of the human immune system is essential to establish their relevance in translational studies. Single human B cells were sorted from bone marrow and periphery of humanized NOD/SCID gamma c(null) (hNSG) mice at 8-10 months post engraftment with human cord blood-derived CD34(+) stem cells. Human IG variable heavy (V-H) and kappa (V-kappa) genes were amplified, cognate V-H-V-kappa gene-pairs assembled as single-chain variable fragment-Fc Abs (scFvFcs) and functional studies were performed. Although overall distribution of V-H genes approximated the normal human Ab repertoire, analysis of the V-H-third complementarity-determining regions in the mature B-cell subset demonstrated an increase in length and positive charges, suggesting autoimmune characteristics. Additionally, >70% of V-kappa sequences utilized V(kappa)4-1, a germline gene associated with autoimmunity. The mature B-cell subset-derived scFvFcs displayed the highest frequency of autoreactivity and polyspecificity, suggesting defects in checkpoint control mechanisms. Furthermore, these scFvFcs demonstrated binding to recombinant HIV envelope corroborating previous observations of poly/autoreactivity in anti-HIVgp140 Abs. These data lend support to the hypothesis that anti-HIV broadly neutralizing antibodies may be derived from auto/polyspecific Abs that escaped immune elimination and that the hNSG mouse could provide a new experimental platform for studying the origin of anti-HIV-neutralizing Ab responses. C1 [Chang, H.; Biswas, S.; Tallarico, A. S.; Sarkis, P. T. N.; Geng, S.; Panditrao, M. M.; Zhu, Q.; Marasco, W. A.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Chang, H.; Biswas, S.; Tallarico, A. S.; Sarkis, P. T. N.; Geng, S.; Panditrao, M. M.; Zhu, Q.; Marasco, W. A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Marasco, WA (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, JFB824, Boston, MA 02215 USA. EM wayne_marasco@dfci.harvard.edu FU NIH [R21 AI091557, UO1 AI0070343]; National Foundation for Cancer Research; Center For AIDS Research at Harvard University (CFAR-HU) FX We thank the staff at the Animal Research Facility at Dana-Farber Cancer Institute (DFCI) for excellent maintenance and mice handling and Michael Waring at the Flow Cytometry core facility at Ragon Institute, Massachusetts General Hospital, Charlestown, MA, USA, for assistance with single B-cell sorting. Biostatistical computations performed by Amany Awad and the DFCI Biostatistical Core service (Sandra Lee and Yang Feng), technical guidance from Islay Campbell, ForteBio and assistance from Raymond Moniz of the Marasco Laboratory with the preparation of figures are appreciated. The HIV envelope reactive monoclonal antibodies (4E10 from Hermann Katinger and b12 from Dennis Burton) were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH (Germantown, MD, USA). This work was partially supported by NIH grants R21 AI091557 and UO1 AI0070343 to WAM Financial support provided by the National Foundation for Cancer Research to the Center for Therapeutic Antibody Engineering at DFCI (NFCR-CTAE) is acknowledged. Research support by the Center For AIDS Research at Harvard University (CFAR-HU) is also acknowledged. NR 52 TC 15 Z9 15 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL-AUG PY 2012 VL 13 IS 5 BP 399 EP 410 DI 10.1038/gene.2012.16 PG 12 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 976MA UT WOS:000306587600005 PM 22592523 ER PT J AU Scheuner, MT Hilborne, L Brown, J Lubin, IM AF Scheuner, Maren T. Hilborne, Lee Brown, Julie Lubin, Ira M. CA RAND Mol Genetic Test Report Advis TI A Report Template for Molecular Genetic Tests Designed to Improve Communication Between the Clinician and Laboratory SO GENETIC TESTING AND MOLECULAR BIOMARKERS LA English DT Article ID CANCER-RISK; MEDICINE; GUIDELINES; PHYSICIANS; ERRORS; EXPERIENCE; DISEASE; HEALTH AB Aim: Errors are most likely to occur during the pre- and postanalytic phases of the genetic testing process, which can contribute to underuse, overuse, and misuse of genetic tests. To mitigate these errors, we created a template for molecular genetic test reports that utilizes the combined features of synoptic reporting and narrative interpretation. Methods: A variation of the Delphi consensus process with an expert panel was used to create a draft report template, which was further informed by focus group discussions with primary care physicians. Results: There was agreement that molecular genetic test reports should present information in groupings that flow in a logical manner, and most participants preferred the following order of presentation: patient and physician information, test performed, test results and interpretation, guidance on next steps, and supplemental information. We define data elements for the report as "required," "optional," "possible," and "not necessary"; provide recommendations regarding the grouping of these data elements; and describe the ideal design of the report template, including the preferred order of the report sections, formatting of data, and length of the report. Discussion: With input from key stakeholders and building upon prior work, we created a template for molecular genetic test reports designed to improve clinical decision making at the point of care. The template design should lead to more effective communication between the laboratory and ordering clinician. Studies are needed to assess the usefulness and effectiveness of molecular genetic test reports generated using this template. C1 [Scheuner, Maren T.] Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Scheuner, Maren T.; Hilborne, Lee; Brown, Julie] RAND Corp, Santa Monica, CA USA. [Scheuner, Maren T.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Hilborne, Lee] Quest Diagnost, Canoga Pk, CA USA. [Hilborne, Lee] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Lubin, Ira M.] Ctr Dis Control & Prevent, Div Lab Sci & Stand, Atlanta, GA USA. RP Scheuner, MT (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 500,Room 3218, Los Angeles, CA 90073 USA. EM maren.scheuner@va.gov OI Weck, Karen/0000-0002-8516-333X NR 28 TC 14 Z9 15 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1945-0265 J9 GENET TEST MOL BIOMA JI Genet. Test. Mol. Biomark. PD JUL PY 2012 VL 16 IS 7 BP 761 EP 769 DI 10.1089/gtmb.2011.0328 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 974ZB UT WOS:000306475100021 PM 22731646 ER PT J AU Courtwright, A AF Courtwright, Andrew TI Who Is "Too Sick to Benefit"? SO HASTINGS CENTER REPORT LA English DT Article ID INTENSIVE-CARE-UNIT; INTERVENTION SCORING SYSTEM; CANCER-PATIENTS; BEGETS LETHALITY; CARDIAC-ARREST; ICU; MULTICENTER; MANAGEMENT; ADMISSION; TRISOMY-18 AB A significant number of patients are refused admission to the intensive care unit because physicians believe they are too sick to benefit from ICU care. Criteria for inclusion in this category are murky, though. We can illuminate them by borrowing the concept of a "lethal" disease from neonatal medicine. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Courtwright, A (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 33 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JUL-AUG PY 2012 VL 42 IS 4 BP 41 EP 47 DI 10.1002/hast.51 PG 7 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 971DL UT WOS:000306183800017 PM 22777978 ER PT J AU Kambadakone, A Arasu, VA Samir, AE Eisner, BH Kulkarni, NM Hahn, PF Sahani, DV AF Kambadakone, Avinash Arasu, Vignesh A. Samir, Anthony E. Eisner, Brian H. Kulkarni, Naveen M. Hahn, Peter F. Sahani, Dushyant V. TI Qualitative Assessment of Enhancement in a Renal Mass: Contribution of Subtraction CT SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE renal mass; MDCT; subtraction; enhancement ID CYST PSEUDOENHANCEMENT; IMAGE SUBTRACTION; CELL CARCINOMA; PHANTOM AB Purpose: To evaluate the impact of subtraction CT on reader confidence and diagnostic accuracy when characterizing renal masses. Materials and Methods: In this institutional review board-approved retrospective study, 159 patients (85 men and 74 women; mean age, 62.6 years; range, 22-88 years) underwent routine unenhanced and contrast-enhanced multidetector computed tomography (MDCT) for renal lesion characterization. Subtraction images were subsequently generated on scanner console. Two readers independently reviewed the MDCT images to characterize presence of enhancement using a 6-point scale during 3 blinded review sessions of (1) only subtraction, (2) routine, and (3) combined subtraction and routine images. The standard of reference consisted of either histopathology or follow-up imaging and clinical data. Results: Of the 240 lesions evaluated, 60 lesions (mean, 3.2 cm; range, 1-7.5 cm) were enhancing and 180 lesions (mean, 2.7 cm; range, 0.5-12 cm) were nonenhancing. For determination of lesion enhancement, a combined evaluation of routine MDCT and subtraction images improved reader confidence in 60% to 63% of lesions (P < 0.001). The combined evaluation also provided the highest sensitivity (97%), specificity (99%), and accuracy (98.9%). Conclusion: When used in combination with routine image interpretation, subtraction CT improves reader confidence and diagnostic accuracy in identifying enhancement in renal lesions. C1 [Kambadakone, Avinash; Arasu, Vignesh A.; Samir, Anthony E.; Kulkarni, Naveen M.; Hahn, Peter F.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Imaging, Boston, MA 02114 USA. [Eisner, Brian H.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Imaging, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org OI Samir, Anthony/0000-0002-7801-8724 NR 22 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD JUL-AUG PY 2012 VL 36 IS 4 BP 381 EP 387 DI 10.1097/RCT.0b013e318256b1ba PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 976DZ UT WOS:000306562200004 PM 22805664 ER PT J AU Uomoto, JM AF Uomoto, Jay M. TI Best Practices in Veteran Traumatic Brain Injury Care Preface SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER C1 US Dept Vet Affairs, Off Mental Hlth Serv, Washington, DC USA. RP Uomoto, JM (reprint author), US Dept Vet Affairs, Off Mental Hlth Serv, Washington, DC USA. NR 9 TC 1 Z9 1 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-9701 J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD JUL-AUG PY 2012 VL 27 IS 4 BP 241 EP 243 DI 10.1097/HTR.0b013e31825ee26a PG 3 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 975PJ UT WOS:000306523000001 PM 22767071 ER PT J AU Williams, RM Bambara, J Turner, AP AF Williams, Rhonda M. Bambara, Jennifer Turner, Aaron P. TI A Scoping Study of One-to-One Peer Mentorship Interventions and Recommendations for Application With Veterans With Postdeployment Syndrome SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Article DE mutual support; OIF/OEF; peer mentorship; polytrauma; postdeployment syndrome; Veterans ID RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC BRAIN-INJURY; QUALITY-OF-LIFE; SELF-EFFICACY; PROVIDED SERVICES; MENTORING PROGRAM; SUPPORT PROGRAM; SOCIAL SUPPORT; BREAST-CANCER; CARE AB Background: We employ the term postdeployment syndrome (PDS) to characterize the combinations of physical, psychological, and social difficulties frequently encountered by Veterans returning from combat. Objectives: To conduct a scoping review to identify and describe one-to-one peer mentorship (PM) interventions, identify elements associated with positive outcome and of relevance to Veterans with PDS, and summarize current practice in a way that informs the development of such interventions for this population. Methods: Scoping review methodology was used to identify and summarize key practices and concepts in the one-to-one PM literature between 1980 and 2012. Of 196 articles initially identified, 33 were retained for further examination. Eighteen met full-study criteria and were retained in the analyses. Three reviewers reached consensus on articles to include, and 2 coders independently extracted information from each article. Results: A range of populations was targeted in the interventions. Most identified the provision of support as the primary goal, although some also included other educational and behavioral goals. Most employed selection and training strategies for their mentors and offered ongoing supervision and consultation. Most studies indicated that participants found PM to be beneficial. Conclusions: This review supports the application in this population and proposes next steps for the development and systematic evaluation of PM interventions. C1 [Williams, Rhonda M.] VA Puget Sound Hlth Care Syst, Dept Rehabil Med, Rehabil Care Serv, Seattle, WA 98108 USA. [Williams, Rhonda M.; Turner, Aaron P.] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. RP Williams, RM (reprint author), VA Puget Sound Hlth Care Syst, Dept Rehabil Med, Rehabil Care Serv, S-117 RCS,1660 S Columbian Way, Seattle, WA 98108 USA. EM Rhonda.Williams1@va.gov OI Turner, Aaron/0000-0001-6897-8003 FU US Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Polytrauma and Blast-Related QUERI [07-289, 09-134]; Langeloth Foundation; US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development [B4927W] FX This material is based upon the work supported by the US Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Polytrauma and Blast-Related QUERI (RRP # 07-289 and RRP # 09-134; Dr Williams, PI), the Langeloth Foundation, and by the US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development (Career Development Award B4927W; Dr Turner, PI). NR 53 TC 4 Z9 4 U1 5 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-9701 J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD JUL-AUG PY 2012 VL 27 IS 4 BP 261 EP 273 DI 10.1097/HTR.0b013e3182585cb6 PG 13 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 975PJ UT WOS:000306523000004 PM 22767074 ER PT J AU Faris, JE Zhu, AX AF Faris, Jason E. Zhu, Andrew X. TI Targeted therapy for biliary tract cancers SO JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES LA English DT Article DE Cholangiocarcinoma; Gallbladder carcinoma; Epidermal growth factor receptor (EGFR); Vascular endothelial growth factor (VEGF); Mitogen-activated protein kinase (MAPK); Phosphatidylinositol-3-kinase (PI3K)-targeted therapy ID GROWTH-FACTOR-RECEPTOR; METASTATIC COLORECTAL-CANCER; K-RAS MUTATION; INTRAHEPATIC CHOLANGIOCARCINOMA; GALLBLADDER CARCINOMAS; C-MET; MICROSATELLITE INSTABILITY; UNITED-STATES; PHASE-II; HEPATOCELLULAR-CARCINOMA AB Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, with a historically poor prognosis as a whole. Until recently, the development of effective therapeutics was hampered by the relatively low incidence, heterogeneity in patients and tumors, and correspondingly poor clinical trial enrollments. With the publication of the landmark phase III ABC-02 trial demonstrating the superiority of gemcitabine and cisplatin combination chemotherapy, the landscape changed for the development of new agents. Despite this progress, there are currently no approved targeted agents for BTC. This review will focus on recent developments in targeted therapeutics, directed against several key signaling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway. Data from recent phase I and II trials will be discussed, along with a preview of upcoming trials involving targeted therapies. C1 [Faris, Jason E.; Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tucker Gosnell Ctr Gastrointestinal Canc,Canc Ctr, Boston, MA 02114 USA. RP Faris, JE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tucker Gosnell Ctr Gastrointestinal Canc,Canc Ctr, 55 Fruit St,Yawkey 7E, Boston, MA 02114 USA. EM jfaris@partners.org; azhu@partners.org NR 81 TC 15 Z9 16 U1 0 U2 10 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 1868-6974 J9 J HEPATO-BIL-PAN SCI JI J. Hepato-Biliary-Pancreat. Sci. PD JUL PY 2012 VL 19 IS 4 BP 326 EP 336 DI 10.1007/s00534-011-0496-0 PG 11 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 975ZN UT WOS:000306550400005 PM 22318523 ER PT J AU Albandar, JM Khattab, R Monem, F Barbuto, SM Paster, BJ AF Albandar, Jasim M. Khattab, Razan Monem, Fawza Barbuto, Sara M. Paster, Bruce J. TI The Subgingival Microbiota of Papillon-Lefevre Syndrome SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Dental plaque; microbiology; Papillon-Lefevre syndrome; periodontitis; periodontal diseases; risk factors ID CATHEPSIN-C GENE; AGGRESSIVE PERIODONTITIS; AGGREGATIBACTER-ACTINOMYCETEMCOMITANS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; BACTERIAL DIVERSITY; IMMUNOGLOBULIN-G; FOLLOW-UP; MUTATIONS; THERAPY; IDENTIFICATION AB Background: There is little information about the microbiologic profiles of periodontal lesions in Papillon-Lefevre syndrome (PLS) and the significance of bacteria in the pathogenesis of periodontitis in these patients. This comprehensive analysis of the subgingival microbiota in patients with PLS used 16S ribosomal RNA (rRNA) clonal analysis and the 16S rRNA-based Human Oral Microbe Identification Microarray (HOMIM). Methods. Thirteen patients with PLS from seven unrelated families volunteered for this microbiologic study. Subgingival plaque was collected with sterile paper points from multiple sites with >= 5 mm probing depth, and whole genomic DNA was extracted. The 16S rRNA genes were amplified, cloned, and sequenced. The samples were then probed for approximate to 300 predominant oral bacterial species using the HOMIM. Results: The most commonly detected phylotypes in the clonal analysis were Gemella morbillorum, Gemella haemolysans, Granulicatella adiacens, Lachnospiraceae OT 100 (EI074), Parvimonas micra, Selenomonas noxia, and Veillonella parvula. As a group, streptococci were commonly detected in these individuals. In the HOMIM analysis, a total of 170 bacterial species/phylotypes were detected, with a range of 40 to 80 species per patient with PLS. Of these, 12 bacterial species were detected in medium to high levels in >= 50% of the individuals. The high-frequency strains were clustered into eight groups: Aggregatibacter actinomycetemcomitans, Campylobacter spp., Capnocytophaga granulosa, G. morbillorum, P. micra, Porphyromonas endodontalis, Streptococcus spp., and Tannerella forsythia. Conclusions: The subgingival microbiota in PLS is diverse. Periodontal pathogens commonly associated with chronic and aggressive periodontitis and opportunistic pathogens may be associated with the development of severe periodontitis in patients with PLS. J Periodontol 2012;83:902-908. C1 [Albandar, Jasim M.] Temple Univ, Kornberg Sch Dent, Dept Periodontol & Oral Implantol, Periodontal Diagnost Res Lab, Philadelphia, PA 19140 USA. [Khattab, Razan] Univ Damascus, Coll Dent, Dept Periodontol, Damascus, Syria. [Monem, Fawza] Damascus Univ Hosp, Dept Clin Labs, Damascus, Syria. [Barbuto, Sara M.; Paster, Bruce J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immunity, Boston, MA 02115 USA. RP Albandar, JM (reprint author), Temple Univ, Kornberg Sch Dent, Dept Periodontol & Oral Implantol, Periodontal Diagnost Res Lab, 3223 N Broad St, Philadelphia, PA 19140 USA. EM Jasim.Albandar@temple.edu OI Albandar, Jasim M./0000-0001-7801-3811 FU National Institutes of Health [DE11443] FX This study is supported in part by National Institutes of Health Grant DE11443 (BJP). The authors report no conflicts of interest related to this study. NR 31 TC 9 Z9 10 U1 0 U2 4 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD JUL PY 2012 VL 83 IS 7 BP 902 EP 908 DI 10.1902/jop.2011.110450 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 975TZ UT WOS:000306535700012 PM 22141356 ER PT J AU Jeon, HJ Kang, ES Lee, EH Jeong, EG Jeon, JR Mischoulon, D Lee, D AF Jeon, Hong Jin Kang, Eun-Suk Lee, Eun Ho Jeong, Eu-Gene Jeon, Ju-Ri Mischoulon, David Lee, Dongsoo TI Childhood trauma and platelet brain-derived neurotrophic factor (BDNF) after a three month follow-up in patients with major depressive disorder SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Major depressive disorder; Childhood trauma; Sexual abuse; Brain-derived neurotrophic factor; Platelet ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; EARLY MATERNAL-DEPRIVATION; SEXUAL-ABUSE; LIFE EVENTS; PSYCHOMETRIC PROPERTIES; MOOD DISORDERS; DSM-IV; SERUM; RELEASE; DISEASE AB A large amount of brain-derived neurotrophic factor (BDNF) is stored in the human platelets and only small amounts of it circulate in the plasma. However, a few studies have focused on platelet BDNF in patients with major depressive disorder (MDD) and childhood trauma. Our study population consisted of 105 MDD patients and 50 healthy controls. We used the Mini-International Neuropsychiatric Interview (M.I.N.I), the Early Trauma Inventory Self Report-Short Form (ETISR-SF), as well as measured serum, plasma, and platelet BDNF at baseline, 1 month, and 3 month periods. There was a significant association between childhood trauma and platelet BDNF at baseline, 1 month, and 3 months, after adjusting for age, gender, education, body mass index, severity of depression, anxiety, alcohol consumption, and current stress. Conversely, plasma and serum BDNF did not have a significant association with childhood trauma. MDD patients revealed significantly higher levels of platelet BDNF in those with childhood trauma than in those without (t = 2.4, p = 0.018), and platelet BDNF was significantly higher in cases with sexual abuse on post-hoc analysis (p = 0.042). However, no significant differences were found in healthy controls, according to whether or not they had experienced childhood trauma. Platelet BDNF showed a significant correlation with severity of childhood trauma at baseline (r = 0.25, p = 0.012) and at 3 months (r = 0.38, p = 0.003) in MOD. In conclusion, platelet BDNF was significantly higher in MDD patients with childhood trauma than in those without, and it was correlated with severity of trauma. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Jeon, Hong Jin; Lee, Eun Ho; Jeong, Eu-Gene; Jeon, Ju-Ri; Lee, Dongsoo] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul 135710, South Korea. [Kang, Eun-Suk] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med, Seoul 135710, South Korea. [Mischoulon, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Depress Clin & Res Program, Boston, MA 02114 USA. RP Lee, D (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, 50 Irwon Dong, Seoul 135710, South Korea. EM dongsoolee@skku.edu OI Lee, Eun-ho/0000-0003-2550-8225 FU Samsung Social Mental Health Institute [SMHI 2010-04]; Samsung Biomedical Research Institute [C-B1-311]; National Research Foundation of Korea (NRF) [2011-0013064]; Ministry of Education, Science and Technology [2011-0013064]; Bristol-Myers Squibb Co.; Cederroth; Fisher Wallace; Ganeden; Lichtwer Pharma; Nordic Naturals FX Funding for this study was provided by Samsung Social Mental Health Institute (SMHI 2010-04), Samsung Biomedical Research Institute (C-B1-311), and National Research Foundation of Korea (NRF) (No. 2011-0013064). They had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.; Prof. Hong Jin Jeon was a principal investigator of Samsung Social Mental Health Institute (SMHI 2010-04), Samsung Biomedical Research Institute Grant (C-B1-311), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064). Prof. Hong Jin Jeon, and Dongsoo Lee designed the study, and educated and supervised the interviewers, and checked the whole data.; Dr. Mischoulon has received research support from Bristol-Myers Squibb Co., Cederroth, Fisher Wallace, Ganeden, Lichtwer Pharma, and Nordic Naturals. He has received honoraria for consulting, speaking, and writing from Pamlab, Bristol-Myers Squibb Co., Nordic Naturals. He has received royalties from Back Bay Scientific for PMS Escape, Book published by Lippincott Williams & Wilkins, "Natural Medications for Psychiatric Disorders: Considering the Alternatives." NR 50 TC 13 Z9 13 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD JUL PY 2012 VL 46 IS 7 BP 966 EP 972 DI 10.1016/j.jpsychires.2012.04.006 PG 7 WC Psychiatry SC Psychiatry GA 975UD UT WOS:000306536100019 PM 22551661 ER PT J AU Lyddon, R Navarrett, S Dracheva, S AF Lyddon, Rebecca Navarrett, Scott Dracheva, Stella TI Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article ID SEROTONIN 2C RECEPTOR; MOLECULAR DETERMINANT; KINETIC-PROPERTIES; KAINATE RECEPTORS; 5-HT2C RECEPTOR; MOTOR-NEURONS; AMPA; EPILEPSY; CHANNELS; GLUR2 AB Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the analysis of potential medication effects. Conclusion: We found that iGluR RNA editing status was not associated with bipolar disorder, schizophrenia or suicide. Differences in editing between flip and flop splicoforms suggest that glutamate sensitivity of receptors containing GluA3 and/or GluA4 flop subunits is moderated as a result of increased editing. C1 [Lyddon, Rebecca; Navarrett, Scott; Dracheva, Stella] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Navarrett, Scott; Dracheva, Stella] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Dracheva, S (reprint author), Bronx VA Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Stella.Dracheva@mssm.edu FU Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; VA Merit award; NIMH/NIH [MH090352]; American Foundation for Suicide Prevention; VISN3 Mental Illness Research and Education Clinical Center; Stanley Medical Research Institute FX This study was supported by the Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, by a VA Merit award (S. Dracheva), NIMH/NIH grant MH090352 (S. Dracheva), a grant from the American Foundation for Suicide Prevention (S. Dracheva) and by the VISN3 Mental Illness Research and Education Clinical Center (S. Dracheva). Postmortem brain tissue was donated by The Stanley Medical Research Institute. NR 43 TC 5 Z9 5 U1 0 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD JUL PY 2012 VL 37 IS 4 BP 267 EP 272 DI 10.1503/jpn.110107 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 974LV UT WOS:000306437800008 PM 22469055 ER PT J AU Dantas, PRS Maesta, I Cortes-Charry, R Growdon, WB Braga, A Rudge, MVC Berkowitz, RS AF Sobral Dantas, Patricia Range Maesta, Izildinha Cortes-Charry, Rafael Growdon, Whitfield B. Braga, Antonio Cunha Rudge, Marilza Vieira Berkowitz, Ross S. TI Influence of Hydatidiform Mole Follow-Up Setting on Postmolar Gestational Trophoblastic Neoplasia Outcomes A Cohort Study SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article; Proceedings Paper CT 16th World Congress on Gestational Trophoblastic Diseases CY OCT 16-19, 2011 CL Budapest, HUNGARY SP Ctr Univ Venezuela, Council Sci & Humanist Dev (CDCH-UCV), Natl Reserve Sci, Technol & Innovat (FONACIT) DE gestational trophoblastic neoplasia; hydatidiform mole; management setting ID HUMAN CHORIONIC-GONADOTROPIN; DISEASE; MANAGEMENT; PREGNANCY; RISK; DIAGNOSIS AB OBJECTIVE: To assess the influence of hydatidiform mole (HM) management setting (reference center versus other institutions) on gestational trophoblastic neoplasia (GTN) outcomes. METHODS: This cohort study included 270 HM patients attending Botucatu Trophoblastic Diseases Center (BTDC, Sao Paulo State University, Brazil) between January 1.990 and December 2009 (204 undergoing evacuation and entire postmolar follow-up at BTDC and 66 from other institutions [OIs]). GTN characteristics and outcomes were analyzed and compared according to HM management setting. The confounding variables assessed included age, gravidity, parity, number of abortions and HM type (complete or partial). Postmolar GTN outcomes were compared using Mann-Whitney's test, chi(2) test or Fisher's exact test. RESULTS: Postmolar GTN occurred in 34 (34/204= 16.7%) BTDC patients and in 27 (27/66=40.9%) of those initially treated in other institutions. BTDC patients showed lower metastasis rate (5.8% vs. 48%, p = 0.003) and lower median FIGO (2002) score (2.00 0.00, 3.001 vs. 4.00 [2.00, 7.00], p = 0.003]. Multiagent chemotherapy to treat postmolar GTN was required in 2 BTDC cases (5.9%) and in 8 OI cases (29.6%) (p = 0.017). Median time interval between molar evacuation and chemotherapy onset was shorter among BTDC patients (7.0 [6.0, 10.0] vs. 10.0[7.0, 16.0], p = 0.040). CONCLUSION: BTDC patients showed GTN characteristics indicative of better prognosis. This underscores the importance of GTD specialist centers. (J Reprod Med 2012;57:305-309) C1 [Maesta, Izildinha] Sao Paulo State Univ, Dept Gynecol & Obstet, Botucatu Med Sch, UNESP,Trophoblast Dis Ctr, BR-18618970 Botucatu, SP, Brazil. Cent Univ Venezuela, Hosp Univ Caracas, Dept Obstet & Gynecol, Caracas, Venezuela. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gynecol Oncol,Dept Obstet & Gynecol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Maesta, I (reprint author), Sao Paulo State Univ, Dept Gynecol & Obstet, Botucatu Med Sch, UNESP,Trophoblast Dis Ctr, POB 530, BR-18618970 Botucatu, SP, Brazil. EM imaesta@fmb.unesp.br RI Braga, Antonio/F-7144-2014; Rudge, Marilza /C-8338-2012 OI Braga, Antonio/0000-0002-2942-6182; Rudge, Marilza /0000-0002-9227-832X NR 19 TC 5 Z9 7 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD JUL-AUG PY 2012 VL 57 IS 7-8 BP 305 EP 309 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 975TC UT WOS:000306533400007 PM 22838246 ER PT J AU Ferreira, CG Barrios, C Shaw, AT Shi, YK De Pas, TM Yang, PC Riely, GJ Crino, L Iyer, S Polli, A Lanzalone, S Kim, DW AF Ferreira, Carlos G. Barrios, C. Shaw, Alice T. Shi, Yuankai De Pas, Tommaso M. Yang, Pan C. Riely, Greg J. Crino, Lucio Iyer, Shrividya Polli, Anna Lanzalone, Silvana Kim, Dong W. TI EFFICACY AND SAFETY OF CRIZOTINIB IN ADVANCED ALK-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) RESULTS FROM A PHASE II GLOBAL TRIAL SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Ferreira, Carlos G.] Inst Nacl Canc, Div Clin & Translat Res, Rio De Janeiro, Brazil. [Barrios, C.] Pucrs Sch Med, Dept Med, Porto Alegre, RS, Brazil. [Shaw, Alice T.] Massachusetts Gen Hosp, Dept Thorac Oncol, Boston, MA 02114 USA. [Shi, Yuankai] Chinese Acad Med Sci Cams, Dept Med Oncol, Beijing, Peoples R China. [De Pas, Tommaso M.] European Inst Oncol, Med Oncol Unit Resp Tract & Sarcomas, Milan, Italy. [Yang, Pan C.] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Riely, Greg J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Crino, Lucio] S Maria Della Misericordia Hosp, Perugia, Italy. [Iyer, Shrividya] Pfizer, Oncol, New York, NY USA. [Kim, Dong W.] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Polli, Anna; Lanzalone, Silvana] Pfizer, Oncol, Milan, Italy. RI Barrios, Carlos/G-8525-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2012 VL 7 IS 7 BP S107 EP S108 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 974TA UT WOS:000306458700012 ER PT J AU O'Byrne, K Schuler, M Yamamoto, N Hirsh, V Mok, T Massey, D Zazulina, V Shahidi, M Sequist, L Yang, J AF O'Byrne, Ken Schuler, Martin Yamamoto, Nobuyuki Hirsh, Vera Mok, Tony Massey, Dan Zazulina, Victoria Shahidi, Mehdi Sequist, Lecia Yang, James TI LUX-LUNG 3: A RANDOMIZED, OPEN-LABEL, PHASE III STUDY OF AFATINIB VS. PEMETREXED AND CISPLATIN AS FIRST-LINE TREATMENT FOR PATIENTS WITH ADVANCED ADENOCARCINOMA OF THE LUNG HARBORING EGFR ACTIVATING MUTATIONS SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [O'Byrne, Ken] St James Hosp, Dublin 8, Ireland. [Schuler, Martin] Univ Duisburg Essen, West German Canc Ctr, Duisburg, Germany. [Yamamoto, Nobuyuki] Shizuoka Canc Ctr, Shizuoka, Japan. [Hirsh, Vera] McGill Univ, Montreal, PQ H3A 2T5, Canada. [Mok, Tony] Prince Wales Hosp, Hong Kong, Hong Kong, Peoples R China. [Massey, Dan; Zazulina, Victoria; Shahidi, Mehdi] Boehringer Ingelheim Limited, Ingelheim, Germany. [Sequist, Lecia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yang, James] Natl Taiwan Univ Hosp, Taipei, Taiwan. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2012 VL 7 IS 7 BP S102 EP S102 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 974TA UT WOS:000306458700003 ER PT J AU Gomperts, SN Locascio, JJ Marquie, M Santarlasci, AL Rentz, DM Maye, J Johnson, KA Growdon, JH AF Gomperts, Stephen N. Locascio, Joseph J. Marquie, Marta Santarlasci, Andrea L. Rentz, Dorene M. Maye, Jacqueline Johnson, Keith A. Growdon, John H. TI Brain amyloid and cognition in Lewy body diseases SO MOVEMENT DISORDERS LA English DT Article DE dementia; Lewy; Parkinson; amyloid; PiB ID POSITRON-EMISSION-TOMOGRAPHY; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; SENILE-DEMENTIA; BODIES; ALLELE; ONSET; LOAD; PET AB Many patients with PD develop PD with dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account, in part, for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases. Twenty-nine cognitively healthy PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD, and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and Pittsburgh compound B (PiB) imaging with PET. Apolipoprotein E (ApoE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference. PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the ApoE e4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition. DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD, or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism. (c) 2012 Movement Disorder Society C1 [Gomperts, Stephen N.; Locascio, Joseph J.; Marquie, Marta; Santarlasci, Andrea L.; Maye, Jacqueline; Johnson, Keith A.; Growdon, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rentz, Dorene M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Marquie, Marta] Autonomous Univ Barcelona, Barcelona, Spain. RP Growdon, JH (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WAC 729G, Boston, MA 02114 USA. EM growdon@helix.mgh.harvard.edu OI Marquie, Marta/0000-0002-0660-0950 FU Michael J. Fox Foundation for Parkinson's Research; National Alzheimer's Coordinating Center [5 U01 AG016976-11]; National Institute of Neurological Disorders and Stroke; National Institute on Aging; Alzheimer's Disease Association; Caja Madrid Foundation FX This work was supported by the Michael J. Fox Foundation for Parkinson's Research (to S.N.G. and J. H. G.), National Alzheimer's Coordinating Center Collaborative Project 5 U01 AG016976-11 (to S.N.G., K. A. J., and J. H. G.), the National Institute of Neurological Disorders and Stroke (to K. A. J.), the National Institute on Aging (to K. A. J.), the Alzheimer's Disease Association (to K. A. J.), and the Caja Madrid Foundation scholarship for postgraduate studies (to M.M.). NR 70 TC 62 Z9 62 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2012 VL 27 IS 8 BP 965 EP 973 DI 10.1002/mds.25048 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 974ZY UT WOS:000306477400006 PM 22693110 ER PT J AU Palacios, N Gao, X O'Reilly, E Schwarzschild, M McCullough, ML Mayo, T Gapstur, SM Ascherio, AA AF Palacios, Natalia Gao, Xiang O'Reilly, Eilis Schwarzschild, Michael McCullough, Marjorie L. Mayo, Tinisha Gapstur, Susan M. Ascherio, Alberto A. TI Alcohol and risk of Parkinson's disease in a large, prospective cohort of men and women SO MOVEMENT DISORDERS LA English DT Article DE Parkinson; alcohol; epidemiology; cohort; prospective ID SOCIETY CANCER PREVENTION; FOOD-FREQUENCY QUESTIONNAIRE; II NUTRITION COHORT; CIGARETTE-SMOKING; COFFEE CONSUMPTION; ASSOCIATION; EXPOSURE; DRINKING; TOBACCO; DESIGN AB Addictive behaviors, such as cigarette smoking and coffee drinking, have been associated with a reduced risk of Parkinson's disease (PD). Whether alcohol consumption is also associated with PD risk is less certain. We prospectively followed 132,403 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Alcohol intake was assessed at baseline. Incident cases of PD (n = 605; 389 male and 216 female) were confirmed by treating physicians and medical record review. Relative risks (RRs) were estimated using proportional hazards models, adjusting for age, smoking, and other risk factors. Alcohol consumption was not significantly associated with PD risk. After adjustment for age, smoking, and other risk factors, the RR comparing men consuming 30 or more grams of alcohol per day (highest category) to nondrinker men was 1.29 (95% confidence interval [CI]: 0.90, 1.86; P trend: 0.40), and the RR comparing women consuming 15 or more grams of alcohol (highest category) per day to nondrinker women was 0.77 (95% CI: 0.41, 1.45; P trend: 0.87). Consumption of beer, wine, or liquor was also not associated with PD risk. The results of this large, prospective study do not support an association between alcohol intake and risk of PD. (c) 2012 Movement Disorder Society C1 [Palacios, Natalia; Gao, Xiang; O'Reilly, Eilis; Ascherio, Alberto A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Schwarzschild, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McCullough, Marjorie L.; Mayo, Tinisha; Gapstur, Susan M.] Epidemiol Res Program, Atlanta, GA USA. [Ascherio, Alberto A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto A.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Gao, Xiang; Ascherio, Alberto A.] Harvard Univ, Sch Med, Boston, MA USA. RP Palacios, N (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM palacios@hsph.harvard.edu FU NIEHS NIH HHS [K01 ES019183]; NINDS NIH HHS [R01 NS061858] NR 45 TC 16 Z9 18 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2012 VL 27 IS 8 BP 980 EP 987 DI 10.1002/mds.25050 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 974ZY UT WOS:000306477400008 PM 22714720 ER PT J AU McCarthy, JR Sazonova, IY Erdem, SS Hara, T Thompson, BD Patel, P Botnaru, I Lin, CP Reed, GL Weissleder, R Jaffer, FA AF McCarthy, Jason R. Sazonova, Irina Y. Erdem, S. Sibel Hara, Tetsuya Thompson, Brian D. Patel, Purvish Botnaru, Ion Lin, Charles P. Reed, Guy L. Weissleder, Ralph Jaffer, Farouc A. TI Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy SO NANOMEDICINE LA English DT Article DE fibrinolytic; imaging; iron oxide; multimodal; theranostic; therapy; thrombosis ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE MYOCARDIAL-INFARCTION; ACUTE ISCHEMIC-STROKE; IN-VIVO; CONTRAST AGENT; FACTOR-XIII; THROMBOLYSIS; BLOOD; NANOPARTICLES; MICROSCOPY AB Background: Current thrombolytic therapies utilize exogenous plasminogen activators (PAs) to effectively lyse clots, restoring blood flow, and preventing tissue and organ death. These PAs may also impair normal hemostasis, leading to life-threatening bleeding, including intracerebral hemorrhage. Aims: This study aims to develop new thrombus-targeted fibrinolytic agents that harness the multifunctional theranostic capabilities of nanomaterials, potentially allowing for the generation of efficacious thrombolytics while minimizing deleterious side effects. Materials & methods: A thrombus-targeted nano-fibrinolytic agent was synthesized using a magnetofluorescent crosslinked dextran-coated iron oxide nanoparticle platform that was conjugated to recombinant tissue PA (tPA). Thrombus-targeting was achieved by derivatizing the nanoparticle with an activated factor XIII (FXIIIa)-sensitive peptide. Human plasma clot binding ability of the targeted and control agents was assessed by fluorescence reflectance imaging. Next, the in vitro enzymatic activity of the agents was assessed by S2288-based amidolytic activity, and an ELISA D-dimer assay for fibrinolysis. In vivo targeting of the nanoagent was next examined by intravital fluorescence microscopy of murine arterial and venous thrombosis. The fibrinolytic activity of the targeted nanoagent compared to free tPA was then evaluated in vivo in murine pulmonary embolism. Results: In vitro, the targeted thrombolytic nanoagent demonstrated superior binding to fresh-frozen plasma clots compared to control nanoagents (analysis of variance, p < 0.05). When normalized by S2288-based amidolytic activity, targeted, control and free tPA samples demonstrated equivalent in vitro fibrinolytic activity against human plasma clots, as determined by ELISA D-dimer assays. The FXIIIa targeted fibrinolytic nanoagent efficiently bound the margin of intravascular thrombi as detected by intravital fluorescence microscopy. In in vivo fibrinolysis studies the FXII la-targeted agent lysed pulmonary emboli with similar efficacy as free tPA (p > 0.05). Conclusion: The applicability of a FXIIIa-targeted thrombolytic nanoagent in the treatment of thromboembolism was demonstrated in vitro and in vivo. Future studies are planned to investigate the safety profile and overall efficacy of this class of nanoagents. C1 [McCarthy, Jason R.; Erdem, S. Sibel; Thompson, Brian D.; Lin, Charles P.; Weissleder, Ralph] Harvard Univ, Sch Med, Ctr Syst Biol, Charlestown, MA 02129 USA. [McCarthy, Jason R.; Erdem, S. Sibel; Thompson, Brian D.; Lin, Charles P.; Weissleder, Ralph] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Sazonova, Irina Y.] Georgia Hlth Sci Univ, Med Coll Georgia, Dept Med, Cardiol Sect, Augusta, GA USA. [Hara, Tetsuya; Patel, Purvish; Botnaru, Ion; Jaffer, Farouc A.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Div Cardiol, Boston, MA USA. [Hara, Tetsuya; Thompson, Brian D.; Patel, Purvish; Botnaru, Ion; Lin, Charles P.; Jaffer, Farouc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thompson, Brian D.; Lin, Charles P.; Jaffer, Farouc A.] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02115 USA. [Reed, Guy L.] Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. RP McCarthy, JR (reprint author), Harvard Univ, Sch Med, Ctr Syst Biol, 149 13th St,6th Floor, Charlestown, MA 02129 USA. EM jason_mccarthy@hms.harvard.edu OI Jaffer, Farouc/0000-0001-7980-384X FU NIH NHLBI [R21HL093607, R01 HL108229, U01-HL080731]; American Heart Association Scientist Development Grant [0830309N, 0830352N]; Howard Hughes Medical Institute Career Development Award; [HHSN268201000044C] FX This work was supported in part by funds from the NIH NHLBI under grant number R21HL093607 (J McCarthy), R01 HL108229 (F Jaffer), U01-HL080731 (J McCarthy, F Jaffer, G Reed and R Weissleder) and contract number HHSN268201000044C (J McCarthy and R Weissleder), the American Heart Association Scientist Development Grant 0830309N (I Sazonova) the American Heart Association Scientist Development Grant 0830352N (F Jaffer), and the Howard Hughes Medical Institute Career Development Award (F Jaffer). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 31 TC 19 Z9 19 U1 4 U2 34 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD JUL PY 2012 VL 7 IS 7 BP 1017 EP 1028 DI 10.2217/NNM.11.179 PG 12 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 976XM UT WOS:000306620700017 PM 22348271 ER PT J AU Shrestha, Y Schafer, EJ Boehm, JS Thomas, SR He, F Du, J Wang, S Barretina, J Weir, BA Zhao, JJ Polyak, K Golub, TR Beroukhim, R Hahn, WC AF Shrestha, Y. Schafer, E. J. Boehm, J. S. Thomas, S. R. He, F. Du, J. Wang, S. Barretina, J. Weir, B. A. Zhao, J. J. Polyak, K. Golub, T. R. Beroukhim, R. Hahn, W. C. TI PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling SO ONCOGENE LA English DT Article DE PAK1; transformation; MAPK; MET; merlin ID COMPARATIVE GENOMIC HYBRIDIZATION; TUMOR-SUPPRESSOR GENE; ANTITUMOR-ACTIVITY; OVARIAN-CARCINOMA; TYROSINE KINASE; PROTEIN-KINASE; EGF RECEPTOR; IN-VIVO; PATHWAY; CELLS AB Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30-33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation. Oncogene (2012) 31, 3397-3408; doi:10.1038/onc.2011.515; published online 21 November 2011 C1 [Shrestha, Y.; Schafer, E. J.; Thomas, S. R.; Barretina, J.; Weir, B. A.; Polyak, K.; Beroukhim, R.; Hahn, W. C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shrestha, Y.; Schafer, E. J.; Boehm, J. S.; Thomas, S. R.; He, F.; Du, J.; Barretina, J.; Weir, B. A.; Golub, T. R.; Beroukhim, R.; Hahn, W. C.] Broad Inst Harvard & MIT, Cambridge, MA USA. [He, F.; Du, J.; Golub, T. R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Wang, S.] Dana Farber Harvard Canc Ctr, Cytogenet Core Facil, Boston, MA USA. [Barretina, J.; Polyak, K.; Golub, T. R.; Hahn, W. C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Zhao, J. J.; Beroukhim, R.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Polyak, K.; Beroukhim, R.; Hahn, W. C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Polyak, K.; Beroukhim, R.; Hahn, W. C.] Harvard Univ, Sch Med, Boston, MA USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 1538, Boston, MA 02215 USA. EM William_Hahn@dfci.harvard.edu OI Boehm, Jesse/0000-0002-6795-6336 FU Department of Defense [W81XWH-08-1-0767]; US National Cancer Institute [R33 CA128625, R01 CA130988]; Cancer Center Support Grant [NIH 5 P30 CA06516] FX We thank Nicole A Spardy, Christine L Nguyen and Yaara C Zwang for critical reading of the manuscript. We also thank the Dana-Farber/Harvard Cancer Center Cytogenetics Core for their assistance with fluorescence in situ hybridization studies. This work was supported in part by a Department of Defense Breast Cancer Research Program Pre-doctoral Fellowship (W81XWH-08-1-0767, YS), grants from the US National Cancer Institute (R33 CA128625 and R01 CA130988, WCH) and a Cancer Center Support Grant no. NIH 5 P30 CA06516 (Cytogenetics Core). NR 60 TC 55 Z9 60 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL PY 2012 VL 31 IS 29 BP 3397 EP 3408 DI 10.1038/onc.2011.515 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 976FN UT WOS:000306566400001 PM 22105362 ER PT J AU Lim, E Lin, NU AF Lim, Elgene Lin, Nancy U. TI New Insights and Emerging Therapies for Breast Cancer Brain Metastases SO ONCOLOGY-NEW YORK LA English DT Article ID NERVOUS-SYSTEM METASTASES; GRADED PROGNOSTIC ASSESSMENT; LAPATINIB PLUS CAPECITABINE; TRASTUZUMAB-BASED THERAPY; PHASE-II TRIAL; STEREOTACTIC RADIOSURGERY; ADJUVANT CHEMOTHERAPY; SOLID TUMORS; SURVIVAL; CARCINOMA AB Breast cancer brain metastases (BCBMs) are the second most frequent secondary central nervous system metastases following those associated with non-small-cell lung cancer. It is increasingly evident that BCBM arises as a function of the biology of the primary tumor and the metastatic niche, which combine to create a unique microenvironment in the brain impacting both metastatic colonization and therapeutic response. Clinical outcomes are improving for BCBM patients as a result of modern combinatorial therapies, challenging the traditionally nihilistic approach to this patient subgroup. This review will focus on the breast cancer subtypes with the highest incidence of BCBM-human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) breast cancer (TNBC)-and Will characterize differences in the clinical behavior of brain metastases that arise from these different subtypes. We will also highlight some of the recent preclinical studies that may shed light on the biological mechanisms and mediators underlying brain metastases. Finally, we will review published and current prospective trials of systemic therapies specifically for BCBM, including novel pathway-specific therapies. C1 [Lim, Elgene; Lin, Nancy U.] Dana Farber Canc Inst, Womens Canc Program, Boston, MA 02115 USA. RP Lim, E (reprint author), Dana Farber Canc Inst, Womens Canc Program, Boston, MA 02115 USA. FU GlaxoSmithKline; Genentech; Geron; Boehringer Ingelheim; Bayer; Breast Cancer Research Foundation FX Dr. Lim has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Lin has received research funding from GlaxoSmithKline, Genentech, Geron, Boehringer Ingelheim, and Bayer; she serves as a consultant to GlaxoSmithKline, Geron, Novartis, and to-BBB. Dr. Lin also wishes to acknowledge receiving research support from the Breast Cancer Research Foundation. NR 53 TC 10 Z9 11 U1 0 U2 8 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUL PY 2012 VL 26 IS 7 BP 652 EP + PG 9 WC Oncology SC Oncology GA 976XA UT WOS:000306619500010 PM 22888567 ER PT J AU Barbano, RL Hill, DF Snively, BM Light, LS Boggs, N McCall, WV Stacy, M Ozelius, L Sweadner, KJ Brashear, A AF Barbano, Richard L. Hill, Deborah F. Snively, Beverly M. Light, Laney S. Boggs, Niki McCall, W. Vaughn Stacy, Mark Ozelius, Laurie Sweadner, Kathleen J. Brashear, Allison TI New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Dystonia; RDP; DYT-12; Rapid-onset dystonia-parkinsonism ID MUTATION CARRIERS; MAJOR DEPRESSION; DYT1 DYSTONIA; RATING-SCALE; GENE; DISORDER; ATP1A3; RDP AB Background: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized. Methods: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews. Results: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder. Conclusions: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Hill, Deborah F.; Brashear, Allison] Wake Forest Univ, Dept Neurol, Wake Forest Sch Med, Baptist Med Ctr, Winston Salem, NC 27157 USA. [Barbano, Richard L.] Univ Rochester, Sch Med, Dept Neurol, Rochester, NY USA. [Snively, Beverly M.; Light, Laney S.] Wake Forest Univ, Dept Publ Hlth Sci, Wake Forest Sch Med, Baptist Med Sch, Winston Salem, NC 27157 USA. [Boggs, Niki; McCall, W. Vaughn] Wake Forest Univ, Dept Psychiat, Wake Forest Sch Med, Baptist Med Ctr, Winston Salem, NC 27157 USA. [Stacy, Mark] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA. [Ozelius, Laurie] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Ozelius, Laurie] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Sweadner, Kathleen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Brashear, A (reprint author), Wake Forest Univ, Dept Neurol, Wake Forest Sch Med, Baptist Med Ctr, Winston Salem, NC 27157 USA. EM abrashea@wakehealth.edu RI Brashear, Allison/G-3853-2015 FU NINDS [5R01NS058949-03] FX This study was supported by NINDS 5R01NS058949-03 (AB). NR 26 TC 14 Z9 15 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2012 VL 18 IS 6 BP 737 EP 741 DI 10.1016/j.parkreldis.2012.03.020 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 975WC UT WOS:000306541200005 PM 22534615 ER PT J AU Pass, M Belkora, J Moore, D Volz, S Sepucha, K AF Pass, Margot Belkora, Jeffrey Moore, Dan Volz, Shelley Sepucha, Karen TI Patient and observer ratings of physician shared decision making behaviors in breast cancer consultations SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Breast cancer; Decision making; Decision analysis; Physician-patient relations; Informed consent; Patient participation; Health communication; Psychometrics ID PRIMARY-CARE; MEDICAL DECISIONS; HEALTH-CARE; INVOLVEMENT; QUALITY; COMMUNICATION; SATISFACTION; VALIDATION; FRAMEWORK; CONTEXT AB Objective: Explore the validity of using patient reports to measure shared decision making (SDM). Methods: 178 patients diagnosed with breast cancer obtained SDM assistance in a university-based clinic. Trained observers rated physician SDM behaviors and surveyed patients. We calculated the frequency with which patients and observers reported maximum SDM behaviors for each survey item. We also calculated agreement frequency between patients and observers. Results: Over 90% of patients rated doctors as reflecting SDM competencies. Patients reported doctors making recommendations more than soliciting their preferred choice (90% vs. 69%, p < 0.001). Patients heard benefits discussed "a lot" more often than they heard risks and side effects discussed "a lot" (81% vs. 58%, p < 0.001). Agreement between patients and observers was 75%. In cases of disagreement, patients more frequently perceived SDM behaviors than did observers (15% vs. 9%, p = 0.002), suggesting a possible agreement bias. Conclusions: High agreement supports further investigation into using patients as efficient and effective raters of SDM. Patient ratings may be inflated by agreement bias. Practice implications: Doctors presentations may be biased toward discussing benefits more than risks. Policy makers can solicit patient ratings of SDM as long as they are aware of possibly inflated ratings due to agreement bias. (C) 2012 Published by Elsevier Ireland Ltd. C1 [Pass, Margot; Belkora, Jeffrey; Volz, Shelley] Univ Calif San Francisco, Inst Hlth Policy Studies, San Francisco, CA USA. [Moore, Dan] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Sepucha, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Belkora, J (reprint author), Calif St,Suite 265, San Francisco, CA 94118 USA. EM jeff.belkora@ucsf.edu FU Foundation for Informed Medical Decision Making FX We would like to thank the patients who participated in this study, as well as the observers who collected the data. Thanks also to the physicians who agreed to have their appointments observed as part four Shared Decision Making implementation. We thank Laura Esserman, MD, MBA Professor of Surgery and Director of the UCSF Breast Care Center and Meredith Buxton, MPH, Research Director at the Breast Care Center, for their comments. We are grateful to the Foundation for Informed Medical Decision Making for funding this work. We presented this study at the 2011 International Shared Decision Making conference in Maastricht, Netherlands. NR 23 TC 8 Z9 8 U1 4 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUL PY 2012 VL 88 IS 1 BP 93 EP 99 DI 10.1016/j.pec.2012.01.008 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 975WD UT WOS:000306541300013 PM 22322069 ER PT J AU Brown, RE Basheer, R McKenna, JT Strecker, RE McCarley, RW AF Brown, Ritchie E. Basheer, Radhika McKenna, James T. Strecker, Robert E. McCarley, Robert W. TI CONTROL OF SLEEP AND WAKEFULNESS SO PHYSIOLOGICAL REVIEWS LA English DT Review ID EYE-MOVEMENT SLEEP; PONTINE RETICULAR-FORMATION; RESTLESS LEGS SYNDROME; HIPPOCAMPAL-THETA-RHYTHM; NITRIC-OXIDE-SYNTHASE; BASAL FOREBRAIN NEURONS; VENTROLATERAL PREOPTIC NUCLEUS; VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; DORSAL RAPHE NUCLEUS AB Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of Sleep and Wakefulness. Physiol Rev 92: 1087-1187, 2012; doi:10.1152/physrev.00032.2011.-This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making. C1 [McCarley, Robert W.] VA Boston Healthcare Syst, Lab Neurosci, Dept Psychiat, Brockton, MA 02301 USA. [McCarley, Robert W.] Harvard Univ, Sch Med, VA Med Ctr Brockton, Brockton, MA 02301 USA. RP McCarley, RW (reprint author), VA Boston Healthcare Syst, Lab Neurosci, Dept Psychiat, Res 116A,940 Belmont St, Brockton, MA 02301 USA. EM Robert_McCarley@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Brown, Ritchie/0000-0002-7164-4132 FU Department of Veterans Affairs Medical Research Service Awards; National Institutes of Health Grants [R01 MH-039683, R21 MH-094803, P01 HL-095491] FX This work was supported by Department of Veterans Affairs Medical Research Service Awards (to R. W. McCarley, R. Basheer, and R. E. Strecker) and by National Institutes of Health Grants R01 MH-039683 (to R. W. McCarley), R21 MH-094803 (to R. E. Brown), and P01 HL-095491 (to R. W. McCarley and R. E. Strecker). NR 1471 TC 259 Z9 263 U1 27 U2 234 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 EI 1522-1210 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2012 VL 92 IS 3 BP 1087 EP 1187 DI 10.1152/physrev.00032.2011 PG 101 WC Physiology SC Physiology GA 976FO UT WOS:000306566500004 PM 22811426 ER PT J AU Nogueiras, R Habegger, KM Chaudhary, N Finan, B Banks, AS Dietrich, MO Horvath, TL Sinclair, DA Pfluger, PT Tschop, MH AF Nogueiras, Ruben Habegger, Kirk M. Chaudhary, Nilika Finan, Brian Banks, Alexander S. Dietrich, Marcelo O. Horvath, Tamas L. Sinclair, David A. Pfluger, Paul T. Tschoep, Matthias H. TI SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM SO PHYSIOLOGICAL REVIEWS LA English DT Review ID ACTIVATED PROTEIN-KINASE; DNA-DAMAGE RESPONSE; FATTY-ACID OXIDATION; LIFE-SPAN EXTENSION; FOXO TRANSCRIPTION FACTORS; SMALL-MOLECULE ACTIVATORS; PANCREATIC BETA-CELLS; SUPRACHIASMATIC NUCLEUS LESIONS; DEPENDENT HISTONE DEACETYLASE; STIMULATED INSULIN-SECRETION AB Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschop MH. Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism. Physiol Rev 92: 1479-1514, 2012; doi:10.1152/physrev.00022.2011.-The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease. C1 Univ Santiago de Compostela, Dept Physiol, Sch Med, Inst Invest Sanitarias, Santiago De Compostela, Spain. CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela, Spain. Univ Cincinnati, Dept Med, Metab Dis Inst, Cincinnati, OH 45221 USA. Hemholtz Ctr Munich, Inst Diabet & Obes, Munich, Germany. Tech Univ Munich, Munich, Germany. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA. Yale Univ, Sch Med, Comparat Med Sect, Program Cell & Neurobiol Energy Metab, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Paul F Glenn Labs Biol Mech Aging, Boston, MA USA. RP Tschop, MH (reprint author), German Res Ctr Environm Hlth GmbH, Inst Diabet & Obes, German Ctr Diabet Res, Helmholtz Ctr Munich, Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany. EM tschoep@helmholtz-muenchen.de RI Banks, Alexander/B-4832-2012; Dietrich, Marcelo/A-9928-2009; Tschoep, Matthias/I-5443-2014; OI Banks, Alexander/0000-0003-1787-6925; Dietrich, Marcelo/0000-0001-9781-2221; Sinclair, David/0000-0002-9936-436X; Tschoep, Matthias/0000-0002-4744-371X FU NIA NIH HHS [R01 AG019719, R01 AG028730, R37 AG028730]; NIDDK NIH HHS [DP1 DK098058] NR 376 TC 137 Z9 143 U1 6 U2 61 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 EI 1522-1210 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2012 VL 92 IS 3 BP 1479 EP 1514 DI 10.1152/physrev.00022.2011 PG 36 WC Physiology SC Physiology GA 976FO UT WOS:000306566500010 PM 22811431 ER PT J AU Bander, J Elmariah, S Aledort, LM Dlott, J Stelzer, P Halperin, JL Kini, AS Sharma, SK AF Bander, Jeffrey Elmariah, Sammy Aledort, Louis M. Dlott, Jeffrey Stelzer, Paul Halperin, Jonathan L. Kini, Annapoorna S. Sharma, Samin K. TI Cianges in von Willebrand factor-cleaving protease (ADAMTS-13) in patients with aortic stenosis undergoing valve replacement or ball valvull plasty SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Acquired coagulation disorders; ADAMTS-13; aortic valve stenosis; balloon aortic valvuloplasty; von Willebrand factor ID VONWILLEBRAND-FACTOR MULTIMERS; SHEAR-STRESS; PLATELET-AGGREGATION; DOPPLER ULTRASOUND; CARDIAC-SURGERY; DISEASE; DESMOPRESSIN; ABNORMALITIES; PROTEOLYSIS; INFUSION AB It was the objective of this study to determine whether reduced cleavage of von Willebrand factor (VWF) multimers following aortic valve replacement (AVR) is a consequence of reduced shear stress or postoperative changes in VWF cleavage protease (ADAMTS-13) activity. Aortic stenosis (AS) may be complicated by acquired von Willebrand disease. Aortic valve replacement (AVR) corrects the associated haematologic abnormalities. We enrolled 114 patients with severe AS scheduled for either balloon aortic valvuloplasty (BAV; n=64) or AVR (n=50). Haematologic assessments of VWF levels and activity and ADAMTS-13 were performed before and 24 hours after valve intervention. The VWF:RCo to VWF:Ag ratio, a surrogate for large VWF multimer activity, increased by 37% (p < 0.0001) after AVR and by 10% (p = 0.0002) after BAV. ADAMTS-13 activity significantly decreased after AVR (579 +/- 127 to 468 +/- 135 ng/ml; p<0.0001), but not after BAV (484 153 to 529 185 ng/ml; p = 0.10). By multivariable analysis, the change in VWF:RCo ratio after AVR was more strongly associated with the fall in ADAMTS-13 than with reduction of valve gradient; whereas the change in gradient better predicted the rise in VWF:RCo after BAV. In conclusion, both BAV and AVR reverse the haematological abnormalities of the acquired von Willebrand syndrome of AS and ADAMTS-13 levels decrease after AVR. These findings suggest that a portion of the haematologic benefit of AVR may be due to a postoperative decline in ADAMTS-13 rather than solely to relief of AS as previously thought. C1 [Bander, Jeffrey; Elmariah, Sammy; Stelzer, Paul; Halperin, Jonathan L.; Kini, Annapoorna S.; Sharma, Samin K.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Elmariah, Sammy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Aledort, Louis M.] Mt Sinai Sch Med, Dept Med Hematol, New York, NY 10029 USA. [Dlott, Jeffrey] Quest Diagnost Nichols Inst, Chantilly, VA USA. RP Bander, J (reprint author), Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM jeffrey.bander@mssm.edu FU GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease; National Heart Lung, and Blood Institute [T32 HL007824] FX Dr. Elmariah was supported by the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease, and by a grant from the National Heart Lung, and Blood Institute (T32 HL007824). NR 30 TC 6 Z9 7 U1 0 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2012 VL 108 IS 1 BP 86 EP 93 DI 10.1160/TH11-12-0803 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 975VA UT WOS:000306538400013 PM 22627470 ER PT J AU Fryer, SL AF Fryer, Susanna L. TI Another Step Forward in Relating Facial and Brain Dysmorphologies Associated with Prenatal Alcohol Exposure SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article ID SPECTRUM DISORDERS; CORPUS-CALLOSUM; CHILDREN; ADULTS; FMRI C1 Univ Calif San Francisco, Dept Psychiat, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Fryer, SL (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco VA Med Ctr, Psychiat Serv 116D,4150 Clement St, San Francisco, CA 94121 USA. EM susanna.fryer@ucsf.edu FU [T32MH089920] FX This work was funded by T32MH089920. NR 13 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2012 VL 36 IS 7 BP 1131 EP 1133 DI 10.1111/j.1530-0277.2012.01849.x PG 3 WC Substance Abuse SC Substance Abuse GA 971QR UT WOS:000306219400003 PM 22780985 ER PT J AU Kelly, JF Urbanoski, K AF Kelly, John F. Urbanoski, Karen TI Youth Recovery Contexts: The Incremental Effects of 12-Step Attendance and Involvement on Adolescent Outpatient Outcomes SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Recovery; Adolescents; Alcoholics Anonymous; Narcotics Anonymous; Groups; Self-Help; Mutual Help; Treatment; Substance Use Disorder ID SELF-HELP GROUPS; MULTIVARIATE PROCESS MODEL; INPATIENT TREATMENT; SUBSTANCE-ABUSE; SINGLE-ITEM; PARTICIPATION; ALCOHOL; DEPENDENCE; ADDICTION; BEHAVIORS AB Background A major barrier to youth recovery is finding suitable sobriety-supportive social contexts. National studies reveal most adolescent addiction treatment programs link youths to community 12-step fellowships to help meet this challenge, but little is known empirically regarding the extent to which adolescents attend and benefit from 12-step meetings or whether they derive additional gains from active involvement in prescribed 12-step activities (e.g., contact with a sponsor and other fellowship members). Greater knowledge in this area would enhance the efficiency of clinical continuing care recommendations. Methods Adolescent outpatients (N = 127; M age 16.7; 75% male; 87% white) enrolled in a naturalistic study of treatment effectiveness were assessed at intake and 3, 6, and 12 months later using standardized assessments. Mixed-effects models, controlling for static and time-varying confounds, examined the concurrent and lagged effects of 12-step attendance and active involvement on abstinence over time. Results The proportion attending 12-step meetings was relatively low across follow-up (24 to 29%), but more frequent attendance was independently associated with greater abstinence in concurrent and, to a lesser extent, lagged models. An 8-item composite measure of 12-step involvement did not enhance outcomes over and above attendance, but separate components did; specifically, greater contact with a 12-step sponsor outside of meetings and more verbal participation during meetings. Conclusions The benefits of 12-step participation observed among adult samples extend to adolescent outpatients. Community 12-step fellowships appear to provide a useful sobriety-supportive social context for youths seeking recovery, but evidence-based youth-specific 12-step facilitation strategies are needed to enhance outpatient attendance rates. C1 [Kelly, John F.; Urbanoski, Karen] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Kelly, John F.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, 60 Staniford St, Boston, MA 02114 USA. EM jkelly11@partners.org OI Urbanoski, Karen/0000-0001-7287-7176 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [5R01AA015526-04] FX Study was supported by a grant award from National Institute on Alcohol Abuse and Alcoholism (NIAAA; JFK, 5R01AA015526-04). NR 56 TC 20 Z9 20 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2012 VL 36 IS 7 BP 1219 EP 1229 DI 10.1111/j.1530-0277.2011.01727.x PG 11 WC Substance Abuse SC Substance Abuse GA 971QR UT WOS:000306219400015 PM 22509904 ER PT J AU Carrillo, MC Bain, LJ Frisoni, GB Weiner, MW AF Carrillo, Maria C. Bain, Lisa J. Frisoni, Giovanni B. Weiner, Michael W. TI Worldwide Alzheimer's Disease Neuroimaging Initiative SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; Neuroimaging; Biomarkers ID ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; RECOMMENDATIONS; DISCOVERY; MILD AB The Alzheimer's Disease Neuroimaging Initiative (ADNI) was launched in 2003 to speed drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public private partnership, the first phase of ADNI (ADNI 1) set a new standard for data sharing without embargo. In addition, it has been extended to 2017 by additional funding (North American-ADNI Grand Opportunities and ADNI 2) as well as multiple projects around the world, collectively known as Worldwide ADNI (WW-ADNI). The goal of WW-ADNI is to harmonize projects and results across different geographical sites and to encourage and harmonize data management and availability to investigators around the world. WW-ADNI projects are currently underway in North America, Europe, Japan, Australia, Korea, Taiwan, and Argentina, with a nascent program in China and a possible future program in Brazil. (C) 2012 The Alzheimer's Association. All rights reserved. C1 [Carrillo, Maria C.] Alzheimers Assoc, Med cfc Sci Relat, Chicago, IL USA. [Frisoni, Giovanni B.] IRCCS, Ctr San Giovanni Dio Fatebenefratelli, Lab Neuroimaging, Brescia, Italy. [Weiner, Michael W.] San Francisco VA Med Ctr, No Calif Inst Res, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP Carrillo, MC (reprint author), Alzheimers Assoc, Med cfc Sci Relat, Chicago, IL USA. EM Maria.Carrillo@alz.org RI Frisoni, Giovanni B/K-1360-2016 OI Frisoni, Giovanni B/0000-0002-6419-1753 FU National Institute on Aging of the National Institutes of Health [U01-AG024904]; Alzheimer's Association; PharmaCog from the European Commission's Innovative Medicine Initiative [115009]; grant Programma Strategico [RF07.39.2]; grant Programma Strategico 2007, conv. PS39 [RF07.39.2] FX NA-ADNI was supported with a grant (U01-AG024904) from the National Institute on Aging of the National Institutes of Health. The pilot E-ADNI was funded by the Alzheimer's Association. E-ADNI is funded through PharmaCog from the European Commission's Innovative Medicine Initiative under grant agreement number 115009 (Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development, PharmaCog). Italian ADNI has been funded by the grant Programma Strategico 2007 (RF07.39.2), conv. PS39. NR 14 TC 42 Z9 43 U1 4 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD JUL PY 2012 VL 8 IS 4 BP 337 EP 342 DI 10.1016/j.jalz.2012.04.007 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 973XW UT WOS:000306394900010 PM 22748939 ER PT J AU Schopfer, DW Whooley, MA Stamos, TD AF Schopfer, David W. Whooley, Mary A. Stamos, Thomas D. TI Hospital compliance with performance measures and 30-day outcomes in patients with heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-CARE; OPTIMIZE-HF; MORTALITY; ASSOCIATION; SURVIVAL; DEFIBRILLATOR; MORBIDITY; ENALAPRIL; PROGRAM; TRIAL AB Background In 2005, the American College of Cardiology/American Heart Association published performance measures to provide a standard of care for hospitalized patients with heart failure ( HF). Despite increasing compliance with these measures, hospital mortality and readmission rates remain stagnant. Whether compliance with HF performance measures improves patient outcomes at the hospital level is unclear. Methods We evaluated compliance with HF performance measures at 3,655 US hospitals. Patients admitted with a diagnosis of HF in 2008 were identified using the US Department of Health and Human Services Hospital Compare database. Compliance with 4 specific performance measures was examined: evaluation of left ventricular systolic function, administration of angiotensin-converting enzyme inhibitor I or angiotensin-receptor blocker for left ventricular systolic dysfunction, offering smoking cessation advice and counseling, and providing discharge instructions. Thirty-day mortality and readmission rate were recorded. Results Hospitals reporting greater compliance with the 4 performance measures had significantly lower 30-day mortality rates. However, these hospitals were also located in areas of higher socioeconomic status and treated higher volumes of patients with HF. After adjusting for socioeconomic and hospital factors, only evaluation of left ventricular systolic function was associated with lower 30-day mortality, and evaluation of left ventricular systolic function and smoking cessation counseling were associated with lower readmission rates. Conclusions We found that socioeconomic factors and hospital volume were stronger predictors of mortality than compliance with HF performance measures. After adjusting for socioeconomic factors and hospital volume, only 1 of the 4 performance measures was associated with lower 30-day mortality and 2 were associated with lower readmissions. (Am Heart J 2012;164:80-6.) C1 [Schopfer, David W.; Stamos, Thomas D.] Univ Illinois, Coll Med, Cardiol Sect, Chicago, IL USA. [Whooley, Mary A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Schopfer, DW (reprint author), 4150 Clement St,111A1, San Francisco, CA 94121 USA. EM david.schopfer@ucsf.edu NR 31 TC 4 Z9 4 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUL PY 2012 VL 164 IS 1 BP 80 EP 86 DI 10.1016/j.ahj.2012.04.017 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 973NM UT WOS:000306366900012 PM 22795286 ER PT J AU Howard, SAH Krajewski, KM Thornton, E Jagannathan, JP O'Regan, K Cleary, J Ramaiya, N AF Howard, Stephanie Anne Holler Krajewski, Katherine M. Thornton, Eavan Jagannathan, Jyothi P. O'Regan, Kevin Cleary, James Ramaiya, Nikhil TI Decade of Molecular Targeted Therapy: Abdominal Manifestations of Drug Toxicities-What Radiologists Should Know SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE abdominal toxicities; bevacizumab; drug; molecular targeted therapy; targeted therapy; toxicity ID RENAL-CELL CARCINOMA; CHOLECYSTITIS; PATIENT; SORAFENIB; SUNITINIB; ERLOTINIB; LIVER AB OBJECTIVE. Novel drugs targeting molecular pathways involved in tumor development have revolutionized cancer treatment. Radiologists often focus on therapeutic response when evaluating cancer patients and may miss important signs of drug toxicity. This article familiarizes radiologists with the complications of molecular targeted agents in abdominal solid organs, enabling early identification and appropriate intervention and thus reducing patient morbidity and mortality. CONCLUSION. Knowledge of the common abdominal toxicities-including hepatitis, cholecystitis, pancreatitis, fluid retention, and infection-is crucial for early diagnosis, which may spare patients devastating complications or the need for surgery. C1 [Howard, Stephanie Anne Holler; Krajewski, Katherine M.; Thornton, Eavan; Jagannathan, Jyothi P.; O'Regan, Kevin; Cleary, James; Ramaiya, Nikhil] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. RP Howard, SAH (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02115 USA. EM sahoward@partners.org NR 15 TC 21 Z9 21 U1 2 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2012 VL 199 IS 1 BP 58 EP 64 DI 10.2214/AJR.11.7432 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 965YP UT WOS:000305804000031 PM 22733894 ER PT J AU Shah, SH Jagannathan, JP Krajewski, K O'Regan, KN George, S Ramaiya, NH AF Shah, Shaan H. Jagannathan, Jyothi P. Krajewski, Katherine O'Regan, Kevin N. George, Suzanne Ramaiya, Nikhil H. TI Uterine Sarcomas: Then and Now SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE carcinosarcoma; gynecologic imaging; leiomyosarcoma; oncologic imaging; uterine sarcoma; uterus; women's imaging ID ENDOMETRIAL STROMAL SARCOMA; GYNECOLOGIC-ONCOLOGY-GROUP; MIXED MULLERIAN TUMORS; SMOOTH-MUSCLE TUMORS; MR-IMAGING FINDINGS; POSITRON-EMISSION-TOMOGRAPHY; F-18 FLUORODEOXYGLUCOSE; PROGNOSTIC PARAMETERS; STAGE-II; UTERUS AB OBJECTIVE. The purpose of this article is to provide an updated review of uterine sarcomas. The traditionally described neoplasms are reviewed as well as several recently characterized entities in terms of their imaging and clinical aspects. We attempt to provide a longitudinal imaging overview, from initial presentation to follow-up. Imaging features are also described of response to traditional therapeutic agents and newer targeted agents. CONCLUSION. A greater understanding of the pathogenesis has improved our ability to image and treat uterine sarcomas, both at initial staging and on follow-up. Targeted therapy is assuming an increasingly important role in the management of these lesions. It is imperative for radiologists to be aware of response characteristics and potential complications of these agents as well as conventional chemotherapeutic agents. C1 [Shah, Shaan H.; Jagannathan, Jyothi P.; Krajewski, Katherine; George, Suzanne; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, Brookline, MA 02446 USA. [Jagannathan, Jyothi P.; Krajewski, Katherine; O'Regan, Kevin N.; George, Suzanne; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dept Radiol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Shah, SH (reprint author), Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, 20 Chapel St,Unit B401, Brookline, MA 02446 USA. EM sshah18@partners.org NR 73 TC 25 Z9 26 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2012 VL 199 IS 1 BP 213 EP 223 DI 10.2214/AJR.11.7287 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 965YP UT WOS:000305804000052 PM 22733915 ER PT J AU Kaewlai, R Abujudeh, H AF Kaewlai, Rathachai Abujudeh, Hani TI Nephrogenic Systemic Fibrosis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE gadolinium-based contrast agents; kidney function; MRI; nephrogenic systemic fibrosis (NSF) ID IMAGING CONTRAST AGENTS; RENAL-FAILURE; MEDICAL LITERATURE; GADOLINIUM; DERMOPATHY; GADODIAMIDE; RISK; SKIN; GADOPENTETATE; DIMEGLUMINE AB OBJECTIVE. The purpose of this article is to discuss nephrogenic systemic fibrosis (NSF) in detail regarding its history, possible pathophysiology, clinical and pathologic presentations, diagnosis, and implications for the radiology community. CONCLUSION. NSF is a potentially lethal disorder that occurs in patients with reduced kidney function. Current evidence suggests a strong association with gadolinium-based contrast agents-mostly used in MRI-in this patient group. This has urged the radiology community to emphasize careful screening for the presence of renal dysfunction among patients for whom gadolinium-enhanced MRI is contemplated. Appropriate selection of gadolinium-based contrast agent type, avoidance of nonstandard dosage, patient education, and informed consent have been recommended by authorities. C1 [Abujudeh, Hani] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kaewlai, Rathachai] Ramathibodi Hosp, Div Emergency Radiol, Dept Radiol, Bangkok, Thailand. [Kaewlai, Rathachai] Mahidol Univ, Bangkok 10700, Thailand. RP Abujudeh, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM habjujdeh@partners.org OI Kaewlai, Rathachai/0000-0002-0650-9380 NR 60 TC 39 Z9 40 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2012 VL 199 IS 1 BP W17 EP W23 DI 10.2214/AJR.11.8144 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 965YP UT WOS:000305804000002 PM 22733927 ER PT J AU Walker, CM Chung, JH Abbott, GF Little, BP El-Sherief, AH Shepard, JAO Lanuti, M AF Walker, Christopher M. Chung, Jonathan H. Abbott, Gerald F. Little, Brent P. El-Sherief, Ahmed H. Shepard, Jo-Anne O. Lanuti, Michael TI Mediastinal Lymph Node Staging: From Noninvasive to Surgical SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE bronchogenic carcinoma; lung cancer; lung carcinoma; lymph node staging ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; GUIDELINES 2ND EDITION; FDG-PET SCAN; RADIOFREQUENCY ABLATION; TNM CLASSIFICATION; TUMORS; CT; METAANALYSIS; METASTASES AB OBJECTIVE. The purpose of this review is to describe the current lymph node stations and lymph node staging of non-small cell lung carcinoma. Minimally invasive and invasive methods of mediastinal lymph node staging are emphasized, and the relative accuracy and limitations of each modality are described. CONCLUSION. Lung carcinoma remains the most common cause of cancer death in the United States. Accurate staging of lung cancer is imperative for implementing the correct therapy and assessing patient prognosis. C1 [Walker, Christopher M.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Chung, Jonathan H.] Natl Jewish Hlth, Dept Radiol, Denver, CO USA. [Abbott, Gerald F.; Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Little, Brent P.] Emory Univ, Atlanta, GA 30322 USA. [El-Sherief, Ahmed H.] Cleveland Clin, Sect Thorac Radiol, Imaging Inst, Cleveland, OH 44106 USA. [Lanuti, Michael] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Walker, CM (reprint author), Univ Washington, Med Ctr, Dept Radiol, Box 357115,1959 NE Pacific St, Seattle, WA 98195 USA. EM walk0060@uw.edu FU Siemens Healthcare FX Supported by a research grant from Siemens Healthcare (J. H. Chung). NR 37 TC 11 Z9 12 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2012 VL 199 IS 1 BP W54 EP W64 DI 10.2214/AJR.11.7446 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 965YP UT WOS:000305804000007 PM 22733932 ER PT J AU Merchant-Borna, K Rodrigues, EG Smith, KW Proctor, SP Mcclean, MD AF Merchant-Borna, Kian Rodrigues, Ema G. Smith, Kristen W. Proctor, Susan P. Mcclean, Michael D. TI Characterization of Inhalation Exposure to Jet Fuel among U.S. Air Force Personnel SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE exposure assessment; hydrocarbons; inhalation; jet fuel; JP-8; mixture ID DERMAL EXPOSURE; JP-8; HYDROCARBONS; NAPHTHALENE; BENZENE; SMOKE; PAHS; SKIN; JP8 AB Jet propulsion fuel-8 (JP-8) is the primary jet fuel used by the US military, collectively consuming similar to 2.5 billion gallons annually. Previous reports suggest that JP-8 is potentially toxic to the immune, respiratory, and nervous systems. The objectives of this study were to evaluate inhalation exposure to JP-8 constituents among active duty United States Air Force (USAF) personnel while performing job-related tasks, identify significant predictors of inhalation exposure to JP-8, and evaluate the extent to which surrogate exposure classifications were predictive of measured JP-8 exposures. Seventy-three full-time USAF personnel from three different air force bases were monitored during four consecutive workdays where personal air samples were collected and analyzed for benzene, ethylbenzene, toluene, xylenes, total hydrocarbons (THC), and naphthalene. The participants were categorized a priori into high- and low-exposure groups, based on their exposure to JP-8 during their typical workday. Additional JP-8 exposure categories included job title groups and self-reported exposure to JP-8. Linear mixed-effects models were used to evaluate predictors of personal air concentrations. The concentrations of THC in air were significantly different between a priori exposure groups (2.6 mg m(-3) in high group versus 0.5 mg m(-3) in low, P < 0.0001), with similar differences observed for other analytes in air. Naphthalene was strongly correlated with THC (r = 0.82, P < 0.0001) and both were positively correlated with the relative humidity of the work environment. Exposures to THC and naphthalene varied significantly by job categories based on USAF specialty codes and were highest among personnel working in fuel distribution/maintenance, though self-reported exposure to JP-8 was an even stronger predictor of measured exposure in models that explained 72% (THC) and 67% (naphthalene) of between-worker variability. In fact, both self-report JP-8 exposure and a priori exposure groups explained more between-worker variability than job categories. Personal exposure to JP-8 varied by job and was positively associated with the relative humidity. However, self-reported exposure to JP-8 was an even stronger predictor of measured exposure than job title categories, suggesting that self-reported JP-8 exposure is a valid surrogate metric of exposure when personal air measurements are not available. C1 [Merchant-Borna, Kian; Rodrigues, Ema G.; Smith, Kristen W.; Proctor, Susan P.; Mcclean, Michael D.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [Merchant-Borna, Kian] Univ Rochester, Dept Environm Med, Sch Med & Dent, Rochester, NY 14642 USA. [Rodrigues, Ema G.; Smith, Kristen W.] Harvard Univ, Dept Environm Hlth, Sch Publ Hlth, Boston, MA 02115 USA. [Proctor, Susan P.] USA, Environm Med Res Inst, Natick, MA 01760 USA. [Proctor, Susan P.] VA Boston Healthcare Syst, Boston, MA 02132 USA. RP Mcclean, MD (reprint author), Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. EM mmcclean@bu.edu RI McClean, Michael/J-2934-2015; OI McClean, Michael/0000-0002-3902-8823 FU US Army Medical Research and Materiel Command [W81XWH-06-1-0105] FX US Army Medical Research and Materiel Command award (W81XWH-06-1-0105) to the Henyt M. Jackson Foundation of the Advancement of Military Medicine, Inc. (PI: SP Proctor). NR 27 TC 4 Z9 4 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JUL PY 2012 VL 56 IS 6 BP 736 EP 745 DI 10.1093/annhyg/mes014 PG 10 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 974DA UT WOS:000306408800009 PM 22433121 ER PT J AU Koo, HJ Burns, JA Kobler, JB Heaton, JT Zeitels, SM AF Koo, Hae Jin Burns, James A. Kobler, James B. Heaton, James T. Zeitels, Steven M. TI Novel Device for Tissue Cooling During Endoscopic Laryngeal Laser Surgery: Thermal Damage Study in an Ex Vivo Calf Model SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE cooling; laser; microlaryngoscopy; thermal damage; vocal cord; vocal fold ID CO2-LASER SURGERY; THULIUM LASER; COMPLICATIONS; TEMPERATURE; LESIONS; AIR AB Objectives: Minimizing collateral thermal damage during endoscopic laryngeal laser surgery remains a priority, and tissue cooling is one way to achieve this goal. Cooling systems utilizing compressed air have been shown to reduce the extent of thermal trauma on the vocal folds, but these units are not ideal for endoscopic applications because cooling is inefficient at the low airflows needed. We examined whether a novel vortex cooling device that generates cooled air at low flow rates would provide a cooling benefit beyond that which could be obtained by using room-temperature air for cooling tissue or by using no cooling during simulated laryngeal laser surgery. Methods: A continuous-wave thulium laser was used to incise glottic tissue in 12 calf vocal folds. Cooling was achieved with a prototype vortex cooler (9 degrees C air output; flow rate, 3 L/min), and tissue temperature measurements were compared to those with room-air cooling and no cooling. Thermal damage was analyzed histologically by measuring the depth of lactate dehydrogenase inactivation surrounding the mucosal incision. The cooling conditions were tested during time-constant cuts (8 seconds) and depth-constant cuts (into the thyroarytenoid muscle). Results: During time-constant cuts, comparison between vortex cooling and room-air cooling revealed that vortex cooling resulted in a thermal damage zone that was 14% smaller (519 versus 603 mu m; p < 0.05). During depth-constant cuts, vortex cooling created a thermal damage zone that was 32% smaller than that created with no cooling (p < 0.01) and 9% smaller than that created with room-air cooling (p < 0.01). Conclusions: Vortex cooling reduces thermal damage more effectively than room-air cooling or no cooling during both time-constant and depth-constant thulium laser cuts. C1 [Burns, James A.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Burns, JA (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. FU Institute of Laryngology and Voice Restoration; The "V" Foundation FX From the Department of Surgery, Harvard Medical School, and the Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Boston, Massachusetts. Mr Koo is currently at the Korea Advanced Institute of Technology, Daejeon, Republic of Korea. This work was supported in part by the Institute of Laryngology and Voice Restoration and The "V" Foundation. NR 11 TC 3 Z9 3 U1 0 U2 2 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JUL PY 2012 VL 121 IS 7 BP 485 EP 489 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 973XT UT WOS:000306394500010 PM 22844869 ER PT J AU Hadlock, TA Urban, LS AF Hadlock, Tessa A. Urban, Luke S. TI Toward a Universal, Automated Facial Measurement Tool in Facial Reanimation SO ARCHIVES OF FACIAL PLASTIC SURGERY LA English DT Article ID FREE-MUSCLE TRANSFER; NERVE GRADING SYSTEMS; LONG-TERM OUTCOMES; HOUSE-BRACKMANN; SMILE RESTORATION; MOTION ANALYSIS; PARALYSIS; MOVEMENT; PALSY; FACE AB Objective: To describe a highly quantitative facial function measuring tool that yields accurate, objective measures of facial position in significantly less time than existing methods. Methods: Facial Assessment by Computer Evaluation (FACE) software was designed for facial analysis. Outputs report the static facial landmark positions and dynamic facial movements relevant in facial reanimation. Fifty individuals underwent facial movement analysis using Photoshop-based measurements and the new software; comparisons of agreement and efficiency were made. Comparisons were made between individuals with normal facial animation and patients with paralysis to gauge sensitivity to abnormal movements. Results: Facial measurements were matched using FACE software and Photoshop-based measures at rest and during expressions. The automated assessments required significantly less time than Photoshop-based assessments. FACE measurements easily revealed differences between individuals with normal facial animation and patients with facial paralysis. Conclusions: FACE software produces accurate measurements of facial landmarks and facial movements and is sensitive to paralysis. Given its efficiency, it serves as a useful tool in the clinical setting for zonal facial movement analysis in comprehensive facial nerve rehabilitation programs. C1 [Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Hadlock, Tessa A.] Harvard Univ, Sch Med, Boston, MA USA. [Urban, Luke S.] MIT, Dept Comp Sci, Cambridge, MA 02139 USA. RP Hadlock, TA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM tessa_hadlock@meei.harvard.edu NR 46 TC 24 Z9 26 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1521-2491 J9 ARCH FACIAL PLAST S JI Arch. Facial Plast. Surg. PD JUL-AUG PY 2012 VL 14 IS 4 BP 277 EP 282 DI 10.1001/archfacial.2012.111 PG 6 WC Surgery SC Surgery GA 973SP UT WOS:000306380400009 PM 22508895 ER PT J AU Daniels, AB Sandberg, MA Chen, JJ Weigel-DiFranco, C Hejtmancik, JF Berson, EL AF Daniels, Anthony B. Sandberg, Michael A. Chen, Jianjun Weigel-DiFranco, Carol Hejtmancik, J. Fielding Berson, Eliot L. TI Genotype-Phenotype Correlations in Bardet-Biedl Syndrome SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID RETINITIS-PIGMENTOSA; OBESITY SYNDROME; MUTATIONS; DISEASE; GENES; POPULATION; COMPLEX; IDENTIFICATION; TRANSPORT; PROTEINS AB Objective: To determine whether mutations in different Bardet-Biedl syndrome (BBS) genes result in different ocular phenotypes. Methods: Thirty-seven patients from 31 families were enrolled who met the clinical criteria for BBS and for whom a BBS mutation had been identified. Seventeen patients harbored mutations in BBS1, 10 in BBS10, and 10 in other genes (BBS2, BBS3, BBS5, BBS7, and BBS12). All the patients underwent ocular examination; 36 patients had computerized full-field electroretinograms (ERGs). Results: Visual acuity was significantly better in BBS1 patients than in patients with other BBS mutations (P=.01), and a larger proportion of BBS1 patients had good (>= 20/50) visual acuity (P=.01). The ERG amplitudes were significantly higher in BBS1 patients than in patients with other BBS mutations in response to 0.5-Hz and 30-Hz flashes (P <.001 for both). All the BBS1 patients harbored at least 1 missense mutation compared with only 45% of patients with mutations in other BBS genes (P <.001); the rest harbored only null alleles. However, multivariate analysis demonstrated that visual acuity or ERG amplitude did not depend on the type of mutation present (missense or null) when controlling for BBS gene. Prevalences of bone spicule pigmentation and cataract were comparable in BBS subtypes. Conclusions: Patients with BBS1 mutations had a milder phenotype than did patients with mutations in other BBS genes. Clinically, this manifested as significantly better visual acuity and larger ERG amplitudes. C1 [Daniels, Anthony B.; Sandberg, Michael A.; Weigel-DiFranco, Carol; Berson, Eliot L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Dept Ophthalmol,Med Sch, Boston, MA 02114 USA. [Chen, Jianjun; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Berson, EL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Dept Ophthalmol,Med Sch, 243 Charles St, Boston, MA 02114 USA. EM linda_berard@meei.harvard.edu FU Foundation Fighting Blindness FX This work was supported in part by a center grant from the Foundation Fighting Blindness (Dr Berson). NR 28 TC 13 Z9 13 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUL PY 2012 VL 130 IS 7 BP 901 EP 907 DI 10.1001/archophthalmol.2012.89 PG 7 WC Ophthalmology SC Ophthalmology GA 974FR UT WOS:000306416900014 PM 22410627 ER PT J AU Perry, LJP Jakobiec, FA Rubin, PAD AF Perry, Lynn J. Poole Jakobiec, Frederick A. Rubin, Peter A. D. TI Conjunctival Pediatric Follicular Lymphoma SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID TUMORS C1 [Perry, Lynn J. Poole; Jakobiec, Frederick A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Perry, Lynn J. Poole; Jakobiec, Frederick A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Rubin, Peter A. D.] Univ Tennessee, Dept Ophthalmol, Memphis, TN USA. [Rubin, Peter A. D.] Ophthalm Plast & Orbital Surg, W Palm Beach, FL USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Ste 321, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 10 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUL PY 2012 VL 130 IS 7 BP 941 EP 943 PG 4 WC Ophthalmology SC Ophthalmology GA 974FR UT WOS:000306416900031 PM 22776942 ER PT J AU Ingraham, AM Haas, B Cohen, ME Ko, CY Nathens, AB AF Ingraham, Angela M. Haas, Barbara Cohen, Mark E. Ko, Clifford Y. Nathens, Avery B. TI Comparison of Hospital Performance in Trauma vs Emergency and Elective General Surgery Implications for Acute Care Surgery Quality Improvement SO ARCHIVES OF SURGERY LA English DT Article ID SURGICAL CARE; RISK; MARKER AB Hypotheses: As emergency general surgery (EMGS) and trauma care are increasingly being provided by the same personnel with overlapping resources, we postulated that the quality of care provided to EMGS and trauma patients would be similar. We also evaluated the relationship between trauma and elective general surgery (ELGS) care, believing that performance would be similar across these services as it reflects institutional culture. Design: Retrospective cohort study comparing hospital performance in trauma and EMGS care and in trauma and ELGS care. Regression models for mortality and serious morbidity were constructed for trauma, EMGS, and ELGS hospitals contributing to both the National Trauma Data Bank (2007) and American College of Surgeons National Surgical Quality Improvement Program (2005-2008). Setting: Forty - six hospitals. Main Outcome Measures: Correlations of observed to expected ratios were examined. Outlier status (hospitals with CIs of observed to expected ratios excluding 1.0) was compared using weighted kappa. Results: There was no significant relationship between trauma and EMGS mortality (r=-0.01, P=.94; kappa=-0.10, P=.61) or between trauma and ELGS mortality (r=0.23, P=.12; kappa=0.07, P=.62). There was no significant relationship between trauma and EMGS morbidity (r=0.21, P=.17; kappa=0.04, P=.63) or between trauma and ELGS morbidity (r=0.16, P=.30; kappa=0.11, P=.37). No hospitals were consistently low or high outliers across all 3 groups. Conclusions: Trauma performance improvement programs are well established compared with those for EMGS. Although EMGS patients use similar structures and processes as trauma patients, there is a lack of correlation between the quality of care provided to trauma and EMGS patients; EMGS should be incorporated into trauma performance improvement programs. C1 [Ingraham, Angela M.] Univ Cincinnati, Dept Surg, Coll Med, Cincinnati, OH 45267 USA. [Ingraham, Angela M.; Cohen, Mark E.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Haas, Barbara; Nathens, Avery B.] Inst St Michaels Hosp, Div Surg & Trauma, Keenan Res Ctr Li Ka Shing Knowledge, Toronto, ON, Canada. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. RP Ingraham, AM (reprint author), Univ Cincinnati, Dept Surg, Coll Med, Mail Locat 0558,231 Albert Sabin Way,Room 1586, Cincinnati, OH 45267 USA. EM angieingraham@gmail.com FU Clinical Scholars in Residence Program at the ACS; Canadian Institutes of Health Research; Canada Research Chair in Systems of Trauma Care FX Dr Ingraham is supported by the Clinical Scholars in Residence Program at the ACS. Dr Haas is supported by a Canadian Institutes of Health Research fellowship. Dr Nathens is supported by a Canada Research Chair in Systems of Trauma Care. NR 20 TC 9 Z9 9 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JUL PY 2012 VL 147 IS 7 BP 591 EP 598 DI 10.1001/archsurg.2012.71 PG 8 WC Surgery SC Surgery GA 974GB UT WOS:000306417900004 PM 22430094 ER PT J AU Maciejewski, ML Livingston, EH Smith, VA Kahwati, LC Henderson, WG Arterburn, DE AF Maciejewski, Matthew L. Livingston, Edward H. Smith, Valerie A. Kahwati, Leila C. Henderson, William G. Arterburn, David E. TI Health Expenditures Among High-Risk Patients After Gastric Bypass and Matched Controls SO ARCHIVES OF SURGERY LA English DT Article ID MORBIDLY OBESE-PATIENTS; LONG-TERM MORTALITY; BARIATRIC SURGERY; COST-EFFECTIVENESS; MEDICAL EXPENDITURES; PROPENSITY SCORE; SELECTION BIAS; WEIGHT-LOSS; CARE COSTS; ADJUSTMENT AB Objective: To determine whether bariatric surgery is associated with reduced health care expenditures in a multisite cohort of predominantly older male patients with a substantial disease burden. Design: Retrospective cohort study of bariatric surgery. Outpatient, inpatient, and overall health care expenditures within Department of Veterans Affairs (VA) medical centers were examined via generalized estimating equations in the propensity-matched cohorts. Setting: Bariatric surgery programs in VA medical centers. Participants: Eight hundred forty-seven veterans who were propensity matched to 847 nonsurgical control subjects from the same 12 VA medical centers. Intervention: Bariatric surgical procedures. Main Outcome Measure: Health expenditures through December 2006. Results: Outpatient, inpatient, and total expenditures trended higher for bariatric surgical cases in the 3 years leading up to the procedure and then converged back to the lower expenditure levels of nonsurgical controls in the 3 years after the procedure. Conclusions: Based on analyses of a cohort of predominantly older men, bariatric surgery does not appear to be associated with reduced health care expenditures 3 years after the procedure. C1 [Maciejewski, Matthew L.; Smith, Valerie A.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC 27705 USA. [Maciejewski, Matthew L.] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. [Kahwati, Leila C.] Vet Hlth Adm, Natl Ctr Hlth Promot & Dis Prevent, Off Patient Care Serv, Durham, NC USA. [Livingston, Edward H.] Univ Texas SW Med Ctr Dallas, Div Gastrointestinal & Endocrine Surg, Dallas, TX 75390 USA. [Livingston, Edward H.] VA N Texas Hlth Care Syst, Dallas, TX USA. [Livingston, Edward H.] Univ Texas Arlington, Biomed Engn Grad Program, Arlington, TX USA. [Henderson, William G.] Denver VA Med Ctr, Denver, CO USA. [Henderson, William G.] Univ Colorado, Dept Biostat, Sch Publ Hlth, Aurora, CO USA. [Henderson, William G.] Univ Colorado, Colorado Hlth Outcomes Program, Aurora, CO USA. [Arterburn, David E.] Univ Washington, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Arterburn, David E.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. RP Maciejewski, ML (reprint author), Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Mail Stop 152,411 W Chapel Hill St,Ste 600, Durham, NC 27705 USA. EM matthew.maciejewski@va.gov FU Takeda Pharmaceuticals, Novartis; Surgical Review Corporation; Texas Instruments; Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs [IIR 05-201, SHP 08-137]; Department of Veterans Affairs [RCS 10-391] FX Dr Maciejewski has received consultation funds from Takeda Pharmaceuticals, Novartis, and the Surgical Review Corporation and owns stock in Amgen. Dr Livingston has received consulting funds from Texas Instruments and serves as a contributing editor to JAMA. Dr Arterburn receives research funding and has received salary support as a medical editor for the not-for-profit (501[c][3]) Foundation for Informed Medical Decision Making (http://www.fimdm.org), which develops content for patient education programs. The Foundation has an arrangement with a for-profit company, Health Dialog, to coproduce and market these programs to health care organizations. Dr Arterburn was formerly with the Cincinnati VA, and Dr Livingston was formerly with the Dallas VA.; This study was supported by grants IIR 05-201 and SHP 08-137 from the Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs, and by Research Career Scientist award RCS 10-391 from the Department of Veterans Affairs (Dr Maciejewski). NR 37 TC 25 Z9 25 U1 5 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JUL PY 2012 VL 147 IS 7 BP 633 EP 640 PG 8 WC Surgery SC Surgery GA 974GB UT WOS:000306417900014 PM 22802057 ER PT J AU Kim, JY Jo, MW Brauner, SC Ferrufino-Ponce, Z Ali, R Cremers, SL Henderson, BA AF Kim, J. Y. Jo, M-W Brauner, S. C. Ferrufino-Ponce, Z. Ali, R. Cremers, S. L. Henderson, B. A. TI Comment to 'First postoperative day intraocular pressure rise in resident-performed cataract surgery' SO EYE LA English DT Letter C1 [Kim, J. Y.] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Ophthalmol, Seoul, South Korea. [Kim, J. Y.] Univ Ulsan, Coll Med, Asan Med Ctr, Res Inst Biomacromol, Seoul, South Korea. [Kim, J. Y.; Brauner, S. C.; Cremers, S. L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Ferrufino-Ponce, Z.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Jo, M-W] Univ Ulsan, Coll Med, Dept Prevent Med, Seoul, South Korea. [Ali, R.] Univ Texas Med Branch, Dept Ophthalmol & Visual Sci, Galveston, TX USA. [Henderson, B. A.] Harvard Univ, Sch Med, Ophthalm Consultants Boston, Boston, MA USA. RP Kim, JY (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Ophthalmol, Seoul, South Korea. EM jykim2311@amc.seoul.kr NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD JUL PY 2012 VL 26 IS 7 BP 1026 EP 1027 DI 10.1038/eye.2012.71 PG 4 WC Ophthalmology SC Ophthalmology GA 973LE UT WOS:000306360800023 ER PT J AU Gewirtz, H AF Gewirtz, Henry TI Myocardial Imaging for Mitochondrial Membrane Potential SO JACC-CARDIOVASCULAR IMAGING LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gewirtz, H (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW 5, Boston, MA 02114 USA. EM hgewirtz@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUL PY 2012 VL 5 IS 7 BP 758 EP 760 DI 10.1016/j.jcmg.2012.04.004 PG 4 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 973ZU UT WOS:000306400200013 PM 22789946 ER PT J AU Khosla, S Bilezikian, JP Dempster, DW Lewiecki, EM Miller, PD Neer, RM Recker, RR Shane, E Shoback, D Potts, JT AF Khosla, Sundeep Bilezikian, John P. Dempster, David W. Lewiecki, E. Michael Miller, Paul D. Neer, Robert M. Recker, Robert R. Shane, Elizabeth Shoback, Dolores Potts, John T. TI Benefits and Risks of Bisphosphonate Therapy for Osteoporosis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FRACTURE INTERVENTION TRIAL; RANDOMIZED CONTROLLED-TRIAL; DIAPHYSEAL FEMUR FRACTURES; ATYPICAL FEMORAL FRACTURES; ZOLEDRONIC ACID; POSTMENOPAUSAL OSTEOPOROSIS; ATRIAL-FIBRILLATION; ORAL BISPHOSPHONATES; VERTEBRAL FRACTURES; ESOPHAGEAL CANCER AB Context: There has been considerable concern recently in the scientific and lay media regarding the benefits vs. the risks of bisphosphonates for the treatment of osteoporosis. Risks include possible associations with osteonecrosis of the jaw (ONJ) and atypical femur fractures. In this perspective, we review the use of bisphosphonates for the treatment of osteoporosis, including an objective assessment of the risks vs. the benefits of these drugs. Evidence Acquisition: Authors' knowledge of the field and results of focused literature searches are presented. Evidence Synthesis: Bisphosphonates have proven efficacy in the prevention of bone loss and in the reduction of fractures in postmenopausal women and men with established osteoporosis. Although bisphosphonates, at doses used to treat osteoporosis, may be associated with an increased risk of ONJ and atypical femur fractures, many more fractures are prevented by the use of these drugs compared to the relatively low risk of these complications. Although oral bisphosphonates are associated with upper gastrointestinal side effects and iv bisphosphonates with acute phase reactions, the association of bisphosphonate use with esophageal cancer and atrial fibrillation is not well supported by current data. Conclusions: Bisphosphonates have been proven to prevent fractures in patients with established osteoporosis or those who are at high risk of fracture. In contrast, the incidence of major complications associated with bisphosphonate use, such as ONJ and atypical femur fractures, is very low. (J Clin Endocrinol Metab 97: 2272-2282, 2012) C1 [Khosla, Sundeep] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Bilezikian, John P.; Shane, Elizabeth] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Dempster, David W.] Helen Hayes Hosp, W Haverstraw, NY 10993 USA. [Lewiecki, E. Michael] Univ New Mexico, Sch Med, Albuquerque, NM 87102 USA. [Miller, Paul D.] Colorado Ctr Bone Res, Lakewood, CO 80227 USA. [Neer, Robert M.; Potts, John T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Neer, Robert M.; Potts, John T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Recker, Robert R.] Creighton Univ, Omaha, NE 68178 USA. [Shoback, Dolores] Univ Calif San Francisco, San Francisco Dept Vet Affairs, San Francisco, CA 94121 USA. RP Khosla, S (reprint author), Mayo Clin, Coll Med, Guggenheim 7,200 1st St SW, Rochester, MN 55905 USA. EM khosla.sundeep@mayo.edu; jpb2@columbia.edu OI Khosla, Sundeep/0000-0002-2936-4372 FU NPS; Lilly; Amgen; Merck; Warner Chilcott; Pfizer; Procter Gamble; Roche; Novartis; Chugai FX Sundeep Khosla, consultant or member of advisory board to Bone Therapeutics and Amgen. John P. Bilezikian, research grant or financial support from NPS; consultant or member of advisory board to Amgen, Merck, Novartis, NPS, Warner Chilcott, Lilly, Radius, and GSK; and participant in a speaker's bureau with Amgen, Novartis, and Lilly. David W. Dempster, research grant or financial support from Lilly; consultant or member of advisory board to Amgen, Lilly, Merck, and NPS; participant in a speaker's bureau with Amgen and Lilly. E. Michael Lewiecki, research grant or financial support from Amgen, Lilly, and Merck; consultant or member of advisory board to Amgen, GSK, Lilly, Merck, Novartis, Warner Chilcott; participant in a speaker's bureau with Amgen, Lilly, Merck, Novartis, and Warner Chilcott. Paul D. Miller, research grant or financial support from Amgen, Lilly, and Warner Chilcott; consultant or member of advisory board to Amgen, Merck, Novartis, and Warner Chilcott; participant in a speaker's bureau with Amgen, Novartis, and Warner Chilcott. Robert M. Neer, research grant or financial support from Amgen; and consultant or member of advisory board to Lilly and Novartis. Robert R. Recker, research grant or financial support from Merck, Lilly, Pfizer, Procter & Gamble, Amgen, Roche, and Novartis; and consultant or member of advisory board to Merck, Lilly, Pfizer, Procter & Gamble, Amgen, Roche, and Novartis. Elizabeth Shane, research grant or financial support from Merck, Novartis, and Lilly. Dolores Shoback, research grant or financial support from Lilly. John T. Potts, research grant or financial support from Amgen and Chugai; consultant or member of advisory board to Biosante, Merck, and Radius; and stock holdings in Biosante and Radius. NR 98 TC 80 Z9 84 U1 2 U2 21 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 JUL PY 2012 VL 97 IS 7 BP 2272 EP 2282 DI 10.1210/jc.2012-1027 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 972OJ UT WOS:000306286100046 PM 22523337 ER PT J AU Marshall, DT Savage, SJ Garrett-Mayer, E Keane, TE Hollis, BW Horst, RL Ambrose, LH Kindy, MS Gattoni-Celli, S AF Marshall, David T. Savage, Stephen J. Garrett-Mayer, Elizabeth Keane, Thomas E. Hollis, Bruce W. Horst, Ronald L. Ambrose, Linda H. Kindy, Mark S. Gattoni-Celli, Sebastiano TI Vitamin D-3 Supplementation at 4000 International Units Per Day for One Year Results in a Decrease of Positive Cores at Repeat Biopsy in Subjects with Low-Risk Prostate Cancer under Active Surveillance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CONSERVATIVE MANAGEMENT; SOLAR-RADIATION; LEUKEMIA-CELLS; DOUBLE-BLIND; LNCAP CELLS; MORTALITY; TRIAL; APOPTOSIS; CALCIUM; WOMEN AB Context: We wanted to investigate vitamin D in low-risk prostate cancer. Objectives: The objective of the study was to determine whether vitamin D-3 supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression. Design: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy. Setting: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC. Patients and Other Participants: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives. Intervention: The intervention included vitamin D-3 soft gels (4000 IU). Main Outcome Measures: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation. Results: No adverse events associated with vitamin D-3 supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score. Conclusion: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D-3 supplementation at 4000 IU/d. (J Clin Endocrinol Metab 97: 2315-2324, 2012) C1 [Marshall, David T.; Ambrose, Linda H.; Gattoni-Celli, Sebastiano] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Savage, Stephen J.; Keane, Thomas E.] Med Univ S Carolina, Dept Urol, Charleston, SC 29425 USA. [Garrett-Mayer, Elizabeth] Med Univ S Carolina, Dept Med Biostat, Charleston, SC 29425 USA. [Hollis, Bruce W.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Kindy, Mark S.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Savage, Stephen J.; Kindy, Mark S.; Gattoni-Celli, Sebastiano] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Horst, Ronald L.] Iowa State Univ, Dept Anim Sci, Ames, IA 50011 USA. RP Gattoni-Celli, S (reprint author), Strom Thurmond Biomed Res Bldg,Room 338C,114 Doug, Charleston, SC 29403 USA. EM gattonis@musc.edu FU Gateway for Cancer Research Grant [G-06-068]; Health Services Research and Development Program of the Department of Veterans Affairs, Veterans Affairs Merit Award [CX000163]; Biostatistics Shared Resource, Hollings Cancer Center's Support Grant [P30 CA138313]; National Institutes of Health/National Center for Research Resources [UL1 RR029881]; South Carolina Clinical and Translational Research Institute [UL1 RR029882] FX This work was supported in part by Gateway for Cancer Research Grant G-06-068), the Health Services Research and Development Program of the Department of Veterans Affairs, Veterans Affairs Merit Award CX000163, the Biostatistics Shared Resource, Hollings Cancer Center's Support Grant P30 CA138313 (National Institutes of Health/National Center for Research Resources Grant UL1 RR029881), and South Carolina Clinical and Translational Research Institute Grant UL1 RR029882. NR 40 TC 35 Z9 35 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2012 VL 97 IS 7 BP 2315 EP 2324 DI 10.1210/jc.2012-1451 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 972OJ UT WOS:000306286100054 PM 22508710 ER PT J AU Beauharnais, CC Roberts, DJ Wexler, DJ AF Beauharnais, Catherine C. Roberts, Drucilla J. Wexler, Deborah J. TI High Rate of Placental Infarcts in Type 2 Compared with Type 1 Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID REACTION PATTERNS; PREGNANCY; WOMEN; RISK; REPRODUCIBILITY; SINGLETON; NOSOLOGY AB Context: Timing and cause of pregnancy loss differ between type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Objective: The objective of the study was to determine whether placental histology corresponds to differing causes of pregnancy loss in T1DM and T2DM. We hypothesized that placentas from mothers with T2DM would be more likely to demonstrate vascular pathology than those from mothers with T1DM. Research Design/Setting/Participants: We reviewed medical histories, pregnancy outcomes, and placental histology of women with pregestational T1DM and T2DM with singleton pregnancies between 2001 and 2009 at a single tertiary care medical center. Main Outcome Measures: Placental weight, placental dysmaturity, villous maturation, villitis of unclear etiology, and histological evidence of placental infarction were measured. Results: Ninety-eight placentas were available for review, 53 from T1DM mothers (56%) and 45 from T2DM mothers (46%). Mean age and glycemic control each trimester did not differ between diabetes types. T2DM placentas had a higher prevalence of placental infarcts (22 vs. 6%, P = 0.02) and a lower prevalence of placental dysmaturity (12 vs. 29%, P = 0.05) compared with T1DM; rates differed from those reported in the general population. There was no difference in placental weight, villous maturity, or villitis of unclear etiology between diabetes types. Conclusions: There were many similarities in placental histological findings between diabetes types. Still, one in five T2DM placentas displayed histological infarcts, consistent with a vascular, rather than glycemic, etiology of pregnancy complications, whereas T1DM placentas showed signs of abnormal development. (J Clin Endocrinol Metab 97: E1160-E1164, 2012) C1 [Beauharnais, Catherine C.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02118 USA. [Wexler, Deborah J.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02118 USA. [Roberts, Drucilla J.; Wexler, Deborah J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Wexler, DJ (reprint author), Massachusetts Gen Hosp, Diabet Unit, Bulfinch 408A,55 Fruit St, Boston, MA 02114 USA. EM dwexler@partners.org FU National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award [K23 DK 080 228] FX D.J.W. is supported by National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award K23 DK 080 228. NR 20 TC 9 Z9 9 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2012 VL 97 IS 7 BP E1160 EP E1164 DI 10.1210/jc.2011-3326 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 972OJ UT WOS:000306286100009 PM 22492874 ER PT J AU Ingram, KH Hill, H Moellering, DR Hill, BG Lara-Castro, C Newcomer, B Brandon, LJ Ingalls, CP Penumetcha, M Rupp, JC Garvey, WT AF Ingram, Katherine H. Hill, Helliner Moellering, Douglas R. Hill, Bradford G. Lara-Castro, Cristina Newcomer, Bradley Brandon, L. Jerome Ingalls, Christopher P. Penumetcha, Meera Rupp, Jeffrey C. Garvey, W. Timothy TI Skeletal Muscle Lipid Peroxidation and Insulin Resistance in Humans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID OXIDATIVE STRESS; BIOMARKERS; ALDEHYDES; EXERCISE; OBESITY; DISEASE; PLASMA AB Objective: The relationships among skeletal muscle lipid peroxidation, intramyocellular lipid content (IMCL), and insulin sensitivity were evaluated in nine insulin-sensitive (IS), 13 insulin-resistant (IR), and 10 adults with type 2 diabetes (T2DM). Design: Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp [ glucose disposal rate (GDR)]. Lipid peroxidation was assessed by 4-hydroxynonenal (HNE)-protein adducts and general oxidative stress by protein carbonyl content. All patients were sedentary. Results: Protein-HNE adducts were elevated 1.6-fold in T2DM compared with IS adults, whereas IR showed intermediate levels of HNE-modified proteins. Protein-HNE adducts correlated with GDR, waist circumference, and body mass index. IMCL was increased by 4.0- and 1.9-fold in T2DM and IR patients, respectively, compared with IS, and was correlated with GDR and waist circumference but not BMI. Protein carbonyls were not different among groups and did not correlate with any of the measured variables. Correlations were detected between IMCL and protein-HNE. Conclusion: Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance. (J Clin Endocrinol Metab 97: E1182-E1186, 2012) C1 [Ingram, Katherine H.; Moellering, Douglas R.; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Newcomer, Bradley] Univ Alabama Birmingham, Dept Clin & Diagnost Sci, Birmingham, AL 35294 USA. [Hill, Helliner] Novo Nordisk, Dept Field Med Affairs, Div Diabet, Princeton, NJ 08540 USA. [Hill, Bradford G.] Univ Louisville, Inst Mol Cardiol, Louisville, KY 40202 USA. [Lara-Castro, Cristina] Univ S Carolina, Sch Med, Dept Internal Med, Columbia, SC 29208 USA. [Brandon, L. Jerome; Ingalls, Christopher P.] Georgia State Univ, Dept Kinesiol & Hlth, Atlanta, GA 30302 USA. [Rupp, Jeffrey C.] Life Univ, Marietta, GA 30060 USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Penumetcha, Meera] Georgia State Univ, Dept Nutr, Atlanta, GA 30302 USA. RP Ingram, KH (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, 232 Webb Nutr Sci Bldg,1675 Univ Blvd, Birmingham, AL 35294 USA. EM khingram@uab.edu RI Hill, Bradford/F-9228-2011; Hill, Bradford/I-4154-2013 OI Hill, Bradford/0000-0001-5332-8286 FU National Institutes of Health [DK-038765, DK-083562, PO1 HL-55782]; T32 Training Grant "UAB Obesity Training Program" [HL-079888]; Department of Veterans Affairs; Gatorade Sports Science Institute; UAB Center for Clinical and Translational Science [UL1 RR025777]; Nutrition and Obesity Research Center [P30 DK56336]; Diabetes Research and Training Center [P60 DK079626] FX This work was supported by Grants DK-038765, DK-083562, and PO1 HL-55782 from the National Institutes of Health; T32 Training Grant (HL-079888) entitled "UAB Obesity Training Program"; the Merit Review program of the Department of Veterans Affairs; and the Gatorade Sports Science Institute (dissertation grant). We also acknowledge support from the UAB Center for Clinical and Translational Science (Grant UL1 RR025777), the Nutrition and Obesity Research Center (Grant P30 DK56336), and the Diabetes Research and Training Center (Grant P60 DK079626). NR 19 TC 14 Z9 15 U1 0 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2012 VL 97 IS 7 BP E1182 EP E1186 DI 10.1210/jc.2011-2963 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 972OJ UT WOS:000306286100013 PM 22496506 ER PT J AU Welt, CK Styrkarsdottir, U Ehrmann, DA Thorleifsson, G Arason, G Gudmundsson, JA Ober, C Rosenfield, RL Saxena, R Thorsteinsdottir, U Crowley, WF Stefansson, K AF Welt, Corrine K. Styrkarsdottir, Unnur Ehrmann, David A. Thorleifsson, Gudmar Arason, Gudmundur Gudmundsson, Jens A. Ober, Carole Rosenfield, Robert L. Saxena, Richa Thorsteinsdottir, Unnur Crowley, William F. Stefansson, Kari TI Variants in DENND1A Are Associated with Polycystic Ovary Syndrome in Women of European Ancestry SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CHROMOSOME 2P16.3; PREVALENCE; IMPUTATION; FEATURES; CRITERIA; 9Q33.3; FAMILY; 2P21 AB Context: A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry. Objective: The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry. Design: This was a case-control study. Setting: The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States. Patients: Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively. Intervention: There were no interventions. Main Outcomes: Main outcomes were allele frequencies for seven variants in PCOS cases and controls. Results: Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria. Conclusions: We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS. (J Clin Endocrinol Metab 97: E1342-E1347, 2012) C1 [Welt, Corrine K.] Massachusetts Gen Hosp, BHX 511, Reprod Endocrine Unit, Boston, MA 02114 USA. [Saxena, Richa] Massachusetts Gen Hosp, Dept Anaesthesia, Boston, MA 02114 USA. [Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, DeCODE Genet, IS-101 Reykjavik, Iceland. [Arason, Gudmundur] Univ Iceland, ARTmedica IVF Iceland, IS-101 Reykjavik, Iceland. [Gudmundsson, Jens A.] Univ Iceland, Landspitali Univ Hosp, Dept Obstet & Gynecol, IS-101 Reykjavik, Iceland. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Ehrmann, David A.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ober, Carole] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Rosenfield, Robert L.] Univ Chicago, Sect Adult & Pediat Endocrinol Diabet & Metab, Chicago, IL 60637 USA. RP Welt, CK (reprint author), Massachusetts Gen Hosp, BHX 511, Reprod Endocrine Unit, 55 Fruit St, Boston, MA 02114 USA. EM cwelt@partners.org; karistefansson@decode.is OI Welt, Corrine/0000-0002-8219-5504 FU National Institutes of Health [U01 HD 4417, 1R01HD065029]; American Diabetes Association [1-10-CT-57, HL-075079, P50-HD057796, 1 UL1 RR025758]; Harvard Clinical and Translational Science Center; National Center for Research Resources [M01-RR-01066]; University of Chicago Diabetes Research and Training Center Laboratory [P60-DK20595]; University of Chicago Clinical and Translational Science Award-General and Clinical Research Center [5UL1RR024999] FX This work was supported by the National Institutes of Health Grants U01 HD 4417 (to W. F. C.) and 1R01HD065029 (to C. K. W.); American Diabetes Association Grant 1-10-CT-57 (to C. K. W.), HL-075079 (to D. A. E.), P50-HD057796 (to D. A. E.), and 1 UL1 RR025758; Harvard Clinical and Translational Science Center (to Harvard University and its affiliates); Grant M01-RR-01066 from the National Center for Research Resources; Grant P60-DK20595 (The University of Chicago Diabetes Research and Training Center Laboratory); and Grant 5UL1RR024999 (The University of Chicago Clinical and Translational Science Award-General and Clinical Research Center). NR 20 TC 61 Z9 64 U1 1 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2012 VL 97 IS 7 BP E1342 EP E1347 DI 10.1210/jc.2011-3478 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 972OJ UT WOS:000306286100036 PM 22547425 ER PT J AU Karmali, F Merfeld, DM AF Karmali, Faisal Merfeld, Daniel M. TI A distributed, dynamic, parallel computational model: the role of noise in velocity storage SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE sensory estimation; Bayesian; particle filter ID QUALITATIVELY DIFFERENT MECHANISMS; BAYESIAN STATE ESTIMATION; VESTIBULOOCULAR REFLEX; SEMICIRCULAR CANALS; SPATIAL ORIENTATION; VESTIBULAR PERCEPTION; INTERNAL-MODELS; SQUIRREL-MONKEY; HAIR-CELLS; INFORMATION-TRANSMISSION AB Karmali F, Merfeld DM. A distributed, dynamic, parallel computational model: the role of noise in velocity storage. J Neurophysiol 108: 390-405, 2012. First published April 18, 2012; doi:10.1152/jn.00883.2011.-Networks of neurons perform complex calculations using distributed, parallel computation, including dynamic "real-time" calculations required for motion control. The brain must combine sensory signals to estimate the motion of body parts using imperfect information from noisy neurons. Models and experiments suggest that the brain sometimes optimally minimizes the influence of noise, although it remains unclear when and precisely how neurons perform such optimal computations. To investigate, we created a model of velocity storage based on a relatively new technique-"particle filtering"-that is both distributed and parallel. It extends existing observer and Kalman filter models of vestibular processing by simulating the observer model many times in parallel with noise added. During simulation, the variance of the particles defining the estimator state is used to compute the particle filter gain. We applied our model to estimate one-dimensional angular velocity during yaw rotation, which yielded estimates for the velocity storage time constant, afferent noise, and perceptual noise that matched experimental data. We also found that the velocity storage time constant was Bayesian optimal by comparing the estimate of our particle filter with the estimate of the Kalman filter, which is optimal. The particle filter demonstrated a reduced velocity storage time constant when afferent noise increased, which mimics what is known about aminoglycoside ablation of semicircular canal hair cells. This model helps bridge the gap between parallel distributed neural computation and systems-level behavioral responses like the vestibuloocular response and perception. C1 [Karmali, Faisal] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Karmali, F (reprint author), Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, 243 Charles St, Boston, MA 02114 USA. EM faisal_karmali@yahoo.com OI Karmali, Faisal/0000-0002-1140-4954 FU National Institute on Deafness and Other Communication Disorders [DC0-4158]; National Center for Research Resources Shared Equipment [1-S10-RR-028832] FX This work was supported by National Institute on Deafness and Other Communication Disorders Grant DC0-4158. The Orchestra computational cluster is supported by National Center for Research Resources Shared Equipment Grant 1-S10-RR-028832. NR 83 TC 12 Z9 12 U1 0 U2 13 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2012 VL 108 IS 2 BP 390 EP 405 DI 10.1152/jn.00883.2011 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 974FO UT WOS:000306416400003 PM 22514288 ER PT J AU Maison, SF Usubuchi, H Vetter, DE Elgoyhen, AB Thomas, SA Liberman, MC AF Maison, Stephane F. Usubuchi, Hajime Vetter, Douglas E. Belen Elgoyhen, A. Thomas, Steven A. Liberman, M. Charles TI Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE efferent; inner ear; middle-ear muscles; sympathetic nervous system ID PRODUCT OTOACOUSTIC EMISSIONS; OUTER HAIR-CELLS; OLIVOCOCHLEAR EFFERENTS; GUINEA-PIG; ELECTRICAL-STIMULATION; RECEPTOR SUBUNITS; ACOUSTIC INJURY; CBA MICE; REFLEX; SYSTEM AB Maison SF, Usubuchi H, Vetter DE, Elgoyhen AB, Thomas SA, Liberman MC. Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway. J Neurophysiol 108: 491-500, 2012. First published April 18, 2012; doi:10.1152/jn.01050.2011.-Suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) by contralateral noise is used in humans and animals to assay the strength of sound-evoked negative feedback from the medial olivocochlear (MOC) efferent pathway. However, depending on species and anesthesia, contributions of other feedback systems to the middle or inner ear can cloud the interpretation. Here, contributions of MOC and middle-ear muscle reflexes, as well as autonomic feedback, to contra-noise suppression in anesthetized mice are dissected by selectively eliminating each pathway by surgical transection, pharmacological blockade, or targeted gene deletion. When ipsilateral DPOAEs were evoked by low-level primaries, contra-noise suppression was typically similar to 1 dB with contra-noise levels around 95 dB SPL, and it always disappeared upon contralateral cochlear destruction. Lack of middle-ear muscle contribution was suggested by persistence of contra-noise suppression after paralysis with curare, tensor tympani cauterization, or section of the facial nerve. Contribution of cochlear sympathetics was ruled out by studying mutant mice lacking adrenergic signaling (dopamine beta-hydroxylase knockouts). Surprisingly, contra-noise effects on low-level DPOAEs were also not diminished by eliminating the MOC system pharmacologically (strychnine), surgically, or by deletion of relevant cholinergic receptors (alpha 9/alpha 10). In contrast, when ipsilateral DPOAEs were evoked by high-level primaries, the contra-noise suppression, although comparable in magnitude, was largely eliminated by MOC blockade or section. Possible alternate pathways are discussed for the source of contra-noise-evoked effects at low ipsilateral levels. C1 [Maison, Stephane F.; Usubuchi, Hajime; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Maison, Stephane F.; Usubuchi, Hajime; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Maison, Stephane F.; Liberman, M. Charles] Harvard MIT, Program Speech & Hearing Biosci & Technol, Cambridge, MA USA. [Vetter, Douglas E.] Univ Mississippi, Med Ctr, Dept Neurobiol & Anat Sci, Jackson, MS 39216 USA. [Belen Elgoyhen, A.] Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, Buenos Aires, DF, Argentina. [Thomas, Steven A.] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. RP Maison, SF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM stephane_maison@meei.harvard.edu OI Vetter, Douglas/0000-0003-4580-3491 FU National Institutes of Health [RO1 DC-0188, RO1 DC-006258, RO1 MH-063352, P30 DC-5029, P30 NS-047243] FX This work was supported by National Institutes of Health Grants RO1 DC-0188 (M. C. Liberman), RO1 DC-006258 (D. E. Vetter), RO1 MH-063352 (S. A. Thomas), P30 DC-5029 (M. C. Liberman), and P30 NS-047243 (D. E. Vetter). NR 52 TC 6 Z9 6 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2012 VL 108 IS 2 BP 491 EP 500 DI 10.1152/jn.01050.2011 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 974FO UT WOS:000306416400011 PM 22514298 ER PT J AU Walcott, BP Nahed, BV Sheth, SA Yanamadala, V Caracci, JR Asaad, WF AF Walcott, Brian P. Nahed, Brian V. Sheth, Sameer A. Yanamadala, Vijay Caracci, James R. Asaad, Wael F. TI Bilateral Hemicraniectomy in Non-Penetrating Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE bilateral; craniectomy; brain injury; intensive care unit; trauma ID ACUTE SUBDURAL-HEMATOMA; TRANSORBITAL VENTRICULAR PUNCTURE; SEVERE HEAD-INJURY; DECOMPRESSIVE CRANIECTOMY; TRANSTENTORIAL HERNIATION; COMPUTERIZED-TOMOGRAPHY; COMATOSE PATIENTS; DURET HEMORRHAGE; MORTALITY; EVACUATION AB Traumatic brain injury is a heterogeneous entity that encompasses both surgical and non-surgical conditions. Surgery may be indicated with traumatic lesions such as hemorrhage, fractures, or malignant cerebral edema. However, the neurological exam may be clouded by the effects of medications administered in the field, systemic injuries, and inaccuracies in hyperacute prognostication. Typically, neurological injury is considered irreversible if diffuse loss of grey/white matter differentiation or if brainstem hemorrhage (Duret hemorrhage) exists. We aim to characterize a cohort of patients undergoing bilateral hemicraniectomy for severe traumatic brain injury. A retrospective consecutive cohort of adult patients undergoing craniectomy for trauma was established between the dates of January 2008 and November 2011. The primary outcome of the study was in-hospital mortality. Secondary outcomes were ICU length of stay, surgical complications, and Glasgow Outcome Score at most recent follow-up. During the study period, 210 patients undergoing craniectomy for traumatic mass-occupying lesion (epidural hematoma, subdural hematoma, or parenchymal contusion) were analyzed. Of those, 9 met study criteria. In-hospital mortality was 67% (6 of 9 patients). The average ICU length of stay was 12 days. The GOS score was 3 in surviving patients. Bilateral hemicraniectomy is a heroic intervention for patients with severe TBI, but can be a life-saving procedure. C1 [Walcott, Brian P.; Nahed, Brian V.; Sheth, Sameer A.; Yanamadala, Vijay; Caracci, James R.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Walcott, Brian P.; Nahed, Brian V.; Sheth, Sameer A.; Yanamadala, Vijay; Caracci, James R.] Harvard Univ, Sch Med, Boston, MA USA. [Asaad, Wael F.] Brown Univ, Sch Med, Dept Neurosurg, Providence, RI 02912 USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg,Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu RI Asaad, Wael/I-8485-2012 OI Asaad, Wael/0000-0003-4406-9096 NR 37 TC 7 Z9 7 U1 2 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP 1879 EP 1885 DI 10.1089/neu.2012.2382 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400392 PM 22452418 ER PT J AU Dixon, CE Yan, HQ Jenkins, LW Ma, XC Li, YM Shin, SS Dixon, CE AF Dixon, C. Edward Yan, Hong Q. Jenkins, Larry W. Ma, Xiecheng Li, Youming Shin, Samuel S. Dixon, C. Edward TI THE EFFECTS OF TBI ON HIPPOCAMPAL SNARE-COMPLEX ASSEMBLY AND ATTENUATION BY CHRONIC LITHIUM THERAPY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE TBI; vesicles; lithium; hippocampus C1 [Shin, Samuel S.] Univ Pittsburgh, Sch Med, Ctr Neurosci & Neurosurg, Pittsburgh, PA 15260 USA. [Dixon, C. Edward] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A22 EP A23 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400034 ER PT J AU Liu, Q Zhu, XX Park, J Zhang, J Qiu, JH Whalen, MJ AF Liu, Qiong Zhu, Xiaoxia Park, Juyeon Zhang, Jimmy Qiu, Jianhua Whalen, Michael J. TI MECHANISMS OF COGNITIVE DYSFUNCTION AFTER CONCUSSION TRAUMATIC BRAIN INJURY IN MICE: ROLE OF SURVIVAL AND DEATH PATHWAY KINASES SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE necrostatin; Akt; mTOR; mice; concussion C1 [Zhang, Jimmy] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Whalen, Michael J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A105 EP A105 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400178 ER PT J AU Lok, J Zhao, S Leung, W Seo, JH Navaratna, D Whalen, MJ Wang, XY Lo, E AF Lok, Josephine Zhao, Song Leung, Wendy Seo, Ji Hae Navaratna, Deepti Whalen, Michael J. Wang, Xiaoying Lo, Eng TI NEUREGULIN-1 EFFECTS ON ENDOTHELIAL AND BLOOD-BRAIN-BARRIER PERMEABILITY AFTER EXPERIMENTAL INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE neuregulin-1; endothelial permeability; blood-brain barrier C1 [Lok, Josephine; Leung, Wendy; Seo, Ji Hae; Navaratna, Deepti; Whalen, Michael J.; Wang, Xiaoying; Lo, Eng] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A54 EP A54 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400089 ER PT J AU Mannix, R Meehan, W Zhang, J Berglass, J Gray, T Lee, C Whalen, MJ AF Mannix, Rebekah Meehan, William Zhang, Jimmy Berglass, Jacqueline Gray, Tory Lee, Christopher Whalen, Michael J. TI APOE4 IS NOT A RISK FACTOR FOR POOR COGNITIVE OUTCOME IN A MOUSE MODEL OF REPEATED MILD CONCUSSIVE BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE traumatic brain injury; concussion; APOE4 C1 [Mannix, Rebekah; Meehan, William; Whalen, Michael J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Zhang, Jimmy; Gray, Tory; Lee, Christopher] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Berglass, Jacqueline] Childrens Hosp Boston, Dept Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A174 EP A174 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400300 ER PT J AU Mannix, R Berglass, J Zhang, J Stanley, R Whalen, MJ AF Mannix, Rebekah Berglass, Jacqueline Zhang, Jimmy Stanley, Rachel Whalen, Michael J. TI AGE DEPENDENT DIFFERENCES IN THE EFFECT OF PROGESTERONE AFTER CCI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE Traumatic Brain Injury; progesterone; neuroprotection C1 [Mannix, Rebekah; Whalen, Michael J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Berglass, Jacqueline] Childrens Hosp Boston, Dept Med, Boston, MA USA. [Zhang, Jimmy] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Stanley, Rachel] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A104 EP A104 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400176 ER PT J AU Mannix, R Berglass, J Zhang, J Qui, JH Whalen, MJ AF Mannix, Rebekah Berglass, Jacqueline Zhang, Jimmy Qui, Jianhua Whalen, Michael J. TI BENEFICIAL EFFECT OF AMYLOID BETA AFTER CONTROLLED CORTICAL IMPACT SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE Traumatic Brain Injury; Beta Amyloid C1 [Mannix, Rebekah; Qui, Jianhua; Whalen, Michael J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Berglass, Jacqueline] Childrens Hosp Boston, Dept Med, Boston, MA USA. [Zhang, Jimmy] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A53 EP A53 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400087 ER PT J AU Sierra-Mercado, D Lee, C Zhang, J Eskandar, EN Whalen, MJ AF Sierra-Mercado, Demetrio Lee, Christopher Zhang, Jimmy Eskandar, Emad N. Whalen, Michael J. TI POST-TRAUMATIC STRESS DISORDER PHENOTYPE IDENTIFIED BY IMPAIRED EXTINCTION OF FEAR LEARNING AFTER CONTROLLED CORTICAL IMPACT IN MICE SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 30th Annual National Neurotrauma Symposium CY JUL 22-25, 2012 CL Phoenix, AZ DE Post traumatic stress disorder; mice C1 [Sierra-Mercado, Demetrio] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Lee, Christopher; Zhang, Jimmy] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Whalen, Michael J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2012 VL 29 IS 10 BP A14 EP A14 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 971YV UT WOS:000306244400021 ER PT J AU Wernimont, SM Clark, AG Stover, PJ Wells, MT Litonjua, AA Weiss, ST Gaziano, JM Vokonas, PS Tucker, KL Cassano, PA AF Wernimont, Susan M. Clark, Andrew G. Stover, Patrick J. Wells, Martin T. Litonjua, Augusto A. Weiss, Scott T. Gaziano, J. Michael Vokonas, Pantel S. Tucker, Katherine L. Cassano, Patricia A. TI Folate Network Genetic Variation Predicts Cardiovascular Disease Risk in Non-Hispanic White Males SO JOURNAL OF NUTRITION LA English DT Article ID CORONARY-HEART-DISEASE; CYTOPLASMIC SERINE HYDROXYMETHYLTRANSFERASE; SINGLE NUCLEOTIDE POLYMORPHISMS; PLASMA HOMOCYSTEINE; METHYLENETETRAHYDROFOLATE REDUCTASE; COMMON MUTATION; ISCHEMIC-STROKE; BLOOD FOLATE; FOLIC-ACID; METAANALYSIS AB Genes functioning in folate-mediated 1-carbon metabolism are hypothesized to play a role in cardiovascular disease (CVD) risk beyond the current narrow focus on the MTHFR 677 C -> T (rs1801133) polymorphism. Using a cohort study design, we investigated whether sequence variants in the network of folate-related genes, particularly in genes encoding proteins related to SHMT1, predict CVD risk in 1131 men from the Normative Aging Study. A total of 330 single nucleotide polymorphisms (SNPs) in 52 genes, selected for function and gene coverage, were assayed on the Illumina GoldenGate platform. Age- and smoking-adjusted genotype-phenotype associations were estimated in regression models. Using a nominal P <= 5.00 x 10(-3) significance threshold, 8 SNPs were associated with CVD risk in single locus analyses. Using a false discovery rate (FDR) threshold (P-adjusted <= 1.00 x 10(-1)), a SNP in the GGH gene remained associated with reduced CVD risk, with a stronger association in early onset CVD cases (<55 y). A gene x folate interaction (MAT2B) and 2 gene x vitamin B-12 interactions (BHMT, SLC25A32) reached the FDR P-adjusted <= 2.00 x 10-1 threshold. Three biological hypotheses related to SHMT1 were explored and significant gene x gene interactions were identified for TYMS by UBE2N, FTH1 by CELF1, and TYMS by MTHFR. Variations in genes other than MTHFR and those directly involved in homocysteine metabolism are associated with CVD risk in non-Hispanic white males. This work supports a role for SHMT1-related genes and nuclear folate metabolism, including the thymidylate biosynthesis pathway, in mediating CVD risk. J. Nutr. 142: 1272-1279, 2012. C1 [Wernimont, Susan M.; Stover, Patrick J.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. [Wells, Martin T.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA. [Litonjua, Augusto A.; Weiss, Scott T.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Gaziano, J. Michael; Vokonas, Pantel S.] VA Boston Healthcare Syst, VA Normat Aging Study, Boston, MA USA. [Litonjua, Augusto A.; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Vokonas, Pantel S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Tucker, Katherine L.] Northeastern Univ, Sch Hlth Profess, Boston, MA 02115 USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM pac6@cornell.edu OI Litonjua, Augusto/0000-0003-0422-5875; Tucker, Katherine/0000-0001-7640-662X FU Center for Vertebrate Genomics at Cornell University; Presidents Council for Cornell Women at Cornell University; Bronfenbrenner Life Course Center at Cornell University; USDA (Cooperative State Research, Education, and Extension Service, CSREES) [2003-34324-13135]; National Institute of Diabetes, Digestive and Kidney Diseases. Genotyping services; Johns Hopkins University under from National Heart, Lung, and Blood Institute [N01-HV-48195]; Department of Veterans Affairs Cooperative Studies Program/Epidemiology Researach and Information Center; [T32DK007158] FX Supported in part by the Center for Vertebrate Genomics (P.A.C.), the Presidents Council for Cornell Women (P.A.C.), and the Bronfenbrenner Life Course Center (P.A.C.), all at Cornell University; by USDA (Cooperative State Research, Education, and Extension Service, CSREES) grant 2003-34324-13135 (subproject to P.A.C.); and by T32DK007158 (S.M.W.), National Institute of Diabetes, Digestive and Kidney Diseases. Genotyping services were provided (to PAC.) by the Johns Hopkins University under federal contract no. N01-HV-48195 from the National Heart, Lung, and Blood Institute. The VA Normative Aging Study is supported by the Department of Veterans Affairs Cooperative Studies Program/Epidemiology Researach and Information Center and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, or the NIH. NR 45 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2012 VL 142 IS 7 BP 1272 EP 1279 DI 10.3945/jn.111.157180 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 963AP UT WOS:000305592800014 PM 22649255 ER PT J AU Halvey, PJ Ferrone, CR Liebler, DC AF Halvey, Patrick J. Ferrone, Cristina R. Liebler, Daniel C. TI GeLC-MRM Quantitation of Mutant KRAS Oncoprotein in Complex Biological Samples SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE KRAS; GeLC-MRM; targeted proteomics; colorectal cancer; pancreatic cyst fluid ID SIGNALING PATHWAYS; MASS-SPECTROMETRY; IDENTIFICATION; PROTEINS; PROTEOMICS; GENES AB Tumor-derived mutant KRAS (v-Ki-ras-2 Kirsten rat sarcoma viral oncogene) oncoprotein is a critical driver of cancer phenotypes and a potential biomarker for many epithelial cancers. Targeted mass spectrometry analysis by multiple reaction monitoring (MRM) enables selective detection and quantitation of wild-type and mutant KRAS proteins in complex biological samples. A recently described immunoprecipitation approach (Proc. Nat. Acad. Sci. 2011, 108, 2444-2449) can be used to enrich KRAS for MRM analysis, but requires large protein inputs (2-4 mg). Here, we describe sodium dodecyl sulfate-polyacrylamide gel electrophoresis-based enrichment of KRAS in a low molecular weight (20-25 kDa) protein fraction prior to MRM analysis (GeLC-MRM). This approach reduces background proteome complexity, thus, allowing mutant KRAS to be reliably quantified in low protein inputs (5-50 mu g). GeLC-MRM detected KRAS mutant variants (G12D, G13D, G12V, G12S) in a panel of cancer cell lines. GeLC-MRM analysis of wild-type and mutant was linear with respect to protein input and showed low variability across process replicates (CV = 14%). Concomitant analysis of a peptide from the highly similar HRAS and NRAS proteins enabled correction of KRAS-targeted measurements for contributions from these other proteins. KRAS peptides were also quantified in fluid from benign pancreatic cysts and pancreatic cancers at concentrations from 0.08 to 1.1 fmol/mu g protein. GeLC-MRM provides a robust, sensitive approach to quantitation of mutant proteins in complex biological samples. C1 [Halvey, Patrick J.; Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Dept Biochem, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Halvey, Patrick J.; Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Jim Ayers Inst Precanc Detect & Diag, Nashville, TN 37232 USA. [Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ferrone, Cristina R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Liebler, DC (reprint author), Vanderbilt Univ, Sch Med, Dept Biochem, Vanderbilt Ingram Canc Ctr, Med Res Bldg 3,U1213,465 21st Ave S, Nashville, TN 37232 USA. EM daniel.liebler@vanderbilt.edu OI Liebler, Daniel/0000-0002-7873-3031 FU NIH [U24CA126479, U24CA159988, U01CA152647] FX We thank Dr. Robbert J.C. Slebos for helpful discussion. This work was supported in part by NIH grants U24CA126479, U24CA159988, and U01CA152647. NR 14 TC 22 Z9 22 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL PY 2012 VL 11 IS 7 BP 3908 EP 3913 DI 10.1021/pr300161j PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 969IV UT WOS:000306049800034 PM 22671702 ER PT J AU Crittenden, DB Lehmann, RA Schneck, L Keenan, RT Shah, B Greenberg, JD Cronstein, BN Sedlis, SP Pillinger, MH AF Crittenden, Daria B. Lehmann, R. Aaron Schneck, Laura Keenan, Robert T. Shah, Binita Greenberg, Jeffrey D. Cronstein, Bruce N. Sedlis, Steven P. Pillinger, Michael H. TI Colchicine Use Is Associated with Decreased Prevalence of Myocardial Infarction in Patients with Gout SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE GOUT; COLCHICINE; MYOCARDIAL INFARCTION; MORTALITY; C-REACTIVE PROTEIN ID C-REACTIVE PROTEIN; FAMILIAL MEDITERRANEAN FEVER; CORONARY-ARTERY-DISEASE; ENDOTHELIAL-CELLS; HUMAN LEUKOCYTES; ORAL COLCHICINE; T-LYMPHOCYTES; L-SELECTIN; INFLAMMATION; ATHEROSCLEROSIS AB Objective. The ability of antiinflammatory strategies to alter cardiovascular risk has not been rigorously examined. Colchicine is an antiinflammatory agent that affects macrophages, neutrophils, and endothelial cells, all of which are implicated in the pathogenesis of cardiovascular disease. We examined whether colchicine use was associated with a reduced risk of myocardial infarction (MI) in patients with gout. Methods. We conducted a retrospective, cross-sectional study of all patients with an International Classification of Diseases, 9th ed, code for gout in the electronic medical record (EMR) of the New York Harbor Healthcare System Veterans Affairs network and 1 hospital visit between August 2007 and August 2008. Hospital pharmacy data were used to identify patients who had filled at least 1 colchicine prescription versus those who had not. Demographics and CV comorbidities were collected by EMR review. The primary outcome was diagnosis of MI. Secondary outcomes included all-cause mortality and C-reactive protein (CRP) level. Results. In total. 1288 gout patients were identified. Colchicine (n = 576) and no colchicine (n = 712) groups had similar baseline demographics and serum urate levels. Prevalence of MI was 1.2% in the colchicine versus 2.6% in the no-colchicine group (p = 0.03). Colchicine users also had fewer deaths and lower CRP levels, although these did not achieve statistical significance. Colchicine effects persisted when allopurinol users were excluded from the analysis. Conclusion. In this hypothesis-generating study, gout patients who took colchicine had a significantly lower prevalence of MI and exhibited trends toward reduced all-cause mortality and lower CRP level versus those who did not take colchicine. (First Release June 1 2012; J Rheumatol 2012;39:1458-64; doi:10.3899/jrheum.111533) C1 NYU, Div Rheumatol, Crystal Dis Study Grp, Sch Med, New York, NY 10003 USA. NYU, Div Cardiol, Sch Med, New York, NY 10003 USA. US Dept Vet Affairs, Dept Med, New York Harbor Healthcare Syst, New York, NY USA. Duke Univ, Med Ctr, Div Rheumatol, Durham, NC USA. [Shah, Binita; Greenberg, Jeffrey D.; Cronstein, Bruce N.] NYU, Clin & Translat Sci Inst, Sch Med, New York, NY 10003 USA. RP Crittenden, DB (reprint author), NYU, Hosp Joint Dis, Div Rheumatol, 301 E 17th St,Room 1410, New York, NY 10003 USA. EM daria.crittenden@nyumc.org OI Sedlis, Steven/0000-0002-8194-8017; Pillinger, Michael/0000-0003-3168-1542 FU US National Institutes of Health [5T32AR007176] FX Drs. Keenan and Lehmann were supported by US National Institutes of Health T32 training grant 5T32AR007176. NR 59 TC 42 Z9 43 U1 0 U2 8 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2012 VL 39 IS 7 BP 1458 EP 1464 DI 10.3899/jrheum.111533 PG 7 WC Rheumatology SC Rheumatology GA 973VQ UT WOS:000306388300024 PM 22660810 ER PT J AU Shastri, S Katz, R Rifkin, DE Fried, LF Odden, MC Peralta, CA Chonchol, M Siscovick, D Shlipak, MG Newman, AB Sarnak, MJ AF Shastri, Shani Katz, Ronit Rifkin, Dena E. Fried, Linda F. Odden, Michelle C. Peralta, Carmen A. Chonchol, Michel Siscovick, David Shlipak, Michael G. Newman, Anne B. Sarnak, Mark J. TI Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE octogenarians; kidney function; mortality ID SERUM CYSTATIN-C; GLOMERULAR-FILTRATION-RATE; OLDER-ADULTS; ELDERLY PERSONS; HEART-FAILURE; RISK-FACTOR; DISEASE; PREVALENCE; CREATININE; OUTCOMES AB Objectives To examine the association between kidney function and all-cause mortality in octogenarians. Design Retrospective analysis of prospectively collected data. Setting Community. Participants Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants. Measurements Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models. Results Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (6475 mL/min per 1.73 m2), the highest (=75 mL/min per 1.73 m2) and lowest (=43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.364.55; HR = 2.28, 95% CI = 1.264.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.123.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2). Conclusion Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. C1 [Shastri, Shani] Univ Texas SW, Div Nephrol, Dallas, TX USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rifkin, Dena E.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Fried, Linda F.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Odden, Michelle C.] Oregon State Univ, Sch Biol & Populat Hlth Sci, Dept Epidemiol, Corvallis, OR 97331 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Chonchol, Michel] Univ Colorado, Div Renal Dis & Hypertens, Denver, CO 80202 USA. [Siscovick, David] Univ Washington, Dept Med & Epidemiol, Seattle, WA 98195 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Newman, Anne B.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Dept Epidemiol, Pittsburgh, PA USA. [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. RP Shastri, S (reprint author), UT SW, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Shani.Shastri@UTSouthwestern.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging (NIA) [AG-023629]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133]; NHLBI [HL080295]; Department of Veterans Affairs, Veterans Integrated Service Network 4 from the National Heart, Lung and Blood Institute [R01 HL-075366]; University of Pittsburgh Claude. D. Pepper Older Americans Independence Center [P30-AG-024827]; [K24 DK078204] FX The research reported in this article was supported by National Institute on Aging (NIA) Grant AG-023629. CHS was supported by National Heart, Lung, and Blood Institute (NHLBI) Contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and NHLBI Grant HL080295, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. A full list of principal CHS investigators and institutions can be found at http://www.chsnhlbi.org/pi.htm. This material is also based on work supported in part by the Department of Veterans Affairs, Veterans Integrated Service Network 4, R01 HL-075366 from the National Heart, Lung and Blood Institute, and the University of Pittsburgh Claude. D. Pepper Older Americans Independence Center P30-AG-024827. Dr. Sarnak is supported by K24 DK078204. NR 27 TC 19 Z9 19 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2012 VL 60 IS 7 BP 1201 EP 1207 DI 10.1111/j.1532-5415.2012.04046.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 972WJ UT WOS:000306311600001 PM 22724391 ER PT J AU Gellad, WF Good, CB Amuan, ME Marcum, ZA Hanlon, JT Pugh, MJV AF Gellad, Walid F. Good, Chester B. Amuan, Megan E. Marcum, Zachary A. Hanlon, Joseph T. Pugh, Mary Jo V. TI Facility-Level Variation in Potentially Inappropriate Prescribing for Older Veterans SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE potentially inappropriate prescribing; HEDIS measures; quality of care; pharmacoepidemiology ID ADVERSE DRUG-REACTIONS; RISK-ADJUSTED MORTALITY; MEDICATION USE; BEERS CRITERIA; EXPLICIT CRITERIA; ELDERLY PEOPLE; ADULTS; OUTCOMES; QUALITY; CARE AB Objectives To describe facility-level variation in two measures of potentially inappropriate prescribing prevalent in Veterans Affairs (VA) facilitiesexposure to high-risk medications in elderly adults (HRME) and drugdisease interactions (Rx-DIS)and to identify facility characteristics associated with high-quality prescribing. Design Cross-sectional. Setting VA Healthcare System. Participants Veterans aged 65 and older with at least one inpatient or outpatient visit in 20052006 (N = 2,023,477; HRME exposure) and a subsample with a history of falls or hip fractures, dementia, or chronic renal failure (n = 305,059; Rx-DIS exposure). Measurements Incident use of any HRME (iHRME) and incident Rx-DIS (iRx-DIS) and facility-level rates and facility-level predictors of iHRME and iRx-DIS exposure, adjusting for differences in patient characteristics. Results Overall, 94,692 (4.7%) veterans had iHRME exposure. At the facility level, iHRME exposure ranged from 1.6% at the lowest facility to 12.8% at the highest (median 4.7%). In the subsample, 9,803 (3.2%) veterans had iRx-DIS exposure, with a facility-level range from 1.3% to 5.8% (median 3.2%). In adjusted analyses, veterans seen in facilities with formal geriatric education had lower odds of iHRME (odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.770.96) and iRx-DIS (OR = 0.95, 95% CI = 0.881.01). Patients seen in facilities caring for fewer older veterans had greater odds of iHRME (OR = 1.54, 95% CI = 1.351.75) and iRx-DIS exposure (OR = 1.22, 95% CI = 1.111.33). Conclusion Substantial variation in the quality of prescribing for older adults exists across VA facilities, even after adjusting for patient characteristics. Higher-quality prescribing is found in facilities caring for a larger number of older veterans and facilities with formal geriatric education. C1 [Gellad, Walid F.; Good, Chester B.; Hanlon, Joseph T.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Gellad, Walid F.; Good, Chester B.] Univ Pittsburgh, Div Gen Med, Pittsburgh, PA USA. [Gellad, Walid F.; Hanlon, Joseph T.] Univ Pittsburgh, Div Geriatr Pharmaceut, Pittsburgh, PA USA. [Gellad, Walid F.; Hanlon, Joseph T.] Univ Pittsburgh, Geroinformat Res & Training Program, Pittsburgh, PA USA. [Gellad, Walid F.] RAND Corp, Pittsburgh, PA USA. [Good, Chester B.] Dept Vet Affairs, Pharm Benefits Management Serv, Hines, IL USA. [Amuan, Megan E.] Edith Nourse Rogers Mem Vet Hosp, Vet Affairs Ctr Hlth Qual, Bedford, MA USA. [Marcum, Zachary A.; Hanlon, Joseph T.] Univ Pittsburgh, Dept Med, Div Geriatr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Pittsburgh Vet Affairs, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Pugh, Mary Jo V.] S Texas Vet Healthcare Syst, Vet Evidence Based Res Disseminat & Implementat C, Res Enhancement Award Program, San Antonio, TX USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Geriatr & Gerontol, San Antonio, TX 78229 USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM walid.gellad@va.gov OI Pugh, Mary Jo/0000-0003-4196-7763 FU VA Career Development Award CDA [09-207]; VA Health Services Research and Development Grant [IIR 06-062]; National Institute on Aging [P30AG024827, T32 AG021885, K07AG033174, R01AG034056, R56AG027017]; National Institute of Nursing Research [R01 NR010135]; Agency for Healthcare Research and Quality [R01 HS017695, R01 HS018721, K12 HS019461]; VA HSRD DHI [09-237]; VA HSRD [IIR-06-062, SDR-07-042, IIR-05-121, IAF-06-080, IIR-09-335, SHP 08-140, TRX 01-091]; VA HSR D IIR [08-274]; Department of Defense CDMRP [09090014]; National Institutes of Health [R01-NR010828]; Kelsey Seybold Research Foundation FX Conflict of Interest: All authors are employed by the VA. This study was supported by VA Career Development Award CDA 09-207 and a VA Health Services Research and Development Grant (IIR 06-062); National Institute on Aging Grants P30AG024827, T32 AG021885, K07AG033174, R01AG034056, and R56AG027017; National Institute of Nursing Research Grant R01 NR010135; and Agency for Healthcare Research and Quality Grants R01 HS017695, R01 HS018721, and K12 HS019461. Dr. Pugh has received research funding from VA HSR&D DHI 09-237 (PI); VA HSR&D IIR-06-062 PI, Epilepsy Foundation PI, VA HSR&D PPO 09-295 PI, VA HSR&D IIR 02-274 PI. Pugh as co-I: VA HSR&D IIR 08-274, VA HSR&D SDR-07-042, IIR-05-121, IAF-06-080, IIR-09-335, SHP 08-140, TRX 01-091 Department of Defense CDMRP 09090014, National Institutes of Health R01-NR010828, Pugh Speaker Honoraria: 2009 Kelsey Seybold Research Foundation $ 400. NR 42 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2012 VL 60 IS 7 BP 1222 EP 1229 DI 10.1111/j.1532-5415.2012.04042.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 972WJ UT WOS:000306311600004 PM 22726206 ER PT J AU Spira, AP Covinsky, K Rebok, GW Stone, KL Redline, S Yaffe, K AF Spira, Adam P. Covinsky, Kenneth Rebok, George W. Stone, Katie L. Redline, Susan Yaffe, Kristine TI Objectively Measured Sleep Quality and Nursing Home Placement in Older Women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE sleep; actigraphy; nursing home; placement; women ID ELDERLY PERSONS; DEPRESSION; INFLAMMATION; VARIABILITY; DURATION; DISEASE AB Objectives To determine the association between objectively measured sleep and subsequent placement in a nursing home or a personal care home. Design Prospective cohort. Setting Participants' homes and sites of the Study of Osteoporotic Fractures. Participants One thousand six hundred sixty-four community-dwelling women with a mean age of 83 +/- 4. Measurements At baseline, participants completed an average of 4 nights of wrist actigraphy; they provided data on place of residence at baseline and at follow-up, 5 years later. Results At baseline, participants had a mean total sleep time of 408 +/- 72 minutes, mean wake after sleep onset of 71 +/- 43 minutes, and mean sleep efficiency of 79 +/- 11%. At follow-up, 71 (4%) were residing in a nursing home, and 127 (8%) were in a personal care home. Women with the most wake after sleep onset (by quartile) had more than twice the odds as those with the least of placement in a nursing home (adjusted odds ratio (AOR) = 2.94, 95% confidence interval (CI) = 1.346.44) or a personal care home (AOR = 2.33, 95% CI = 1.264.30). Similarly, women with the lowest sleep efficiency had more than three times the odds as those with the highest of nursing home placement (AOR = 3.25, 95% CI = 1.35, 7.82) and more than twice the odds of placement in a personal care home (AOR = 2.38, 95% CI = 1.33, 4.24). There was no association between sleep duration and placement. Conclusion In very old community-dwelling women, greater wake after sleep onset and lower sleep efficiency are risk factors for placement in a nursing home or personal care home. Sleep duration alone does not appear to increase the risk of placement in these long-term care settings. C1 [Spira, Adam P.; Rebok, George W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Covinsky, Kenneth] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. [Covinsky, Kenneth] San Francisco VA Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Stone, Katie L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Redline, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Sleep Med, Boston, MA USA. [Redline, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Spira, AP (reprint author), 624 N Broadway,Hampton House,Rm 794, Baltimore, MD 21205 USA. EM aspira@jhsph.edu FU National Institutes of Health (NIH) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG026720, R01 AG027574, R01 AG027576, R01 AG005394]; Alzheimer's Association [IIRG-08-88872]; National Institute on Aging (NIA) [K01AG033195, K24AG031155]; NIH, National Heart, Lung, and Blood Institute; ResMed Foundation; NIH; National Institute of Mental Health; National Institute of Diabetes and Digestive and Kidney Diseases; Department of Defense; Department of Veterans Affairs; Alzheimer's Association FX Conflict of Interest: Supported by National Institutes of Health (NIH) Grants R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG026720, R01 AG027574, R01 AG027576, and R01 AG005394 and Alzheimer's Association Award IIRG-08-88872. Dr. Spira is supported by Mentored Research Scientist Development Award K01AG033195 from the National Institute on Aging (NIA). Dr. Yaffe is partially supported by Midcareer Investigator Award in Patient-Oriented Research K24AG031155 from the NIA. Dr. Spira received honoraria while serving as a clinical editor for the International Journal of Sleep and Wakefulness-Primary Care, which receives pharmaceutical company support, and from a private sleep medicine practice for a continuing education presentation on adverse outcomes of late-life sleep disturbance. Drs. Covinsky and Rebok are supported by grants from the National Institute on Aging. Dr. Redline is supported by grants from the NIH, National Heart, Lung, and Blood Institute and has received a subcontract from California Pacific Medical Center for work on this study. She also has received a research grant from ResMed Foundation to support ancillary data collection for an NIHfunded clinical trial. She is a member of the Board of Directors for the American Academy of Sleep Medicine and is the first incumbent of an endowed professorship donated to the Harvard Medical School by Dr. Peter Farrell, the founder and Board Chairman of ResMed, through a charitable remainder trust instrument, with annual support equivalent to the endowment payout provided to the Harvard Medical School during Dr. Farrell's lifetime by the ResMed Company through an irrevocable gift agreement. Dr. Stone reports that NIH funding has been obtained for this work. Dr. Yaffe has received grants from the NIA, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, Department of Defense, Department of Veterans Affairs, the Alzheimer's Association, and an anonymous donor. She has served on data safety monitoring bards for Pfizer and Medivation, and received honoraria from Novartis as an advisory board member. She is a member of the boards of the Beeson Program; National Institute of Mental Health; and National Heart, Lung, and Blood Institute. NR 22 TC 11 Z9 11 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2012 VL 60 IS 7 BP 1237 EP 1243 DI 10.1111/j.1532-5415.2012.04044.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 972WJ UT WOS:000306311600006 PM 22702839 ER PT J AU Holmes, HM Luo, R Hanlon, JT Elting, LS Suarez-Almazor, M Goodwin, JS AF Holmes, Holly M. Luo, Ruili Hanlon, Joseph T. Elting, Linda S. Suarez-Almazor, Maria Goodwin, James S. TI Ethnic Disparities in Adherence to Antihypertensive Medications of Medicare Part D Beneficiaries SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE medication adherence; ethnic disparities; Medicare Part D ID D PROGRAMS; NONADHERENCE; IMPACT; PREDICTORS; DIAGNOSIS; SURVIVAL; OUTCOMES; BENEFIT; BREAST; CANCER AB Objectives To determine the level of adherence to medications and characteristics of Part D beneficiaries associated with higher levels of antihypertensive medication adherence. Design Retrospective cohort study. Setting Medicare claims and Part D event files. Participants Medicare Part D enrollees with prevalent uncomplicated hypertension who filled at least one antihypertensive prescription in 2006 and two prescriptions in 2007. Measurements Medication adherence was defined as an average medication possession ratio of 80% or greater. Potential factors associated with adherence evaluated were age, sex, race or ethnicity, socioeconomic factors, comorbidity, medication use, copayments, being in the coverage gap, and number of unique prescribers. Results Overall adherence was 79.5% of 168,522 Medicare Part D enrollees with prevalent uncomplicated hypertension receiving antihypertensive medicines in 2007. In univariate analysis, adherence varied significantly according to most patient factors. In multivariable analysis, lower odds of adherence persisted for blacks (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.510.55), Hispanics (OR = 0.58, 95% CI = 0.550.61), and other non-white races (OR = 0.80 95% CI = 0.750.85) than for whites. Greater comorbidity and concurrent medication use were also associated with poorer adherence. Adherence was significantly different across several geographic regions. Conclusion A number of associations were identified between patient factors and adherence to antihypertensive drugs, with significant differences in adherence according to ethnicity. Improving adherence could have significant public health implications and could improve outcomes specific to hypertension, as well as improving cost and healthcare utilization. C1 [Holmes, Holly M.; Luo, Ruili; Suarez-Almazor, Maria] UT MD Anderson Canc Ctr, Dept Gen Internal Med, Houston, TX 77030 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Pharm & Therapeut, Div Geriatr Med, Pittsburgh, PA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Div Geriatr Med, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Elting, Linda S.] UT MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Goodwin, James S.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX USA. [Goodwin, James S.] Univ Texas Med Branch, Sealy Ctr Aging, Galveston, TX USA. RP Holmes, HM (reprint author), UT MD Anderson Canc Ctr, Dept Gen Internal Med, 1515 Holcombe Blvd,Unit 1465, Houston, TX 77030 USA. EM hholmes@mdanderson.org FU Hartford Geriatrics Health Outcomes Research Scholars Award; National Institute on Aging [K23AG038476, R56AG 0207017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056, 3U01 AG012553]; National Institute of Mental Health [R34 MH082682]; National Institute of Nursing Research [R01 NR010135]; Agency for Healthcare Research and Quality [R01 HS017695, K12 HS019461, R01HS018721]; Veterans Affairs Health Services Research [IIR-06062]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR053593]; Cancer Prevention and Research Institute of Texas [RP 101207]; National Cancer Institute [K05 CA134923] FX Conflict of Interest: Dr. Holmes was supported by a Hartford Geriatrics Health Outcomes Research Scholars Award and by a grant from the National Institute on Aging (K23AG038476). Dr. Hanlon was supported in part by National Institute on Aging grants and contracts (R56AG 0207017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056, 3U01 AG012553), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01 NR010135), Agency for Healthcare Research and Quality grants (R01 HS017695, K12 HS019461, R01HS018721), and a Veterans Affairs Health Services Research grant (IIR-06062). Dr. Suarez-Almazor is supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24 AR053593). Drs. Elting, Suarez-Almazor, and Goodwin are supported by a grant from the Cancer Prevention and Research Institute of Texas (RP 101207). Dr. Goodwin was supported by an Established Investigator Grant from the National Cancer Institute (K05 CA134923). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 22 Z9 22 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2012 VL 60 IS 7 BP 1298 EP 1303 DI 10.1111/j.1532-5415.2012.04037.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 972WJ UT WOS:000306311600015 PM 22702464 ER PT J AU Bhatia, S Frangioni, JV Hoffman, RM Iafrate, AJ Polyak, K AF Bhatia, Sangeeta Frangioni, John V. Hoffman, Robert M. Iafrate, A. John Polyak, Kornelia TI The challenges posed by cancer heterogeneity SO NATURE BIOTECHNOLOGY LA English DT Article AB A panel of five experts discuss the implications of cancer heterogeneity for diagnostics and therapy. C1 [Bhatia, Sangeeta] MIT, Cambridge, MA 02139 USA. [Bhatia, Sangeeta] Brigham & Womens Hosp, Boston, MA 02115 USA. [Frangioni, John V.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Iafrate, A. John] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Polyak, Kornelia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hoffman, Robert M.] Univ Calif San Diego, Dept Surg, La Jolla, CA 92093 USA. [Hoffman, Robert M.] AntiCancer Inc, San Diego, CA USA. RP Bhatia, S (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. FU NIEHS NIH HHS [P30 ES002109] NR 1 TC 44 Z9 45 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2012 VL 30 IS 7 BP 604 EP 610 DI 10.1038/nbt.2294 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 972QV UT WOS:000306293400015 PM 22781679 ER PT J AU Zhang, YA Benmohamed, R Zhang, W Kim, J Edgerly, CK Zhu, YQ Morimoto, RI Ferrante, RJ Kirsch, DR Silverman, RB AF Zhang, Yinan Benmohamed, Radhia Zhang, Wei Kim, Jinho Edgerly, Christina K. Zhu, Yaoqiu Morimoto, Richard I. Ferrante, Robert J. Kirsch, Donald R. Silverman, Richard B. TI Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1-Dependent Protein Aggregation for the Treatment of ALS SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Cyclohexane 1,3-diones; superoxide dismutase 1 (SOD1); protein aggregation; amyotrophic lateral sclerosis (ALS); mutant SOD1; PC-12 cells; cortical neurons ID AMYOTROPHIC-LATERAL-SCLEROSIS; POTENTIAL APPLICATION; RILUZOLE; TOXICITY; DESIGN AB Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons, and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC 12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS. C1 [Zhang, Yinan; Zhang, Wei; Silverman, Richard B.] Northwestern Univ, Dept Chem, Chem Life Proc Inst,Ctr Mol Innovat & Drug Discov, Dept Mol Biosci, Evanston, IL 60208 USA. [Benmohamed, Radhia; Kirsch, Donald R.] Cambria Pharmaceut, Cambridge, MA 02142 USA. [Kim, Jinho; Edgerly, Christina K.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina K.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina K.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina K.; Ferrante, Robert J.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr 00 GR H, Pittsburgh, PA 15206 USA. [Zhu, Yaoqiu] MetabQuest Res & Consulting, Beijing 100871, Peoples R China. [Morimoto, Richard I.] Northwestern Univ, Rice Inst Biomed Res, Dept Mol Biosci, Evanston, IL 60208 USA. RP Silverman, RB (reprint author), Northwestern Univ, Dept Chem, Chem Life Proc Inst,Ctr Mol Innovat & Drug Discov, Dept Mol Biosci, 2145 Sheridan Rd, Evanston, IL 60208 USA. EM Agman@chem.northwestern.edu RI Zhu, Yaoqiu/D-4624-2013; Zhang, Yinan/D-5769-2016 OI Zhang, Yinan/0000-0002-0362-1473 FU National Institutes of Health [1R43NS057849] FX We thank the National Institutes of Health (Grant 1R43NS057849), the ALS Association (TREAT program), and the Department of Defense (AL093052), for their generous support of this research. NR 19 TC 6 Z9 6 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JUL PY 2012 VL 3 IS 7 BP 584 EP 587 DI 10.1021/ml3000963 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 972GP UT WOS:000306265600014 PM 22837812 ER PT J AU Matas, AJ Delmonico, FL AF Matas, Arthur J. Delmonico, Francis L. TI Living Donation: The Global Perspective SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Donation; Living donation; Ethics; Outcomes ID LIVE KIDNEY DONOR; TRANSPLANT TOURISM; FOLLOW-UP; ORGAN-TRANSPLANTATION; MEDICAL GUIDELINES; REGULATED SYSTEM; VANCOUVER FORUM; RENAL-FUNCTION; SINGLE-CENTER; MORTALITY AB Of 195 independent countries in the world, 83 have transplant programs. Some countries (areas) have emphasized living donation; others, decreased donation. As a consequence, rates of living donation vary widely between geographic areas and often between countries within the same geographic area. The major ethical issue in living donation is the risk to the donor. Internationally, numerous guidelines have been developed outlining acceptable donor evaluation and criteria for approval. An ongoing issue is that there remains considerable variation between countries (and programs within a country) in evaluation and in acceptance criteria. A major problem for most countries is the shortage of organs. As a consequence, illegal or quasi-legal unregulated markets have developed in some areas. These markets have not provided protection for either donor or recipient. The transplant community has taken a unified stand against these underground unregulated markets. (C) 2012 by the National Kidney Foundation, Inc. All rights reserved. C1 [Matas, Arthur J.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Matas, AJ (reprint author), Univ Minnesota, Dept Surg, MMC 328,420 Delaware St SE, Minneapolis, MN 55455 USA. EM matas001@umn.edu NR 56 TC 7 Z9 7 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JUL PY 2012 VL 19 IS 4 BP 269 EP 275 DI 10.1053/j.ackd.2012.05.003 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 972RC UT WOS:000306296600012 PM 22732048 ER PT J AU Jensen, J Tantiwong, P Stuenaes, JT Molina-Carrion, M DeFronzo, RA Sakamoto, K Musi, N AF Jensen, Jorgen Tantiwong, Puntip Stuenaes, Jorid T. Molina-Carrion, Marjorie DeFronzo, Ralph A. Sakamoto, Kei Musi, Nicolas TI Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE insulin resistance ID HUMAN SKELETAL-MUSCLE; GLUCOSE-UPTAKE; INSULIN-RESISTANCE; EPITROCHLEARIS MUSCLES; SYNTHETASE ACTIVITY; ACTIVITY CONTRIBUTE; KINETIC-PROPERTIES; UDP-GLUCOSE; PHOSPHORYLATION; ACTIVATION AB Jensen J, Tantiwong P, Stuenaes JT, Molina-Carrion M, DeFronzo RA, Sakamoto K, Musi N. Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects. Am J Physiol Endocrinol Metab 303: E82-E89, 2012. First published April 17, 2012; doi: 10.1152/ajpendo.00658.2011.-Insulin stimulates glycogen synthase (GS) through dephosphorylation of serine residues, and this effect is impaired in skeletal muscle from insulin-resistant [obese and type 2 diabetic (T2DM)] subjects. Exercise also increases GS activity, yet it is not known whether the ability of exercise to affect GS is impaired in insulin-resistant subjects. The objective of this study was to examine the effect of acute exercise on GS phosphorylation and enzyme kinetic properties in muscle from insulin-resistant individuals. Lean normal glucose-tolerant (NGT), obese NGT, and obese T2DM subjects performed 40 min of moderate-intensity cycle exercise (70% of Vo(2max)). GS kinetic properties and phosphorylation were measured in vastus lateralis muscle before exercise, immediately after exercise, and 3.5 h postexercise. In lean subjects, GS fractional activity increased twofold after 40 min of exercise, and it remained elevated after the 3.5-h rest period. Importantly, exercise also decreased GS K-m for UDP-glucose from approximate to 0.5 to approximate to 0.2 mM. In lean subjects, exercise caused significant dephosphorylation of GS by 50-70% (Ser(641), Ser(645), and Ser(645,649,653,657)), and phosphorylation of these sites remained decreased after 3.5 h; Ser(7) phosphorylation was not regulated by exercise. In obese NGT and T2DM subjects, exercise increased GS fractional activity, decreased K-m for UDP-glucose, and decreased GS phosphorylation as effectively as in lean NGT subjects. We conclude that the molecular regulatory process by which exercise promotes glycogen synthesis in muscle is preserved in insulin-resistant subjects. C1 [Jensen, Jorgen] Norwegian Sch Sport Sci, Dept Phys Performance, Oslo, Norway. [Jensen, Jorgen; Stuenaes, Jorid T.] Natl Inst Occupat Hlth, Dept Work Related Musculoskeletal Disorders, Oslo, Norway. [Tantiwong, Puntip; Molina-Carrion, Marjorie; DeFronzo, Ralph A.; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Diabet Div, San Antonio, TX 78229 USA. [Tantiwong, Puntip; Molina-Carrion, Marjorie; DeFronzo, Ralph A.; Musi, Nicolas] Texas Diabet Inst, San Antonio, TX USA. [Sakamoto, Kei] Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat Unit, Dundee, Scotland. [Musi, Nicolas] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. RP Musi, N (reprint author), Audie L Murphy VA Hosp, GRECC 182,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM musi@uthscsa.edu RI Jensen, Jorgen/O-2245-2013 FU American Diabetes Association; National Institutes of Health [AG-030979, DK-80157, DK-089229, DK-24092]; San Antonio Nathan Shock Center; South Texas Health Research Center; US Department of Veterans Affairs; Novo Nordisk Foundation; United Kingdom (UK) Medical Research Council; Diabetes UK; Dundee and District of Diabetes UK Volunteer Group FX This study was supported by grants from the American Diabetes Association (N. Musi and R. A. DeFronzo), the National Institutes of Health (AG-030979, DK-80157, and DK-089229 to N. Musi and DK-24092 to R. A. DeFronzo), the San Antonio Nathan Shock Center (N. Musi), the South Texas Health Research Center (N. Musi), the US Department of Veterans Affairs (R. A. DeFronzo), the Novo Nordisk Foundation (J. Jensen), the United Kingdom (UK) Medical Research Council (K. Sakamoto), Diabetes UK (K. Sakamoto), and the Dundee and District of Diabetes UK Volunteer Group (K. Sakamoto). NR 45 TC 4 Z9 4 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUL PY 2012 VL 303 IS 1 BP E82 EP E89 DI 10.1152/ajpendo.00658.2011 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 974EG UT WOS:000306412000007 PM 22510711 ER PT J AU Aoyagi, T Kusakari, Y Xiao, CY Inouye, BT Takahashi, M Scherrer-Crosbie, M Rosenzweig, A Hara, K Matsui, T AF Aoyagi, Toshinori Kusakari, Yoichiro Xiao, Chun-Yang Inouye, Brendan T. Takahashi, Masaya Scherrer-Crosbie, Marielle Rosenzweig, Anthony Hara, Kenta Matsui, Takashi TI Cardiac mTOR protects the heart against ischemia-reperfusion injury SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE myocardial infarction; left ventricular remodeling; transgenic mice; heart failure ID MITOCHONDRIAL PERMEABILITY TRANSITION; TUMOR-NECROSIS-FACTOR; MYOCARDIAL-INFARCTION; ISCHEMIA/REPERFUSION INJURY; AKT ACTIVATION; CELL-DEATH; P70S6 KINASE; CARDIOMYOCYTES; MECHANISMS; APOPTOSIS AB Aoyagi T, Kusakari Y, Xiao C, Inouye BT, Takahashi M, Scherrer-Crosbie M, Rosenzweig A, Hara K, Matsui T. Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 303: H75-H85, 2012. First published May 4, 2012; doi: 10.1152/ajpheart.00241.2012.-Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-alpha, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response. C1 [Aoyagi, Toshinori; Inouye, Brendan T.; Matsui, Takashi] Univ Hawaii, John A Burns Sch Med, Cardiovasc Res Ctr, Honolulu, HI 96813 USA. [Kusakari, Yoichiro; Xiao, Chun-Yang; Rosenzweig, Anthony; Matsui, Takashi] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Inst, Boston, MA 02215 USA. [Takahashi, Masaya] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiol, Boston, MA 02215 USA. [Scherrer-Crosbie, Marielle] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. [Hara, Kenta] Kobe Univ, Kobe, Hyogo 657, Japan. RP Matsui, T (reprint author), Univ Hawaii, John A Burns Sch Med, Cardiovasc Res Ctr, 651 Ilalo St,BSB 311D, Honolulu, HI 96813 USA. EM tmatsui@hawaii.edu FU National Heart, Lung, and Blood Institute [HL-098423, HL-094677]; Leducq Network for Research Excellence FX This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-098423 (to T. Matsui) and HL-094677 (to A. Rosenzweig) and a Leducq Network for Research Excellence (to A. Rosenzweig). NR 45 TC 47 Z9 50 U1 0 U2 11 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL 1 PY 2012 VL 303 IS 1 BP H75 EP H85 DI 10.1152/ajpheart.00241.2012 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 973DG UT WOS:000306333700008 PM 22561297 ER PT J AU Gohda, T Walker, WH Wolkow, P Lee, JE Warram, JH Krolewski, AS Niewczas, MA AF Gohda, Tomohito Walker, William H. Wolkow, Pawel Lee, Jung Eun Warram, James H. Krolewski, Andrzej S. Niewczas, Monika A. TI Elevated urinary excretion of immunoglobulins in nonproteinuric patients with type 1 diabetes SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE diabetic nephropathy; glomerular filtration barrier; microalbuminuria ID GLOMERULAR-FILTRATION-RATE; PROXIMAL TUBULE CELLS; CHARGE-SELECTIVITY; SIZE-SELECTIVITY; RENAL-FUNCTION; ALBUMIN; NEPHROPATHY; SERUM; MELLITUS; IGG AB Gohda T, Walker WH, Wolkow P, Lee JE, Warram JH, Krolewski AS, Niewczas MA. Elevated urinary excretion of immunoglobulins in nonproteinuric patients with type 1 diabetes. Am J Physiol Renal Physiol 303: F157-F162, 2012. First published April 18, 2012; doi:10.1152/ajprenal.00443.2011.-Increased albuminuria is a hallmark of early diabetic nephropathy, whereas the role of immunoglobulins (Igs), such as IgG (its 1-4 subtypes), IgA, and IgM, different in charge and size, has not been examined in early nephropathy in the past due to lack of a sensitive and reliable method. Our study group consisted of subjects with type 1 diabetes (T1D) and normoalbuminuria (n = 78), microalbuminuria (n = 78), and of 75 healthy subjects (HS). A Luminex-based immunoassay (1,000 time more sensitive than nephelometry-based method) was validated for the urine matrix and used for the measurements of IgG1-4, IgA, and IgM in our study groups. The Luminex-based assay detected Igs in 87% of HS subjects and in 100% of T1D subjects. Recovery of known amounts of Igs added to urine was 92-118%. In the normoalbuminuria group, urinary concentrations of albumin, IgG2, IgA, and IgM were significantly higher than in HS, whereas in the microalbuminuria, further elevation of IgG2, IgG4, and IgA was the most pronounced. In all three groups, fractional excretion of Igs was at least 100 times lower than that of albumin. Fractional excretion of IgG2 was the highest among all Igs. We validated a sensitive method for measuring Igs in urine using Luminex. We found that elevated concentrations of Igs, particularly in IgG2 and IgA, is present in subjects with T1D and no proteinuria. Elevation of those particular Ig subtypes suggests a contribution of novel mechanisms in early diabetic nephropathy, different from charge and size barrier impairment. C1 [Niewczas, Monika A.] Harvard Univ, Div Res, Sect Genet & Epidemiol, Joslin Diabet Ctr,Med Sch, Boston, MA 02215 USA. [Gohda, Tomohito; Wolkow, Pawel; Lee, Jung Eun; Warram, James H.; Krolewski, Andrzej S.; Niewczas, Monika A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo, Japan. [Wolkow, Pawel] Jagiellonian Univ, Dept Pharmacol, Fac Med, Krakow, Poland. [Lee, Jung Eun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul, South Korea. RP Niewczas, MA (reprint author), Harvard Univ, Div Res, Sect Genet & Epidemiol, Joslin Diabet Ctr,Med Sch, 1 Joslin Pl,R 368A, Boston, MA 02215 USA. EM monika.niewczas@joslin.harvard.edu RI lee, je/O-6247-2014 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK041526, DK067638]; Uehara Memorial Foundation; Juntendo University, Tokyo, Japan; American Diabetes Association [7-03-MN-28] FX This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK041526 and DK067638 to A. S. Krolewski, the Uehara Memorial Foundation to T. Gohda, a personal grant from Yasuhiko Tomino (Juntendo University, Tokyo, Japan) to T. Gohda, and by American Diabetes Association mentor-based fellowship 7-03-MN-28 to M. A. Niewczas. NR 35 TC 5 Z9 5 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUL PY 2012 VL 303 IS 1 BP F157 EP F162 DI 10.1152/ajprenal.00443.2011 PG 6 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 971EC UT WOS:000306185500019 PM 22513848 ER PT J AU Reichardt, P Blay, JY Gelderblom, H Schlemmer, M Demetri, GD Bui-Nguyen, B McArthur, GA Yazji, S Hsu, Y Galetic, I Rutkowski, P AF Reichardt, P. Blay, J. -Y. Gelderblom, H. Schlemmer, M. Demetri, G. D. Bui-Nguyen, B. McArthur, G. A. Yazji, S. Hsu, Y. Galetic, I. Rutkowski, P. TI Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib SO ANNALS OF ONCOLOGY LA English DT Article DE gastrointestinal stromal tumors; GIST; imatinib; nilotinib; sunitinib; tyrosine kinase inhibitor ID KINASE INHIBITOR NILOTINIB; TYROSINE KINASE; RESPONSE EVALUATION; DOSE IMATINIB; SARCOMA GROUP; SOLID TUMORS; MESYLATE; TRIAL; PROGRESSION; SURVIVAL AB This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure. Patients were randomized 2 : 1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC + imatinib, or BSC + sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib. Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P = 0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P = 0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P = 0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of > 4 months in favor of nilotinib (405 versus 280 days; P = 0.02). Nilotinib was well tolerated. In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS. C1 [Reichardt, P.] HELIOS Klinikum Bad Saarow, Sarcoma Ctr Berlin Brandenburg, DE-15526 Bad Saarow Pieskow, Germany. [Blay, J. -Y.] Univ Lyon 1, Leon Berar Comprehens Canc Ctr, F-69365 Lyon, France. [Gelderblom, H.] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. [Schlemmer, M.] Univ Munich, Univ Hosp Grosshadern, Dept Internal Med 3, Munich, Germany. [Demetri, G. D.] Dana Farber Canc Inst, Ludwig Ctr, Dana Farber Harvard Canc Ctr, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Bui-Nguyen, B.] Inst Bergonie, Bordeaux, France. [McArthur, G. A.] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Yazji, S.; Hsu, Y.] Novartis Pharmaceut, Florham Pk, NJ USA. [Galetic, I.] Novartis Pharma AG, Basel, Switzerland. [Rutkowski, P.] M Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Rutkowski, P.] Inst Oncol, Warsaw, Poland. RP Reichardt, P (reprint author), HELIOS Klinikum Bad Saarow, Sarcoma Ctr Berlin Brandenburg, Pieskower Str 33, DE-15526 Bad Saarow Pieskow, Germany. EM peter.reichardt@helios-kliniken.de RI Blay, Jean-Yves/N-3966-2016; OI Blay, Jean-Yves/0000-0001-7190-120X; Rutkowski, Piotr/0000-0002-8920-5429 FU Novartis Pharmaceuticals; Novartis Pharma AG, Basel, Switzerland FX We thank the patients, their families, and the clinical investigators and staff involved in the study. The authors acknowledge Robert Gillespie, PhD, of Chameleon Communications International, who provided medical writing services with funding from Novartis Pharmaceuticals.; Novartis Pharma AG, Basel, Switzerland. NR 32 TC 41 Z9 44 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUL PY 2012 VL 23 IS 7 BP 1680 EP 1687 DI 10.1093/annonc/mdr598 PG 8 WC Oncology SC Oncology GA 970MS UT WOS:000306135200006 PM 22357255 ER PT J AU Schoenfeld, JD Mauch, PM Das, P Silver, B Marcus, KJ Stevenson, MA Ng, AK AF Schoenfeld, J. D. Mauch, P. M. Das, P. Silver, B. Marcus, K. J. Stevenson, M. A. Ng, A. K. TI Lung malignancies after Hodgkin lymphoma: disease characteristics, detection methods and clinical outcome SO ANNALS OF ONCOLOGY LA English DT Article DE detection; Hodgkin lymphoma; lung cancer; screening; second malignancy; thoracic neoplasm ID COLLABORATIVE BRITISH COHORT; LONG-TERM SURVIVORS; 2ND CANCER-RISK; FOLLOW-UP; RADIOTHERAPY; CHEMOTHERAPY; MORTALITY; RADIATION; TOMOGRAPHY; AGE AB Hodgkin lymphoma (HL) survivors have an increased risk of secondary malignancies. We analyzed outcomes in patients with lung cancers following HL treatment. Cases of thoracic malignancies were retrospectively identified from a multi-institutional database of 1976 patients treated for HL from 1969 to 2007. Data regarding risk factors, disease characteristics and outcomes were obtained from medical records. Lung malignancies were identified in 55 patients a median of 19.5 years after initial HL therapy. Thirty-one patients (56%) had a > 10 pack-year history of tobacco use, 48 (87%) received thoracic irradiation and 26 (47%) received alkylating chemotherapy. Of the 42 patients with known stage at lung cancer diagnosis, 23 (55%) were stage IV and 5 (12%) were stage III. The method of lung cancer detection was known for 35 patients; of these, 12 (34%) were detected incidentally. Median survival time after diagnosis was 10 months for all 55 patients. Median survival time for patients with incidentally detected tumors has not been reached with a median follow-up of 39 months. Lung malignancies diagnosed in patients successfully treated for HL generally have a dismal prognosis. However, a subset of patients diagnosed incidentally may have potentially curable disease. C1 [Schoenfeld, J. D.; Mauch, P. M.; Silver, B.; Marcus, K. J.; Ng, A. K.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Schoenfeld, J. D.] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Mauch, P. M.; Silver, B.; Marcus, K. J.; Ng, A. K.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Das, P.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Marcus, K. J.] Childrens Hosp, Boston, MA 02115 USA. [Stevenson, M. A.] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Schoenfeld, JD (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM jdschoenfeld@partners.org NR 31 TC 13 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUL PY 2012 VL 23 IS 7 BP 1813 EP 1818 DI 10.1093/annonc/mdr551 PG 6 WC Oncology SC Oncology GA 970MS UT WOS:000306135200025 PM 22104573 ER PT J AU Kerfoot, BP Baker, H AF Kerfoot, B. Price Baker, Harley TI An Online Spaced-Education Game for Global Continuing Medical Education A Randomized Trial SO ANNALS OF SURGERY LA English DT Article ID FINANCIAL INCENTIVES; CANCER; ADULTS AB Objective: To assess the efficacy of a "spaced-education" game as a method of continuing medical education (CME) among physicians across the globe. Background: The efficacy of educational games for the CME has yet to be established. We created a novel online educational game by incorporating game mechanics into "spaced education" (SE), an evidence-based method of online CME. Methods: This 34-week randomized trial enrolled practicing urologists across the globe. The SE game consisted of 40 validated multiple-choice questions and explanations on urology clinical guidelines. Enrollees were randomized to 2 cohorts: cohort A physicians were sent 2 questions via an automated e-mail system every 2 days, and cohort B physicians were sent 4 questions every 4 days. Adaptive game mechanics re-sent the questions in 12 or 24 days if answered incorrectly and correctly, respectively. Questions expired if not answered on time (appointment dynamic). Physicians retired questions by answering each correctly twice-in-a-row (progression dynamic). Competition was fostered by posting relative performance among physicians. Main outcome measures were baseline scores (percentage of questions answered correctly upon initial presentation) and completion scores (percentage of questions retired). Results: A total of 1470 physicians from 63 countries enrolled. Median baseline score was 48% (interquartile range [IQR] 17) and, in multivariate analyses, was found to vary significantly by region (Cohen d(max) = 0.31, P = 0.001) and age (d(max) = 0.41, P < 0.001). Median completion score was 98% (IQR 25) and varied significantly by age (d(max) = 0.21, P < 0.001) and American Board of Urology certification (d = 0.10, P = 0.033) but not by region (multivariate analyses). Question clustering reduced physicians' performance (d = 0.43, P < 0.001). Seventy-six percent of enrollees (1111/1470) requested to participate in future SE games. C1 [Kerfoot, B. Price] VA Boston Healthcare Syst, Urol Sect, Surg Serv, Jamaica Plain, MA 02130 USA. [Baker, Harley] Calif State Univ, Camarillo, CA USA. [Kerfoot, B. Price] Harvard Univ, Sch Med, Boston, MA USA. RP Kerfoot, BP (reprint author), VA Boston Healthcare Syst, Urol Sect, Surg Serv, 150 S Huntington Ave,151DIA, Jamaica Plain, MA 02130 USA. EM price.kerfoot@gmail.com FU American Urological Association (Linthicum, MD); American Urological Association Foundation (Linthicum, MD); Astellas Pharma US, Inc; United States Agency for Healthcare Research and Quality FX This study was supported in part by the American Urological Association (Linthicum, MD), the American Urological Association Foundation (Linthicum, MD), Astellas Pharma US, Inc, and the United States Agency for Healthcare Research and Quality. NR 25 TC 9 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2012 VL 256 IS 1 BP 33 EP 38 DI 10.1097/SLA.0b013e31825b3912 PG 6 WC Surgery SC Surgery GA 969TZ UT WOS:000306083300010 PM 22664558 ER PT J AU Separovic, D Breen, P Joseph, N Bielawski, J Pierce, JS Van Buren, E Gudz, TI AF Separovic, Duska Breen, Paul Joseph, Nicholas Bielawski, Jacek Pierce, Jason S. Van Buren, Eric Gudz, Tatyana I. TI siRNA-Mediated Down-regulation of Ceramide Synthase 1 Leads to Apoptotic Resistance in Human Head and Neck Squamous Carcinoma Cells after Photodynamic Therapy SO ANTICANCER RESEARCH LA English DT Article DE Apoptosis; ceramide; ceramide synthase 1; dihydroceramide; PDT; sphingolipids; head and neck squamous carcinomas cells UM-SCC-22A ID LONGEVITY ASSURANCE GENE-1; DE-NOVO SPHINGOLIPIDS; PHOTOSENSITIZED CELLS; FAMILY-MEMBERS; ACCUMULATION; 1-PHOSPHATE; SPECIFICITY; INHIBITION; GROWTH; DEATH AB Background: The effectiveness of photodynamic therapy (PDT) for cancer treatment correlates with apoptosis. We previously observed that the knockdown of ceramide synthase 6, an enzyme from the de novo sphingolipid biosynthesis pathway, is associated with marked reduction in C18-dihydroceramide and makes cells resistant to apoptosis post-PDT. Down-regulation of ceramide synthase 1 (CERS1) can also render cells resistant to anticancer drugs. Aim: To explore the impact of CERS1 knockdown on apoptosis and the sphingolipid profile, post-PDT, with the silicone phthalocyanine Pc 4, in a human head and neck squamous carcinoma cell line. Materials and Methods: Besides siRNA transfection and PDT treatment, the following methods were used: immunoblotting for protein expression, mass spectrometry for sphingolipid analysis, spectroflurometry and flow cytometry for apoptosis detection, and trypan blue assay for cell viability evaluation. Results: CERS1 knockdown led to inhibition of PDT-induced caspase 3-like (DEVDase) activation, of apoptosis and cell death. CERS1 knockdown was associated with global and selective decreases in ceramides and dihydroceramides, in particular C18-, C18:1- and C20-ceramide post-PDT. Conclusion: Our novel findings are consistent with the notion that CERS1 regulates apoptotic resistance to PDT, partly via C18- and C20-ceramide, and that CERS1 is a molecular target for controlling resistance to PDT. C1 [Separovic, Duska; Breen, Paul; Joseph, Nicholas] Wayne State Univ, Dept Pharmaceut Sci, Eugene Applebaum Coll Pharm & Hlth Sci, Detroit, MI 48201 USA. [Separovic, Duska; Van Buren, Eric] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Bielawski, Jacek; Pierce, Jason S.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Gudz, Tatyana I.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Gudz, Tatyana I.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. RP Separovic, D (reprint author), Wayne State Univ, Dept Pharmaceut Sci, Eugene Applebaum Coll Pharm & Hlth Sci, 259 Mack Ave, Detroit, MI 48201 USA. EM dseparovic@wayne.edu FU U.S. Public Health Service from the National Cancer Institute, National Institutes of Health [R01 CA77475]; Veterans Administration; NCI [IPO1CA097132, P30 CA 138313]; NIH/NCRR SC COBRE [P20 RR017677]; NIH; Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823] FX This work was supported by U.S. Public Health Service Grant R01 CA77475 from the National Cancer Institute, National Institutes of Health (DS) and the Veterans Administration Merit Awards from RR&D and BLRD programs (TIG). The MS-related work was performed by the Lipidomics Shared Resource (Medical University of South Carolina), supported by NCI grants: IPO1CA097132 and P30 CA 138313 and NIH/NCRR SC COBRE Grant P20 RR017677. Laboratory space for the Lipidomics Shared Resource was supported by the NIH, grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. We thank Drs. Besim Ogretmen and Can Emre Senkal for helpful discussions over the manuscript. NR 29 TC 9 Z9 9 U1 0 U2 4 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL PY 2012 VL 32 IS 7 SI SI BP 2479 EP 2485 PG 7 WC Oncology SC Oncology GA 972CO UT WOS:000306254300010 PM 22753704 ER PT J AU Koyama, A Okereke, OI Yang, T Blacker, D Selkoe, DJ Grodstein, F AF Koyama, Alain Okereke, Olivia I. Yang, Ting Blacker, Deborah Selkoe, Dennis J. Grodstein, Francine TI Plasma Amyloid-beta as a Predictor of Dementia and Cognitive Decline A Systematic Review and Meta-analysis SO ARCHIVES OF NEUROLOGY LA English DT Review ID ALZHEIMERS-DISEASE; A-BETA; FOLLOW-UP; RISK; METAANALYSIS; ASSOCIATION; HOMOCYSTEINE; IMPAIRMENT; CONVERSION; A-BETA-42 AB Background: Preclinical prediction of Alzheimer disease (AD) is important and critical to effective intervention. Plasma levels of amyloid-beta (A beta) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data. Objective: To conduct a systematic review and meta-analysis of relevant prospective studies to determine whether plasma amyloid-beta levels may predict development of dementia, AD, and cognitive decline. Design: We searched prospective studies published between 1995 and 2011 indexed in the MEDLINE, EMBASE, and PsycINFO databases. Selected studies included those measuring at least 1 relevant plasma amyloid-beta species (A beta(40), A beta(42), or A beta(42): A beta(40) ratio) and reporting an effect estimate for dementia, AD, or cognitive change. Main Outcome Measures: Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcomewere extracted. Random effects models were used to generate summary risk ratios and 95% confidence intervals comparing the bottom vs top quantiles for each plasma measure. Results: Thirteen studies with a total of 10 303 subjects met inclusion criteria for meta-analysis. Lower A beta(42): A beta(40) ratios were significantly associated with development of AD (summary risk ratio, 1.60; 95% CI, 1.04-2.46; P=.03) and dementia (risk ratio, 1.67; 95% CI, 1.02-2.75; P=.04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants' age, sex distribution, the study's follow-up time, or year of publication. Plasma levels of A beta(40) and A beta(42) alone were not significantly associated with either outcome. Conclusions: Overall, the literature indicates that plasma A beta(42): A beta(40) ratios predict development of AD and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid-beta levels as a preclinical biomarker. C1 [Koyama, Alain] Univ Calif San Francisco, Dept Psychiat, Boston, MA USA. [Okereke, Olivia I.; Blacker, Deborah; Grodstein, Francine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Okereke, Olivia I.; Grodstein, Francine] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Yang, Ting; Selkoe, Dennis J.] Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Boston, MA USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Koyama, A (reprint author), 4150 Clement St,VAMC 116H, San Francisco, CA 94121 USA. EM alain.koyama@va.gov RI Okereke, Olivia/R-9934-2016 FU National Institutes of Health [AG24215] FX This study was funded by grant AG24215 from the National Institutes of Health. NR 27 TC 66 Z9 69 U1 3 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JUL PY 2012 VL 69 IS 7 BP 824 EP 831 DI 10.1001/archneurol.2011.1841 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 971FO UT WOS:000306189400004 PM 22451159 ER PT J AU Rosas, HD Chen, YI Doros, G Salat, DH Chen, NK Kwong, KK Bush, A Fox, J Hersch, SM AF Rosas, H. Diana Chen, Y. Iris Doros, Gheorghe Salat, David H. Chen, Nan-kuei Kwong, Ken K. Bush, Ashley Fox, Jonathan Hersch, Steven M. TI Alterations in Brain Transition Metals in Huntington Disease An Evolving and Intricate Story SO ARCHIVES OF NEUROLOGY LA English DT Article ID HUMAN CEREBRAL-CORTEX; BASAL GANGLIA; GRADIENT-ECHO; MOUSE MODEL; IRON; HETEROGENEITY; PATHOGENESIS; COMPLEXITY; EXPRESSION; DISTORTION AB Background: Aberrant accumulation of transition metals in the brain may have an early and important role in the pathogenesis of several neurodegenerative disorders, including Huntington disease (HD). Objective: To comprehensively evaluate and validate the distribution of metal deposition in the brain using advanced magnetic resonance imaging methods from the premanifest through symptomatic stages of HD. Design: Observational study. Setting: University imaging center. Participants: Twenty-eight HD expanded gene carriers, 34 patients with symptomatic HD, and 56 age-and sex-matched healthy control subjects were included in the study. Interventions: Participants underwent magnetic resonance imaging for the quantification of the phase evolution of susceptibility-weighted images. Main Outcome Measures: To verify the identity of the metals responsible for the changes in the phase evolution of the susceptibility signal in the brain and to assess correlations with systemic levels. Inductively coupled plasma mass spectrometry was used to measure transition metal concentrations in postmortem brains. Results: In the basal ganglia, progressive increases in the phase evolution were found in HD, beginning in premanifest individuals who were far from expected onset and increasing with proximity to expected onset and thereafter. Increases in the cerebral cortex were regionally selective and present only in symptomatic HD. Increases were verified by excessive deposition of brain iron, but a complex alteration in other transition metals was found. Conclusion: An important and early role of altered metal homeostasis is suggested in the pathogenesis of HD. C1 [Rosas, H. Diana; Hersch, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Salat, David H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosas, H. Diana; Salat, David H.] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Boston, MA 02114 USA. [Rosas, H. Diana; Fox, Jonathan; Hersch, Steven M.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat, Boston, MA 02114 USA. [Chen, Y. Iris; Salat, David H.; Kwong, Ken K.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Chen, Y. Iris; Salat, David H.; Kwong, Ken K.] Harvard Univ, Sch Med, Boston, MA USA. [Doros, Gheorghe] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Chen, Nan-kuei] Duke Univ, Brain Imaging & Anal Ctr, Durham, NC USA. [Bush, Ashley] Univ Melbourne, Mental Hlth Res Inst, Oxidat Biol Lab, Melbourne, Vic, Australia. [Fox, Jonathan] Univ Wyoming, Dept Vet Sci, Laramie, WY 82071 USA. RP Rosas, HD (reprint author), Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, 149 13th St,Room 2275, Charlestown, MA 02129 USA. EM rosas@helix.mgh.harvard.edu RI Chen, Nan-kuei/E-7791-2016 OI Chen, Nan-kuei/0000-0001-6564-4219 FU National Institutes of Health from the National Institute for Neurological Disorders and Stroke [R01NS042861, NS058793]; National Institute of Biomedical Imaging and Bioengineering [AT000613, P01AT002048]; National Center for Complementary and Alternative Medicine [R21EB005690]; HDSA Coalition for the CURE; Food and Drug Administration [FD003359]; International Foundation for Gastrointestinal Disorders [SFCA07-101]; National Institute of Nursing Research [NR010827]; National Health and Medical Research Council FX This research was supported in part by the National Institutes of Health, including the following grants: R01NS042861 and NS058793 from the National Institute for Neurological Disorders and Stroke (Drs Rosas, Y. I. Chen, Doros, Salat, and Hersch), AT000613 (Drs Rosas, Y. I. Chen, and Hersch) and P01AT002048 from the National Institute of Biomedical Imaging and Bioengineering (Dr Kwong), R21EB005690 from the National Center for Complementary and Alternative Medicine (Dr N.-k. Chen), HDSA Coalition for the CURE (Dr Fox), FD003359 from the Food and Drug Administration (Drs Rosas, Y. I. Chen, and Hersch), SFCA07-101 from the International Foundation for Gastrointestinal Disorders, NR010827 from the National Institute of Nursing Research (Dr Salat), and National Health and Medical Research Council (Dr Bush). NR 30 TC 34 Z9 34 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JUL PY 2012 VL 69 IS 7 BP 887 EP 893 DI 10.1001/archneurol.2011.2945 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 971FO UT WOS:000306189400012 PM 22393169 ER PT J AU Schwartz, GF Bartelink, H Burstein, HJ Cady, B Cataliotti, L Fentiman, IS Holland, R Hughes, KS Masood, S McCormick, B Palazzo, JA Pressman, PI Reis, J Pusztai, L Rutgers, EJT Seidman, AD Solin, LJ Sparano, JA AF Schwartz, Gordon F. Bartelink, Harry Burstein, Harold J. Cady, Blake Cataliotti, Luigi Fentiman, Ian S. Holland, Roland Hughes, Kevin S. Masood, Shahla McCormick, Beryl Palazzo, Juan A. Pressman, Peter I. Reis-Filho, Jorge Pusztai, Lajos Rutgers, Emiel J. T. Seidman, Andrew D. Solin, Lawrence J. Sparano, Joseph A. TI Adjuvant Therapy in Stage I Carcinoma of the Breast: The Influence of Multigene Analyses and Molecular Phenotyping SO BREAST JOURNAL LA English DT Article DE adjuvant therapy; breast carcinoma; estrogen receptors; gene analysis; Her-2-neu; progesterone receptors; Ki-67 ID CANCER; EXPRESSION; RECURRENCE; RISK; CHEMOTHERAPY; PREDICTION; PROGNOSIS; TAMOXIFEN; SUBTYPES; MARKERS AB A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients. C1 [Schwartz, Gordon F.] Breast Care Ctr, Philadelphia, PA 19107 USA. [Palazzo, Juan A.] Jefferson Med Coll, Dept Pathol, Philadelphia, PA 19107 USA. [Bartelink, Harry] Antoni Van Leeuwenhoek Ziekenhuis, Inst Canc, NL-1066 CX Amsterdam, Netherlands. [Burstein, Harold J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cataliotti, Luigi] Univ Florence, I-50134 Florence, Italy. [Fentiman, Ian S.] Guys Hosp, London SE1 9RT, England. [Holland, Roland] Univ Nijmegen Hosp, Natl Expert & Training Ctr Breast Canc Screening, NL-6500 HB Nijmegen, Netherlands. [Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Masood, Shahla] Univ Florida, Hlth Sci Ctr, Jacksonville, FL 32209 USA. [McCormick, Beryl] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Pressman, Peter I.] New York Presbyterian Hosp, New York, NY USA. [Reis-Filho, Jorge] Inst Canc Res, Chester Beatty Labs, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Pusztai, Lajos] UT MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX USA. [Rutgers, Emiel J. T.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Surg, NL-1066 CX Amsterdam, Netherlands. [Seidman, Andrew D.] Cornell Univ, Breast Canc Med Serv, Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Seidman, Andrew D.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Solin, Lawrence J.] Albert Einstein Med Ctr, Dept Radiat Oncol, Philadelphia, PA 19141 USA. [Sparano, Joseph A.] Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10467 USA. RP Schwartz, GF (reprint author), Breast Care Ctr, Philadelphia, PA 19107 USA. EM Gordon.schwartz@jefferson.edu OI Hughes, Kevin/0000-0003-4084-6484 NR 33 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-122X J9 BREAST J JI Breast J. PD JUL-AUG PY 2012 VL 18 IS 4 BP 303 EP 311 DI 10.1111/j.1524-4741.2012.01264.x PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 968HP UT WOS:000305968600003 PM 22759093 ER PT J AU Rock, CL Doyle, C Demark-Wahnefried, W Meyerhardt, J Courneya, KS Schwartz, AL Bandera, EV Hamilton, KK Grant, B McCullough, M Byers, T Gansler, T AF Rock, Cheryl L. Doyle, Colleen Demark-Wahnefried, Wendy Meyerhardt, Jeffrey Courneya, Kerry S. Schwartz, Anna L. Bandera, Elisa V. Hamilton, Kathryn K. Grant, Barbara McCullough, Marji Byers, Tim Gansler, Ted TI Nutrition and Physical Activity Guidelines for Cancer Survivors SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article ID QUALITY-OF-LIFE; BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIAL; STAGE BREAST-CANCER; RECEIVING ADJUVANT CHEMOTHERAPY; CELL LUNG-CANCER; III COLON-CANCER; CIRCULATING 25-HYDROXYVITAMIN-D LEVELS; AMERICAN-DIETETIC-ASSOCIATION; BONE-MARROW-TRANSPLANTATION AB Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplements to improve their treatment outcomes, quality of life, and overall survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information with which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity guidelines during the continuum of cancer care, briefly highlighting important issues during cancer treatment and for patients with advanced cancer, but focusing largely on the needs of the population of individuals who are disease free or who have stable disease following their recovery from treatment. It also discusses select nutrition and physical activity issues such as body weight, food choices, food safety, and dietary supplements; issues related to selected cancer sites; and common questions about diet, physical activity, and cancer survivorship. CA Cancer J Clin 2012;62:242-274. (C) 2012 American Cancer Society. C1 [Doyle, Colleen; McCullough, Marji; Gansler, Ted] Amer Canc Soc, Atlanta, GA 30303 USA. [Rock, Cheryl L.] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Webb Endowed Chair Nutr Sci, Birmingham, AL USA. [Meyerhardt, Jeffrey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Courneya, Kerry S.] Univ Alberta, Canada Res Chair Phys Act & Canc, Edmonton, AB, Canada. [Schwartz, Anna L.] Idaho State Univ, Pocatello, ID USA. [Schwartz, Anna L.] Univ Washington, Seattle, WA 98195 USA. [Bandera, Elisa V.] Canc Inst New Jersey, Dept Epidemiol, New Brunswick, NJ USA. [Hamilton, Kathryn K.] Morristown Mem Hosp, Carol G Simon Canc Ctr, Morristown, NJ USA. [Grant, Barbara] Canc Care Ctr, St Alphonsus Reg Med Ctr, Boise, ID USA. [Byers, Tim] Univ Colorado, Ctr Canc, Aurora, CO USA. [Byers, Tim] Colorado Sch Publ Hlth, Aurora, CO USA. RP Doyle, C (reprint author), Amer Canc Soc, 250 Williams St NW,Suite 600, Atlanta, GA 30303 USA. EM colleen.doyle@cancer.org RI Bandera, Elisa/M-4169-2014 OI Bandera, Elisa/0000-0002-8789-2755 FU NCI NIH HHS [R01 CA081191] NR 295 TC 279 Z9 286 U1 11 U2 115 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD JUL-AUG PY 2012 VL 62 IS 4 BP 243 EP 274 DI 10.3322/caac.21142 PG 32 WC Oncology SC Oncology GA 970JJ UT WOS:000306123900005 PM 22539238 ER PT J AU Shearin, AL Hedan, B Cadieu, E Erich, SA Schmidt, EV Faden, DL Cullen, J Abadie, J Kwon, EM Grone, A Devauchelle, P Rimbault, M Karyadi, DM Lynch, M Galibert, F Breen, M Rutteman, GR Andre, C Parker, HG Ostrander, EA AF Shearin, Abigail L. Hedan, Benoit Cadieu, Edouard Erich, Suzanne A. Schmidt, Emmett V. Faden, Daniel L. Cullen, John Abadie, Jerome Kwon, Erika M. Grone, Andrea Devauchelle, Patrick Rimbault, Maud Karyadi, Danielle M. Lynch, Mary Galibert, Francis Breen, Matthew Rutteman, Gerard R. Andre, Catherine Parker, Heidi G. Ostrander, Elaine A. TI The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID WHOLE-GENOME ASSOCIATION; HISTIOCYTIC SARCOMA; WIDE ASSOCIATION; POPULATION-STRUCTURE; P16(INK4A); MODEL; BREED; DOG; P16; DELETION AB Background: Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD). Methods: Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results: Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions: We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds. Impact: Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region. Cancer Epidemiol Biomarkers Prey; 21(7); 1019-27. (C)2012 AACR. C1 [Shearin, Abigail L.; Cadieu, Edouard; Schmidt, Emmett V.; Faden, Daniel L.; Kwon, Erika M.; Rimbault, Maud; Karyadi, Danielle M.; Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. [Shearin, Abigail L.; Faden, Daniel L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Hedan, Benoit; Galibert, Francis; Andre, Catherine] Univ Rennes 1, CNRS, UMR 6290, Rennes, France. [Erich, Suzanne A.; Rutteman, Gerard R.] Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands. [Grone, Andrea] Univ Utrecht, Fac Vet Med, Dept Pathol, Utrecht, Netherlands. [Schmidt, Emmett V.; Lynch, Mary] Massachusetts Gen Hosp, Canc Res Ctr, Boston, MA 02114 USA. [Schmidt, Emmett V.; Lynch, Mary] Harvard Univ, Boston, MA 02115 USA. [Hedan, Benoit; Cullen, John; Breen, Matthew] N Carolina State Univ, Dept Populat Hlth, Raleigh, NC 27695 USA. [Hedan, Benoit; Cullen, John] N Carolina State Univ, Dept Pathobiol, Raleigh, NC 27695 USA. [Breen, Matthew] N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27695 USA. [Breen, Matthew] N Carolina State Univ, Ctr Comparat Med & Translat Res, Raleigh, NC 27695 USA. [Abadie, Jerome] ONIRIS, Ecole Natl Vet Agroalimentaire & Alimentation Nan, Nantes, France. [Breen, Matthew] UNC Lineberger Comprehens Canc Ctr, Canc Genet Program, Chapel Hill, NC USA. RP Ostrander, EA (reprint author), NHGRI, NIH, Canc Genet Branch, 50 S Dr,Bldg 50 Room,5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural Program of the National Human Genome Research Institute at NIH; AKC-Canine Health Foundation [2667, 760, 336, 935]; CNRS and French Association for Swiss dogs; NIH NCI [R01 CA69069, NIH U01 AI07033]; Harvard Breast Cancer SPORE [P50 CA89393]; Alberto Vittoni Award; Committee of Preventive Health Care of the Netherlands Royal Society of Veterinary Medicine; breed societies for Bernese mountain dogs in the Netherlands; breed societies for Bernese mountain dogs in the Germany; breed societies for Bernese mountain dogs in the Austria; breed societies for Bernese mountain dogs in the Belgium FX This work was supported by the Intramural Program of the National Human Genome Research Institute at NIH. Additional support was received from the AKC-Canine Health Foundation grants 2667 and 760 (M. Breen), 336 and 935 (E.A. Ostrander and C. Andre); the CNRS and French Association for Swiss dogs (C. Andre); NIH NCI R01 CA69069, NIH U01 AI07033, and the Harvard Breast Cancer SPORE P50 CA89393 (E. V. Schmidt); the Alberto Vittoni Award (B. Hedan, E. Cadieu, and G.R. Rutteman); the Committee of Preventive Health Care of the Netherlands Royal Society of Veterinary Medicine and the breed societies for Bernese mountain dogs in the Netherlands, Belgium, Germany and Austria (CR. Rutteman). NR 54 TC 24 Z9 24 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2012 VL 21 IS 7 BP 1019 EP 1027 DI 10.1158/1055-9965.EPI-12-0190-T PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 971NH UT WOS:000306210100004 PM 22623710 ER PT J AU Buchbinder, D Mertens, AC Zeltzer, LK Leisenring, W Goodman, P Lown, EA Alderfer, MA Recklitis, C Oeffinger, K Armstrong, GT Hudson, M Robison, LL Casillas, J AF Buchbinder, David Mertens, Ann C. Zeltzer, Lonnie K. Leisenring, Wendy Goodman, Pam Lown, E. Anne Alderfer, Melissa A. Recklitis, Christopher Oeffinger, Kevin Armstrong, Gregory T. Hudson, Melissa Robison, Leslie L. Casillas, Jacqueline TI Cancer Prevention and Screening Practices of Siblings of Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BRIEF SYMPTOM INVENTORY-18; ADULT SURVIVORS; COLORECTAL-CANCER; HEALTH OUTCOMES; UNITED-STATES; TOXIC STRESS; CHILDREN; ADAPTATION; PREVALENCE; ADJUSTMENT AB Background: To compare the skin and breast/cervical cancer prevention /screening practices of adult siblings of childhood cancer survivors with controls and to identify modifying factors for these practices. Methods: Cross-sectional, self-report data from 2,588 adult siblings of 5+ year survivors of childhood cancer were analyzed to assess cancer prevention/screening practices. Two age, sex, and race/ethnicity-matched samples (N = 5,915 and N = 37,789) of the Behavioral Risk Factor Surveillance System participants served as the comparison populations. Sociodemographic and cancer-related data were explored as modifying factors for sibling cancer prevention/screening practices through multivariable logistic regression. Results: Compared with controls, siblings were more likely to practice skin cancer prevention behaviors: use of protective clothing [OR, 2.85; 95% confidence interval (CI), 2.39-3.39], use of shade (OR, 2.11; 95% CI, 1.88-2.36), use of sunscreen (OR, 1.27; 95% CI, 1.14-1.40), and wearing a hat (OR, 1.77; 95% CI, 1.58-1.98). No differences were noted for breast/cervical cancer screening including mammography and Pap testing. Having less than a high school education and lack of health insurance were associated with diminished cancer prevention/screening behaviors. Survivor diagnosis, treatment intensity, adverse health, chronic health conditions, and second cancers were not associated with sibling cancer prevention /screening behaviors. Conclusions: Siblings of cancer survivors report greater skin cancer prevention practices when compared with controls; however, no differences were noted for breast/cervical cancer screening practices. Access to care and lack of education may be associated with decreased cancer prevention /screening behaviors. Interventions are needed to address these barriers. Impact: Research should be directed at understanding the impact of the cancer experience on sibling health behaviors. Cancer Epidemiol Bioinarkers Prev; 21(7); 1078-88. (C)2012 AACR. C1 [Buchbinder, David] Childrens Hosp Orange Cty, Dept Pediat, Orange, CA 92868 USA. [Buchbinder, David] Childrens Hosp Orange Cty, Div Hematol, Orange, CA 92868 USA. [Mertens, Ann C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Zeltzer, Lonnie K.; Casillas, Jacqueline] Univ Calif Los Angeles, Dept Pediat, Div Hematol Oncol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Zeltzer, Lonnie K.; Casillas, Jacqueline] UCLA Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. [Zeltzer, Lonnie K.; Casillas, Jacqueline] Univ Calif Los Angeles, David Geffen Sch Med, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA. [Leisenring, Wendy; Goodman, Pam] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Lown, E. Anne] Alcohol Res Grp, Emeryville, CA USA. [Alderfer, Melissa A.] Univ Penn, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Alderfer, Melissa A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Recklitis, Christopher] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Oeffinger, Kevin] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Armstrong, Gregory T.; Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Hudson, Melissa] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. RP Buchbinder, D (reprint author), Childrens Hosp Orange Cty, Dept Pediat, 455 S Main St, Orange, CA 92868 USA. EM dbuchbinder@choc.org FU National Cancer Institute [U24 CA55727]; American Lebanese Syrian Associated Charities (ALSAC) FX The work on this study was supported by a grant U24 CA55727 (to L.L. Robison, Principal Investigator) from the National Cancer Institute and by support to St. Jude Children's Research Hospital from the American Lebanese Syrian Associated Charities (ALSAC). NR 52 TC 1 Z9 1 U1 2 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2012 VL 21 IS 7 BP 1078 EP 1088 DI 10.1158/1055-9965.EPI-11-1095 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 971NH UT WOS:000306210100010 PM 22576363 ER PT J AU Khan, BA Guzman, O Campbell, NL Walroth, T Tricker, JL Hui, SL Perkins, A Zawahiri, M Buckley, JD Farber, MO Ely, EW Boustani, MA AF Khan, Babar A. Guzman, Oscar Campbell, Noll L. Walroth, Todd Tricker, Jason L. Hui, Siu L. Perkins, Anthony Zawahiri, Mohammed Buckley, John D. Farber, Mark O. Ely, E. Wesley Boustani, Malaz A. TI Comparison and Agreement Between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in Evaluating Patients' Eligibility for Delirium Assessment in the ICU SO CHEST LA English DT Article ID INTENSIVE-CARE-UNIT; MECHANICALLY VENTILATED PATIENTS; CRITICALLY-ILL PATIENTS; CONFUSION ASSESSMENT METHOD; MONITORING SEDATION; ADULT; RELIABILITY; VALIDITY; EFFICACY; PROTOCOL AB Background: Delirium evaluation in patients in the ICU requires the use of an arousal/sedation assessment tool prior to assessing consciousness. The Richmond Agitation-Sedation Scale (BASS) and the Riker Sedation-Agitation Scale (SAS) are well-validated arousal/sedation tools. We sought to assess the concordance of BASS and SAS assessments in determining eligibility of patients in the ICU for delirium screening using the confusion assessment method for the ICU (CAM-ICU). Methods: We performed a prospective cohort study in the adult medical, surgical, and progressive (step-down) ICUs of a tertiary care, university-affiliated, urban hospital in Indianapolis, Indiana. The cohort included 975 admissions to the ICU between January and October 2009. Results: The outcome measures of interest were the correlation and agreement between RASS and SAS measurements. In 2,469 RASS and SAS paired screens, the rank correlation using the Spearman correlation coefficient was 0.91, and the agreement between the two screening tools for assessing CAM-ICU eligibility as estimated by the K coefficient was 0.93. Analysis showed that 70.1% of screens were eligible for CAM-ICU assessment using BASS (7.1% sedated [BASS -3 to -1]; 62.6% calm [0]; and 0.4% restless, agitated [+1 to +3]), compared with 72.1% using SAS (5% sedated [SAS 3]; 66.5% calm [4]; and 0.6% anxious, agitated [5, 6]). In the mechanically ventilated subgroup, RASS identified 19.1% CAM-ICU eligible patients compared with 24.6% by SAS. The correlation coefficient in this subgroup was 0.70 and the agreement was 0.81. Conclusion: Both SAS and BASS led to similar rates of delirium assessment using the CAM-ICU. CHEST 2012; 142(1):48-54 C1 [Khan, Babar A.; Hui, Siu L.; Buckley, John D.; Farber, Mark O.; Boustani, Malaz A.] Indiana Univ Sch Med, Indianapolis, IN USA. [Guzman, Oscar] Westchester Cty Med Ctr, Dept Pharm, Westchester, NY USA. [Khan, Babar A.; Campbell, Noll L.; Hui, Siu L.; Perkins, Anthony; Zawahiri, Mohammed; Boustani, Malaz A.] Regenstrief Inst Inc, Indianapolis, IN USA. [Walroth, Todd; Tricker, Jason L.] Wishard Hlth Serv, Indianapolis, IN USA. [Khan, Babar A.; Campbell, Noll L.; Hui, Siu L.; Boustani, Malaz A.] Indiana Univ, Ctr Aging Res, Indianapolis, IN 46204 USA. [Campbell, Noll L.] Purdue Univ, Coll Pharm, Dept Pharm Practice, W Lafayette, IN 47907 USA. [Ely, E. Wesley] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ely, E. Wesley] US Dept Vet Affairs, Tennessee Valley Geriatr Res Educ Clin Ctr, Nashville, TN USA. RP Khan, BA (reprint author), 410 W 10th St,Ste 2000, Indianapolis, IN 46202 USA. EM bakhan@iupui.edu FU National Institute on Aging [R01AG034205-01A1]; National Institutes of Health; Forest Pharmaceuticals; Novartis FX The study was supported by a grant from the National Institute on Aging [Grant R01AG034205-01A1].; Financial/nonfinancial disclosures: Dr Boustani has received grant funds from the National Institute on Aging and the National Institutes of Health, grant funds from Forest Pharmaceuticals and Novartis, and serves on the speakers' bureau for Pfizer Inc and an advisory board for Eli Lilly and Company. All other authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. NR 34 TC 14 Z9 17 U1 3 U2 12 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2012 VL 142 IS 1 BP 48 EP 54 DI 10.1378/chest.11-2100 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 971NE UT WOS:000306209800013 PM 22539644 ER PT J AU Leung, JM Udris, EM Uman, J Au, DH AF Leung, Janice M. Udris, Edmunds M. Uman, Jane Au, David H. TI The Effect of End-of-Life Discussions on Perceived Quality of Care and Health Status Among Patients With COPD SO CHEST LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; LUNG-CANCER; COMMUNICATION; VENTILATION; PREFERENCES; CLINICIAN; PROGNOSIS; INSIGHTS; BARRIERS; DEATH AB Background: Despite strong preferences for discussions about end-of-life care, patients with COPD do not often have these discussions with their providers. Our objective was to determine whether patients who reported having end-of-life discussions also reported higher perceived markers of quality of care and health status. Methods: A cross-sectional study of data collected at baseline for a trial to improve the occurrence and quality of end-of-life communication in patients with COPD was conducted. The primary exposure was self-reported acknowledgment of having discussions about end-of-life planning with their physicians. The primary outcome measures were patient-reported quality of care and satisfaction with care, which were dichotomized as best imaginable quality of care vs other ratings of quality and highest satisfaction vs other ratings of satisfaction. We adjusted for confounding factors, including patient and provider characteristics, using logistic regression clustered by provider. Results: Three hundred seventy-six patients were enrolled, of whom 55 (14.6%) reported having end-of-life discussions. Individuals who reported having end-of-life discussions with their physicians were significantly more likely to rate their quality of care as the best imaginable (OR, 2.07; 95% CI, 1.05-4.09) and to be very satisfied with their medical care (OR, 1.98; 95% CI, 1.10-3.55). Discussions were more likely to have occurred among patients with worse health status as measured by St. George Respiratory Questionnaire total and impact scores. Conclusions: Patients who reported having end-of-life care discussions with their physicians had higher perceived quality of care and satisfaction with their physicians. Discussing end-of-life care with patients who have COPD may improve their perceived overall quality of and satisfaction with care. CHEST 2012; 142(1):128-133 C1 [Leung, Janice M.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Leung, Janice M.; Au, David H.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Udris, Edmunds M.; Uman, Jane; Au, David H.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. RP Leung, JM (reprint author), 10 Ctr Dr,2C145, Bethesda, MD 20892 USA. EM Janice.Leung@nih.gov FU Department of Veterans Affairs [IIR-0292]; Department of Veterans Affairs; National Heart, Lung, and Blood Institute; Agency of Healthcare Research and Quality; Gilead Sciences FX This study was supported by the Department of Veterans Affairs [IIR-0292].; Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Au is a research advisor for Bosch. He receives research funding from the Department of Veterans Affairs; the National Heart, Lung, and Blood Institute; Agency of Healthcare Research and Quality; and Gilead Sciences. Dr Leung, Mr Udris, and Ms Uman have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. NR 24 TC 10 Z9 10 U1 0 U2 13 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2012 VL 142 IS 1 BP 128 EP 133 DI 10.1378/chest.11-2222 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 971NE UT WOS:000306209800022 PM 22241761 ER PT J AU Montesi, SB Bajwa, EK Malhotra, A AF Montesi, Sydney B. Bajwa, Ednan K. Malhotra, Atul TI Biomarkers of Sleep Apnea SO CHEST LA English DT Article ID POSITIVE AIRWAY PRESSURE; C-REACTIVE PROTEIN; OXIDATIVE STRESS; HEART HEALTH; CARDIOVASCULAR-DISEASE; HYPERTENSIVE PATIENTS; PLASMA HOMOCYSTEINE; BREATH CONDENSATE; BLOOD-PRESSURE; OBESE-PATIENTS AB Obstructive sleep apnea (OSA) is a condition of repetitive upper airway collapse, which occurs during sleep. Recent literature has emphasized the role of OSA in contributing to glucose intolerance, dyslipidemia, and hypertension. OSA is associated with the development of cardiovascular disease, although definitive data are sparse with regard to the prevention of cardiovascular disease and CPAP therapy. CPAP provides effective treatment for OSA, but patient adherence remains challenging. Aside from daytime symptom improvement, it is difficult to monitor the adequacy of treatment response. Thus, the search for a biomarker becomes critical. The discovery of an ideal biomarker for OSA has the potential to provide information related to diagnosis, severity, prognosis, and response to treatment. In addition, because large-scale randomized controlled trials are both ethically and logistically challenging in assessing hard cardiovascular outcomes, certain biomarkers may be reasonable surrogate outcome measures. This article reviews the literature related to potential biomarkers of OSA with the recognition that an ideal biomarker does not exist at this time. CHEST 2012; 142(1):239-245 C1 [Montesi, Sydney B.; Bajwa, Ednan K.] Massachusetts Gen Hosp, Dept Pulm & Crit Care Med, Boston, MA 02114 USA. [Malhotra, Atul] Brigham & Womens Hosp, Dept Sleep Med, Boston, MA 02115 USA. RP Montesi, SB (reprint author), Massachusetts Gen Hosp, Dept Pulm & Crit Care Med, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM sbmontesi@partners.org FU National Institutes of Health [K23 HL087934, R01 AG035117, P01 HL095491, K24 HL093218, R01 HL090897, R01 HL085188]; American Heart Association [0840159N] FX Dr Bajwa is funded by National Institutes of Health [Grant K23 HL087934]. Dr Malhotra is funded by National Institutes of Health [Grants R01 AG035117, P01 HL095491, K24 HL093218, R01 HL090897, and R01 HL085188] and American Heart Association [Grant 0840159N]. NR 62 TC 26 Z9 30 U1 0 U2 8 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2012 VL 142 IS 1 BP 239 EP 245 DI 10.1378/chest.11-2322 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 971NE UT WOS:000306209800037 PM 22796846 ER PT J AU Gaggin, HK Januzzi, JL AF Gaggin, Hanna K. Januzzi, James L., Jr. TI What Is the Role of Serial High-Sensitivity Troponin Measurements in Chronic Heart Failure? SO CLINICAL CHEMISTRY LA English DT Editorial Material ID NATRIURETIC PEPTIDE C1 [Gaggin, Hanna K.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,55 Fruit St, Boston, MA 02114 USA. EM jjanuzzi@partners.org NR 6 TC 5 Z9 5 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2012 VL 58 IS 7 BP 1079 EP 1081 DI 10.1373/clinchem.2012.183244 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 970AA UT WOS:000306099300001 PM 22473030 ER PT J AU Van Cott, EM AF Van Cott, Elizabeth M. TI A 24-Year-Old Man with Previously Diagnosed Hemophilia Commentary SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Van Cott, EM (reprint author), Massachusetts Gen Hosp, GRJ 235,55 Fruit St, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2012 VL 58 IS 7 BP 1089 EP 1089 DI 10.1373/clinchem.2011.172791 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 970AA UT WOS:000306099300004 PM 22745258 ER PT J AU Castellanos-Rizaldos, E Liu, PF Milbury, CA Guha, M Brisci, A Cremonesi, L Ferrari, M Mamon, H Makrigiorgos, GM AF Castellanos-Rizaldos, E. Liu, Pingfang Milbury, Coren A. Guha, Minakshi Brisci, Angela Cremonesi, Laura Ferrari, Maurizio Mamon, Harvey Makrigiorgos, G. Mike TI Temperature-Tolerant COLD-PCR Reduces Temperature Stringency and Enables Robust Mutation Enrichment SO CLINICAL CHEMISTRY LA English DT Article ID RESOLUTION MELTING ANALYSIS; SENSITIVE DETECTION; COLORECTAL-CANCER; KRAS MUTATIONS; AMPLIFICATION; DNA; PRODUCTS; COAMPLIFICATION; PRIMERS; SAMPLES AB BACKGROUND: Low-level mutations in clinical tumor samples often reside below mutation detection limits, thus leading to false negatives that may impact clinical diagnosis and patient management. COLD-PCR (co-amplification at lower denaturation temperature PCR) is a technology that magnifies unknown mutations during PCR, thus enabling downstream mutation detection. However, a practical difficulty in applying COLD-PCR has been the requirement for strict control of the denaturation temperature for a given sequence, to within +/- 0.3 degrees C. This requirement precludes simultaneous mutation enrichment in sequences of substantially different melting temperature (T-m) and limits the technique to a single sequence at a time. We present a temperature-tolerant (TT) approach (TT-COLD-PCR) that reduces this obstacle. METHODS: We describe thermocycling programs featuring a gradual increase of the denaturation temperature during COLD-PCR. This approach enabled enrichment of mutations when the cycling achieves the appropriate critical denaturation temperature of each DNA amplicon that is being amplified. Validation was provided for KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) and TP53 (tumor protein p53) exons 6-9 by use of dilutions of mutated DNA, clinical cancer samples, and plasma-circulating DNA. RESULTS: A single thermocycling program with a denaturation-temperature window of 2.5-3.0 degrees C enriches mutations in all DNA amplicons simultaneously, despite their different T(m)s. Mutation enrichments of 6-9-fold were obtained with TT-full-COLD-PCR. Higher mutation enrichments were obtained for the other 2 forms of COLD-PCR, fast-COLD-PCR, and ice-COLD-PCR. CONCLUSIONS: Low-level mutations in diverse amplicons with different Tins can be mutation enriched via TT-COLD-PCR provided that their T(m)s fall within the denaturation-temperature window applied during amplification. This approach enables simultaneous enrichment of mutations in several amplicons and increases significantly the versatility of COLD-PCR. (c) 2012 American Association for Clinical Chemistry C1 [Castellanos-Rizaldos, E.; Liu, Pingfang; Milbury, Coren A.; Guha, Minakshi; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Div DNA Repair & Genome Stabil, Boston, MA 02115 USA. [Brisci, Angela; Cremonesi, Laura; Ferrari, Maurizio] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, Genom Unit Diag Human Pathol, I-20132 Milan, Italy. [Ferrari, Maurizio] Univ Vita Salute San Raffaele, Milan, Italy. [Ferrari, Maurizio] Diagnost & Ric San Raffaele SpA, Milan, Italy. [Mamon, Harvey; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol, Boston, MA 02115 USA. RP Makrigiorgos, GM (reprint author), Brigham & Womens Hosp, Dana Farber Brigham & Womens Canc Ctr, 75 Francis St, Boston, MA 02115 USA. EM mmakrigiorgos@lroc.harvard.edu RI Ferrari, Maurizio/D-9107-2013 FU NCI; Innovative Molecular Analysis Technologies Program of the NCI [CA-111994, CA-151164] FX H. Mamon, NCI; G.M. Makrigiorgos, Innovative Molecular Analysis Technologies Program of the NCI, grants CA-111994 and CA-151164. NR 30 TC 14 Z9 17 U1 1 U2 8 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2012 VL 58 IS 7 BP 1130 EP 1138 DI 10.1373/clinchem.2012.183095 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 970AA UT WOS:000306099300013 PM 22587896 ER PT J AU Rodriguez, RA AF Rodriguez, Rudolph A. TI Dialysis and Mortality: Does It Matter Where You Live? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID PERITONEAL-DIALYSIS; KIDNEY-TRANSPLANTATION; UNITED-STATES; REMOTE C1 [Rodriguez, Rudolph A.] Puget Sound VA Med Ctr, Nephrol & Renal Dialysis Unit, Seattle, WA 98108 USA. [Rodriguez, Rudolph A.] Univ Washington, Seattle, WA 98195 USA. [Rodriguez, Rudolph A.] VA Puget Sound Healthcare Syst, Seattle, WA 98195 USA. RP Rodriguez, RA (reprint author), Puget Sound VA Med Ctr, Nephrol & Renal Dialysis Unit, Bldg 100,Room 5B113,1660 S Columbian Way, Seattle, WA 98108 USA. EM rudyrod@u.washington.edu NR 10 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2012 VL 7 IS 7 BP 1055 EP 1057 DI 10.2215/CJN.05410512 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 970QX UT WOS:000306148500001 PM 22723448 ER PT J AU Yenchek, RH Ix, JH Shlipak, MG Bauer, DC Rianon, NJ Kritchevsky, SB Harris, TB Newman, AB Cauley, JA Fried, LF AF Yenchek, Robert H. Ix, Joachim H. Shlipak, Michael G. Bauer, Douglas C. Rianon, Nahiof J. Kritchevsky, Stephen B. Harris, Tamara B. Newman, Anne B. Cauley, Jane A. Fried, Linda F. CA Hlth Aging & Body Composition Stud TI Bone Mineral Density and Fracture Risk in Older Individuals with CKD SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; HEMODIALYSIS-PATIENTS; HIP FRACTURE; DIALYSIS PATIENTS; OSTEOPOROTIC FRACTURE; RENAL OSTEODYSTROPHY; DIABETES-MELLITUS; HOMOCYSTEINE; ULTRASOUND AB Background and objectives Kidney Disease Improving Global Outcomes guidelines recommend against bone mineral density (BMD) screening in CKD patients with mineral bone disease, due to a lack of association of BMD with fractures in cross-sectional studies in CKD. We assessed whether BMD is associated with fractures in participants with and without CKD in the Health, Aging, and Body Composition study, a prospective study of well functioning older individuals. Design, setting, participants, & measurements Hip BMD was measured by dual-energy x-ray absorptiometry. Osteoporosis was defined as a femoral neck BMD (FNBMD) T score below -2.5 and CKD as an estimated GFR <60 ml/min per 1.73 m(2). The association of BMD with incident nonspine, fragility fractures to study year 11 was analyzed using Cox proportional hazards analyses, adjusting for age, race, sex, body mass index, hyperparathyroidism, low vitamin D level, and CKD. Interaction terms were used to assess whether the association of BMD with fracture differed in those with and without CKD. Results There were 384 incident fractures in 2754 individuals (mean age 73.6 years). Lower FNBMD was associated with greater fracture, regardless of CKD status. After adjustment, the hazard ratios (95% confidence intervals) were 2.74 (1.99, 3.77) and 2.15 (1.80, 2.57) per lower SD FNBMD for those with and without CKD, respectively (interaction P=0.68), and 2.10 (1.23, 3.59) and 1.63 (1.18, 2.23) among those with osteoporosis in patients with and without CKD, respectively (interaction P=0.75). Conclusions BMD provides information on risk for fracture in older individuals with or without moderate CKD. Clin J Am Soc Nephrol 7: 1130-1136, 2012. doi: 10.2215/CJN.12871211 C1 [Yenchek, Robert H.] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Sch Med, Pittsburgh, PA 15213 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.; Bauer, Douglas C.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA. [Rianon, Nahiof J.] Univ Texas Houston, Sch Med, Dept Family & Community Med, Houston, TX USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Stricht Ctr Aging, Wake Forest, NC USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Newman, Anne B.; Cauley, Jane A.; Fried, Linda F.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Fried, Linda F.] Vet Affairs Pittsburgh Hlth Care Syst, Renal Sect, Pittsburgh, PA USA. RP Yenchek, RH (reprint author), Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Sch Med, 200 Lothrop St,C1100 PUH, Pittsburgh, PA 15213 USA. EM yenchekrh@upmc.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781; Cauley, Jane A/0000-0003-0752-4408 FU Intramural Research Program of the National Institutes of Health; National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01-AG029364]; National Institute of Nursing Research [R01-NR012459]; NIDDK [T32DK061296] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, as well as the National Institute on Aging (Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; and Grants R01-AG028050 and R01-AG029364) and the National Institute of Nursing Research (Grant R01-NR012459). R.H.Y. is supported by NIDDK Grant T32DK061296. NR 32 TC 48 Z9 50 U1 1 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2012 VL 7 IS 7 BP 1130 EP 1136 DI 10.2215/CJN.12871211 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 970QX UT WOS:000306148500012 PM 22516286 ER PT J AU Guerin, A Chen, L Wu, EQ de Leon, DP Griffin, JD AF Guerin, Annie Chen, Lei Wu, Eric Q. de Leon, Diego Ponce Griffin, James D. TI A retrospective analysis of therapy adherence in imatinib resistant or intolerant patients with chronic myeloid leukemia receiving nilotinib or dasatinib in a real-world setting SO CURRENT MEDICAL RESEARCH AND OPINION LA English DT Article DE Adherence; Chronic myeloid leukemia; Second-line; Tyrosine kinase inhibitor ID CHRONIC MYELOGENOUS LEUKEMIA; INTERRUPTIONS; NONADHERENCE; COSTS AB Objectives: To compare adherence to second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) receiving second-line therapies. Methods: Two U. S. administrative claims databases were reviewed (January 1997 to March 2011) for CML patients previously treated with imatinib, who received >= 1 prescription of dasatinib or nilotinib and had continuous enrollment >= 1 month before and after the index date (first dasatinib or nilotinib prescription date). Medication possession ratios (MPRs) and proportion of days covered (PDCs) were evaluated between the treatment initiation date until the end of continuous eligibility, for a maximum of 12 months. Sensitivity analyses were conducted to compare patients initiated on nilotinib to patients who initiated dasatinib 100 mg/day and 140 mg/day separately. This study provides updated results of a previously published study. Results: In total, 878 CML patients who received second-line treatment with either dasatinib (n = 550) or nilotinib (n = 328) were studied. Dasatinib users were less adherent compared to nilotinib users; mean MPR was 0.739 (standard deviation [SD] 0.246) for dasatinib and 0.800 (SD 0.246) for nilotinib (adjusted difference 0.061; P = 0.002). Subgroup analyses of patients who initiated dasatinib 100 mg/day and 140 mg/day separately presented similar trends; after multivariate adjustment, adherence was 0.039 points lower in the 100 mg/day group (P = 0.034) and 0.120 points lower in the 140 mg/day group (P<0.001). Conclusions: Among patients treated in the second-line CML setting, those treated with nilotinib had significantly higher adherence compared to patients treated with dasatinib, regardless of dasatinib dose (100 mg/day and 140 mg/day). Limitations: The study was subject to common limitations of claims data, which lack clinical information, may contain inaccuracies in diagnosis and procedure coding, and may not truly reflect actual drug consumption. Moreover, daily doses calculated based on refill records may not reflect accurate dosing regimens. C1 [Guerin, Annie; Wu, Eric Q.; de Leon, Diego Ponce] Anal Grp, Boston, MA USA. [Chen, Lei] Novartis Pharmaceut, E Hanover, NJ USA. [Griffin, James D.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Guerin, A (reprint author), Anal Grp Inc, 1000 Rue Gauchetiere Ouest,Bur 1200, Montreal, PQ H3B 4W5, Canada. EM aguerin@analysisgroup.com FU Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Novartis Pharmaceuticals Corporation FX This study was sponsored by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.; A. G. and E. Q. W. are employees of Analysis Group, Inc.; D.P.d.L. was an employee of Analysis Group, Inc. when the study was conducted. Analysis Group, Inc. received research funding from Novartis Pharmaceuticals Corporation for this study. J.D.G. receives consultancy fees and research funding from Novartis Pharmaceuticals Corporation. NR 19 TC 14 Z9 15 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-7995 J9 CURR MED RES OPIN JI Curr. Med. Res. Opin. PD JUL PY 2012 VL 28 IS 7 BP 1155 EP 1162 DI 10.1185/03007995.2012.705264 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 970LP UT WOS:000306130800008 PM 22738777 ER PT J AU Hernandez-Tejada, MA Campbell, JA Walker, RJ Smalls, BL Davis, KS Egede, LE AF Hernandez-Tejada, Melba A. Campbell, Jennifer A. Walker, Rebekah J. Smalls, Brittany L. Davis, Kimberly S. Egede, Leonard E. TI Diabetes Empowerment, Medication Adherence and Self-Care Behaviors in Adults with Type 2 Diabetes SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID EDUCATION-PROGRAM; MANAGEMENT; KNOWLEDGE; SCALE AB Background: Evidence suggests that empowerment is an important factor to address everyday aspects of dealing with a chronic disease. This study evaluated the effect of diabetes empowerment on medication adherence and self-care behaviors in adults with type 2 diabetes. Subjects and Methods: Data on 378 subjects with type 2 diabetes recruited from two primary care clinics in the southeastern United States were examined. Previously validated scales were used to measure diabetes empowerment, medication adherence, diabetes knowledge, and diabetes self-care behaviors (including diet, physical activity, blood sugar testing, and foot care). Multiple linear regression was used to assess the independent effect of diabetes empowerment on medication adherence and self-care behaviors controlling for relevant covariates. Results: Eighty-three percent were non-Hispanic blacks, 69% were women, 22% were 65 years or older, 68% were not married, 26% had less than high school education, 60% were unemployed, 39% were uninsured, and 47% had a yearly income <$10,000. Empowerment had significant correlations with medication adherence (r = 0.17, P < 0.003), diabetes knowledge (r = 0.16, P = 0.007), diet (r = 0.24, P < 0.001), exercise (r = 0.25, P < 0.001), blood sugar testing (r = 0.12, P = 0.043), and foot care (r = 0.18, P = 0.002). In the regression model, diabetes empowerment was significantly associated with medication adherence (beta = -0.04, P = 0.001), diabetes knowledge (beta = 0.09, P = 0.012), diet (beta = 0.09, P < 0.001), exercise (beta = 0.10, P < 0.001), blood sugar testing (beta = 0.07, P = 0.016), and foot care (beta = 0.08, P = 0.001). Conclusions: In this sample, diabetes empowerment was related to better diabetes knowledge, medication adherence and improved self-care behaviors. Emphasis on empowerment and self-efficacy is relevant to improve outcomes in the management of diabetes. C1 [Hernandez-Tejada, Melba A.; Campbell, Jennifer A.; Walker, Rebekah J.; Smalls, Brittany L.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Davis, Kimberly S.; Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, Charleston, SC 29425 USA. [Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston VA REAP, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280G,POB 250593, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute for Diabetes and Digestive and Kidney Diseases [T35DK007431] FX This work was supported by grant T35DK007431 from the National Institute for Diabetes and Digestive and Kidney Diseases. NR 28 TC 14 Z9 15 U1 0 U2 19 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD JUL PY 2012 VL 14 IS 7 BP 630 EP 634 DI 10.1089/dia.2011.0287 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 971ZF UT WOS:000306245600014 PM 22524548 ER PT J AU de Vlaming, A Sauls, K Hajdu, Z Visconti, RP Mehesz, AN Levine, RA Slaugenhaupt, SA Hagege, A Chester, AH Markwald, RR Norris, RA AF de Vlaming, Annemarieke Sauls, Kimberly Hajdu, Zoltan Visconti, Richard P. Mehesz, Agnes Nagy Levine, Robert A. Slaugenhaupt, Susan A. Hagege, Albert Chester, Adrian H. Markwald, Roger R. Norris, Russell A. TI Atrioventricular valve development: New perspectives on an old theme SO DIFFERENTIATION LA English DT Article DE Valve development; EMT; Post-EMT; Valve disease; Cushions; Fibroblasts ID EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; DEVELOPING CARDIOVASCULAR-SYSTEM; ENDOCARDIAL CELL-TRANSFORMATION; THORACIC AORTIC-ANEURYSMS; CARDIAC CONDUCTION SYSTEM; EMBRYONIC CHICK HEART; FLUID SHEAR-STRESS; TGF-BETA; EXTRACELLULAR-MATRIX AB Atrioventricular valve development commences with an EMT event whereby endocardial cells transform into mesenchyme. The molecular events that induce this phenotypic change are well understood and include many growth factors, signaling components, and transcription factors. Besides their clear importance in valve development, the role of these transformed mesenchyme and the function they serve in the developing prevalve leaflets is less understood. Indeed, we know that these cells migrate, but how and why do they migrate? We also know that they undergo a transition to a mature, committed cell, largely defined as an interstitial fibroblast due to their ability to secrete various matrix components including collagen type I. However, we have yet to uncover mechanisms by which the matrix is synthesized, how it is secreted, and how it is organized. As valve disease is largely characterized by altered cell number, cell activation, and matrix disorganization, answering questions of how the valves are built will likely provide us with information of real clinical relevance. Although expression profiling and descriptive or correlative analyses are insightful, to advance the field, we must now move past the simplicity of these assays and ask fundamental, mechanistic based questions aimed at understanding how valves are "built". Herein we review current understandings of atrioventricular valve development and present what is known and what isn't known. In most cases, basic, biological questions and hypotheses that were presented decades ago on valve development still are yet to be answered but likely hold keys to uncovering new discoveries with relevance to both embryonic development and the developmental basis of adult heart valve diseases. Thus, the goal of this review is to remind us of these questions and provide new perspectives on an old theme of valve development. Published by Elsevier B.V. on behalf of International Society of Differentiation C1 [de Vlaming, Annemarieke; Sauls, Kimberly; Hajdu, Zoltan; Visconti, Richard P.; Mehesz, Agnes Nagy; Markwald, Roger R.; Norris, Russell A.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Sch Med, Cardiovasc Dev Biol Ctr,Childrens Res Inst, Charleston, SC 29425 USA. [Levine, Robert A.] Massachusetts Gen Hosp, Dept Med, Noninvas Cardiac Lab, Boston, MA 02114 USA. [Slaugenhaupt, Susan A.] Harvard Univ, Ctr Human Genet Res, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hagege, Albert] Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Cardiol, Paris, France. [Chester, Adrian H.] Univ London Imperial Coll Sci Technol & Med, Heart Sci Ctr, Harefield, Middx, England. RP Norris, RA (reprint author), Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Sch Med, Cardiovasc Dev Biol Ctr,Childrens Res Inst, Charleston, SC 29425 USA. EM norrisra@musc.edu FU National Institutes of Health, Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823]; NIH NHLBI [RO1-HL33756]; NIH-NCRR [COBRE P20RR016434-07, P20RR016434-09S1]; American Heart Association [11SDG5270006]; National Science Foundation [EPS-0902795]; The Foundation Leducq (Paris, France) Transatlantic Mitral Network of Excellence Grant [07CVD04] FX This work was conducted in a facility constructed with support from the National Institutes of Health, Grant no. C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Other funding sources: NIH NHLBI: RO1-HL33756 (RRM), NIH-NCRR: COBRE P20RR016434-07 (RRM, RAN), P20RR016434-09S1 (RRM and RAN); American Heart Association: 11SDG5270006 (RAN), National Science Foundation: EPS-0902795 (RRM and RAN); The Foundation Leducq (Paris, France) Transatlantic Mitral Network of Excellence Grant 07CVD04 (RAN, RRM, RAL, SAS, AH, AC, ZH, RV). NR 165 TC 24 Z9 25 U1 0 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD JUL PY 2012 VL 84 IS 1 DI 10.1016/j.diff.2012.04.001 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 968QW UT WOS:000306000500010 PM 22579502 ER PT J AU Hawkins, EJ Malte, CA Imel, ZE Saxon, AJ Kivlahan, DR AF Hawkins, Eric J. Malte, Carol A. Imel, Zac E. Saxon, Andrew J. Kivlahan, Daniel R. TI Prevalence and trends of benzodiazepine use among Veterans Affairs patients with posttraumatic stress disorder, 2003-2010 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Trends in benzodiazepine use; Posttraumatic stress disorder; Opioid analgesics use ID SUBSTANCE USE DISORDERS; CHRONIC NONCANCER PAIN; MENTAL-HEALTH; PHARMACOLOGICAL-TREATMENT; ADMINISTRATIVE DATA; ANXIETY DISORDERS; OPIOID OVERDOSE; ALCOHOL-USE; RISK; ASSOCIATION AB Background: Although the Veterans Affairs and Department of Defense (VA/DoD) clinical guidelines for management of posttraumatic stress disorder (PTSD) recommend against routine benzodiazepine use, little is known about the trends and clinical and prescription profiles of benzodiazepine use since these guidelines were released in 2004. Methods: This retrospective study included 64,872 patients with a PTSD diagnosis received from care at facilities in VA Northwest Veterans Integrated Service Network (VISN 20) during 2003-2010. Annual prevalence of any use was defined as any prescription for benzodiazepines, and long-term use was defined as >90 days' supply, in a year. Gender-specific logistic regressions were fit to estimate any and long-term benzodiazepine use, test for linear trends over 8-years and explore factors associated with trends. Results: The trend of age-adjusted benzodiazepine use over 8-years rose significantly from 25.0 to 26.8% among men and 31.2 to 38.8% among women. Long-term use in men and women increased from 15.4 to 16.4% and 18.0 to 22.7%, respectively. Comorbid psychiatric and alcohol use disorders (AUD) were associated with a greater increase in long-term use of benzodiazepines. In 2010, 61% of benzodiazepine users received >90 days' supply. Among those prescribed benzodiazepines long-term, 11% had AUD and 47% were also prescribed opioids long-term. Conclusion: Despite VA/DoD clinical guidelines recommending against routine use of benzodiazepines for PTSD, the adjusted prevalence of long-term use increased among men and women with PTSD in VISN 20. Widespread concomitant use of benzodiazepines and opioids suggests risk management systems and research on the efficacy and safety of these medications are needed. Published by Elsevier Ireland Ltd. C1 [Hawkins, Eric J.] VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Hawkins, Eric J.; Malte, Carol A.; Saxon, Andrew J.; Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. [Saxon, Andrew J.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Hawkins, Eric J.; Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Imel, Zac E.] Univ Utah, Dept Educ Psychol, Salt Lake City, UT 84112 USA. RP Hawkins, EJ (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Eric.Hawkins@va.gov OI imel, zachary/0000-0001-9645-7184 FU VA Puget Sound Health Care System, Center of Excellence in Substance Abuse Treatment & Education, Seattle, WA FX This material is the result of work supported by resources from the VA Puget Sound Health Care System, Center of Excellence in Substance Abuse Treatment & Education, Seattle, WA. Supporting organizations had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the University of Washington. NR 52 TC 21 Z9 21 U1 2 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2012 VL 124 IS 1-2 BP 154 EP 161 DI 10.1016/j.drugalcdep.2012.01.003 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 969IJ UT WOS:000306048600021 PM 22305658 ER PT J AU Hinton, DE AF Hinton, Devon E. TI Pain's Description: Beginning Grammar and Biological Philology SO EMOTION REVIEW LA English DT Editorial Material DE Cambodians; cognitive; emotion; empathy; ethnopsychology; pain ID REFUGEES AB How can pain complaints be elicited and analyzed so as to increase the empathic bond between patient and clinician? I will argue that though Wierzbicka's approach to this question is useful-an exploration of certain abstract dimensions of pain's meaning-it fails to examine key aspects that are the most useful and crucial for cultural analysis and for building empathic bonds between the clinician and patient. Not just a grammar of pain is needed; rather a biological philology of pain. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Hinton, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu NR 5 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1754-0739 J9 EMOT REV JI Emot. Rev. PD JUL PY 2012 VL 4 IS 3 BP 322 EP 323 DI 10.1177/1754073912439768 PG 2 WC Psychology, Multidisciplinary SC Psychology GA 972KX UT WOS:000306277100030 ER PT J AU Larson, AM Ryther, RC Jennesson, M Geffrey, AL Bruno, PL Anagnos, CJ Shoeb, AH Thibert, RL Thiele, EA AF Larson, Anna M. Ryther, Robin C. C. Jennesson, Melanie Geffrey, Alexandra L. Bruno, Patricia L. Anagnos, Christina J. Shoeb, Ali H. Thibert, Ronald L. Thiele, Elizabeth A. TI Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents SO EPILEPSIA LA English DT Article DE Seizures; Nocturnal seizures; Child sleep dysfunction; Parental sleep dysfunction; Parental fatigue; Room sharing; Cosleeping ID SCHOOL-AGED CHILDREN; CHILDHOOD EPILEPSY; HABITS QUESTIONNAIRE; DAYTIME BEHAVIOR; MATERNAL SLEEP; DISTURBANCE; QUALITY; PREVALENCE; INSTRUMENT; SEVERITY AB Purpose: Disrupted sleep patterns in children with epilepsy and their parents are commonly described clinically. A number of studies have shown increased frequency of sleep disorders among pediatric epilepsy patients; however, few have characterized the association between epilepsy and parental sleep quality and household sleeping arrangements. The purpose of this study was to explore the effect of pediatric epilepsy on child sleep, parental sleep and fatigue, and parent-child sleeping arrangements, including room sharing and cosleeping. Methods: Parents of children 2 to 10 years of age with and without epilepsy completed written questionnaires assessing seizure history, child and parent sleep, and household sleeping arrangements. Childrens Sleep Habits Questionnaire (CSHQ) scores were used to evaluate sleep disturbances for the child. The Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) were used to evaluate parental sleep and fatigue, respectively. The Early Childhood Epilepsy Severity Scale (E-Chess) was used to assess epilepsy severity. Key Findings: One hundred five households with a child with epilepsy and 79 controls participated in this study. Households with a child with epilepsy reported increased rates of both parentchild room sharing (p < 0.001) and cosleeping (p = 0.005) compared to controls. Children with epilepsy were found to have greater sleep disturbance by total CSHQ score (p < 0.001) and the following subscores: parasomnias (p < 0.001), night wakings (p < 0.001), sleep duration (p < 0.001), daytime sleepiness (<0.001), sleep onset delay (p = 0.009), and bedtime resistance (p = 0.023). Parents of children with epilepsy had increased sleep dysfunction (p = 0.005) and were more fatigued (p < 0.001). Severity of epilepsy correlated positively with degree of child sleep dysfunction (0.192, p = 0.049), parental sleep dysfunction (0.273, p = 0.005), and parental fatigue (0.324, p = 0.001). Antiepileptic drug polytherapy was predictive of greater childhood sleep disturbances. Nocturnal seizures were associated with parental sleep problems, whereas room sharing and cosleeping behavior were associated with child sleep problems. Within the epilepsy cohort, 69% of parents felt concerned about night seizures and 44% reported feeling rested rarely or never. Finally, 62% of parents described decreased sleep quality and/or quantity with cosleeping. Significance: Pediatric epilepsy can significantly affect sleep patterns for both the affected child and his or her parents. Parents frequently room share or cosleep with their child, adaptations which may have detrimental effects for many households. Clinicians must not only be attentive to the sleep issues occurring in pediatric patients with epilepsy, but also for the household as a whole. These data provide evidence of a profound clinical need for improved epilepsy therapeutics and the development of nocturnal seizure monitoring technologies. C1 [Larson, Anna M.; Ryther, Robin C. C.; Jennesson, Melanie; Geffrey, Alexandra L.; Bruno, Patricia L.; Anagnos, Christina J.; Shoeb, Ali H.; Thibert, Ronald L.; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Pediat Epilepsy Program, Dept Neurol, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Pediat Epilepsy Program, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NIH ) [UL1 RR 025758]; Harvard University FX Our deepest thanks to the families who participated in this study, for their overwhelming generosity of time and willingness to share information with investigators. We would like to thank the staff and physicians of the pediatric neurology department at MGH, particularly Dr. Catherine Chu-Shore and Diana Caraballo. Also we would like to thank Jennifer Accomando and Drs. Marjorie Curran and Shannon Scott-Vernaglia for their support of this project. Finally, special thanks to Dr. Hang Lee for his help with the statistical analyses. This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. NR 45 TC 20 Z9 20 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUL PY 2012 VL 53 IS 7 BP 1162 EP 1169 DI 10.1111/j.1528-1167.2012.03515.x PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 967YR UT WOS:000305944600012 PM 22594377 ER PT J AU Smalls, BL Walker, RJ Hernandez-Tejada, MA Campbell, JA Davis, KS Egede, LE AF Smalls, Brittany L. Walker, Rebekah J. Hernandez-Tejada, Melba A. Campbell, Jennifer A. Davis, Kimberly S. Egede, Leonard E. TI Associations between coping, diabetes knowledge, medication adherence and self-care behaviors in adults with type 2 diabetes SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Coping; Medication adherence; Self-care; Diabetes ID EMOTIONAL APPROACH; MANAGEMENT; SCALE AB Background: Few studies have examined the emotional approach to coping on diabetes outcomes. This study examined the relationship between emotional coping and diabetes knowledge, medication adherence and self-care behaviors in adults with type 2 diabetes. Methods: Data on 378 subjects with type 2 diabetes recruited from two primary care clinics in the southeastern United States were examined. Previously validated scales were used to measure coping, medication adherence, diabetes knowledge and diabetes self-care behaviors (including diet, physical activity, blood sugar testing and foot care). Multiple linear regression was used to assess the independent effect of coping through emotional approach on medication adherence and self-care behaviors while controlling for relevant covariates. Results: Significant correlations were observed between emotional coping [as measured by emotional expression (EE) and emotional processing (EP)] and self-care behaviors. In the linear regression model, EP was significantly associated with medication adherence [beta -0.17, 95% confidence interval (CI) -0.32 to -0.015], diabetes knowledge (beta 0.76, 95% CI 0.29 to 1.24), diet (beta 0.52, 95% CI 0.24 to 0.81), exercise (beta 0.51, 95% CI 0.19 to 0.82), blood sugar testing (beta 0.54, 95% CI 0.16 to 0.91) and foot care (beta 0.32, 95% CI -0.02 to 0.67). On the other hand, EE was associated with diet (beta 0.38, 95% CI 0.13 to 0.64), exercise (beta 0.54, 95% CI 0.27 to 0.82), blood sugar testing (beta 0.42, 95% CI 0.09 to 0.76) and foot care (beta 0.36, 95% CI 0.06 to 0.66), but it was not associated with diabetes knowledge. Conclusion: These findings indicate that coping through an emotional approach is significantly associated with behaviors that lead to positive diabetes outcomes. (C) 2012 Elsevier Inc. All rights reserved. C1 [Smalls, Brittany L.; Walker, Rebekah J.; Hernandez-Tejada, Melba A.; Campbell, Jennifer A.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Davis, Kimberly S.; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Charleston VA REAP, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, POB 250593 Charleston, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute for Diabetes, Digestive and Kidney Disease [T35DK007431] FX Supported by grant no. T35DK007431 from the National Institute for Diabetes, Digestive and Kidney Disease. NR 19 TC 13 Z9 13 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2012 VL 34 IS 4 BP 385 EP 389 DI 10.1016/j.genhosppsych.2012.03.018 PG 5 WC Psychiatry SC Psychiatry GA 972TI UT WOS:000306302700009 PM 22554428 ER PT J AU Chang, G Weiss, AP Orav, EJ Smallwood, JA Gonzalez, S Kosowsky, JM Rauch, SL AF Chang, Grace Weiss, Anthony P. Orav, E. John Smallwood, Jennifer A. Gonzalez, Stephanie Kosowsky, Joshua M. Rauch, Scott L. TI Bottlenecks in the Emergency Department: the psychiatric clinicians' perspective SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Emergency department; Mental health; Psychiatric patients ID LENGTH-OF-STAY; PERCEPTIONS; VISITS; ROOM AB Objective: To ask psychiatric clinicians for their perspectives on the rate-limiting steps (RLS) in patient care in the Emergency Department (ED) and to compare them to the patient's actual length of stay. Method: Prospective cohort study of clinicians' perspectives on the RLS among 1092 adult ED patients. Medical records were abstracted for ED time and other data. Results: Clinicians identified five RLS: limited availability of staff, limited availability of beds after discharge, need for clinical stability, need for additional history and patient's financial issues. The last RLS was the only one not associated with increased wait times in the ED. There were significant differences in the patterns of RLS by trainee status and hospital. For example, significantly higher proportions of trainees reported that RLS in patient care were due to the need for clinical stability and additional history and lack of bed availability. In contrast, non-trainee clinicians were more likely to cite problems with the availability of ED staff as an RLS. Conclusions: Most of the RLS in patient care identified by clinicians were associated with actual increases in ED wait time for their patients. Next steps include asking clinicians for possible solutions to the delays their patients experience. Published by Elsevier Inc. C1 [Chang, Grace] VA Boston Healthcare Syst, Dept Vet Affairs 116A, Brockton, MA 02301 USA. [Chang, Grace; Weiss, Anthony P.; Orav, E. John; Smallwood, Jennifer A.; Gonzalez, Stephanie; Rauch, Scott L.] Partners Psychiat & Mental Hlth, Div Hlth Serv Res, Boston, MA 02115 USA. [Chang, Grace; Weiss, Anthony P.; Orav, E. John; Kosowsky, Joshua M.; Rauch, Scott L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chang, Grace; Orav, E. John; Smallwood, Jennifer A.; Gonzalez, Stephanie; Kosowsky, Joshua M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Weiss, Anthony P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauch, Scott L.] Mc Lean Hosp, Belmont, MA 02478 USA. RP Chang, G (reprint author), VA Boston Healthcare Syst, Dept Vet Affairs 116A, Brockton, MA 02301 USA. EM grace.chang2@va.gov FU Partners Psychiatry and Mental Health, Boston, MA [K 24 AA 00289] FX This study was supported in part by Partners Psychiatry and Mental Health, Boston, MA and K 24 AA 00289 (GC). NR 22 TC 5 Z9 5 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2012 VL 34 IS 4 BP 403 EP 409 DI 10.1016/j.genhosppsych.2012.03.005 PG 7 WC Psychiatry SC Psychiatry GA 972TI UT WOS:000306302700012 PM 22516215 ER PT J AU Kim, H D'Andrea, AD AF Kim, Hyungjin D'Andrea, Alan D. TI Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway SO GENES & DEVELOPMENT LA English DT Review DE Fanconi anemia; ubiquitination; DNA interstrand cross-link; DNA repair; translesion DNA synthesis; homologous recombination ID STRUCTURE-SPECIFIC ENDONUCLEASE; NUCLEOTIDE EXCISION-REPAIR; CELL NUCLEAR ANTIGEN; BINDING ZINC-FINGER; HOLLIDAY JUNCTION RESOLVASE; REV1 PROTEIN INTERACTS; CORE-COMPLEX PROTEIN; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; UBIQUITIN-BINDING AB The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation. C1 [Kim, Hyungjin; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu FU Leukemia and Lymphoma Society Career Development Fellowship; NIH [R01DK43889, R01HL52725, 2P01HL048546] FX We thank Kalindi Parmar, George-Lucian Moldovan, Jenny Xie, and Grace Hsieh for critical reading of the manuscript. H.K. is a recipient of the Leukemia and Lymphoma Society Career Development Fellowship. Research in the D'Andrea laboratory related to this work is supported by NIH grants R01DK43889, R01HL52725, and 2P01HL048546. NR 185 TC 215 Z9 220 U1 9 U2 43 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2012 VL 26 IS 13 BP 1393 EP 1408 DI 10.1101/gad.195248.112 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 971AY UT WOS:000306175400001 PM 22751496 ER PT J AU Phillips, CM Montgomery, TA Breen, PC Ruvkun, G AF Phillips, Carolyn M. Montgomery, Taiowa A. Breen, Peter C. Ruvkun, Gary TI MUT-16 promotes formation of perinuclear Mutator foci required for RNA silencing in the C. elegans germline SO GENES & DEVELOPMENT LA English DT Article DE RNAi; C. elegans; mutator; MUT-16; siRNA; P granule ID CAENORHABDITIS-ELEGANS; P-GRANULES; CHROMOSOME SEGREGATION; RICH REGIONS; INTERFERENCE; DROSOPHILA; GENE; LOCALIZATION; SIRNAS; BIOGENESIS AB RNA silencing can be initiated by endogenous or exogenously delivered siRNAs. In Caenorhabditis elegans, RNA silencing guided by primary siRNAs is inefficient and therefore requires an siRNA amplification step involving RNA-dependent RNA polymerases (RdRPs). Many factors involved in RNA silencing localize to protein- and RNA-rich nuclear pore-associated P granules in the germline, where they are thought to surveil mRNAs as they exit the nucleus. Mutator class genes are required for siRNA-mediated RNA silencing in both germline and somatic cells, but their specific roles and relationship to other siRNA factors are unclear. Here we show that each of the six mutator proteins localizes to punctate foci at the periphery of germline nuclei. The Mutator foci are adjacent to P granules but are not dependent on core P-granule components or other RNAi pathway factors for their formation or stability. The glutamine/asparagine (Q/N)-rich protein MUT-16 is specifically required for the formation of a protein complex containing the mutator proteins, and in its absence, Mutator foci fail to form at the nuclear periphery. The RdRP RRF-1 colocalizes with MUT-16 at Mutator foci, suggesting a role for Mutator foci in siRNA amplification. Furthermore, we demonstrate that genes that yield high levels of siRNAs, indicative of multiple rounds of siRNA amplification, are disproportionally affected in mut-16 mutants compared with genes that yield low levels of siRNAs. We propose that the mutator proteins and RRF-1 constitute an RNA processing compartment required for siRNA amplification and RNA silencing. C1 [Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu RI Phillips, Carolyn/E-8305-2011; OI Phillips, Carolyn/0000-0002-6228-6468; Montgomery, Taiowa/0000-0001-7857-3253 FU National Institutes of Health Grant [GM44619]; Massachusetts General Hospital Executive Committee of Research Tosteson Post-doctoral Fellowship FX We thank A. Soukas, C. Mello, the Caenorhabditis Genetics Center (CGC), and Shohei Mitani of the Japanese National Bioresources Project for providing antibodies and strains. This work was supported in part by the National Institutes of Health Grant GM44619 (to G.R.) and the Massachusetts General Hospital Executive Committee of Research Tosteson Post-doctoral Fellowship (to C.M.P). T.A.M. is a Damon Runyon fellow (DRG 2029-09), and C.M.P. is the Marion Abbe fellow of the Damon Runyon Cancer Research Foundation (DRG 1988-08). NR 63 TC 16 Z9 23 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2012 VL 26 IS 13 BP 1433 EP 1444 DI 10.1101/gad.193904.112 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 971AY UT WOS:000306175400005 PM 22713602 ER PT J AU Chen, AJ Paik, JH Zhang, HL Shukla, SA Mortensen, R Hu, J Ying, HQ Hu, BL Hurt, J Farny, N Dong, C Xiao, YH Wang, YA Silver, PA Chin, L Vasudevan, S DePinho, RA AF Chen, An-Jou Paik, Ji-Hye Zhang, Hailei Shukla, Sachet A. Mortensen, Richard Hu, Jian Ying, Haoqiang Hu, Baoli Hurt, Jessica Farny, Natalie Dong, Caroline Xiao, Yonghong Wang, Y. Alan Silver, Pamela A. Chin, Lynda Vasudevan, Shobha DePinho, Ronald A. TI STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA SO GENES & DEVELOPMENT LA English DT Article DE cancer; GBM; miRNA; p53; TGF beta; QKI ID GROWTH-FACTOR-BETA; ARRAY CGH DATA; MESSENGER-RNA; GLIOBLASTOMA-MULTIFORME; SIGNAL-TRANSDUCTION; MUSCLE DEVELOPMENT; MIR-17-92 CLUSTER; INDUCED APOPTOSIS; MICRORNA CLUSTER; HUMAN GLIOMA AB Multidimensional cancer genome analysis and validation has defined Quaking (QKI), a member of the signal transduction and activation of RNA (STAR) family of RNA-binding proteins, as a novel glioblastoma multiforme (GBM) tumor suppressor. Here, we establish that p53 directly regulates QKI gene expression, and QKI protein associates with and leads to the stabilization of miR-20a; miR-20a, in turn, regulates TGF beta R2 and the TGF beta signaling network. This pathway circuitry is substantiated by in silico epistasis analysis of its components in the human GBM TCGA (The Cancer Genome Atlas Project) collection and by their gain- and loss-of-function interactions in in vitro and in vivo complementation studies. This p53-QKI-miR-20a-TGF beta pathway expands our understanding of the p53 tumor suppression network in cancer and reveals a novel tumor suppression mechanism involving regulation of specific cancer-relevant microRNAs. C1 [Chen, An-Jou; Paik, Ji-Hye; Zhang, Hailei; Shukla, Sachet A.; Hu, Jian; Ying, Haoqiang; Hu, Baoli; Dong, Caroline; Xiao, Yonghong; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Chen, An-Jou; Paik, Ji-Hye; Zhang, Hailei; Shukla, Sachet A.; Hu, Jian; Ying, Haoqiang; Hu, Baoli; Dong, Caroline; Xiao, Yonghong; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chen, An-Jou; Paik, Ji-Hye; Hu, Jian; Ying, Haoqiang; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. [Mortensen, Richard; Vasudevan, Shobha] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Hu, Jian; Ying, Haoqiang; Hu, Baoli; Wang, Y. Alan; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Hurt, Jessica; Farny, Natalie; Silver, Pamela A.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Brigham & Womens Hosp, Boston, MA 02115 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM rdepinho@mdanderson.org FU Leukemia and Lymphoma Society Fellowship; Goldhirsh Foundation; NIH [RO1CA99041, 5P01CA95616, GM057476]; Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science FX We thank H. Zheng, J. Stommel, E. Sahin, and F. Muller, as well as the members of the DePinho, Chin, and Vasudevan laboratories for advice and support. J.H.P. was supported by the Damon Runyon Cancer Research Foundation. J.H. was supported by a Leukemia and Lymphoma Society Fellowship. Grant support comes from the Goldhirsh Foundation (to R.A.D.) and NIH grants RO1CA99041 (to L.C.), 5P01CA95616 (to L.C. and R.A.D.), and GM057476 (to P.A.S.). R.A.D. is an American Cancer Society Research Professor supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. NR 56 TC 40 Z9 40 U1 2 U2 13 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2012 VL 26 IS 13 BP 1459 EP 1472 DI 10.1101/gad.189001.112 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 971AY UT WOS:000306175400007 PM 22751500 ER PT J AU Mercado, RC Hampel, H Kastrinos, F Steyerberg, E Balmana, J Stoffel, E Cohn, DE Backes, FJ Hopper, JL Jenkins, MA Lindor, NM Casey, G Haile, R Madhavan, S de la Chapelle, A Syngal, S AF Mercado, Rowena C. Hampel, Heather Kastrinos, Fay Steyerberg, Ewout Balmana, Judith Stoffel, Elena Cohn, David E. Backes, Floor J. Hopper, John L. Jenkins, Mark A. Lindor, Noralane M. Casey, Graham Haile, Robert Madhavan, Subha de la Chapelle, Albert Syngal, Sapna CA Colon Canc Family Registry TI Performance of PREM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases SO GENETICS IN MEDICINE LA English DT Article DE endometrial cancer; genetic screening; genetic testing; Lynch syndrome; prediction models ID NONPOLYPOSIS COLORECTAL-CANCER; POPULATION-BASED COHORT; MISMATCH-REPAIR GENES; LOWER UTERINE SEGMENT; GERMLINE MUTATIONS; PREDICTIVE MODELS; COLON-CANCER; MLH1; CARCINOMA; WOMEN AB Purpose: Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases. Methods: Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM1,2,6, MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases. Results: A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM1,2,6, MMRpredict, and MMRpro were able to distinguish mutation carriers from -noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among -population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM1,2,6, 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases. Conclusion: Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients. C1 [Mercado, Rowena C.; Stoffel, Elena; Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Hampel, Heather; de la Chapelle, Albert] Ohio State Univ, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA. [Kastrinos, Fay] Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Kastrinos, Fay] Columbia Univ, Med Ctr, Div Digest & Liver Dis, New York, NY USA. [Steyerberg, Ewout] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Balmana, Judith] Univ Autonoma Barcelona, Hosp Vall dHebron, Dept Med, Dept Med Oncol, E-08193 Barcelona, Spain. [Stoffel, Elena; Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Stoffel, Elena; Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Cohn, David E.; Backes, Floor J.] Ohio State Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Columbus, OH 43210 USA. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Carlton, Vic 3053, Australia. [Jenkins, Mark A.] Victorian Canc Registry, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Lindor, Noralane M.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Casey, Graham; Haile, Robert] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Madhavan, Subha] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. EM ssyngal@partners.org RI Jenkins, Mark/P-7803-2015 OI Jenkins, Mark/0000-0002-8964-6160 FU National Cancer Institute [R01CA132829, K24 CA113433, R01 CA67941]; Ohio State University Comprehensive Cancer Center [P30 CA16058]; National Cancer Institute, National Institutes of Health [RFA CA-95-011]; Colon Cancer Family Registry, Australasian Colorectal Cancer Family Registry [U01 CA097735]; Familial Colorectal Neoplasia Collaborative Group [U01 CA074799]; Mayo Clinic Cooperative Family Registry for Colon Cancer Studies [U01 CA074800] FX The study was supported by the National Cancer Institute through the following grants: R01CA132829 (S.S.), K24 CA113433 (S.S.), R01 CA67941 (A.d.l.C.), and P30 CA16058 (Ohio State University Comprehensive Cancer Center). This work was also supported by the National Cancer Institute, National Institutes of Health, under RFA CA-95-011, and through cooperative agreements with the members of the Colon Cancer Family Registry and principal investigators, including the Australasian Colorectal Cancer Family Registry (U01 CA097735); the Familial Colorectal Neoplasia Collaborative Group (U01 CA074799); and the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800). NR 31 TC 15 Z9 15 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL PY 2012 VL 14 IS 7 BP 670 EP 680 DI 10.1038/gim.2012.18 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 971YB UT WOS:000306241800006 PM 22402756 ER PT J AU Collins, EG O'Connell, S McBurney, C Jelinek, C Butler, J Reda, D Gerber, BS Hurt, C Grabiner, M AF Collins, Eileen G. O'Connell, Susan McBurney, Conor Jelinek, Christine Butler, Jolene Reda, Domenic Gerber, Ben S. Hurt, Christopher Grabiner, Mark TI Comparison of Walking With Poles and Traditional Walking for Peripheral Arterial Disease Rehabilitation SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Article DE peripheral arterial disease; rehabilitation; walking exercise ID INTERMITTENT CLAUDICATION; NORDIC WALKING; PHYSIOLOGICAL-RESPONSES; ENERGY-EXPENDITURE; EXERCISE; PAIN AB PURPOSE: The purpose of this study was to compare the effects of a 24-week walking with poles rehabilitation program with a traditional 24-week walking program on physical function in patients with peripheral arterial disease (PAD). METHODS: Patients with PAD (n = 103, age = 69.7 +/- 8.9 years, ankle-brachial index < 0.90 or evidence of calcified vessels) were randomized into a rehabilitation program of traditional walking (n = 52) or walking with poles (n = 51). Patients exercised 3 times per week for 24 weeks. Exercise endurance was measured by time walked on a constant work rate treadmill test at 6, 12, and 24 weeks. Perceived physical function was measured by the Medical Outcomes Study Short Form-36 and Walking Impairment Questionnaire. Tissue oxygenation was measured using near-infrared spectroscopy. RESULTS: Patients assigned to the traditional walking group walked longer at 24 weeks than those assigned to the pole walking group (21.10 +/- 17.07 minutes and 15.02 +/- 12.32 minutes, respectively, P = .037). There were no differences between the groups in tissue oxygenation. However, there was a significant lengthening of time for which it took to reach minimum tissue oxygenation values (P < .001) within the groups on the constant work rate test. There were no differences between the groups in perceived physical function as measured by the Physical Function subscale on the Medical Outcomes Study Short Form-36 or perceived walking distance as measured by the Walking Distance subscale on the Walking Impairment Scale. CONCLUSIONS: Traditional walking was superior to walking with poles in increasing walking endurance on a constant work rate treadmill test for patients with PAD. C1 [Collins, Eileen G.; O'Connell, Susan; McBurney, Conor; Jelinek, Christine; Butler, Jolene; Gerber, Ben S.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Ctr Management Complex Chron Care, Dept Vet Affairs, Hines, IL 60141 USA. [Reda, Domenic] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Cooperat Studies Program, Dept Vet Affairs, Hines, IL 60141 USA. [Collins, Eileen G.] Univ Illinois, Dept Biobehav Hlth Sci, Coll Nursing, Chicago, IL 60612 USA. [Gerber, Ben S.] Univ Illinois, Sect Hlth Promot Res, Dept Med, Chicago, IL 60612 USA. [Hurt, Christopher; Grabiner, Mark] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL 60612 USA. RP Collins, EG (reprint author), Univ Illinois, Dept Biobehav Hlth Sci, Coll Nursing MC802, 845 S Damen Ave, Chicago, IL 60612 USA. EM ecollins@uic.edu OI Gerber, Ben/0000-0003-4367-6396 FU National Institute of Nursing Research [RO1 NR008877-01]; Research Career Scientist Award, Rehabilitation Research & Development, Department of Veterans Affairs FX This work was supported by a grant from the National Institute of Nursing Research (RO1 NR008877-01) and a Research Career Scientist Award (Collins), Rehabilitation Research & Development, Department of Veterans Affairs. The contents of this article do not represent the views of the National Institutes of Health, the Department of Veterans Affairs, or the US Government. The authors have no affiliation with Exerstrider. NR 23 TC 8 Z9 8 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-7501 J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD JUL-AUG PY 2012 VL 32 IS 4 BP 210 EP 218 DI 10.1097/HCR.0b013e31825828f4 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 970GF UT WOS:000306115400007 PM 22595894 ER PT J AU Choi, CJ Melki, SA AF Choi, Catherine J. Melki, Samir A. TI Loose anchoring suture to secure a free flap after laser in situ keratomileusis SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID MANAGEMENT; COMPLICATIONS; ASTIGMATISM; LASIK; CAP AB We describe the use of a single loose anchoring suture to secure a free flap with good outcomes. We believe this simple, safe technique combines the advantages of previously reported methods, including stability and minimal invasiveness. C1 [Melki, Samir A.] Harvard Univ, Cornea & Refract Surg Serv, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Melki, Samir A.] Boston Eye Grp, Boston, MA USA. RP Melki, SA (reprint author), Harvard Univ, Cornea & Refract Surg Serv, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM samir_melki@meei.harvard.edu NR 11 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD JUL PY 2012 VL 38 IS 7 BP 1127 EP 1129 DI 10.1016/j.jcrs.2012.05.010 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 970WY UT WOS:000306164200004 PM 22727281 ER PT J AU Ligibel, JA Goodwin, PJ AF Ligibel, Jennifer A. Goodwin, Pamela J. TI NEW and RENEW: Building the Case for Weight Loss in Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; EXERCISE INTERVENTION; FASTING INSULIN; GROWTH-FACTORS; FREE SURVIVAL; FAT; MANAGEMENT C1 [Ligibel, Jennifer A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goodwin, Pamela J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Goodwin, Pamela J.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. RP Ligibel, JA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Goodwin, Pamela/K-1477-2013 NR 32 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2294 EP 2296 DI 10.1200/JCO.2012.42.5496 PG 3 WC Oncology SC Oncology GA 971CW UT WOS:000306182300003 PM 22614991 ER PT J AU Brooks, GA Enzinger, PC Fuchs, CS AF Brooks, Gabriel A. Enzinger, Peter C. Fuchs, Charles S. TI Adjuvant Therapy for Gastric Cancer: Revisiting the Past to Clarify the Future SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LYMPH-NODE DISSECTION; PHASE-III TRIAL; CDH1 PROMOTER; CHEMOTHERAPY; SURGERY; D2; CAPECITABINE; METHYLATION; HIT; S-1 C1 [Brooks, Gabriel A.; Enzinger, Peter C.; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brooks, GA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. OI Brooks, Gabriel/0000-0003-3984-9995 NR 15 TC 11 Z9 12 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2297 EP 2299 DI 10.1200/JCO.2012.42.4069 PG 3 WC Oncology SC Oncology GA 971CW UT WOS:000306182300004 PM 22585690 ER PT J AU Krop, I Demuth, T Guthrie, T Wen, PY Mason, WP Chinnaiyan, P Butowski, N Groves, MD Kesari, S Freedman, SJ Blackman, S Watters, J Loboda, A Podtelezhnikov, A Lunceford, J Chen, C Giannotti, M Hing, J Beckman, R LoRusso, P AF Krop, Ian Demuth, Tim Guthrie, Tina Wen, Patrick Y. Mason, Warren P. Chinnaiyan, Prakash Butowski, Nicholas Groves, Morris D. Kesari, Santosh Freedman, Steven J. Blackman, Samuel Watters, James Loboda, Andrey Podtelezhnikov, Alexei Lunceford, Jared Chen, Cong Giannotti, Maxine Hing, Jeremy Beckman, Robert LoRusso, Patricia TI Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA; STEM-CELLS; PATHWAY; PROLIFERATION; ACTIVATION; LEUKEMIA; TARGET; CANCER; GLIOMA; MYC AB Purpose Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of gamma-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752. Patients and Methods MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition. Results Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas. Conclusion MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent. C1 [Krop, Ian; Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Demuth, Tim; Blackman, Samuel; Watters, James; Loboda, Andrey; Podtelezhnikov, Alexei; Lunceford, Jared; Chen, Cong; Giannotti, Maxine; Hing, Jeremy; Beckman, Robert] Merck Res Labs, N Wales, PA USA. [Guthrie, Tina; LoRusso, Patricia] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Mason, Warren P.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Chinnaiyan, Prakash] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Butowski, Nicholas] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kesari, Santosh] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Groves, Morris D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP LoRusso, P (reprint author), Wayne State Univ, Karmanos Canc Inst, Room 4206 HWCRC,4100 John R St, Detroit, MI 48201 USA. EM lorussop@karmanos.org RI Kesari, Santosh/E-8461-2013 FU Merck FX Supported by Merck. NR 21 TC 109 Z9 114 U1 2 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2307 EP 2313 DI 10.1200/JCO.2011.39.1540 PG 7 WC Oncology SC Oncology GA 971CW UT WOS:000306182300007 PM 22547604 ER PT J AU Nardi, V Winkfield, KM Ok, CY Niemierko, A Kluk, MJ Attar, EC Garcia-Manero, G Wang, SA Hasserjian, RP AF Nardi, Valentina Winkfield, Karen M. Ok, Chi Young Niemierko, Andrzej Kluk, Michael J. Attar, Eyal C. Garcia-Manero, Guillermo Wang, Sa A. Hasserjian, Robert P. TI Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; ALLOGENEIC TRANSPLANTATION; SECONDARY LEUKEMIAS; CYTOSTATIC AGENTS; HODGKINS-LYMPHOMA; RADIOTHERAPY; LEUKAEMIA; PROGNOSIS; ABNORMALITIES; CHEMOTHERAPY AB Purpose Therapy-related myeloid neoplasms (t-MN) represent a unique clinical syndrome occurring in patients treated with chemotherapy and/or external-beam radiation (XRT) and are characterized by poorer prognosis compared with de novo disease. XRT techniques have evolved in recent years and are associated with significantly reduced bone marrow exposure. The characteristics of post-XRT t-MN in the current era have not been studied. Patients and Methods We analyzed patients who developed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after XRT alone (47 patients) or cytotoxic chemotherapy/combined-modality therapy (C/CMT, 181 patients) and compared them with patients with de novo MDS or AML (222 patients). We estimated bone marrow exposure to radiation and compared the clinical, pathologic, and cytogenetic features and outcome of the XRT patients with the C/CMT patients and with patients with de novo MDS and AML. Results Patients with t-MN after XRT alone had superior overall survival (P = .006) and lower incidence of high-risk karyotypes (P = .01 for AML and < .001 for MDS) compared with patients in the C/CMT group. In contrast, there were no significant differences in survival or frequency of high-risk karyotypes between the XRT and de novo groups. Conclusion AML and MDS diagnosed in the past decade in patients after receiving XRT alone differ from t-MN occurring after C/CMT and share genetic features and clinical behavior with de novo AML/MDS. Our results suggest that post-XRT MDS/AML may not represent a direct consequence of radiation toxicity and warrant a therapeutic approach similar to de novo disease. C1 [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kluk, Michael J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ok, Chi Young] Univ Massachusetts, Med Ctr, Worcester, MA USA. [Garcia-Manero, Guillermo; Wang, Sa A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 225, Boston, MA 02114 USA. EM rhasserjian@partners.org FU NCI NIH HHS [P30 CA016672] NR 40 TC 28 Z9 28 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2340 EP 2347 DI 10.1200/JCO.2011.38.7340 PG 8 WC Oncology SC Oncology GA 971CW UT WOS:000306182300011 PM 22585703 ER PT J AU Tolcher, AW Messersmith, WA Mikulski, SM Papadopoulos, KP Kwak, EL Gibbon, DG Patnaik, A Falchook, GS Dasari, A Shapiro, GI Boylan, JF Xu, ZX Wang, K Koehler, A Song, J Middleton, SA Deutsch, J DeMario, M Kurzrock, R Wheler, JJ AF Tolcher, Anthony W. Messersmith, Wells A. Mikulski, Stanislaw M. Papadopoulos, Kyriakos P. Kwak, Eunice L. Gibbon, Darlene G. Patnaik, Amita Falchook, Gerald S. Dasari, Arvind Shapiro, Geoffrey I. Boylan, John F. Xu, Zhi-Xin Wang, Ka Koehler, Astrid Song, James Middleton, Steven A. Deutsch, Jonathan DeMario, Mark Kurzrock, Razelle Wheler, Jennifer J. TI Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER; ANGIOGENESIS AB Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [F-18]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. Conclusion RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity. C1 [Tolcher, Anthony W.; Papadopoulos, Kyriakos P.; Patnaik, Amita] S Texas Accelerated Res Therapeut, Ctr Canc Care, San Antonio, TX 78229 USA. [Falchook, Gerald S.; Kurzrock, Razelle; Wheler, Jennifer J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Messersmith, Wells A.; Dasari, Arvind] Univ Colorado, Ctr Canc, Aurora, CO USA. [Mikulski, Stanislaw M.; Boylan, John F.; Xu, Zhi-Xin; Wang, Ka; Song, James; Middleton, Steven A.; Deutsch, Jonathan; DeMario, Mark] Hoffmann La Roche Inc, Nutley, NJ 07110 USA. [Gibbon, Darlene G.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Kwak, Eunice L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Koehler, Astrid] Roche Diagnost, Penzberg, Germany. RP Tolcher, AW (reprint author), S Texas Accelerated Res Therapeut, Ctr Canc Care, 4383 Med Dr,4th Floor, San Antonio, TX 78229 USA. EM atolcher@start.stoh.com FU Hoffmann-La Roche FX Supported by Hoffmann-La Roche, which also provided support for third-party editing/writing assistance. NR 10 TC 87 Z9 87 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2348 EP 2353 DI 10.1200/JCO.2011.36.8282 PG 6 WC Oncology SC Oncology GA 971CW UT WOS:000306182300012 PM 22529266 ER PT J AU George, S Wang, Q Heinrich, MC Corless, CL Zhu, MJ Butrynski, JE Morgan, JA Wagner, AJ Choy, E Tap, WD Yap, JT Van den Abbeele, AD Manola, JB Solomon, SM Fletcher, JA von Mehren, M Demetri, GD AF George, Suzanne Wang, Qian Heinrich, Michael C. Corless, Christopher L. Zhu, Meijun Butrynski, James E. Morgan, Jeffrey A. Wagner, Andrew J. Choy, Edwin Tap, William D. Yap, Jeffrey T. Van den Abbeele, Annick D. Manola, Judith B. Solomon, Sarah M. Fletcher, Jonathan A. von Mehren, Margaret Demetri, George D. TI Efficacy and Safety of Regorafenib in Patients With Metastatic and/or Unresectable GI Stromal Tumor After Failure of Imatinib and Sunitinib: A Multicenter Phase II Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RESISTANCE; MECHANISMS; KIT; MESYLATE AB Purpose Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-alpha remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients and Methods Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] >= 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. Results From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD >= 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Conclusion Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting. C1 [George, Suzanne] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Choy, Edwin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhu, Meijun; Fletcher, Jonathan A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [George, Suzanne; Butrynski, James E.; Morgan, Jeffrey A.; Wagner, Andrew J.; Choy, Edwin; Van den Abbeele, Annick D.; Fletcher, Jonathan A.; Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Portland, OR USA. [Tap, William D.] Univ Calif Los Angeles, Los Angeles, CA USA. [von Mehren, Margaret] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP George, S (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, D1212,450 Brookline Ave, Boston, MA 02115 USA. EM suzanne_george@dfci.harvard.edu OI Choy, Edwin/0000-0001-9896-8084 FU Bayer HealthCare Pharmaceuticals; National Cancer Institute (NCI) [1P50CA127003, CA06927]; Dana-Farber/Harvard Cancer Center (DFHCC); Department of Veterans Affairs; Virginia and Daniel K. Ludwig Trust for Cancer Research; Ludwig Center at DFHCC; Life Raft Group; GI Stromal Tumor Cancer Research Fund; Bayer; Novartis; Pfizer; ARIAD Pharmaceuticals; AROG Pharmaceuticals; ImClone; AstraZeneca; Bristol-Myers Squibb; Toshiba; Eli Lilly/ImClone; Infinity Pharmaceuticals FX Supported in part by Bayer HealthCare Pharmaceuticals, which provided funding and study drug, and by National Cancer Institute (NCI) GI Specialized Programs of Research Excellence Grant No. 1P50CA127003 to Dana-Farber/Harvard Cancer Center (DFHCC; J.A.F., G. D. D.), a Merit Review grant from the Department of Veterans Affairs (M. C. H.), NCI Grant No. CA06927 (M. V.), the Virginia and Daniel K. Ludwig Trust for Cancer Research and the Ludwig Center at DFHCC (J.A.F., G. D. D.), and the Life Raft Group and the GI Stromal Tumor Cancer Research Fund (M. C. H., C. L. C., J.A.F.).; Research Funding: Suzanne George, Bayer, Novartis, Pfizer; Michael C. Heinrich, ARIAD Pharmaceuticals, AROG Pharmaceuticals, ImClone, Novartis; Edwin Choy, AstraZeneca, Novartis; Jeffrey T. Yap, Bayer, Bristol-Myers Squibb, Toshiba; Annick D. Van den Abbeele, Bayer; Jonathan A. Fletcher, Bayer; George D. Demetri, Bayer, Eli Lilly/ImClone, Infinity Pharmaceuticals, Novartis, Pfizer NR 24 TC 81 Z9 84 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2012 VL 30 IS 19 BP 2401 EP 2407 DI 10.1200/JCO.2011.39.9394 PG 7 WC Oncology SC Oncology GA 971CW UT WOS:000306182300019 PM 22614970 ER PT J AU Aster, JC Blacklow, SC AF Aster, Jon C. Blacklow, Stephen C. TI Targeting the Notch Pathway: Twists and Turns on the Road to Rational Therapeutics SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR; INHIBITION; MUTATIONS; GENE; ANGIOGENESIS; ACTIVATION; RECEPTORS; PEPTIDE; SYSTEM C1 [Aster, Jon C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Blacklow, Stephen C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Aster, JC (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 36 TC 30 Z9 30 U1 0 U2 5 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 JUL 1 PY 2012 VL 30 IS 19 BP 2418 EP 2420 DI 10.1200/JCO.2012.42.0992 PG 3 WC Oncology SC Oncology GA 971CW UT WOS:000306182300021 PM 22585704 ER PT J AU Roth, CP Ganz, DA Nickels, L Martin, D Beckman, R Wenger, NS AF Roth, Carol P. Ganz, David A. Nickels, Lorraine Martin, David Beckman, Robin Wenger, Neil S. TI Nurse Care Manager Contribution to Quality of Care in a Dual-Eligible Special Needs Plan SO JOURNAL OF GERONTOLOGICAL NURSING LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; URINARY-INCONTINENCE; OLDER-PATIENTS; VULNERABLE ELDERS; DEMENTIA; HEALTH; FALLS; MODEL; INTERVENTIONS; DEPRESSION AB We evaluated the quality of care provided to older patients with complex needs in a dual-eligible, community-based Medicare Special Needs Plan that used a nurse care manager model. Care provided by physicians was substantially supplemented by nurse care managers, as measured by Assessing Care of Vulnerable Elders quality indicators. We describe selected nurse care manager activities for six geriatric conditions (falls, dementia, depression, nutrition, urinary incontinence, and end-of-life care) during provision of patient care coordination and management for patients in the highest decile of clinical complexity. We identify areas of high nurse performance (i.e., falls screening, functional assessment, behavioral interventions for dementia problems, advance care planning) and areas of potential missed opportunities (i.e., follow up for new memory problems, targeted dementia counseling, nutrition, and behavioral approaches to urinary incontinence). Increasing the collaborative interaction between nurses providing care in this model and physicians has the potential to enhance nurses' contributions to primary care for vulnerable older adults. C1 [Roth, Carol P.; Ganz, David A.; Beckman, Robin; Wenger, Neil S.] RAND Hlth, Santa Monica, CA 90407 USA. [Nickels, Lorraine] UnitedHealthcare, Clin Qual Improvement, Minnetonka, MN USA. [Martin, David] UnitedHealthcare Medicare & Retirement, Clin Innovat, Minnetonka, MN USA. [Ganz, David A.] VA Greater Los Angeles Healthcare Syst, Hlth Serv Res & Dev Serv, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Wenger, Neil S.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Roth, CP (reprint author), RAND Hlth, 1776 Main St, Santa Monica, CA 90407 USA. EM roth@rand.org FU UnitedHealthcare FX Ms. Roth, Dr. Ganz, Ms. Beckman, and Dr. Wenger have disclosed no potential conflicts of interest, financial or otherwise. Ms. Nickels and Dr. Martin disclose that they are United Healthcare shareholders. This project was supported by a contract from UnitedHealthcare to the RAND Corporation. NR 42 TC 3 Z9 3 U1 3 U2 10 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0098-9134 J9 J GERONTOL NURS JI J. Gerontol. Nurs. PD JUL PY 2012 VL 38 IS 7 BP 44 EP 54 DI 10.3928/00989134-20120606-10 PG 11 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA 971OH UT WOS:000306213200007 PM 22833891 ER PT J AU Alari-Pahissa, E Vega-Ramos, J Zhang, JG Castano, AR Turley, SJ Villadangos, JA Lauzurica, P AF Alari-Pahissa, Elisenda Vega-Ramos, Javier Zhang, Jian-Guo Raul Castano, A. Turley, Shannon J. Villadangos, Jose A. Lauzurica, Pilar TI Differential effect of CD69 targeting on bystander and antigen-specific T cell proliferation SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE rodent; dendritic cell; cell proliferation; transgenic/knockout mice ID COLLAGEN-INDUCED ARTHRITIS; IN-VIVO; DENDRITIC CELLS; SELECTIVE STIMULATION; MONOCLONAL-ANTIBODY; LYMPHOCYTE EGRESS; IL-2 PRODUCTION; ACTIVATION; RECEPTOR; EXPRESSION AB In spite of an initially proposed role as a costimulatory molecule for CD69, in vivo studies showed it as a regulator of immune responses and lymphocyte egress. We found constitutive CD69 expression by T cell subsets and pDC. We examined a possible effect of CD69 on T cell proliferation using transfer models and in vitro assays. In mice locally expressing or receiving antigen, anti-CD692.2 treatment did not affect the proliferation of antigen-specific transgenic T cells in ADLN, although we observed the presence of proliferated T cells in non-ADLN and spleen. This was not affected by FTY720 treatment and thus, not contributed by increased egress of proliferated lymphocytes from ADLN. In the absence of antigen, anti-CD69 2.2 treatment induced bystander proliferation of transferred memory phenotype T cells. This proliferation was mediated by IL-2, as it was inhibited by anti-IL-2 or anti-CD25 antibodies in vitro and by anti-CD25 antibodies in vivo. It was also dependent on CD69 expression by donor T cells and recipient cells. CD69 targeting on T cells enhanced IL-2-mediated proliferation and CD25 expression. However, it did not lead to increased early IL-2 production by T cells. No T cell subset was found to be specifically required in the recipient. Instead, CD69 targeting on pDC induced their expression of IL-2 and CD25, and pDC depletion showed that this subset was involved in the proliferation induction. These results indicate that CD69 targeting induces bystander T cell proliferation through pDC IL-2 production and T cell sensitization to IL-2 without affecting antigen-driven T cell proliferation. J. Leukoc. Biol. 92: 145-158; 2012. C1 [Lauzurica, Pilar] Inst Salud Carlos III, Centro Nacl Microbiol, Madrid 28220, Spain. [Alari-Pahissa, Elisenda; Lauzurica, Pilar] Univ Barcelona, Dept Fisiol, E-08007 Barcelona, Spain. [Vega-Ramos, Javier; Zhang, Jian-Guo; Villadangos, Jose A.] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. [Raul Castano, A.] Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Dept Biol Cel Lular Fisiol & Immunol, Barcelona, Spain. [Turley, Shannon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lauzurica, P (reprint author), Inst Salud Carlos III, Centro Nacl Microbiol, Crtra Majadahonda Pozuelo Km 2,2, Madrid 28220, Spain. EM lauzurica@isciii.es RI lauzurica, pilar/B-4397-2013; Castano, A. Raul/A-5905-2012; Vega-Ramos, Javier/A-9931-2015; OI Castano, A. Raul/0000-0003-2107-8862; Vega-Ramos, Javier/0000-0002-9516-3624; lauzurica, pilar/0000-0001-6579-1948 FU Spanish Ministry of Education and Science; Ministerio de Educacion, Ciencia y Tecnologia [SAF2007-64310, SAF2010-15649]; La Fundacio La Marato de TV3; National Health and Medical Research Council of Australia [461219] FX E.A-P. and J.V-R. were supported by predoctoral fellowships from the Spanish Ministry of Education and Science. This work was supported by grants (SAF2007-64310 and SAF2010-15649) from the Ministerio de Educacion, Ciencia y Tecnologia, and La Fundacio La Marato de TV3 2004. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme. This work was supported in part by the National Health and Medical Research Council of Australia program grant 461219 to JGZ. We thank Dr. J. Cano Ochando for kindly providing anti-SiglecH 440c and anti-CD25 PC61.5 mAb and Dr. B de Andres for providing anti-CD127 (A7R34) and rmIL-7 supernatant. We are grateful to Dr. Jordi Peig for statistical analysis assessment. NR 47 TC 6 Z9 8 U1 3 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2012 VL 92 IS 1 BP 145 EP 158 DI 10.1189/jlb.1011499 PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 966KS UT WOS:000305837100017 PM 22544938 ER PT J AU Saldarriaga, OA Travi, BL Choudhury, GG Melby, PC AF Saldarriaga, Omar A. Travi, Bruno L. Choudhury, Goutam Ghosh Melby, Peter C. TI Identification of hamster inducible nitric oxide synthase (iNOS) promoter sequences that influence basal and inducible iNOS expression SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE C/EBP-beta; transcriptional regulation; NF-IL-6; NOS2 ID BINDING PROTEIN BETA; FACTOR-KAPPA-B; INTERFERON-GAMMA; ALVEOLAR MACROPHAGES; SPECIES-DIFFERENCES; MOUSE MACROPHAGES; RESPONSE ELEMENT; REACTIVE OXYGEN; ENDOTOXIC-SHOCK; MESSENGER-RNA AB IFN-gamma/LPS-activated hamster (Mesocricetus auratus) macrophages express significantly less iNOS (NOS2) than activated mouse macrophages, which contributes to the hamster's susceptibility to intracellular pathogens. We determined a mechanism responsible for differences in iNOS promoter activity in hamsters and mice. The HtPP (1.2 kb) showed low basal and inducible promoter activity when compared with the mouse, and sequences within a 100-bp region (-233 to -133) of the mouse and hamster promoters influenced this activity. Moreover, within this 100 bp, we identified a smaller region (44 bp) in the mouse promoter, which recovered basal promoter activity when swapped into the hamster promoter. The mouse homolog (100-bp region) contained a cis-element for NF-IL-6 (-153/-142), which was absent in the hamster counterpart. EMSA and supershift assays revealed that the hamster sequence did not support the binding of NF-IL-6. Introduction of a functional NF-IL-6 binding sequence into the hamster promoter or its alteration in the mouse promoter revealed the critical importance of this transcription factor for full iNOS promoter activity. Furthermore, the binding of NF-IL-6 to the iNOS promoter (-153/-142) in vivo was increased in mouse cells but was reduced in hamster cells after IFN-gamma/LPS stimulation. Differences in the activity of the iNOS promoters were evident in mouse and hamster cells, so they were not merely a result of species-specific differences in transcription factors. Thus, we have identified unique DNA sequences and a critical transcription factor, NF-IL-6, which contribute to the overall basal and inducible expression of hamster iNOS. J. Leukoc. Biol. 92: 205-218; 2012. C1 [Saldarriaga, Omar A.; Travi, Bruno L.; Choudhury, Goutam Ghosh; Melby, Peter C.] S Texas Vet Hlth Care Syst, Res Serv, Dept Vet Affairs Med Ctr, San Antonio, TX USA. [Saldarriaga, Omar A.; Travi, Bruno L.; Choudhury, Goutam Ghosh; Melby, Peter C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Saldarriaga, Omar A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. RP Melby, PC (reprint author), Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, 301 Univ Blvd,Rte 0435, Galveston, TX 77555 USA. EM pcmelby@utmb.edu FU U.S. National Institutes of Health (NIH) [AI61624]; U.S. NIH [RO1 DK 50,190]; VA Merit Review; JDRF [1-2008-185]; U.S. Department of Veterans Affairs FX This work was supported by U.S. National Institutes of Health (NIH) grant AI61624 (P. C. M.). G. G. C. is supported by U.S. NIH RO1 DK 50,190, VA Merit Review, and JDRF 1-2008-185 grants. G. G. C. is a recipient of a Senior Research Career Scientists award from the U.S. Department of Veterans Affairs. We thank Dr. Sunil Ahuja and Dr. Srinivas Mummidi for their scientific input and Sheela Rani for her advice with the ChiP assays. NR 46 TC 7 Z9 7 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2012 VL 92 IS 1 BP 205 EP 218 DI 10.1189/jlb.1010568 PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 966KS UT WOS:000305837100022 PM 22517919 ER PT J AU Arcenas, RC Spadoni, S Mohammad, A Kiechle, FL Walker, K Fader, RC Perdreau-Remington, F Osiecki, J Liesenfeld, O Hendrickson, S Rao, A AF Arcenas, Rodney C. Spadoni, Stacey Mohammad, Amin Kiechle, Frederick L. Walker, Kimberly Fader, Robert C. Perdreau-Remington, Francoise Osiecki, John Liesenfeld, Oliver Hendrickson, Shelby Rao, Arundhati TI Multicenter Evaluation of the LightCycler MRSA Advanced Test, the Xpert MRSA Assay, and MRSASelect Directly Plated Culture with Simulated Workflow Comparison for the Detection of Methicillin-Resistant Staphylococcus aureus in Nasal Swabs SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID REAL-TIME PCR; CHROMAGAR MRSA; SURVEILLANCE CULTURES; CHROMOGENIC MEDIA; MOLECULAR ASSAYS; RAPID DETECTION; EPIDEMIOLOGY; INFECTIONS; RISK; IDENTIFICATION AB Rapid detection of nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) followed by appropriate infection control procedures reduces MRSA infection and transmission. We compared the performance and workflow of two Food and Drug Administration-approved nucleic acid amplification assays, the LightCycler MRSA Advanced Test and the Xpert MRSA test, with those of directly plated culture (MRSASelect) using 1202 nasal swabs collected at three U.S. sites. The sensitivity of the LightCycler test (95.2%; 95% CI, 89.1% to 98.4%) and Xpert assay (99%; 95% CI, 94.8% to 100%) did not differ compared with that of culture; the specificity of the two assays was identical (95.5%; 95% CI, 94.1% to 96.7%) compared with culture. However, sequencing performed on 71 samples with discordant results among the three methods confirmed the presence of MRSA in 40% of samples that were positive by both molecular methods but negative by culture. Workflow analysis from all sites including batch runs revealed average hands-on sample preparation times of 1.40, 2.35, and 1.44 minutes per sample for the LightCycler, Xpert, and MRSASelect methods, respectively. Discrete event simulation analysis of workflow efficiencies revealed that the LightCycler test used less hands-on time for the assay when greater than eight batched samples were run. The high sensitivity and specificity, low hands-on time, and efficiency gains using hatching capabilities make the LightCycler test suitable for rapid batch screening of MRSA colonization. (J Mol Diagn 2012, 14: 367-375; http://dx.doi.org/10.1016/j.jmoldx.2012.01.015) C1 [Mohammad, Amin; Walker, Kimberly; Fader, Robert C.; Hendrickson, Shelby; Rao, Arundhati] Scott & White Healthcare, Texas A&M Hlth Sci Ctr, Dept Pathol, Temple, TX 76508 USA. [Arcenas, Rodney C.; Kiechle, Frederick L.] Mem Reg Hosp S, Dept Pathol, Hollywood, FL USA. [Spadoni, Stacey] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Dept Pathol, Hines, IL 60141 USA. [Perdreau-Remington, Francoise] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA USA. [Osiecki, John] Roche Diagnost Corp, Med & Sci Affairs, Indianapolis, IN USA. [Liesenfeld, Oliver] Roche Mol Diagnost, Med & Sci Affairs, Pleasanton, CA USA. RP Rao, A (reprint author), Scott & White Healthcare, Texas A&M Hlth Sci Ctr, Dept Pathol, 2401 S 31st St, Temple, TX 76508 USA. EM arao@swmail.sw.org FU Roche Diagnostics Corp. FX Supported in part by Roche Diagnostics Corp. NR 34 TC 4 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2012 VL 14 IS 4 BP 367 EP 375 DI 10.1016/j.jmoldx.2012.01.015 PG 9 WC Pathology SC Pathology GA 972AC UT WOS:000306247900009 PM 22584139 ER PT J AU Healy, BC Arora, A Hayden, DL Ceccarelli, A Tauhid, SS Neema, M Bakshi, R AF Healy, Brian C. Arora, Ashish Hayden, Douglas L. Ceccarelli, Antonia Tauhid, Shahamat S. Neema, Mohit Bakshi, Rohit TI Approaches to Normalization of Spinal Cord Volume: Application to Multiple Sclerosis SO JOURNAL OF NEUROIMAGING LA English DT Article DE 3 Tesla imaging; multiple sclerosis; normalization; spinal cord atrophy ID CORRELATION-COEFFICIENTS; BRAIN ATROPHY; DISABILITY; IMAGES; AREA AB BACKGROUND AND PURPOSE To determine the proper method for the normalization of spinal cord volume. MATERIALS AND METHODS A group of 34 multiple sclerosis (MS) patients (28 relapsing and 6 progressive) and 15 healthy controls had whole spinal cord 3-mm thick T2-weighted axial fast spin-echo magnetic resonance imaging (MRI) images obtained at 3T. For each participant, four volumes were measured (C2-3 volume, cervical cord volume, thoracic cord volume, and whole cord volume). The volumes were normalized by the number of slices and three potential measures of body size (intracranial volume [ICV], body mass index, and body surface area) using the proportional method. RESULTS All raw volumes and volumes normalized by number of slices or ICV were significantly lower in progressive MS patients compared to relapsing MS patients/healthy controls (P < .05). In addition, C2-3 volume and cervical cord volume were significantly correlated with Expanded Disability Status Scale score (P < .05). All regional volumes showed high intercorrelation, and normalization by the number of slices significantly increased some correlations. Regarding reliability, whole cord volume regardless of normalization technique had lower coefficient of variation than C2-3 volume. CONCLUSIONS Since normalization factor had limited impact on reliability and the ability to detect differences, normalization by the number of slices is recommended. C1 [Healy, Brian C.; Arora, Ashish; Ceccarelli, Antonia; Tauhid, Shahamat S.; Neema, Mohit; Bakshi, Rohit] Harvard Univ, Brigham & Womens Hosp, Ctr Biostat, Dept Neurol,Med Sch, Brookline, MA 02445 USA. [Healy, Brian C.; Hayden, Douglas L.] Harvard Univ, Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Lab Neuroimaging Res,Med Sch,Biostat Ctr, Brookline, MA 02445 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Healy, BC (reprint author), Harvard Univ, Brigham & Womens Hosp, Ctr Biostat, Dept Neurol,Med Sch, 1 Brookline Pl,Suite 602, Brookline, MA 02445 USA. EM bchealy@partners.org FU NIH [1 R01 NS055083-01]; National MS Society [NMSS-RG 3705-A-1] FX This research was funded in part by grants received from the NIH (1 R01 NS055083-01) and the National MS Society (NMSS-RG 3705-A-1). NR 19 TC 20 Z9 20 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD JUL PY 2012 VL 22 IS 3 BP E12 EP E19 DI 10.1111/j.1552-6569.2011.00629.x PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 972QU UT WOS:000306293300002 PM 21854479 ER PT J AU Zhao, W Dhar, S AF Zhao, Wei Dhar, Sumitrajit TI Frequency tuning of the contralateral medial olivocochlear reflex in humans SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE spontaneous otoacoustic emissions; cochlear mechanics ID SPONTANEOUS OTOACOUSTIC EMISSIONS; GUINEA-PIG COCHLEA; ACOUSTIC STIMULATION; EFFERENT NEURONS; ELECTRIC STIMULATION; RESPONSE PROPERTIES; STIMULUS VARIABLES; SOUND STIMULATION; BUNDLE; FIBERS AB Zhao W, Dhar S. Frequency tuning of the contralateral medial olivocochlear reflex in humans. J Neurophysiol 108: 25-30, 2012. First published March 28, 2012; doi:10.1152/jn.00051.2012.-Activation of the medial olivocochlear (MOC) efferents attenuates cochlear gain and reduces the amplitudes of mechanical, electrical, and neural cochlear outputs. The functional roles of the MOC efferents are not fully understood, especially in humans, despite postulations that they are involved in protection against acoustic trauma, facilitation of transient-sound perception, etc. Delineating the frequency tuning properties of the MOC efferents would provide critical evidence to support or refute these postulated functional roles. By utilizing spontaneous otoacoustic emissions (SOAEs), a cochlear measure sensitive to MOC modulation, we systematically demonstrate in humans that the contralateral MOC reflex is tuned to a fixed frequency band between 500 and 1,000 Hz independent of SOAE frequency. Our results question the role of the MOC reflex in protection against acoustic trauma or facilitation of transient-sound perception. C1 [Zhao, Wei; Dhar, Sumitrajit] Northwestern Univ, Roxelyn & Richard Pepper Dept Commun Sci & Disord, Evanston, IL USA. [Zhao, Wei; Dhar, Sumitrajit] Northwestern Univ, Interdept Neurosci Program, Evanston, IL USA. [Dhar, Sumitrajit] Northwestern Univ, Knowles Hearing Ctr, Evanston, IL USA. RP Zhao, W (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM wei_zhao@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [DC-008420]; Northwestern University FX This work was supported by National Institute on Deafness and Other Communication Disorders Grant DC-008420 and by Northwestern University. NR 34 TC 9 Z9 9 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2012 VL 108 IS 1 BP 25 EP 30 DI 10.1152/jn.00051.2012 PG 6 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 971GM UT WOS:000306191800004 PM 22457463 ER PT J AU Wen, B Wang, GI Dean, I Delgutte, B AF Wen, Bo Wang, Grace I. Dean, Isabel Delgutte, Bertrand TI Time course of dynamic range adaptation in the auditory nerve SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE adaptation; stimulus statistics; dynamic range problem; anesthetized cat ID SHORT-TERM ADAPTATION; RETINAL GANGLION-CELLS; SOUND-LEVEL STATISTICS; CONTRAST ADAPTATION; FIBER RESPONSES; INFORMATION-TRANSMISSION; INFERIOR COLLICULUS; STIMULUS STATISTICS; NEURAL ADAPTATION; AFFERENT SYNAPSE AB Wen B, Wang GI, Dean I, Delgutte B. Time course of dynamic range adaptation in the auditory nerve. J Neurophysiol 108: 69-82, 2012. First published March 28, 2012; doi:10.1152/jn.00055.2012.-Auditory adaptation to sound-level statistics occurs as early as in the auditory nerve (AN), the first stage of neural auditory processing. In addition to firing rate adaptation characterized by a rate decrement dependent on previous spike activity, AN fibers show dynamic range adaptation, which is characterized by a shift of the rate-level function or dynamic range toward the most frequently occurring levels in a dynamic stimulus, thereby improving the precision of coding of the most common sound levels (Wen B, Wang GI, Dean I, Delgutte B. J Neurosci 29: 13797-13808, 2009). We investigated the time course of dynamic range adaptation by recording from AN fibers with a stimulus in which the sound levels periodically switch from one nonuniform level distribution to another (Dean I, Robinson BL, Harper NS, McAlpine D. J Neurosci 28: 6430-6438, 2008). Dynamic range adaptation occurred rapidly, but its exact time course was difficult to determine directly from the data because of the concomitant firing rate adaptation. To characterize the time course of dynamic range adaptation without the confound of firing rate adaptation, we developed a phenomenological "dual adaptation" model that accounts for both forms of AN adaptation. When fitted to the data, the model predicts that dynamic range adaptation occurs as rapidly as firing rate adaptation, over 100-400 ms, and the time constants of the two forms of adaptation are correlated. These findings suggest that adaptive processing in the auditory periphery in response to changes in mean sound level occurs rapidly enough to have significant impact on the coding of natural sounds. C1 [Wen, Bo; Wang, Grace I.; Delgutte, Bertrand] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Wen, Bo; Delgutte, Bertrand] Harvard Univ, Dept Otol & Laryngol, Sch Med, Boston, MA USA. [Wang, Grace I.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA USA. [Delgutte, Bertrand] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Dean, Isabel] UCL, Ear Inst, London, England. RP Wen, B (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM bo_wen@meei.harvard.edu OI , /0000-0003-1349-9608 FU National Institute of Deafness and Other Communicative Disorders [R03 DC011156, R01 DC002258, P30 DC005209] FX This work was supported by National Institute of Deafness and Other Communicative Disorders Grants R03 DC011156 (to B. Wen), R01 DC002258 (to B. Delgutte), and P30 DC005209. NR 52 TC 13 Z9 14 U1 0 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2012 VL 108 IS 1 BP 69 EP 82 DI 10.1152/jn.00055.2012 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 971GM UT WOS:000306191800008 PM 22457465 ER PT J AU Buxton, OM Hopcia, K Sembajwe, G Porter, JH Dennerlein, JT Kenwood, C Stoddard, AM Hashimoto, D Sorensen, G AF Buxton, Orfeu M. Hopcia, Karen Sembajwe, Grace Porter, James H. Dennerlein, Jack T. Kenwood, Christopher Stoddard, Anne M. Hashimoto, Dean Sorensen, Glorian TI Relationship of Sleep Deficiency to Perceived Pain and Functional Limitations in Hospital Patient Care Workers SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID LOW-BACK-PAIN; MANUAL HANDLING ACTIVITIES; MUSCULOSKELETAL SYMPTOMS; CARDIOVASCULAR-DISEASE; RISK-FACTORS; LONG-SLEEP; NURSES; INJURIES; HEALTH; DURATION AB Objective: Health care workers are at high risk of developing musculoskeletal symptoms and pain. This study tested the hypothesis that sleep deficiency is associated with pain, functional limitations, and physical limitations that interfere with work. Methods: Hospital patient care workers completed a survey (79% response rate) including measures of health, sociodemographic, and workplace factors. Associations of sleep deficiency with pain, work interference due to this pain, and functional limitations were determined. Results: Of 1572 respondents (90% women; mean age, 41 years), 57% reported sleep deficiency, 73% pain in last 3 months, 33% work interference, and 18% functional limitation. Sleep deficiency was associated with higher rates of pain, work interference, and functional limitation controlling for socioeconomic, individual, and workplace characteristics. Conclusions: Sleep deficiency is significantly associated with pain, functional limitation, and workplace interference, suggesting modifiable outcomes for workplace health and safety interventions. C1 [Buxton, Orfeu M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA 02115 USA. [Buxton, Orfeu M.; Hopcia, Karen; Sembajwe, Grace; Porter, James H.; Dennerlein, Jack T.; Kenwood, Christopher; Stoddard, Anne M.; Hashimoto, Dean; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Ctr Work Hlth & Well Being, Boston, MA 02115 USA. [Sembajwe, Grace; Dennerlein, Jack T.; Hashimoto, Dean] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Hlth & Human Dev, Boston, MA 02115 USA. [Buxton, Orfeu M.; Porter, James H.; Hashimoto, Dean] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hopcia, Karen; Sembajwe, Grace; Hashimoto, Dean; Sorensen, Glorian] Partners HealthCare Syst, Partners Occupat Hlth Serv, Boston, MA USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Kenwood, Christopher; Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Buxton, OM (reprint author), Harvard Univ, Sch Med, Div Sleep Med, 221 Longwood Ave,BL1438-K, Boston, MA 02115 USA. EM orfeu_buxton@hms.harvard.edu OI Dennerlein, Jack/0000-0001-7703-643X FU National Institute for Occupational Safety and Health [U19 OH008861]; National Heart, Lung and Blood Institute [R01HL107240]; Cephalon; Sepracor; Minimitter; Takeda FX This work was supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard School of Public Health Center for Work, Health and Well-being. Dr Buxton was supported in part by the National Heart, Lung and Blood Institute (R01HL107240).; There are no conflicts of interest to report, but in the interest of full disclosure, Dr Buxton received investigator-initiated research grants from Cephalon and Sepracor, has received unrestricted educational grants from Minimitter and Takeda (more than 4 years ago), served on the speaker's bureau for Takeda (3 years ago), and previously served as a consultant for Sepracor. Dr Buxton currently consults for Disnmore LLC (as an expert witness). All other authors have no conflicts of interest to report. NR 62 TC 20 Z9 21 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JUL PY 2012 VL 54 IS 7 BP 851 EP 858 DI 10.1097/JOM.0b013e31824e6913 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 972RH UT WOS:000306297100015 PM 22796931 ER PT J AU Volandes, AE Brandeis, GH Davis, AD Paasche-Orlow, MK Gillick, MR Chang, YC Walker-Corkery, ES Mann, E Mitchell, SL AF Volandes, Angelo E. Brandeis, Gary H. Davis, Aretha Delight Paasche-Orlow, Michael K. Gillick, Muriel R. Chang, Yuchiao Walker-Corkery, Elizabeth S. Mann, Eileen Mitchell, Susan L. TI A Randomized Controlled Trial of a Goals-of-Care Video for Elderly Patients Admitted to Skilled Nursing Facilities SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID TRANSITIONS INTERVENTION; POSTHOSPITAL CARE; CLINICAL-TRIAL; LIFE; END; REHOSPITALIZATION; OPPORTUNITIES; PREFERENCES; CHALLENGES; PHYSICIANS AB Objective: To determine the impact of a video on preferences for the primary goal of care. Design, subjects, and intervention: Consecutive subjects 65 years of age or older (n=101) admitted to two skilled nursing facilities (SNFs) were randomized to a verbal narrative (control) or a video (intervention) describing goals-of-care options. Options included: life-prolonging (i.e., cardiopulmonary resuscitation), limited (i.e., hospitalization but no cardiopulmonary resuscitation), or comfort care (i.e., symptom relief). Main measures: Primary outcome was patients' preferences for comfort versus other options. Concordance of preferences with documentation in the medical record was also examined. Results: Fifty-one subjects were randomized to the verbal arm and 50 to the video arm. In the verbal arm, preferences were: comfort, n=29 (57%); limited, n=4 (8%); life-prolonging, n=17 (33%); and uncertain, n=1 (2%). In the video arm, preferences were: comfort, n=40 (80%); limited, n=4 (8%); and life-prolonging, n=6 (12%). Randomization to the video was associated with greater likelihood of opting for comfort (unadjusted rate ratio, 1.4; 95% confidence interval [CI], 1.1-1.9, p=0.02). Among subjects in the verbal arm who chose comfort, 29% had a do-not-resuscitate (DNR) order (kappa statistic 0.18; 95% CI-0.02 to 0.37); 33% of subjects in the video arm choosing comfort had a DNR order (kappa statistic 0.06; 95% CI-0.09 to 0.22). Conclusion: Subjects admitted to SNFs who viewed a video were more likely than those exposed to a verbal narrative to opt for comfort. Concordance between a preference for comfort and a DNR order was low. These findings suggest a need to improve ascertainment of patients' preferences. C1 [Volandes, Angelo E.; Chang, Yuchiao; Walker-Corkery, Elizabeth S.; Mann, Eileen] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. [Volandes, Angelo E.; Davis, Aretha Delight; Gillick, Muriel R.; Chang, Yuchiao; Mann, Eileen; Mitchell, Susan L.] Harvard Univ, Sch Med, Boston, MA USA. [Brandeis, Gary H.; Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Davis, Aretha Delight] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Gillick, Muriel R.] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Mitchell, Susan L.] Hebrew Senior Life, Inst Aging Res, Boston, MA USA. RP Volandes, AE (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St, Boston, MA 02114 USA. EM avolandes@partners.org OI Paasche-Orlow, Michael/0000-0002-9276-7190 FU Foundation for Informed Medical Decision Making; Agency for Healthcare Research and Quality [K08HS018780]; National Institute on Aging [K24AG033640] FX This research was supported by a grant from the Foundation for Informed Medical Decision Making. First author was supported by grant number K08HS018780 from the Agency for Healthcare Research and Quality. Dr. Mitchell was supported by grant K24AG033640 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the National Institute on Aging. None of the funders participated in the collection, analysis, or interpretation of the data or in preparation, review, or approval of the manuscript. NR 26 TC 20 Z9 20 U1 3 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD JUL PY 2012 VL 15 IS 7 BP 805 EP 811 DI 10.1089/jpm.2011.0505 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 973CA UT WOS:000306328700016 PM 22559905 ER PT J AU Brouwer, KM Bolmers, A Ring, D AF Brouwer, Kim M. Bolmers, Annelies Ring, David TI Quantitative 3-dimensional computed tomography measurement of distal humerus fractures SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Computed tomography; fractures; morphology; quantitative; distal humerus; three-dimensional; surface; volume ID SURFACE AB Purpose: To measure the average number, size, shape and articular surface area of articular fracture fragments of the distal humerus using quantitative analysis of 3-dimensional computed tomography (3DCT) images. Materials and methods: Forty-eight computed tomography scans of distal humerus fractures were analyzed with quantitative 3DCT (Q3DCT). Twenty-one patients had a capitellum and trochlea fracture, and 27 patients had bicolumnar fractures of the distal humerus. The volume and articular surface area of each articular fracture fragment were measured. A small fragment was defined of having a volume of less than 500 mm 3 or an articular surface of less than 500 mm(2). Results: Bicolumnar fractures have a mean of 9.3 fragments, 5.4 small fragments, and 3.7 articular fragments per fracture. Trochlea and capitellum fractures have a mean of 3.6 fragments, 1.5 small fragments, and 2.3 articular fragments per fracture. For each fracture type, the number of small fragments correlated with the total number of fragments. Conclusion: Columnar fractures had more articular fragments and more small fragments than trochlea and capitellum fractures. Level of evidence: Basic Science Study, Anatomic Study, Imaging. (C) 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Brouwer, Kim M.; Bolmers, Annelies; Ring, David] Harvard Univ, Sch Med, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp,Yawkey Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Sch Med, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org FU Marti Keuning Eckhardt Stichting; Stichting Michael van Vloten Fonds; VSB Fonds; Stichting Anna Fonds FX Funding: Kim Brouwer-Research foundations: Marti Keuning Eckhardt Stichting, Stichting Michael van Vloten Fonds, VSB Fonds, Stichting Anna Fonds. NR 9 TC 8 Z9 10 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD JUL PY 2012 VL 21 IS 7 BP 977 EP 982 DI 10.1016/j.jse.2011.05.011 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA 973FX UT WOS:000306345900022 PM 21831668 ER PT J AU Hoeppner, BB Barnett, NP Jackson, KM Colby, SM Kahler, CW Monti, PM Read, J Tevyaw, T Wood, M Corriveau, D Fingeret, A AF Hoeppner, Bettina B. Barnett, Nancy P. Jackson, Kristina M. Colby, Suzanne M. Kahler, Christopher W. Monti, Peter M. Read, Jennifer Tevyaw, Tracy Wood, Mark Corriveau, Donald Fingeret, Allan TI Daily College Student Drinking Patterns Across the First Year of College SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID HEAVY ALCOHOL-USE; BINGE-DRINKING; LONGITUDINAL PATTERNS; CONSUMPTION; RISK; 1ST-YEAR; MODEL; PARTY; INTERVENTIONS; PREDICTORS AB Objective: Despite the long recognized importance and well-documented impact of drinking patterns on health and safety, college student drinking patterns are understudied. This study used a daily-level, academic-year-long, multisite sample to identify subpopulations of college student drinking patterns and to describe how these groups differ from one another before, during, and after their first year of college. Method: Two cohorts of first-year college students (n = 588; 59% female) reported daily drinking on a biweekly basis using web-based surveys and completed surveys before and after their first year of college. Results: Cluster analyses based on time series analysis estimates of within-person drinking differences (per weekday, semester, first 6 weeks) and other descriptors of day-to-day drinking identified five drinking patterns: two low (47% and 6%), two medium (24% and 15%), and one high (8%) drinking cluster. Multinomial logistic regression analyses examined cluster differences in pre-college characteristics (i.e., demographics, alcohol outcome expectancies, alcohol problems, depression, other substance use) and first-year college experiences (i.e., academic engagement, alcohol consequences, risky drinking practices, alcohol problems, drinking during academic breaks). Low-drinking students appeared to form a relatively homogeneous group, whereas two distinct patterns were found for medium-drinking students with different weekend and Thursday drinking rates. The Thursday drinking cluster showed lower academic engagement and greater participation in risky drinking practices. Conclusions: These findings highlight quantitative and qualitative differences in day-to-day drinking patterns and suggest a link between motivational differences and drinking patterns, which may be addressed in developing tailored interventional strategies. (J Stud. Alcohol Drugs, 73, 613-624, 2012) C1 [Hoeppner, Bettina B.; Barnett, Nancy P.; Jackson, Kristina M.; Colby, Suzanne M.; Kahler, Christopher W.; Monti, Peter M.] Brown Univ, Providence, RI 02912 USA. [Monti, Peter M.; Tevyaw, Tracy] Providence Vet Affairs Med Ctr, Providence, RI USA. [Read, Jennifer] SUNY Buffalo, Buffalo, NY 14260 USA. [Wood, Mark] Univ Rhode Isl, Kingston, RI 02881 USA. [Corriveau, Donald] Univ Massachusetts, N Dartmouth, MA USA. [Fingeret, Allan] Rhode Isl Coll, Providence, RI 02908 USA. RP Hoeppner, BB (reprint author), Harvard Univ, Sch Med, Ctr Addict Med, Massachusetts Gen Hosp, 60 Staniford St, Boston, MA 02114 USA. EM bhoeppner@partners.org FU National Institute on Alcohol Abuse and Alcoholism [R01AA013970, T32AA007459]; National Institute on Drug Abuse [K01DA027097] FX This study was supported by National Institute on Alcohol Abuse and Alcoholism Grants R01AA013970 and T32AA007459 and National Institute on Drug Abuse Grant K01DA027097. NR 59 TC 26 Z9 26 U1 2 U2 21 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2012 VL 73 IS 4 BP 613 EP 624 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 971KJ UT WOS:000306202500012 PM 22630800 ER PT J AU Burstein, HJ AF Burstein, Harold J. TI Simplifying Guidelines: We Only Need One Adjuvant Chemotherapy Regimen for Breast Cancer SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Burstein, Harold J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA USA. [Burstein, Harold J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Burstein, Harold J.] Harvard Univ, Cambridge, MA USA. RP Burstein, HJ (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2012 VL 10 IS 7 BP 797 EP 798 PG 2 WC Oncology SC Oncology GA 972TR UT WOS:000306303900002 PM 22773794 ER PT J AU Carlson, RW Allred, DC Anderson, BO Burstein, HJ Edge, SB Farrar, WB Forero, A Giordano, SH Goldstein, LJ Gradishar, WJ Hayes, DF Hudis, CA Isakoff, SJ Ljung, BME Mankoff, DA Marcom, PK Mayer, IA McCormick, B Pierce, LJ Reed, EC Smith, ML Soliman, H Somlo, G Theriault, RL Ward, JH Wolff, AC Zellars, R Kumar, R Shead, DA AF Carlson, Robert W. Allred, D. Craig Anderson, Benjamin O. Burstein, Harold J. Edge, Stephen B. Farrar, William B. Forero, Andres Giordano, Sharon Hermes Goldstein, Lori J. Gradishar, William J. Hayes, Daniel F. Hudis, Clifford A. Isakoff, Steven Jay Ljung, Britt-Marie E. Mankoff, David A. Marcom, P. Kelly Mayer, Ingrid A. McCormick, Beryl Pierce, Lori J. Reed, Elizabeth C. Smith, Mary Lou Soliman, Hatem Somlo, George Theriault, Richard L. Ward, John H. Wolff, Antonio C. Zellars, Richard Kumar, Rashmi Shead, Dorothy A. TI Metastatic Breast Cancer, Version 1.2012 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID DISTANT METASTASES AB These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option. (JNCCN 2012;10:821-829) C1 [Carlson, Robert W.] Stanford Canc Inst, Stanford, CA USA. [Allred, D. Craig] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Allred, D. Craig] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Anderson, Benjamin O.; Mankoff, David A.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Burstein, Harold J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Edge, Stephen B.] Roswell Pk Canc Inst, Buffalo, NY USA. [Farrar, William B.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Forero, Andres] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Giordano, Sharon Hermes; Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Gradishar, William J.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Hayes, Daniel F.; Pierce, Lori J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Hudis, Clifford A.; McCormick, Beryl] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Isakoff, Steven Jay] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ljung, Britt-Marie E.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Marcom, P. Kelly] Duke Canc Inst, Durham, NC USA. [Mayer, Ingrid A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Reed, Elizabeth C.] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. [Soliman, Hatem] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Ward, John H.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Carlson, RW (reprint author), Stanford Canc Inst, Stanford, CA USA. OI Wolff, Antonio/0000-0003-3734-1063 FU NCI NIH HHS [K23 CA127469] NR 18 TC 43 Z9 44 U1 0 U2 6 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2012 VL 10 IS 7 BP 821 EP 829 PG 9 WC Oncology SC Oncology GA 972TR UT WOS:000306303900006 PM 22773798 ER PT J AU Zornosa, C Vandergrift, JL Kalemkerian, GP Ettinger, DS Rabin, MS Reid, M Otterson, GA Koczywas, M D'Amico, TA Niland, JC Mamet, R Pisters, KM AF Zornosa, Carrie Vandergrift, Jonathan L. Kalemkerian, Gregory P. Ettinger, David S. Rabin, Michael S. Reid, Mary Otterson, Gregory A. Koczywas, Marianna D'Amico, Thomas A. Niland, Joyce C. Mamet, Rizvan Pisters, Katherine M. TI First-Line Systemic Therapy Practice Patterns and Concordance With NCCN Guidelines for Patients Diagnosed With Metastatic NSCLC Treated at NCCN Institutions SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID CELL LUNG-CANCER; PHASE-III; CHEMOTHERAPY; ERLOTINIB; CARBOPLATIN; CISPLATIN; METAANALYSIS; COMBINATION; GEMCITABINE; PACLITAXEL AB The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) allow many systemic therapy options for patients with metastatic non-small cell lung cancer (NSCLC). This analysis uses the NCCN NSCLC Outcomes Database to report on first-line therapy practice patterns and concordance with NCCN Guidelines. The analysis was limited to patients diagnosed with metastatic NSCLC between September 2006 and November 2009 at 1 of 8 participating NCCN Member Institutions. Patient characteristics, regimens used, and guidelines concordance were analyzed. Institutional variation and changes in practice over time were also measured. A total of 1717 patients were included in the analysis'. Of these, 1375 (80%) were treated with systemic therapy, most often in the form of a carboplatin-based doublet (51%) or carboplatin-based doublet with targeted therapy (17%). Overall, 76% of patients received care that was concordant with NCCN Guidelines. Among patients with good performance status (n = 167), the most common reasons for not receiving first-line therapy were that therapy was not recommended (39%) or death occurred before treatment (33%). The most common reason for receiving nonconcordant drug therapy was the administration of pemetrexed or erlotinib before its incorporation into the NCCN Guidelines for first-line therapy (53%). Most patients in this cohort received care that was concordant with NCCN Guidelines. The NSCLC Outcomes Database is a valuable resource for evaluating practice patterns and concordance with NCCN Guidelines among patients with NSCLC. (JNCCN 2012;10:847-856) C1 [Zornosa, Carrie; Vandergrift, Jonathan L.] Natl Comprehens Canc Network, Ft Washington, PA 19034 USA. [Kalemkerian, Gregory P.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Ettinger, David S.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Rabin, Michael S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Reid, Mary] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Otterson, Gregory A.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Otterson, Gregory A.] Solove Res Inst, Columbus, OH USA. [Koczywas, Marianna; Niland, Joyce C.; Mamet, Rizvan] City Hope Comprehens Canc Ctr, Los Angeles, CA USA. [D'Amico, Thomas A.] Duke Canc Inst, Durham, NC USA. [Pisters, Katherine M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Zornosa, C (reprint author), Natl Comprehens Canc Network, 275 Commerce Dr,Suite 300, Ft Washington, PA 19034 USA. EM zornosa@nccn.org NR 21 TC 10 Z9 10 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2012 VL 10 IS 7 BP 847 EP 856 PG 10 WC Oncology SC Oncology GA 972TR UT WOS:000306303900008 PM 22773800 ER PT J AU Alvarnas, JC Brown, PA Aoun, P Ballen, KK Bellam, N Blum, W Boyer, MW Carraway, HE Coccia, PF Coutre, SE Cultrera, J Damon, LE DeAngelo, DJ Douer, D Frangoul, H Frankfurt, O Goorha, S Millenson, MM O'Brien, S Petersdorf, SH Rao, AV Terezakis, S Uy, G Wetzler, M Zelenetz, AD Naganuma, M Gregory, KM AF Alvarnas, Joseph C. Brown, Patrick A. Aoun, Patricia Ballen, Karen Kuhn Bellam, Naresh Blum, William Boyer, Michael W. Carraway, Hetty E. Coccia, Peter F. Coutre, Steven E. Cultrera, Jennifer Damon, Lloyd E. DeAngelo, Daniel J. Douer, Dan Frangoul, Haydar Frankfurt, Olga Goorha, Salil Millenson, Michael M. O'Brien, Susan Petersdorf, Stephen H. Rao, Arati V. Terezakis, Stephanie Uy, Geoffrey Wetzler, Meir Zelenetz, Andrew D. Naganuma, Maoko Gregory, Kristina M. TI Acute Lymphoblastic Leukemia SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review ID MINIMAL RESIDUAL DISEASE; STEM-CELL TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; CHILDRENS-ONCOLOGY-GROUP; ABL KINASE DOMAIN; BONE-MARROW-TRANSPLANTATION; NERVOUS-SYSTEM INVOLVEMENT; TERM-FOLLOW-UP; THERAPY IMPROVES SURVIVAL AB The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL. (JNCCN 2012;10:858-914) C1 [Aoun, Patricia; Coccia, Peter F.] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. [Ballen, Karen Kuhn] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bellam, Naresh] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Blum, William] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Boyer, Michael W.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Coutre, Steven E.] Stanford Canc Inst, Stanford, CA USA. [Cultrera, Jennifer] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Damon, Lloyd E.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [DeAngelo, Daniel J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Douer, Dan; Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Frangoul, Haydar] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Frankfurt, Olga] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Goorha, Salil] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Millenson, Michael M.] Fox Chase Canc Ctr, Philadelphia, PA USA. [O'Brien, Susan] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Petersdorf, Stephen H.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Rao, Arati V.] Duke Canc Inst, Durham, NC USA. [Uy, Geoffrey] Washington Univ, Sch Med, Siteman Canc Ctr, Barnes Jewish Hosp, St Louis, MO 63130 USA. [Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY USA. RI Blum, William/E-2769-2011 FU NCI NIH HHS [P30 CA016672] NR 205 TC 25 Z9 29 U1 1 U2 14 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2012 VL 10 IS 7 BP 858 EP 913 PG 56 WC Oncology SC Oncology GA 972TR UT WOS:000306303900009 PM 22773801 ER PT J AU Jung, KO Khan, AM Tan, BYL Hu, YL Simon, GG Nascimento, EJM Lemonnier, F Brusic, V Miotto, O Tan, TW Marques, ETA Dhalia, R Salmon, J August, JT AF Jung, Keun-Ok Khan, Asif M. Tan, Benjamin Yong Liang Hu, Yongli Simon, Gregory G. Nascimento, Eduardo J. M. Lemonnier, Francois Brusic, Vladimir Miotto, Olivo Tan, Tin Wee Marques, Ernesto T. A. Dhalia, Rafael Salmon, Jerome August, J. Thomas TI West Nile Virus T-Cell Ligand Sequences Shared with Other Flaviviruses: a Multitude of Variant Sequences as Potential Altered Peptide Ligands SO JOURNAL OF VIROLOGY LA English DT Article ID MHC CLASS-I; DENGUE HEMORRHAGIC-FEVER; DOUBLE-KNOCKOUT MICE; TRANSGENIC MICE; IMMUNE-RESPONSE; DISEASE PATHOGENESIS; EPITOPE DISCOVERY; INFLUENZA-VIRUS; IDENTIFICATION; INFECTION AB Phylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirus protein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restricted West Nile virus (WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in similar to >= 88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design of Flavivirus vaccines. C1 [Jung, Keun-Ok; Khan, Asif M.; Simon, Gregory G.; Salmon, Jerome; August, J. Thomas] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Khan, Asif M.; Hu, Yongli; August, J. Thomas] Perdana Univ, Grad Sch Med, Serdang, Selangor Darul, Malaysia. [Khan, Asif M.; Tan, Benjamin Yong Liang; Hu, Yongli; Tan, Tin Wee] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117595, Singapore. [Nascimento, Eduardo J. M.; Marques, Ernesto T. A.] Univ Pittsburgh, Ctr Vaccine Res, Pittsburgh, PA USA. [Lemonnier, Francois] Inst Pasteur, Unite Immunite Cellulaire Antivirale, Paris, France. [Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Miotto, Olivo] Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand. [Marques, Ernesto T. A.; Dhalia, Rafael] Aggeu Magalhaes Res Ctr, Virol & Expt Therapy Lab, Recife, PE, Brazil. [Salmon, Jerome] Inst Gustave Roussy, Unite Retrovirus Endorgenes & Elements Retroides, Villejuif, France. RP August, JT (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. EM taugust@jhmi.edu RI Saude Publica, Inct/J-9544-2013; Marques, Ernesto/L-4514-2013; Nascimento, Eduardo/J-4590-2014; Tan, Tin Wee/B-8963-2009; Marques, Ernesto/L-4967-2013; Khan, Mohammad Asif/F-4663-2010; OI Marques, Ernesto/0000-0003-3826-9358; Nascimento, Eduardo/0000-0002-9851-2332; Tan, Tin Wee/0000-0002-4062-2854; Marques, Ernesto/0000-0003-3826-9358; Khan, Mohammad Asif/0000-0001-9202-279X; Miotto, Olivo/0000-0001-8060-6771 NR 73 TC 9 Z9 9 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2012 VL 86 IS 14 BP 7616 EP 7624 DI 10.1128/JVI.00166-12 PG 9 WC Virology SC Virology GA 969ZO UT WOS:000306098100015 PM 22573867 ER EF